Boosting Bifunctional Oxygen Electrocatalysis with 3D Graphene Aerogel-Supported Ni/MnO Particles

Abstract

Electrocatalysts for oxygen-reduction and oxygen-evolution reactions (ORR and OER) are crucial for metal–air batteries, where more costly Pt- and Ir/Ru-based materials are the benchmark catalysts for ORR and OER, respectively. Herein, for the first time Ni is combined with MnO species, and a 3D porous graphene aerogel-supported Ni/MnO (Ni–MnO/rGO aerogel) bifunctional catalyst is prepared via a facile and scalable hydrogel route. The synthetic strategy depends on the formation of a graphene oxide (GO) crosslinked poly(vinyl alcohol) hydrogel that allows for the efficient capture of highly active Ni/MnO particles after pyrolysis. Remarkably, the resulting Ni–MnO/rGO aerogels exhibit superior bifunctional catalytic performance for both ORR and OER in an alkaline electrolyte, which can compete with the previously reported bifunctional electrocatalysts. The MnO mainly contributes to the high activity for the ORR, while metallic Ni is responsible for the excellent OER activity. Moreover, such bifunctional catalyst can endow the homemade Zn–air battery with better power density, specific capacity, and cycling stability than mixed Pt/C + RuO₂ catalysts, demonstrating its potential feasibility in practical application of rechargeable metal–air batteries.

A bifunctional 3D porous graphene aerogel-supported Ni/MnO (Ni–MnO/rGO aerogel) catalyst is reported that exhibits excellent electrocatalytic activity and stability for the oxygen-reduction and oxygen-evolution reactions in alkaline media. The Ni–MnO/rGO-driven Zn–air batteries can be stably charged and discharged over 100 cycles with high voltaic efficiency, outperforming the more costly Pt/C + RuO₂ catalyst-driven Zn–air batteries.

http://ift.tt/2yl9SJV

Prolonged Duration Local Anesthesia Using Liposomal Bupivacaine Combined With Liposomal Dexamethasone and Dexmedetomidine

BACKGROUND: The relatively short duration of effect of local anesthetics has been addressed by encapsulation in drug delivery systems. Codelivery with a single compound that produces an adjuvant effect on nerve block but without intrinsic local anesthetic properties can further prolong the nerve block effect. Here, we investigated whether codelivery of more than 1 encapsulated adjuvant compound can further enhance nerve blockade. METHODS: Liposomes loaded with bupivacaine (Bup), dexamethasone phosphate (DexP), or dexmedetomidine (DMED) were synthesized and its in vitro drug release profiles were determined. Animals (Sprague-Dawley rats) were injected with liposomal Bup (Lipo-Bup) and adjuvants at the sciatic nerve and underwent a modified hot plate test to assess the degree of nerve block. The duration of block was monitored and the tissue reaction was assessed. RESULTS: Coinjection of Lipo-Bup with liposomal DexP (Lipo-DexP) and liposomal DMED (Lipo-DMED) prolonged the duration of sciatic nerve block 2.9-fold compared to Lipo-Bup alone (95% confidence interval, 1.9- to 3.9-fold). The duration of the block using this combination was significantly increased to 16.2 ± 3.5 hours compared to Lipo-Bup with a single liposomal adjuvant (8.7 ± 2.4 hours with Lipo-DMED, P = .006 and 9.9 ± 5.9 hours with Lipo-DexP, P = .008). The coinjection of Lipo-Bup with liposomal adjuvants decreased tissue inflammation (P = .014) but did not have a significant effect on myotoxicity when compared to Lipo-Bup alone. Coinjection of Lipo-Bup with unencapsulated adjuvants prolonged the duration of nerve block as well (25.0 ± 6.3 hours; P

http://ift.tt/2nUy6KZ

Meeting Report for the 39th Annual Meeting and Workshops of the Society of Cardiovascular Anesthesiologists

No abstract available

http://ift.tt/2C9Nfvc

Targeted Temperature Management After Cardiac Arrest: Systematic Review and Meta-analyses

BACKGROUND: Targeted temperature management (TTM) with therapeutic hypothermia is an integral component of postarrest care for survivors. However, recent randomized controlled trials (RCTs) have failed to demonstrate the benefit of TTM on clinical outcomes. We sought to determine if the pooled data from available RCTs support the use of prehospital and/or inhospital TTM after cardiac arrest. METHODS: A comprehensive search of SCOPUS, Elsevier's abstract and citation database of peer-reviewed literature, from 1966 to November 2016 was performed using predefined criteria. Therapeutic hypothermia was defined as any strategy that aimed to cool post.cardiac arrest survivors to a temperature ≤34°C. Normothermia was temperature of ≥36°C. We compared mortality and neurologic outcomes in patients by categorizing the studies into 2 groups: (1) hypothermia versus normothermia and (2) prehospital hypothermia versus in-hospital hypothermia using standard meta-analytic methods. A random effects modeling was utilized to estimate comparative risk ratios (RR) and 95% confidence intervals (CIs). RESULTS: The hypothermia and normothermia strategies were compared in 5 RCTs with 1389 patients, whereas prehospital hypothermia and in-hospital hypothermia were compared in 6 RCTs with 3393 patients. We observed no difference in mortality (RR, 0.88; 95% CI, 0.73– 1.05) or neurologic outcomes (RR, 1.26; 95% CI, 0.92–1.72) between the hypothermia and normothermia strategies. Similarly, no difference was observed in mortality (RR, 1.00; 95% CI, 0.97–1.03) or neurologic outcome (RR, 0.96; 95% CI, 0.85–1.08) between the prehospital hypothermia versus in-hospital hypothermia strategies. CONCLUSIONS: Our results suggest that TTM with therapeutic hypothermia may not improve mortality or neurologic outcomes in postarrest survivors. Using therapeutic hypothermia as a standard of care strategy of postarrest care in survivors may need to be reevaluated. Accepted for publication September 19, 2017. The authors Kalra and Arora contributed equally to preparation of this manuscript. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://ift.tt/KegmMq). Funding: This study was supported in part by the Walter B. Frommeyer Investigative Fellowship awarded to P.A. N.S.B. was supported by National Institutes of Health grant 5T32HL094301-07. N.P. was supported by National Institutes of Health grant 1T32HL129948-01A1. The authors declare no conflicts of interest. Reprints will not be available from the authors. Address correspondence to Navkaranbir S. Bajaj, MD, MPH, Division of Cardiovascular Medicine, Department of Radiology, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115. Address e-mail to bajaj.navkaran@gmail.com; Pankaj Arora, MD, FAHA, Division of Cardiovascular Disease, University of Alabama at Birmingham, 1670 University Blvd, Volker Hall B140, Birmingham, AL 35294. Address e-mail to parora@uabmc.edu. © 2017 International Anesthesia Research Society

http://ift.tt/2nVbLx0

Achieving Milestones as a Prerequisite for Proceeding With a Clinical Trial

BACKGROUND: Although the National Institutes of Health (NIH) invests $30 billion in research annually, many funded studies fail to generate results that can inform practice. The National Institutes of Health introduced a phased funding mechanism as one potential solution. Study-specific milestones are established for an initial pilot phase. We assess the utility of this phased approach through the ongoing Electroencephalography (EEG) Guidance of Anesthesia to Alleviate Geriatric Syndromes (ENGAGES) pragmatic clinical trial. The hypothesis of the trial is that EEG guidance of general anesthesia, through prevention of EEG suppression, can decrease postoperative delirium and its downstream negative sequelae. METHODS: In collaboration with study stakeholders, we identified critical milestones for the ENGAGES study, with themes common to many clinical trials. These themes include: regulatory tasks; enrollment targets; feasibility and impact of study intervention; primary outcome incidence; measurement reliability of primary outcome; and follow-up. Progress in achieving the milestones was assessed at regular intervals during the pilot phase by ENGAGES investigators, a National Institute on Aging program officer, and a nonpartisan research organization (Westat). RESULTS: Regulatory tasks, including institutional review board approval, infrastructure establishment, and trial registration, were completed on schedule. A total of 117 patients were randomized, exceeding the target by 51. The EEG-guided protocol was successfully implemented, and a relevant effect on anesthetic practice was demonstrated (decrease in median age–adjusted minimum alveolar anesthetic concentration from 0.93 to 0.78 [P

http://ift.tt/2C9N9nk

Error Grid Analysis for Arterial Pressure Method Comparison Studies

The measurement of arterial pressure (AP) is a key component of hemodynamic monitoring. A variety of different innovative AP monitoring technologies became recently available. The decision to use these technologies must be based on their measurement performance in validation studies. These studies are AP method comparison studies comparing a new method ("test method") with a reference method. In these studies, different comparative statistical tests are used including correlation analysis, Bland-Altman analysis, and trending analysis. These tests provide information about the statistical agreement without adequately providing information about the clinical relevance of differences between the measurement methods. To overcome this problem, we, in this study, propose an "error grid analysis" for AP method comparison studies that allows illustrating the clinical relevance of measurement differences. We constructed smoothed consensus error grids with calibrated risk zones derived from a survey among 25 specialists in anesthesiology and intensive care medicine. Differences between measurements of the test and the reference method are classified into 5 risk levels ranging from "no risk" to "dangerous risk"; the classification depends on both the differences between the measurements and on the measurements themselves. Based on worked examples and data from the Multiparameter Intelligent Monitoring in Intensive Care II database, we show that the proposed error grids give information about the clinical relevance of AP measurement differences that cannot be obtained from Bland-Altman analysis. Our approach also offers a framework on how to adapt the error grid analysis for different clinical settings and patient populations. Accepted for publication September 8, 2017. Funding: None. The authors declare no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://ift.tt/KegmMq). Reprints will not be available from the authors. Address correspondence to Julia Y. Nicklas, MD, Department of Anesthesiology, Center of Anesthesiology and Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany. Address e-mail to jnicklas.science@gmail.com. © 2017 International Anesthesia Research Society

http://ift.tt/2C9b7Pv

In Response

No abstract available

http://ift.tt/2nVbAlk

Treatment of Chronic Pain With Various Buprenorphine Formulations: A Systematic Review of Clinical Studies

Clinical studies demonstrate that buprenorphine is a pharmacologic agent that can be used for the treatment of various types of painful conditions. This study investigated the efficacy of 5 different types of buprenorphine formulations in the chronic pain population. The literature was reviewed on PubMed/MEDLINE, EMBASE, Cochrane Database, clinicaltrials.gov, and PROSPERO that dated from inception until June 30, 2017. Using the population, intervention, comparator, and outcomes method, 25 randomized controlled trials were reviewed involving 5 buprenorphine formulations in patients with chronic pain: intravenous buprenorphine, sublingual buprenorphine, sublingual buprenorphine/naloxone, buccal buprenorphine, and transdermal buprenorphine, with comparators consisting of opioid analgesics or placebo. Of the 25 studies reviewed, a total of 14 studies demonstrated clinically significant benefit with buprenorphine in the management of chronic pain: 1 study out of 6 sublingual and intravenous buprenorphine, the only sublingual buprenorphine/naloxone study, 2 out of 3 studies of buccal buprenorphine, and 10 out of 15 studies for transdermal buprenorphine showed significant reduction in pain against a comparator. No serious adverse effects were reported in any of the studies. We conclude that a transdermal buprenorphine formulation is an effective analgesic in patients with chronic pain, while buccal buprenorphine is also a promising formulation based on the limited number of studies. Accepted for publication 24, 2017. Funding: None. Conflicts of Interest: See Disclosures at the end of the article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://ift.tt/KegmMq). This systematic review discusses off-label use of pharmacologic agents. Reprints will not be available from the authors. Address correspondence to Neel Mehta, MD, Division of Pain Medicine, Weill Cornell Department of Anesthesiology, P300, New York Presbyterian Hospital, 525 E 68th St, New York, NY 10065. Address e-mail to nem9015@med.cornell.edu. © 2017 International Anesthesia Research Society

http://ift.tt/2C9paob

Oxford Textbook of Anaesthesia, 1st Edition

No abstract available

http://ift.tt/2nUCM3r

Labor Analgesia as a Predictor for Reduced Postpartum Depression Scores: A Retrospective Observational Study

BACKGROUND: Using labor, epidural analgesia has been linked to a reduced risk of postpartum depression, but the role of labor pain relief in this association remains unclear. The goal of this study was to test the hypothesis that effective epidural analgesia during labor is associated with reduced postpartum depression symptomatology. METHODS: A single, institutional, retrospective, observational cohort design was chosen. The primary outcome was Edinburgh postnatal depression scale (EPDS) score, measured at the 6-week postpartum visit. Subjects included in the final analysis had (1) received labor epidural analgesia; (2) pain assessed during labor both before and during initiation of labor epidural analgesia by 0–10 numeric rating scores; and (3) depression risk assessed by the EPDS and documented at their 6-week postpartum visit. Simple and multiple linear regression was used to identify the best model for assessing the association between pain improvement, defined as percent improvement in pain (PIP), and depression, after adjusting for a history of anxiety or depression, other psychiatric history, abuse, trauma, mode of delivery, and other maternal or fetal comorbid diseases. RESULTS: Two hundred one patients were included in the final analysis. Women with higher improvements in pain were associated with lower EPDS scores (r = 0.025; P = .002). Variables known to be associated with depression (body mass index, anxiety and/or depression, third- and fourth-degree perineal lacerations, and anemia) were significantly correlated with EPDS score and included in the final model. After we adjusted for these covariates, PIP remained a significant predictor of EPDS score (r = 0.49; P = .008), accounting for 6.6% of the variability in postpartum depression scores. The full model including pain, body mass index, anxiety and/or depression, perineal lacerations, and anemia explained 24% of the variability in postpartum depression scores. CONCLUSIONS: Although the extent of labor pain relief by epidural analgesia predicts lower postpartum depression scores, the relative contribution of PIP to risk for postpartum depression symptoms may be less than other established risk factors for depression. These data support that the clinical significance of labor analgesia in the development of postpartum depression needs to be more clearly defined. Accepted for publication October 30, 2017. Funding: G.L. is supported in part by the National Institutes of Health, T32GM075770 and K12HD043441. The authors declare no conflicts of interest. Institutional Review Board: This study was approved by the University of Pittsburgh Institutional Review Board (PRO15060463), 3500 5th Ave, Hieber Building, Room 106, Pittsburgh, PA 15213. E-mail: askirb@pitt.edu. This study was presented as an abstract at the annual meeting of the Society for Obstetric Anesthesia and Perinatology (SOAP), May 18–22, 2016, Boston, MA, and at the annual meeting of the American Society of Anesthesiologists (ASA), October 26, 2016, Chicago, IL. Reprints will not be available from the authors. Address correspondence to Grace Lim, MD, MS, Department of Anesthesiology, Magee-Women's Hospital of the University of Pittsburgh Medical Center, 300 Halket St, Suite 3510, Pittsburgh, PA 15232. Address e-mail to limkg2@upmc.edu. © 2017 International Anesthesia Research Society

http://ift.tt/2CbMsKg

A Retrospective Analysis of Clinical Research Misconduct Using FDA-Issued Warning Letters and Clinical Investigator Inspection List From 2010 to 2014

BACKGROUND: The US Food and Drug Administration (FDA) conducts inspections of clinical investigation sites as a component of clinical trial regulation. The FDA describes the results of these inspections in the Clinical Investigator Inspection List (CLIIL). More serious violations are followed up in FDA warning letters issued to investigators. The primary objective of the current study is to qualitatively and quantitatively describe the CLIIL data and contents of FDA-issued warning letters from 2010 to 2014. METHODS: We retrospectively analyzed the CLIIL and FDA warning letters. For the CLIIL, we quantified the frequency of each violation among other data points. We compared recent data (2010–2014) to the previous 5 years (2005–2009). To analyze FDA warning letters, we developed a coding system to quantify the frequency of violations found. RESULTS: We analyzed 3637 inspections in the CLIIL database and 60 warning letters. Overall, there was a decrease or no change in all violations in the CLIIL database. The largest violation code reported was "failure to follow investigational plan" in both the 2005–2009 and 2010–2014 timeframes. Coding of FDA warning letters shows that the most common violations reported were failing to maintain accurate case histories (10.82%), enrolling ineligible subjects (8.85%), and failing to perform required tests (8.52%). CONCLUSIONS: The overall decrease in violations is encouraging. But, the high proportion of violations related to failure to follow the investigational plan is concerning as the complexity of trials increases. We conclude that more detailed information is necessary to accurately evaluate these violations. The current study provides a model for creating more granular data of violations to better inform clinical investigators and improve clinical trials. Accepted for publication October 24, 2017. Funding: None. The authors declare no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://ift.tt/KegmMq). Reprints will not be available from the authors. Address correspondence to Christopher A. Romano, BS, Department of Anesthesiology, Montefiore Medical Center, 111 E 210th St, Bronx, NY 10467. Address e-mail to caromano@mail.einstein.yu.edu. © 2017 International Anesthesia Research Society

http://ift.tt/2nXRvKW

The Clinical Utility of Noninvasive Pulse Co-oximetry Hemoglobin Measurements in Dark Skinned Critically Ill Patients

BACKGROUND: The primary objective of this study was to assess the clinical usefulness of a point-of-care device which measures hemoglobin noninvasively (SpHb) in a group of critically ill participants with dark skin pigmentation. METHODS: One hundred forty-six adult and pediatric participants from a multidisciplinary intensive care unit had intermittent readings of noninvasive hemoglobin measurements performed at a minimum of 4 hourly intervals. A total of 371 readings were analyzed. Concurrent blood samples were taken to assess hemoglobin levels using point-of-care blood gas analyzer, as well as sent to a central laboratory where hemoglobin was measured using the sodium lauryl sulfate method. Bland-Altman plots were constructed to assess the agreement between results from the 2 point-of-care devices with the reference standard (laboratory hemoglobin). RESULTS: SpHb exhibited significant bias when compared to laboratory hemoglobin, while blood gas hemoglobin did not. Mean bias for SpHb was +1.64 with limits of agreement of −1.03 to 4.31 compared to blood gas hemoglobin which showed a bias of 0.26 and limits of agreement of −0.84 to 1.37. The magnitude of the bias for SpHb increased with increasing mean hemoglobin levels. Of all the additional study variables assessed for effect on the bias, only Acute Physiology and Chronic Health Evaluation II score in adult patients (P

http://ift.tt/2C99st8

In Response

No abstract available

http://ift.tt/2nXRoiu

The Impact of Prehospital Tranexamic Acid on Blood Coagulation in Trauma Patients

BACKGROUND: There is limited data on prehospital administration of tranexamic acid (TXA) in civilian trauma. The aim of this study was to evaluate changes in coagulation after severe trauma from on-scene to the hospital after TXA application in comparison to a previous study without TXA. METHODS: The study protocol was registered at ClinicalTrials.gov (NCT02354885). A prospective, multicenter, observational study investigating coagulation status in 70 trauma patients receiving TXA (1 g intravenously) on-scene versus a control group of 38 patients previously published without TXA. To account for potential differences in patient and trauma epidemiology, crystalloid and colloidal resuscitation fluid, 2 propensity score matched groups (n = 24 per group) were created. Measurements included ROTEM, standard coagulation tests and blood gas analyses on-scene and emergency department admission. Presented values are mean and [standard deviation], and difference in means and 95% confidence intervals. RESULTS: Patient epidemiology was not different between groups. Coagulation assays on-scene were comparable between the TXA and C. Prehospital hyperfibrinolysis was blunted in all 4 patients in the TXA group. Viscoelastic FIBTEM maximum clot firmness (MCF), representing functional fibrinogen levels, did not change from on-scene to the emergency department in the TXA group, whereas MCF decreased -3.7 [1.8] mm in the control group. Decrease of MCF was significantly reduced in the TXA group in EXTEM by 9.2 (7.2–11.2) mm (P

http://ift.tt/2CbM9iA

Analysis of Inpatient Falls After Total Knee Arthroplasty in Patients With Continuous Femoral Nerve Block

Continuous femoral nerve block (cFNB) is thought to increase the risk of falls after total knee arthroplasty (TKA). Previous studies have failed to consider the timing of cFNB removal in relation to inpatient falls. We investigated all inpatient falls after TKA over a 3-year period using our institutional safety report database. Ninety-five falls were reported from a total of 3745 patients. The frequency of falls after TKA persisted at a similar rate despite removal of cFNB and likely regression of femoral nerve block. Other modifiable risk factors may play a more prominent role in falls risk after TKA. Accepted for publication October 24, 2017. Funding: This work was supported by Sunnybrook Health Sciences Centre, Department of Anesthesia, University of Toronto, Toronto, Ontario, Canada. The authors declare no conflicts of interest. Reprints will not be available from the authors. Address correspondence to Stephen Choi, MD, FRCPC, Department of Anesthesia, Sunnybrook Health Sciences Centre, M3-200, 2075 Bayview Ave, Toronto, Ontario, Canada, M4N 3M5. Address e-mail to stephen.choi@sunnybrook.ca. © 2017 International Anesthesia Research Society

http://ift.tt/2z6paG4

The Anesthesia Workstation: Quo Vadis?

Ensuring adequate ventilation and oxygenation and delivering inhaled anesthetic agent to the patient remain core responsibilities of the anesthesia provider during general anesthesia. Because of the emphasis placed on physiology, pharmacology, clinical sciences, and administrative duties, the stellar anesthesia workstation technology may be underutilized by the anesthesia community. Target-controlled O2 and agent delivery and automated end-expired CO2 control have entered the clinical arena, with only cost, luddism, and administrative hurdles preventing their more widespread use. This narrative review will explain technological aspects of existing and recently introduced anesthesia workstations. Concepts rather than particular anesthesia machines will be addressed, but examples will mostly pertain to the more recently introduced workstations. The anesthesia workstation consists of a ventilator, a carrier gas and agent delivery system, a scavenging system, and monitors. Mainly, the circle breathing circuit configuration, ventilator, and carrier gas and agent delivery technology are discussed. Occasionally, technical details are provided to give the reader a taste of the modern technology. Accepted for publication October 23, 2017. Funding: None. Conflicts of Interest: See Disclosures at the end of the article. Both the authors contributed equally to this article. Reprints will not be available from the authors. Address correspondence to Jan F. A. Hendrickx, MD, PhD, Department of Anesthesiology, OLV Hospital, Moorselbaan 164, 9300, Aalst, Belgium. Address e-mail to jcnwahendrickx@yahoo.com. © 2017 International Anesthesia Research Society

http://ift.tt/2z6eSpb

American College of Surgeons Children’s Surgery Verification Quality Improvement Program: What Anesthesiologists Need to Know Now

A task force of pediatric surgical specialists with the support of The American College of Surgeons recently launched a verification program for pediatric surgery, the Children's Surgery Verification quality improvement program, with the goal of improving pediatric surgical, procedural, and perioperative care. Included in this program are specific standards for the delivery of pediatric anesthesia care across a variety of practice settings. We review the background, available evidence, requirements for verification, and verification process and its implications for the practice of pediatric anesthesia across the country. In addition, we have included a special roundtable interview of 3 recently Children's Surgery Verification–verified program directors to provide an up-to-date real-world perspective of this children's surgery quality improvement program. Accepted for publication October 16, 2017. Funding: None. Conflicts of Interest: See Disclosures at the end of the article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://ift.tt/KegmMq). The authors M. Brooks Peterson and C. S. Houck are equally contributing first authors. Reprints will not be available from the authors. Address correspondence to Melissa Brooks Peterson, MD, 13123 E, 16th Ave, Box 090, Aurora, CO 80045. Address e-mail to melissa.brooks@childrenscolorado.org. © 2017 International Anesthesia Research Society

http://ift.tt/2z6Tdxs

Nerve Blockade and Chronic Opiate Use After Orthopedic Surgery

No abstract available

http://ift.tt/2nUZg4D

Bias in Before–After Studies: Narrative Overview for Anesthesiologists

Before–after study designs are effective research tools and in some cases, have changed practice. These designs, however, are inherently susceptible to bias (ie, systematic errors) that are sometimes subtle but can invalidate their conclusions. This overview provides examples of before–after studies relevant to anesthesiologists to illustrate potential sources of bias, including selection/assignment, history, regression to the mean, test–retest, maturation, observer, retrospective, Hawthorne, instrumentation, attrition, and reporting/publication bias. Mitigating strategies include using a control group, blinding, matching before and after cohorts, minimizing the time lag between cohorts, using prospective data collection with consistent measuring/reporting criteria, time series data collection, and/or alternative study designs, when possible. Improved reporting with enforcement of the Enhancing Quality and Transparency of Health Research (EQUATOR) checklists will serve to increase transparency and aid in interpretation. By highlighting the potential types of bias and strategies to improve transparency and mitigate flaws, this overview aims to better equip anesthesiologists in designing and/or critically appraising before–after studies. Accepted for publication October 13, 2017. Funding: None. The authors declare no conflicts of interest. Reprints will not be available from the authors. Address correspondence to Glenio B. Mizubuti, MD, MSc, Department of Anesthesiology and Perioperative Medicine, Victory 2, Kingston General Hospital, Queen's University, 76 Stuart St, Kingston, Ontario K7L 2V7, Canada. Address e-mail to gleniomizubuti@hotmail.com. © 2017 International Anesthesia Research Society

http://ift.tt/2z6ypG8

Do retreatment tuberculosis patients need special treatment response follow-up beyond the standard regimen? Finding of five-year retrospective study in pastoralist setting

Treatment outcomes serve as proxy measures of the quality of tuberculosis treatment provided by the health care system, and it is essential to evaluate the effectiveness of Directly Observed Therapy-Short cour...

http://ift.tt/2iZjx3C

Elizabethkingia miricola as an opportunistic oral pathogen associated with superinfectious complications in humoral immunodeficiency: a case report

Elizabethkingia miricola is a rare Gram-negative bacterium found in water and clinical specimens. Typical culturing methods often misidentify Elizabethkingia spp. as Flavobacterium or

http://ift.tt/2BghHGe

Genetic diversity and distribution of Mycobacterium tuberculosis genotypes in Limpopo, South Africa

Tuberculosis remains a major health problem and knowledge of the diversity of Mycobacterium tuberculosis strains in specific geographical regions can contribute to the control of the disease. This study describes...

http://ift.tt/2iYFIqF

Pharmacokinetically-targeted dosed everolimus maintenance therapy in lymphoma patients

Abstract

Background

Everolimus, an mTOR inhibitor, is active in refractory lymphomas. However, toxicity with flat dosing limits its usage. Speculatively, pharmacokinetically-targeted dosing could improve tolerability. Therefore, we studied serum-trough dosing with rituximab as maintenance after high-dose cyclophosphamide (HDC) consolidation in lymphoma patients.

Patients/methods

After HDC, everolimus was dosed to serum trough levels (goal 3–15 ng/mL), with quarterly rituximab infusions for 1 year while maintaining < grade II non-hematologic and < grade III hematologic toxicities. Adult patients in first PR/CR with: mantle cell, transformed, double-hit, or high risk chronic lymphocytic leukemia or in second PR for any relapsed B cell lymphoma were eligible. Prophylaxis was given for encapsulated organisms, HSV and PCP. Serum IgG levels were maintained > 500 mg/dL.

Results

49 patients, median age: 59.0 years enrolled; MCL (26), CLL (10), transformed lymphoma (7), and other histologies (6). During the life of the study, the most frequent everolimus dosing has been 2.5 mg daily or 2.5 mg every other day; at these doses, serum levels are within the therapeutic range and non-hematologic toxicity is rare. At a median follow-up of 27.1 months, three patients remain on active therapy. Two patients withdrew secondary to potentially-attributable adverse events including a bacterial pneumonia and a viral pneumonia; this low rate of discontinuation compares well to other long-term everolimus trials. While a 58 and 76% EFS at 30 months for the entire cohort and MCL cohort, respectively, compares similarly to previously published HDC/rituximab data, longer follow-up is required.

Conclusions

Pharmacokinetically-targeted dosing appears to increase everolimus tolerability. This finding may be applicable to other patient populations.

http://ift.tt/2AxuVyR

Is there a role for the international prognostic index in follicular lymphoma?

http://ift.tt/2C9jNoP

V-set and Ig domain-containing 4 (VSIG4)-expressing hepatic F4/80+ cells regulate oral antigen-specific responses in mouse

Abstract

Oral tolerance can prevent unnecessary immune responses against dietary antigens. Members of the B7 protein family play critical roles in the positive and/or negative regulation of T cell responses to interactions between APCs and T cells. V-set and Ig domain-containing 4 (VSIG4), a B7-related co-signaling molecule, has been known to act as a co-inhibitory ligand and may be critical in establishing immune tolerance. Therefore, we investigated the regulation of VSIG4 signaling in a food allergy and experimental oral tolerance murine models. We analyzed the contributions of the two main sites involved in oral tolerance, the mesenteric lymph node (MLN) and the liver, in VSIG4-mediated oral tolerance induction. Through the comparative analysis of major APCs, dendritic cells (DCs), and macrophages, we found that Kupffer cells play a critical role in inducing regulatory T cells (Tregs) and establishing immune tolerance against oral antigens via VSIG4 signaling. Taken together, these results suggest the possibility of VSIG4 signaling-based regulation of orally administered antigens.

This article is protected by copyright. All rights reserved

http://ift.tt/2iY3uTM

“Double-duty” conventional dendritic cells in the amphibian Xenopus as the prototype for antigen presentation to B cells

Abstract

Two populations of dendritic cells (DCs) are found in mammals, one derived from hematopoietic precursors (conventional/cDC), and another derived from mesenchymal precursors, the follicular DC (FDC); the latter is specialized for antigen presentation to B cells, and has only been definitively demonstrated in mammals. Both cDC and FDC are necessary for induction of germinal centers (GC) and GC-dependent class switch recombination (CSR) and somatic hypermutation (SHM). We demonstrate that in Xenopus, an amphibian in which immunoglobulin CSR and SHM occur without GC formation, a single type of DC has properties of both cDC and FDC, including high expression of MHC class II for the former and display of native antigen at the cell surface for the latter. Our data confirm that the advent of FDC functionality preceded emergence of bona fide FDC, which was in turn crucial for the development of GC formation and efficient affinity maturation in mammals.

This article is protected by copyright. All rights reserved

http://ift.tt/2BigXk0

Investigating the effect of sociodemographic factors on 30-day hospital readmission among medical patients in Toronto, Canada: a prospective cohort study

Objective

To examine the influence of patient-level sociodemographic factors on the incidence of hospital readmission within 30 days among medical patients in a large Canadian metropolitan city.

Design

Prospective cohort study.

Setting and participants

Patients admitted to the General Internal Medicine service of an urban teaching hospital in Toronto, Canada participated in a survey of sociodemographic information. Patients were not surveyed if deemed medically unstable, receiving care in medical/surgical step-down beds or were isolated for infection control. Included in the final analysis was a diverse cohort of 1427 adult, non-palliative, patients who were discharged home.

Measures

Thirteen patient-level sociodemographic variables were examined in relation to time to unplanned all-cause readmission within 30 days. Illness level was accounted for by the following covariates: self-perceived health status, previous hospital utilisation, primary diagnosis case mix group, Charlson Comorbidity Index score and inpatient length of stay.

Results

Approximately, 14.4% (n=205) of patients experienced readmission within 30 days. Sociodemographic factors were not significantly associated with time to readmission in unadjusted and adjusted analyses. Indicators of illness level, namely, previous hospitalisations, were the strongest risk factors for readmission within this cohort. One previous admission (adjusted HR 1.78; 95% CI 1.22 to 2.59, P<0.01) and at least four previous emergency department visits (adjusted HR 2.33; 95% CI 1.46 to 4.43, P<0.01) were associated with increased hazard of readmission within 30 days.

Conclusions

Patient-level sociodemographic factors did not influence the incidence of unplanned all-cause readmission within 30 days. Further research is needed to understand the generalisability of our findings and investigate whether contextual factors, such as access to universal health insurance coverage, attenuate the effects of sociodemographic factors.

http://ift.tt/2ykOBQz

Evidence-based recommendations on care for breast cancer survivors for primary care providers: a review of evidence-based breast cancer guidelines

Objective

To review evidence-based (EB) recommendations on survivorship care for primary care providers (PCPs) in EB breast cancer guidelines.

Design and setting

Guidelines were collected via experts and via literature database, guideline database and cancer agency websites searches.

Method

EB guidelines in any language published between 2012 and 2017 were collected. EB recommendations on survivorship care relevant for PCPs were extracted and grouped into three categories (recurrence detection, long-term effects and recurrence prevention). The content of the recommendations was analysed and summarised in the number and type of clinical topics addressed. The Appraisal of Guidelines for Research and Evaluation II instrument was used to evaluate the methodological quality of the guidelines.

Results

Six guidelines, of which two were of acceptable methodological quality, were included. One was specifically made for general practitioners. Fifteen clinical topics were identified. Guidelines differed in the clinical topics addressed and for some identical topics in the content of the recommendations. Many recommendations were based on low-quality evidence. Recurrence detection received most attention, physical examination and mammography were often highlighted. Potential complications largely varied in number and type. Intimacy concerns, vaginal dryness, dyspareunia, fatigue, menopausal symptoms, peripheral neuropathy and lymphedema were reported in more than one guideline. Recurrence prevention was mentioned in four guidelines; all recommended physical activity.

Conclusion

The number of EB recommendations in guidelines is limited. Moreover, recommendations differ between guidelines and most are based on low-quality evidence. More high-quality research is needed to develop and adapt guidelines to support PCPs in providing optimal breast cancer survivorship care.

http://ift.tt/2AyoJXs

Do psychological harms result from being labelled with an unexpected diagnosis of abdominal aortic aneurysm or prostate cancer through screening? A systematic review

Objective

A potential psychological harm of screening is unexpected diagnosis—labelling. We need to know the frequency and severity of this harm to make informed decisions about screening. We asked whether current evidence allows an estimate of any psychological harm of labelling. As case studies, we used two conditions for which screening is common: prostate cancer (PCa) and abdominal aortic aneurysm (AAA).

Design

Systematic review with narrative synthesis.

Data sources and eligibility criteria

We searched the English language literature in PubMed, PsychINFO and Cumulative Index of Nursing and Allied Health Literature (CINAHL) for research of any design published between 1 January 2002 and 23 January 2017 that provided valid data about the psychological state of people recently diagnosed with early stage PCa or AAA. Two authors independently used explicit criteria to review and critically appraise all studies for bias, applicability and the extent to which it provided evidence about the frequency and severity of harm from labelling.

Results

35 quantitative studies (30 of PCa and 5 of AAA) met our criteria, 17 (48.6%) of which showed possible or definite psychological harm from labelling. None of these studies, however, had either appropriate measures or relevant comparisons to estimate the frequency and severity of psychological harm. Four PCa and three AAA qualitative studies all showed clear evidence of at least moderate psychological harm from labelling. Seven population-based studies found increased suicide in patients recently diagnosed with PCa.

Conclusions

Although qualitative and population-based studies show that at least moderate psychological harm due to screening for PCa and AAA does occur, the current quantitative evidence is insufficient to allow a more precise estimation of frequency and severity. More sensitive measures and improved research designs are needed to fully characterise this harm. In the meantime, clinicians and recommendation panels should be aware of the occurrence of this harm.

http://ift.tt/2ykXR7b

EvaLuation Using Cardiac Insertable Devices And TelephonE in Hypertrophic Cardiomyopathy (ELUCIDATE HCM)--rationale and design: a prospective observational study on incidence of arrhythmias in Sweden

Introduction

Hypertrophic cardiomyopathy (HCM) is a heterogeneous disease associated with sudden cardiac death (SCD) mainly due to ventricular tachycardia (VT) or fibrillation even though life-threatening bradycardia occurs. Risk stratification takes several variables into consideration including non-sustained VT (NSVT). An implantable cardioverter defibrillator effectively prevents SCD.

Atrial fibrillation (AF) is common among patients with HCM and warrants anticoagulation even without conventional risk factors according to European guidelines. Routinely, the evaluation of arrhythmias using a 48-hour ambulatory external monitor takes place every 6–24 months if patients do not report palpitations. The remaining time the potential burden arrhythmia is unknown. Therefore, the aim of the present study is to assess NSVT and AF incidence during 18 months by an insertable cardiac monitor (ICM).

Methods

Adult patients, aged 18–65 years, with a validated diagnosis of HCM are eligible for the study. The study sample is planned to include 30 patients. A Confirm Rx is implanted at the level of the fourth rib on the left side subcutaneously after local anaesthesia. The application for monitoring is installed in the patients' smartphone and symptoms registered by the patient activation and VT detection programmed as 160 bpm during ≥8 intervals. An AF episode is recorded based on ≥2 min duration. Bradycardia is recorded at ≤40 bpm or pause ≥3.0 s. The patients are followed during 18 months before explant.

Ethics and dissemination

The study was approved by The Regional Ethical Committee in Umeå (protocol number 2017/13–31). The study protocol, including variables and prespecified research questions, the study was registered at Clinical Trial Registration NCT03259113. Each patient is informed about the study in both oral and written form by a physician and included after written consent.

http://ift.tt/2AyoxaG

Thoracic surgeon and patient focus groups on decision-making in early-stage lung cancer surgery

Future Oncology, Ahead of Print.


http://ift.tt/2Az1xZ5

A critical review on ramucirumab in the treatment of advanced urothelial cancer

Future Oncology, Ahead of Print.


http://ift.tt/2yk99Zy

Use of a Sibling Subtraction Method (SSM) for Identifying Causal Mutations in C. elegans by Whole-Genome Sequencing

Whole-genome sequencing (WGS) is an indispensible tool for identifying causal mutations obtained from genetic screens. To reduce the number of causal mutation candidates typically uncovered by WGS, C. elegans researchers have developed several strategies. One involves crossing N2-background mutants to the polymorphic HA strain, which can be used to simultaneously identify mutant-strain variants and obtain high-density mapping information. This approach, however, is not well suited for uncovering mutations in complex genetic backgrounds, and HA polymorphisms can alter phenotypes. Other approaches make use of DNA variants present in the initial background or introduced by mutagenesis. This information is used to implicate genomic regions with high densities of DNA lesions that persist after backcrossing, but these methods can provide lower resolution than HA mapping. To identify suppressor mutations using WGS, we developed an approach termed the Sibling Subtraction Method (SSM). This method works by eliminating variants present in both mutants and their non-mutant siblings, thus greatly reducing the number of candidates. We used this method with two members of the C. elegans NimA-related kinase family, nekl-2 and nekl-3. Combining weak aphenotypic alleles of nekl-2 and nekl-3 leads to penetrant molting defects and larval arrest. We isolated ~35 suppressors of nekl-2; nekl-3 synthetic lethality using F1-clonal screening methods and a peel-1-based counter-selection strategy. When applied to five of the suppressors, SSM led to only one to four suppressor candidates per strain. Thus SSM is a powerful approach for identifying causal mutations in any genetic background and provides an alternative to current methods.

http://ift.tt/2AQiuep

Genome Assembly and Annotation of the Medicinal Plant Calotropis gigantea, a Producer of Anti-Cancer and Anti-Malarial Cardenolides

Calotropis gigantea produces specialized secondary metabolites known as cardenolides which have anti-cancer and anti-malarial properties. Although transcriptomic studies have been conducted in other cardenolide-producing species, no nuclear genome assembly for an Asterid cardenolide-producing species has been reported to date. A high quality de novo assembly was generated for C. gigantea, representing 157,284,427 bp with an N50 scaffold size of 805,959 bp, for which quality assessments indicated a near complete representation of the genic space. Transcriptome data in the form of RNA-sequencing libraries from a developmental tissue series was generated to aid in annotation and construction of a gene expression atlas. Using an ab initio and evidence-driven gene annotation pipeline, 18,197 high confidence genes were annotated. Homologous and syntenic relationships between C. gigantea and other species within the Apocynaceae family confirmed previously identified evolutionary relationships and suggest the emergence or loss of the specialized cardenolide metabolites after the divergence of the Apocynaceae subfamilies. The C. gigantea genome assembly, annotation, and RNA-sequencing data provide a novel resource to study the cardenolide biosynthesis pathway especially for understanding the evolutionary origin of cardenolides and engineering of cardenolide production in heterologous organisms for existing and novel pharmaceutical applications.

http://ift.tt/2BW6irV

Issue Information

http://ift.tt/2AijO8P

The Changing Role of Sound-Symbolism for Small Versus Large Vocabularies

Abstract

Natural language contains many examples of sound-symbolism, where the form of the word carries information about its meaning. Such systematicity is more prevalent in the words children acquire first, but arbitrariness dominates during later vocabulary development. Furthermore, systematicity appears to promote learning category distinctions, which may become more important as the vocabulary grows. In this study, we tested the relative costs and benefits of sound-symbolism for word learning as vocabulary size varies. Participants learned form-meaning mappings for words which were either congruent or incongruent with regard to sound-symbolic relations. For the smaller vocabulary, sound-symbolism facilitated learning individual words, whereas for larger vocabularies sound-symbolism supported learning category distinctions. The changing properties of form-meaning mappings according to vocabulary size may reflect the different ways in which language is learned at different stages of development.

http://ift.tt/2z64LRC

50 Years Ago in The Journal of Pediatrics

Winter JSD, Kohn G, Mellman WJ, Wagner S. J Pediatr 1968;72:88-93

http://ift.tt/2iWQBt1

Information for Readers

http://ift.tt/2iWwcV1

Somatic Development in Children with Congenital Heart Defects

Somatic development is impaired in children with congenital heart defects (CHDs), and head circumference seems to be a strong predictor of neurodevelopmental prognosis. The aim of this study was to generate up-to-date reference values for the somatic development (head circumference, body weight, and length/height) of children with CHDs.

http://ift.tt/2BfQraS

50 Years Ago in The Journal of Pediatrics

Moffet HL, Shulenberger BS, Burkholder ER. J Pediatr 1968;72:1-14

http://ift.tt/2iWw1Jl

Straight to the Operating Room: An Emergent Surgery Track for Acute Testicular Torsion Transfers

To assess the effect of implementing an emergency surgery track for testicular torsion transfers. We hypothesized that transferring children from other facilities diagnosed with torsion straight to the operating room (STOR) would decrease ischemia time, lower costs, and reduce testicular loss.

http://ift.tt/2BhpYtK

Temporal Association Between Rhinovirus Activity and Kingella kingae Osteoarticular Infections

To determine whether the seasonal distribution of Kingella kingae osteoarticular infections is similar to that of common respiratory viruses.

http://ift.tt/2BfPVts

Cardiorespiratory Capacity and Strength Remain Attenuated in Children with Severe Burn Injuries at Over 3 Years Postburn

To compare physical capacity and body composition between children with burn injuries at approximately 4 years postburn and healthy, fit children.

http://ift.tt/2iYDeIV

Newborn Screening in the US May Miss Mild Persistent Hypothyroidism

To determine if newborn screening (NBS) programs for congenital hypothyroidism in the US use thyroid-stimulating hormone (TSH) cutoffs that are age adjusted to account for the physiologic 4-fold reduction in TSH concentrations over the first few days of life.

http://ift.tt/2iWQhdN

Hearing Loss after Cardiac Surgery in Infancy: An Unintended Consequence of Life-Saving Care

To investigate the prevalence of hearing loss after cardiac surgery in infancy, patient and operative factors associated with hearing loss, and the relationship of hearing loss to neurodevelopmental outcomes.

http://ift.tt/2BhKYAw

Parent Recommendations to Enhance Enrollment in Multidisciplinary Clinical Care for Pediatric Weight Management

To explore parents' recommendations to enhance enrollment in multidisciplinary clinical care for managing pediatric obesity.

http://ift.tt/2iZkuJl

Assessment of Carina Position Antenatally and Postnatally in Infants with Congenital Diaphragmatic Hernia

To determine whether endotracheal tube (ETT) insertion depth should be modified in infants with congenital diaphragmatic hernia (CDH) to reduce the risk of main-stem intubation.

http://ift.tt/2BfFpCp

Predicting Pressure Injury Risk in Pediatric Patients: The Braden QD Scale

To describe the development and initial testing of the Braden QD Scale to predict both immobility-related and medical device–related pressure injury risk in pediatric patients.

http://ift.tt/2BenSL5

Cardiac Biomarkers in Youth with Type 2 Diabetes Mellitus: Results from the TODAY Study

To examine cardiac biomarkers over time in youth-onset type 2 diabetes, and relate serum concentrations to cardiovascular disease risk factors, and left ventricular structure and function.

http://ift.tt/2j0g3O5

A Novel Magnetic Resonance Imaging Score Predicts Neurodevelopmental Outcome After Perinatal Asphyxia and Therapeutic Hypothermia

To assess the predictive value of a novel magnetic resonance imaging (MRI) score, which includes diffusion-weighted imaging as well as assessment of the deep grey matter, white matter, and cerebellum, for neurodevelopmental outcome at 2 years and school age among term infants with hypoxic-ischemic encephalopathy treated with therapeutic hypothermia.

http://ift.tt/2BfDDBo

Peanut Allergy: An Epidemiologic Analysis of a Large Database

To confirm new observations on peanut allergy and answer current concerns that families and healthcare providers have about peanut allergy.

http://ift.tt/2Biw4Ki

Single-staged implant placement using bone ring technique with and without membrane placement: An experimental study in the Beagle dog

Abstract

Aim

To evaluate the impact of a collagen membrane on bone remodeling and osseointegration of implants placed simultaneously with a bone ring technique.

Material and Methods

Standardized, vertical alveolar bone defects in the mandibles of six dogs were created. Tapered dental implants designed for two-stage subcrestal placement were inserted simultaneously with a bone ring technique. On one side of the mandible, the augmented sites were covered with a collagenous membrane. Implants with (M Group) and without membranes (NM Group) were left for an osseointegration period of 3 and 6 months, respectively. Block biopsies of the implants with surrounding bone were harvested and analyzed histologically.

Results

Implant exposure was a common finding (2/3) concomitantly with loss of healing caps. It appeared to be related to advanced bone loss around the implants. Exposure of implants was more frequent in M Group, however, without significant differences when compared to NM Group. The total bone area within the region of the bone ring was greater in the NM Group compared to the M Group. Moreover, in the region of the pristine bone of the M Group, the total bone was greater than at the corresponding NM Group sites at both observation periods. A nonparametric analysis of variance (ANOVA) revealed no significant effects of membrane placement or healing period on the total area of the bone. The total bone-to-implant contact (BIC) for the two groups was similar at each observation time point. However, BIC increased significantly at 6-month compared with 3-month observation period (p = .0088) in both groups.

Conclusions

In vertical bone augmentation applying the bone ring technique, the disruption of soft tissue was a frequent complication. Membrane placement yielded no significant advantage on the osseointegration (BIC) of implants or bone characteristics.

http://ift.tt/2AhV4NN

Autologous dendritic cells pulsed with allogeneic tumor cell lysate in mesothelioma: From mouse to human

Purpose: Mesothelioma has been regarded as a non-immunogenic tumor, which is also shown by the low response rates to treatments targeting the PD-1/PD-L1 axis.  Previously, we demonstrated that autologous tumor lysate-pulsed dendritic cell (DC) immunotherapy increased T-cell response towards malignant mesothelioma. However, the use of autologous tumor material hampers implementation in large clinical trials, which might be overcome by using allogeneic tumor cell lines as tumor antigen source.  The purpose of this study was to investigate if allogeneic lysate pulsed DC immunotherapy is effective in mice and safe in humans. Experimental Design: Firstly, in two murine mesothelioma models, mice were treated with autologous DCs pulsed with either autologous or allogeneic tumor lysate, or injected with PBS (negative control). Survival and tumor-directed T cell responses of these mice were monitored.  Results were taken forward in a first-in-human clinical trial, in which 9 patients were treated with 10, 25 or 50 million DC per vaccination. DC vaccination consisted of autologous monocyte-derived DC pulsed with tumor lysate from 5 mesothelioma cell lines. Results: In mice, allogeneic lysate-pulsed DC immunotherapy induced tumor-specific T cells and led to an increased survival, to a similar extent as DC immunotherapy with autologous tumor lysate. In the first-in-human clinical trial, no dose limiting toxicities were established and radiographic responses were observed. Median PFS was 8.8 months (95% CI 4.1-20.3) and median OS not reached (median follow up 22.8 months). Conclusions: DC immunotherapy with allogeneic tumor lysate is effective in mice and safe and feasible in humans.

http://ift.tt/2iUy00C

Clinical significance of PD-L1+ exosomes in plasma of Head and Neck Cancer patients

Purpose: The microenvironment of head and neck squamous cell carcinomas (HNSCCs) is highly immunosuppressive. HNSCCs expressing elevated levels of PD-L1 have especially poor outcome. Exosomes that carry PD-L1 and suppress T-cell functions have been isolated from plasma of patients with HNSCC. The potential contributions of PD-L1+ exosomes to immune suppression and disease activity are evaluated. Methods: Exosomes isolated from plasma of 40 HNSCC patients by size exclusion chromatography were captured on beads using anti-CD63 Abs, stained for PD-1 and PD-L1 and analyzed by flow cytometry. The percentages and mean fluorescence intensities (MFIs) of PD-L1+ and PD-1+ exosome/bead complexes were correlated with the patients' clinicopathological data. PD-L1high or PD-L1low exosomes were incubated with activated CD69+ human CD8+ T-cells ± PD-1 inhibitor. Changes in CD69 expression levels on T cells were measured. Patients' plasma was tested for soluble PD-L1 (sPD-L1) by ELISA. Results: Levels of PD-L1 carried by exosomes correlated with patients' disease activity, the UICC stage and the lymph node status (p= 0.0008-0.013). In contrast, plasma levels of sPD-L1 or exosome PD-1 levels did not correlate with any clinicopathological parameters. CD69 expression levels were inhibited (p<0.03) by co-incubation with PD-L1high but not by PD-L1low exosomes. Blocking of PD-L1+ exosome signaling to PD-1+ T cells attenuated immune suppression. Conclusions: PD-L1 levels on exosomes, but not levels of sPD-L1, associated correlate with disease progression in HNSCC patients. Circulating PD-L1+ exosomes emerge as useful metrics of disease and immune activity in HNSCC patients.

http://ift.tt/2Bgre01

Neddylation blockade diminishes hepatic metastasis by dampening cancer stem-like cells and angiogenesis in uveal melanoma

Purpose: Liver metastasis is the major and direct cause of death in patients with uveal melanoma (UM). There is no effective therapy for patients with metastatic UM. Improved treatments of hepatic metastatic patients with UM were urgently needed. Inspired by readily detectable key components in neddylation pathway in UM cells, we aimed at exploring whether neddylation pathway was a therapeutic target for liver metastatic UM. Experimental Design: Expression of key proteins in neddylation pathway in UM was detected by Western blotting, real-time quantitative RT-PCR (qRT-PCR), and immunohistochemical staining. Cellular proliferation, apoptosis, cell cycle, migration, and cancer stem-like cells (CSCs) properties were examined upon treatment with MLN4924, a potent and selective NAE inhibitor. Antitumor activity and frequency of CSCs were determined by using NOD-SCID mouse xenograft model. Liver metastasis was evaluated by use of a NOD-scid-IL2Rg–(NSI) mouse model. Results: NAE1 expression was readily detectable in UM. Inhibition of neddylation pathway by MLN4924 repressed the CSCs properties in UM [capacities of tumorsphere formation and serially-replating, aldehyde dehydrogenase positive (ALDH+) cells, and frequency of CSCs] through Slug protein degradation. MLN4924 treatment disturbed the paracrine secretion of NF-B-mediated VEGF-C and its dependent angiogenesis. The inhibitory effect of neddylation blockade on proliferation which was confirmed by xenografted UM tumor in NOD-SCID mice was involved in activation of ATM-Chk1-Cdc25C DNA damage response, and G2/M-phase arrest. Neddylation inhibition profoundly inhibited hepatic metastasis in UM. Conclusions: Our studies validate the neddylation pathway as a promising therapeutic target for the treatment of patients with hepatic metastasis of UM.

http://ift.tt/2iYf6Gk

Had1 Is Required for Cell Wall Integrity and Fungal Virulence in Cryptococcus neoformans

Calcineurin modulates environmental stress survival and virulence of the human fungal pathogen Cryptococcus neoformans. Previously, we identified 44 putative calcineurin substrates and proposed that the calcineurin pathway is branched to regulate targets including Crz1, Pbp1, and Puf4 in C. neoformans. In this study we characterized Had1, which is one of the putative calcineurin substrates and belongs to a ubiquitously conserved haloacid dehalogenase β-phosphoglucomutase protein super-family. Growth of the had1 mutant was found to be compromised at 38°C or higher. In addition, the had1 mutant exhibited increased sensitivity to cell wall perturbing agents including Congo Red, and Calcofluor White, and to an ER stress inducer DTT. Virulence studies revealed that the had1 mutation results in attenuated virulence compared to the wild type strain in a murine inhalation infection model. Genetic epistasis analysis revealed that Had1 and the zinc finger transcription factor Crz1 play roles in parallel pathways that orchestrate stress survival and fungal virulence. Overall, our results demonstrate that Had1 is a key regulator of thermotolerance, cell wall integrity, and virulence of C. neoformans.

http://ift.tt/2BZqAAR

Reference Quality Genome Assemblies of Three Parastagonospora nodorum Isolates Differing in Virulence on Wheat

Parastagonospora nodorum, the causal agent of Septoria nodorum blotch of wheat, has emerged as a model necrotrophic fungal organism for the study of host-microbe interactions. To date, three necrotrophic effectors have been identified and characterized from this pathogen, including SnToxA, SnTox1, and SnTox3. Necrotrophic effector identification was greatly aided by the development of a draft genome of Australian isolate SN15 via Sanger sequencing, yet remained largely fragmented. This research presents the development of near-finished genomes of P. nodorum isolates Sn4, Sn2000, and Sn79-1087 using long-read sequencing technology. RNAseq analysis of isolate Sn4 consisting of eight time-points covering various developmental and infection stages mediated the annotation of 13,379 genes. Analysis of these genomes revealed large-scale polymorphism between the three isolates, including the complete absence of contig 23 from isolate Sn79-1087 and a region of genome expansion on contig 10 in isolates Sn4 and Sn2000. Additionally, these genomes exhibit the hallmark characteristics of a 'two-speed' genome, being partitioned into two distinct GC-equilibrated and AT-rich compartments. Interestingly, isolate Sn79-1087 contains a lower proportion of AT-rich segments, indicating a potential lack of evolutionary hot spots. These newly sequenced genomes, consisting of telomere to telomere assemblies of nearly all 23 P. nodorum chromosomes provides a robust foundation for the further examination of effector biology and genome evolution.

http://ift.tt/2AS285b

Highly Efficient Site-Specific Mutagenesis in Malaria Mosquitoes Using CRISPR

Anopheles mosquitoes transmit at least 200 million annual malaria infections worldwide. Despite considerable genomic resources, mechanistic understanding of biological processes in Anopheles has been hampered by a lack of tools for reverse genetics. Here, we report successful application of the CRISPR/Cas9 system for highly efficient, site-specific mutagenesis in the diverse malaria vectors Anopheles albimanus, Anopheles coluzzii, and Anopheles funestus. When guide RNAs and Cas9 protein are injected at high concentration, germline mutations are common and usually bi-allelic allowing for the rapid creation of stable, mutant lines for reverse genetic analysis. Our protocol should enable researchers to dissect the molecular and cellular basis of anopheline traits critical to successful disease transmission, potentially exposing new targets for malaria control.

http://ift.tt/2BZ45fj

Single-cell RNA-seq reveals a subpopulation of prostate cancer cells with enhanced cell cycle-related transcription and attenuated androgen response

Increasing evidence suggests the presence of minor cell subpopulations in prostate cancer that are androgen independent and poised for selection as dominant clones after androgen-deprivation therapy. In this study, we investigated this phenomenon by stratifying cell subpopulations based on transcriptome profiling of 144 single LNCaP prostate cancer cells treated or untreated with androgen after cell cycle synchronization. Model-based clustering of 397 differentially expressed genes identified eight potential subpopulations of LNCaP cells, revealing a previously unappreciable level of cellular heterogeneity to androgen stimulation. One subpopulation displayed stem-like features with a slower cell doubling rate, increased sphere formation capability, and resistance to G2/M arrest induced by a mitosis inhibitor. Advanced growth of this subpopulation was associated with enhanced expression of 10 cell cycle-related genes (CCNB2, DLGAP5, CENPF, CENPE, MKI67, PTTG1, CDC20, PLK1, HMMR, and CCNB1) and decreased dependence upon androgen receptor signaling. In silico analysis of RNA-seq data from The Cancer Genome Atlas (TCGA) further demonstrated that concordant upregulation of these genes was linked to recurrent prostate cancers. Analysis of receiver-operating characteristic curves implicates aberrant expression of these genes and could be useful for early identification of tumors that subsequently develop biochemical recurrence. Moreover, this single-cell approach provides a better understanding of how prostate cancer cells respond heterogeneously to androgen-deprivation therapies and reveals characteristics of subpopulations resistant to this treatment.

http://ift.tt/2yjQooU

Targeting CDK6 and BCL2 exploits the "MYB addiction" of Ph+ acute lymphoblastic leukemia

Philadelphia Chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is currently treated with BCR-ABL1 tyrosine kinase inhibitors (TKI) in combination with chemotherapy. However, most patients develop resistance to TKI through BCR-ABL1-dependent and -independent mechanisms. Newly developed TKI can target Ph+ ALL cells with BCR-ABL1-dependent resistance; however, overcoming BCR-ABL1-independent mechanisms of resistance remains challenging because transcription factors (TF), which are difficult to inhibit, are often involved. We show here that: i) the growth of Ph+ ALL cell lines and primary cells is highly dependent on MYB-mediated transcriptional upregulation of CDK6, cyclin D3, and BCL2 and ii) restoring their expression in MYB-silenced Ph+ ALL cells rescues their impaired proliferation and survival. Levels of MYB and CDK6 were highly correlated in adult Ph+ ALL (p=0.00008). Moreover, Ph+ ALL cells exhibited a specific requirement for CDK6 but not CDK4 expression, most likely because, in these cells, CDK6 was predominantly localized in the nucleus while CDK4 was almost exclusively cytoplasmic. Consistent with their essential role in Ph+ ALL, pharmacological inhibition of CDK6 and BCL2 markedly suppressed proliferation, colony formation, and survival of Ph+ ALL cells ex vivo and in mice. In summary, these findings provide a proof-of-principle, rational strategy to target the MYB "addiction" of Ph+ ALL.

http://ift.tt/2AA1YlO

Integrated molecular characterization of the lethal pediatric cancer pancreatoblastoma

Pancreatoblastoma (PBL) is a rare pediatric pancreatic malignancy for which the molecular pathogenesis is not understood. In this study, we report the findings of an integrated multi-omics study of whole exome and RNA sequencing as well as genome-wide copy number and methylation analyses of 10 PBL cases. The PBL genome was characterized by a high frequency of aberrant activation of the Wnt signaling pathway, either via somatic mutations of CTNNB1 (90%) and copy-neutral loss of heterozygosity (CN-LOH) of APC (10%). In addition, imprinting dysregulation of IGF2 as a consequence of CN-LOH (80%), gain of paternal allele (10%), and gain of methylation (10%) were universally detected. At the transcriptome level, PBL exhibited an expression profile characteristic of early pancreas progenitor-like cells along with upregulation of the R-spondin/LGR5/RNF43 module. Our results offer a comprehensive description of the molecular basis for PBL and highlight rational therapeutic targets for its treatment.

http://ift.tt/2yjw9rs

Comprehensive mutation and copy number profiling in archived circulating breast cancer tumor cells documents heterogeneous resistance mechanisms

Addressing drug resistance is a core challenge in cancer research, but the degree of heterogeneity in resistance mechanisms in cancer is unclear. In this study, we conducted next-generation sequencing (NGS) of circulating tumor cells (CTC) from patients with advanced cancer, to assess mechanisms of resistance to targeted therapy and reveal opportunities for precision medicine. Comparison of the genomic landscapes of CTC and tissue metastases is complicated by challenges in comprehensive CTC genomic profiling and paired tissue acquisition, particularly in patients who progress after targeted therapy. Thus, we assessed by NGS somatic mutations and copy number alterations (CNA) in archived CTC isolated from patients with metastatic breast cancer who were enrolled in concurrent clinical trials that collected and analyzed CTC and metastatic tissues. In 76 individual and pooled informative CTC from 12 patients, we observed 85% concordance in at least one or more prioritized somatic mutations and CNA between paired CTC and tissue metastases. Potentially actionable genomic alterations were identified in tissue but not CTC, and vice versa. CTC profiling identified diverse intra- and inter-patient molecular mechanisms of endocrine therapy resistance, including loss of heterozygosity (LOH) in individual CTC. For example, in one patient, we observed CTC that were either wildtype for ESR1 (n=5/32), harbored the known activating ESR1 p.Y537S mutation (n=26/32), or harbored a novel ESR1 p.A569S (n=1/32). ESR1 p.A569S was modestly activating in vitro, consistent with its presence as a minority circulating subclone. Our results demonstrate the feasibility and potential clinical utility of comprehensive profiling of archived fixed CTC. Tissue and CTC genomic assessment are complementary, and precise combination therapies will likely be required for effective targeting in advanced breast cancer patients.

http://ift.tt/2ykwoCB

A20 regulates the DNA damage response and mediates tumor cell resistance to DNA damaging therapy

A competent DNA damage response (DDR) helps prevent cancer, but once cancer has arisen DDR can blunt the efficacy of chemotherapy and radiotherapy which cause lethal DNA breakage in cancer cells. Thus, blocking DDR may improve the efficacy of these modalities. Here we report a new DDR mechanism that interfaces with inflammatory signaling and might be blocked to improve anticancer outcomes. Specifically, we report that the ubiquitin-editing enzyme A20 binds and inhibits the E3 ubiquitin ligase RNF168, which is responsible for regulating histone H2A turnover critical for proper DNA repair. A20 induced after DNA damage disrupted RNF168-H2A interaction in a manner independent of its enzymatic activity. Further, it inhibited accumulation of RNF168 and downstream repair protein 53BP1 during DNA repair. A20 was also required for disassembly of RNF168 and 53BP1 from damage sites after repair. Conversely, A20 deletion increased the efficiency of error-prone non-homologous DNA end-joining and decreased error-free DNA homologous recombination, destablizing the genome and increasing sensitivity to DNA damage. In clinical specimens of invasive breast carcinoma, A20 was widely overexpressed consistent with its candidacy as a therapeutic target. Taken together, our findings suggest A20 is critical for proper functioning of the DDR in cancer cells and it establishes a new link between this NF-κB regulated ubiquitin-editing enzyme and the DDR pathway.

http://ift.tt/2AB3fsP

Rapid Responses to Avapritinib (BLU-285) in Mastocytosis [News in Brief]

Targeted therapy produces lasting reductions in mast cells and molecular levels of KIT D816V.

http://ift.tt/2APFdas

Role for Immune Therapy in Advanced Breast Cancer [News in Brief]

Data suggest that pembrolizumab can control growth of trastuzumab-resistant HER2-positive tumors.

http://ift.tt/2BXHdg8

Association between PDE4D rs966221 polymorphism and risk of ischemic stroke: a systematic review and meta-analysis

Abstract

PDE4D polymorphism (SNP83/rs966221) was reported to be associated with the susceptibility to ischemic stroke (IS), however, the results were inconclusive. An electronic search of Embase, PubMed, CNKI and Wan Fang Date was performed to identify relevant studies published throughout April 2017. A total of 26 studies were enrolled in the analysis. No significant association between the rs9662221 polymorphism and IS was observed in the overall analysis. Nevertheless, in the subgroup analysis, our results showed a significant association between the SNP83 polymorphism and IS in CC+ CT vs. TT (OR = 1.19, 95% CI: 1.02–1.38), CT vs.TT (OR = 1.14, 95% CI: 1.01–1.29) and C vs. T (OR = 1.25, 95% CI: 1.06–1.48) in Asian population. But we did not found any association in CC vs. CT + TT (OR = 1.2, 95% CI: 0.9–1.61) and CC vs. TT (OR = 1.26, 95% CI: 0.91–1.75) in the Asian populations. Meantime, no significant correlations were observed under the five genetic model in Caucasian population (p > 0.05). In conclusion, our meta-analysis demonstrated that the SNP83 polymorphism in the PDE4D gene might contribute to IS susceptibility especially in Asian populations. Whereas the relationship of the polymorphism to the disease in Caucasian population was still in controversial. In future, additional well designed studies with larger sample sizes are still required to further elucidate this association.

http://ift.tt/2Bjbk4U

Antigiardial Effect of Kramecyne in Experimental Giardiasis

A variety of drugs are used in giardiasis treatment with different levels of efficiency, presence of side effects, and even formation of resistant strains, so that it is important to search new only-one-dose treatments with high efficiency and less side effects. Kramecyne, an anti-inflammatory compound isolated from methanolic extract of Krameria cytisoides, does not present toxicity, even at doses of 5,000 mg/kg. The objective was to determine the antigiardial effect of kramecyne over Giardia intestinalis in vitro and in vivo and analyze the expression of genes ERK1, ERK2, and AK on kramecyne treated trophozoites by Real Time Polymerase Chain Reaction (RTPCR). The median lethal dose (LD50) was 40 μg/mL and no morphological changes were observed by staining with blue trypan and light microscopy; experimental gerbil infection was eliminated with 320 μg/Kg of weight. After treatment there were no differences between intestines from treated and untreated gerbils. Kramecyne did not have significant effect over ERK1 and AK, but there are differences in ERK2 expression (). Results show antigiardial activity of kramecyne; however the mode of action is still unclear and the evaluation of ultrastructural damage and expressed proteins is an alternative of study to understand the action mechanism.

http://ift.tt/2Ai6iCh

Spinal cord injury induced cardiomyocyte atrophy and impaired cardiac function are severity dependent

Abstract

The principle aim of the present study was to assess how the severity of spinal cord injury (SCI) affects LV mechanics, function, and underlying cardiomyocyte morphology. Here, we utilized different severities of T3 spinal cord contusions (MODERATE, 200Kdyn contusion; SEVERE, 400kdyn contusion; SHAM) and combined standard echocardiography with speckle tracking analyses to investigate in vivo cardiac function and deformation (contractility) after experimental SCI in the Wistar rat. In addition, we investigated changes in the intrinsic structure of cardiac myocytes ex vivo. We demonstrate that SEVERE SCI induces a characteristic decline in left-ventricular chamber size and a reduction in in vivo LV deformation (i.e. radial strain) throughout the entire systolic portion of the cardiac cycle (25.6 ± 3.0 vs. 44.5 ± 8.1 (Pre-injury); P = 0.0029). SEVERE SCI also caused structural changes in cardiomyocytes including decreased length (115.6 μm ± 7.63 vs. 125.8 μm ± 6.75 (SHAM); P = 0.0458), decreased width (7.78 μm ± 0.71 vs. 10.78 μm ± 1.08 (SHAM); P = 0.0015), and an increase in the length/width ratio (14.88 ± 0.66 vs. 11.74 ± 0.89 (SHAM); P = 0.0018), which was significantly correlated with LV flow-generating capacity after SCI (i.e. stroke volume, R² = 0.659; P = 0.0013). MODERATE SCI rodents exhibited no changes in any metric vs. SHAM. This is the first study to demonstrate that the severity of SCI determines the course of changes to the intrinsic structure of cardiomyocytes, which are directly related to contractile function of the LV.

This article is protected by copyright. All rights reserved

http://ift.tt/2Aeem6R

Laparoscopic distal pancreatectomy for intrapancreatic accessory spleen: a case report

http://ift.tt/2Bi1YGL

Start-Up and Aeration Strategies for a Completely Autotrophic Nitrogen Removal Process in an SBR

The start-up and performance of the completely autotrophic nitrogen removal via nitrite (CANON) process were examined in a sequencing batch reactor (SBR) with intermittent aeration. Initially, partial nitrification was established, and then the DO concentration was lowered further, surplus water in the SBR with high nitrite was replaced with tap water, and continuous aeration mode was turned into intermittent aeration mode, while the removal of total nitrogen was still weak. However, the total nitrogen (TN) removal efficiency and nitrogen removal loading reached 83.07% and 0.422 kgN/(m3·d), respectively, 14 days after inoculating 0.15 g of CANON biofilm biomass into the SBR. The aggregates formed in SBR were the mixture of activated sludge and granular sludge; the volume ratio of floc and granular sludge was 7 : 3. DNA analysis showed that Planctomycetes-like anammox bacteria and Nitrosomonas-like aerobic ammonium oxidization bacteria were dominant bacteria in the reactor. The influence of aeration strategies on CANON process was investigated using batch tests. The result showed that the strategy of alternating aeration (1 h) and nonaeration (1 h) was optimum, which can obtain almost the same TN removal efficiency as continuous aeration while reducing the energy consumption, inhibiting the activity of NOB, and enhancing the activity of AAOB.

http://ift.tt/2AdvWI3

3-Amino-1,2,4-triazole Limits the Oxidative Damage in UVA-Irradiated Dysplastic Keratinocytes

Reactive oxygen species (ROS) generated by UVA irradiation affect the keratinocyte cell membrane, DNA, and proteins and may cause serious injury to the skin. Treating human dysplastic keratinocytes (DOK) with 3-amino-1,2,4-triazole (AMT), a common catalase inhibitor, induced a compensatory mechanism for the hydrogen peroxide detoxification, which included a rise in glutathione peroxidase and glutathione reductase activities. Here, we examined a possible role of AMT in protecting a human DOK cell line against UVA-induced damage. In DOK cells exposed to UVA irradiation, we observed a substantial decrease in antioxidant enzymatic activities, such as catalase, glutathione peroxidase, glutathione reductase, and glutathione-S-transferase and an increase in lipid peroxidation and protein oxidation levels. Treating DOK cells with AMT prior to UVA exposure enhanced the activities of glutathione peroxidase, glutathione reductase, and glutathione-S-transferase, relative to nontreated cells. The enhanced antioxidant activities were correlated with decreased protein oxidation levels. Based on these results, we suggest that AMT may protect dysplastic keratinocytes against the harmful effects of UVA radiation.

http://ift.tt/2Bhm3Na

Managing an Older Adult with Cancer: Considerations for Radiation Oncologists

Older adults with cancer present a unique set of management complexities for oncologists and radiation oncologists. Prognosis and resilience to cancer treatments are notably dependent on the presence or risk of "geriatric syndromes," in addition to cancer stage and histology. Recognition, proper evaluation, and management of these conditions in conjunction with management of the cancer itself are critical and can be accomplished by utilization of various geriatric assessment tools. Here we review principles of the geriatric assessment, common geriatric syndromes, and application of these concepts to multidisciplinary oncologic treatment. Older patients may experience toxicities related to treatments that impact treatment effectiveness, quality of life, treatment-related mortality, and treatment compliance. Treatment-related burdens from radiotherapy are increasingly important considerations and include procedural demands, travel, costs, and temporary or permanent loss of functional independence. An overall approach to delivering radiotherapy to an older cancer patient requires a comprehensive assessment of both physical and nonphysical factors that may impact treatment outcome. Patient and family-centered communication is also an important part of developing a shared understanding of illness and reasonable expectations of treatment.

http://ift.tt/2Bi4hJI

Targeting the Raf kinases in human cancer: the Raf dimer dilemma

Targeting the Raf kinases in human cancer: the Raf dimer dilemma

Targeting the Raf kinases in human cancer: the Raf dimer dilemma, Published online: 12 December 2017; doi:10.1038/bjc.2017.399

Targeting the Raf kinases in human cancer: the Raf dimer dilemma

http://ift.tt/2BX6Duh

High Salt Intake Promotes Different Responses to Urodilatin and Uroguanylin in the Isolated Rat Kidney

Horm Metab Res
DOI: 10.1055/s-0043-120669

Urodilatin (UD) and uroguanylin (UGN) have been implicated in the regulation of salt and water homeostasis, particularly in the balance handling of salt intake. In this sense, the aim of the present work was to study the main effects of these peptides in kidneys from animals subjected to high NaCl (2%) intake, during 10 days in metabolic cages. The control group received only normal water, whereas the treated group drank 2% solution of NaCl (NaCl 2%). In addition, we studied effect of subthreshold UD (0.14 nM) and UGN (0.06 μM) doses in NaCl 2% after a 30-min control period. Kidney perfusion was performed with Krebs–Henseleit containing 6 g% bovine albumin previously dialyzed. The effects of UD (0.14 nM) promoted reduction of PP, RVR, and UF in the NaCl 2% group. We also observed an increase in %TNa+ and %TCl−. The main effects of UGN in NaCl 2% were increase in PP, UF, and GFR, followed by a reduction in %TNa+ and %TCl−. After an increased intake of salt, physiological pathways are activated and regulated in order to eliminate excess sodium. In this study, we observed that in a subthreshold dose, UD does not promotes natriuresis and diuresis, suggesting that UGN is an important hormone in inducing salt excretion in a chronic salt overload. Therefore, the effects herein described may play a contributory role in the regulation of kidney function after ingestion of salty meals.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

http://ift.tt/2yjj8hL

Alcohol and oestrogen metabolites in postmenopausal women in the Women’s Health Initiative Observational Study

Alcohol and oestrogen metabolites in postmenopausal women in the Women's Health Initiative Observational Study

Alcohol and oestrogen metabolites in postmenopausal women in the Women's Health Initiative Observational Study, Published online: 12 December 2017; doi:10.1038/bjc.2017.419

Alcohol and oestrogen metabolites in postmenopausal women in the Women's Health Initiative Observational Study

http://ift.tt/2BXy8Ef

ALDH1A3 affects colon cancer in vitro proliferation and invasion depending on CXCR4 status

ALDH1A3 affects colon cancer in vitro proliferation and invasion depending on CXCR4 status

ALDH1A3 affects colon cancer <i>in vitro</i> proliferation and invasion depending on CXCR4 status, Published online: 12 December 2017; doi:10.1038/bjc.2017.363

ALDH1A3 affects colon cancer in vitro proliferation and invasion depending on CXCR4 status

http://ift.tt/2BXyoTJ

Anthropometric measurements and survival after a prostate cancer diagnosis

Anthropometric measurements and survival after a prostate cancer diagnosis

Anthropometric measurements and survival after a prostate cancer diagnosis, Published online: 12 December 2017; doi:10.1038/bjc.2017.440

Anthropometric measurements and survival after a prostate cancer diagnosis

http://ift.tt/2BXykmX

The hypoxia marker CAIX is prognostic in the UK phase III VorteX-Biobank cohort: an important resource for translational research in soft tissue sarcoma

The hypoxia marker CAIX is prognostic in the UK phase III VorteX-Biobank cohort: an important resource for translational research in soft tissue sarcoma

The hypoxia marker CAIX is prognostic in the UK phase III VorteX-Biobank cohort: an important resource for translational research in soft tissue sarcoma, Published online: 12 December 2017; doi:10.1038/bjc.2017.430

The hypoxia marker CAIX is prognostic in the UK phase III VorteX-Biobank cohort: an important resource for translational research in soft tissue sarcoma

http://ift.tt/2BX6JlD

Cell and molecular biology: a new section joins the fight against cancer

Cell and molecular biology: a new section joins the fight against cancer

Cell and molecular biology: a new section joins the fight against cancer, Published online: 12 December 2017; doi:10.1038/bjc.2017.443

Cell and molecular biology: a new section joins the fight against cancer

http://ift.tt/2BXyg6H

Influence of induction chemotherapy in trimodality therapy-eligible oesophageal cancer patients: secondary analysis of a randomised trial

Influence of induction chemotherapy in trimodality therapy-eligible oesophageal cancer patients: secondary analysis of a randomised trial

Influence of induction chemotherapy in trimodality therapy-eligible oesophageal cancer patients: secondary analysis of a randomised trial, Published online: 12 December 2017; doi:10.1038/bjc.2017.423

Influence of induction chemotherapy in trimodality therapy-eligible oesophageal cancer patients: secondary analysis of a randomised trial

http://ift.tt/2BWM5lQ

Retreatment with Vismodegib after Progression in Advanced Basal Cell Carcinoma: First-Time Report of a Single-Institution Experience

Abstract

Retreatment with vismodegib in advanced basal cell carcinoma (BCC) patients who previously discontinued the drug due to disease progression (PD) has not been reported yet. The objective of our report is to determine whether vismodegib is still active when used in BCC patients who progressed during a first vismodegib course (FVC). We conducted a retrospective study on six advanced BCC patients enrolled in a clinical trial (STEVIE, NCT01367665) who discontinued vismodegib due to PD and were then retreated with the same drug. All patients underwent intercurrent therapies between the FVC and the second vismodegib course (SVC). Disease control (complete response, CR; partial response, PR; and stable disease) was achieved in 100% and 80% of cases in FVC and SVC, respectively. The overall response rate was 80% for FVC (50% of CR) and 50% for SVC (only PR). Median treatment duration of FVC and SVC was 19.5 months (range: 13–35) and 8 months (range: 3–14+), respectively. G3-G4 AEs were reported only during SVC (two cases), leading to permanent discontinuation in one case. The median interval between FVC and SVC was 21.5 months (range: 13–30). After a median follow-up of 54 months (range: 46–63) only one patient with metastatic disease had rapid progression, discontinued vismodegib, and died. All other patients are still alive and two are currently on therapy. We concluded that vismodegib rechallenge is feasible and potentially active in advanced BCC patients who previously discontinued the drug due to disease progression.

http://ift.tt/2AdN94b

LMX1B-Associated Nephropathy With Type III Collagen Deposition in the Glomerular and Tubular Basement Membranes

Variants in the LMX1B gene cause nail-patella syndrome, a rare autosomal dominant disorder characterized by dysplasia of nails, patella and elbow abnormalities, iliac "horns," and glaucoma. We describe an adult man with nephrotic syndrome and no systemic manifestations of nail-patella syndrome at the time of his initial kidney biopsy. His kidney biopsy was initially interpreted as a form of segmental sclerosis with unusual fibrillar deposits. At the time of consideration for kidney transplantation, a family history was notable for end-stage renal disease in 3 generations.

http://ift.tt/2yjhb4Z

HLA Epitope Matching in Kidney Transplantation: An Overview for the General Nephrologist

Rapid changes in tissue-typing technology, including the widespread availability of highly specific molecular typing methods and solid-phase assays for the detection of allele-specific anti-HLA antibodies, make it increasingly challenging to remain up to date with developments in organ matching. Terms such as epitopes and eplets abound in the transplantation literature, but often it can be difficult to see what they might mean for the patient awaiting transplantation. In this review, we provide the historical context for current practice in tissue typing and explore the potential role of HLA epitopes in kidney transplantation.

http://ift.tt/2AxSdVr

S-Nitrosohemoglobin Levels and Patient Outcome After Transfusion During Pediatric Bypass Surgery

Abstract

Banked blood exhibits impairments in nitric oxide (NO)-based oxygen delivery capability, reflected in rapid depletion of S-nitrosohemoglobin (SNO-Hb). We hypothesized that transfusion of even freshly-stored blood used in pediatric heart surgery would reduce SNO-Hb levels and worsen outcome. In a retrospective review (n = 29), the percent of estimated blood volume (% eBV) replaced by transfusion directly correlated with ventilator time and inversely correlated with kidney function; similar results were obtained in a prospective arm (n = 20). In addition, an inverse association was identified between SNO-Hb and postoperative increase in Hb (∆Hb), reflecting the amount of blood retained by the patient. Both SNO-Hb and ∆Hb correlated with the probability of kidney dysfunction and oxygenation-related complications. Further, regression analysis identified SNO-Hb as an inverse predictor of outcome. The findings suggest that SNO-Hb and ∆Hb are prognostic biomarkers following pediatric cardiopulmonary bypass, and that maintenance of red blood cell-derived NO bioactivity might confer therapeutic benefit.

http://ift.tt/2AOWgJL

What Interventions Are Most Effective for Emergency Contraception?

Authors included 115 randomized controlled trials (60,479 women) from 2,511 studies screened, 92 of which were conducted in China. Study inclusion and exclusion criteria were similar among included trials, with exclusion of women evaluated after 72 hours and those with multiple episodes of unprotected intercourse, with irregular menstrual periods, or using hormonal contraception. Double blinding occurred in 23 trials.

http://ift.tt/2BXa4kD

Non-invasive brain stimulation and neuro-enhancement in aging

The ability to plan, execute, and control skillful actions was crucial for the survival of our ancestors when throwing projectiles to hunt for food (Stout et al., 2008). In today's society, the required motor repertoire may have changed, but the ability to acquire new motor skills is still essential for most of our daily activities, including independent living. For example, to sufficiently be able to interact with the rest of the world, we need to manipulate small devices such as smartphones or other gadgets with our fingers.

http://ift.tt/2ANzUYZ

Enuresis Management in Children: Retrospective Clinical Audit of 2861 Cases Treated with Practitioner-Assisted Bell-and-Pad Alarm

To establish the treatment efficacy of practitioner-assisted bell-and-pad alarm therapy in children with enuresis between the ages of 5 and 16 years by retrospective medical chart review of 2861 children in multiple clinical settings.

http://ift.tt/2AdYBwG

An Attempt to Standardize the Calculation of Growth Velocity of Preterm Infants—Evaluation of Practical Bedside Methods

To examine how well growth velocity recommendations for preterm infants fit with current growth references: Fenton 2013, Olsen 2010, INTERGROWTH 2015, and the World Health Organization Growth Standard 2006.

http://ift.tt/2z3XIIQ

Resource Use and Morbidities in Pediatric Cardiac Surgery Patients with Genetic Conditions

To evaluate and describe resource use and perioperative morbidities among those patients with genetic conditions undergoing cardiac surgery.

http://ift.tt/2z4yxpM

The First International Conference on Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis Syndrome

In the last 20 years, autoinflammatory syndromes, a new category of immune-mediated diseases, have been described. These diseases are defined as attacks of inflammation, often multisystem, that are unprovoked (or triggered by a minor event) and primarily are related to dysregulation of the innate immune system.1 Many of the syndromes are monogenically inherited. Unlike autoimmune diseases, there is a relative deficiency of both autoantibodies and autoreactive T lymphocytes. The inflammatory response is usually mediated by proinflammatory cytokines, especially interleukin (IL)-1 secreted by granulocytes and monocytes.

http://ift.tt/2AdYIbA

Acute-On-Chronic Liver Failure, Human Serum Albumin and Immune-Modulation: The Beginning of an Exciting Adventure

http://ift.tt/2yiOogE

Cost-Effectiveness and Decision Analysis in Clinical Gastroenterology and Hepatology: From Evidence to Informed Decision Making

http://ift.tt/2AwJB0Z

Is the Over the Scope Clip Device a First-line or Rescue Therapy for Patients at High Risk for Gastrointestinal Bleeding?

http://ift.tt/2yjqMsk

Nomogram to Predict Survival of Patients with Recurrence of Hepatocellular Carcinoma After Surgery

We aimed to establish and validate a nomogram to predict survival at 2 and 5 years after recurrence of hepatocellular carcinoma (HCC) in patients who have undergone curative resection.

http://ift.tt/2AyC3Lq

Primary Adenocarcinoma Arising at a Colostomy Site

http://ift.tt/2yj77IX

Effects of Diabetes and Glycemia Control on Risk of Hepatocellular Carcinoma After Seroclearance of Hepatitis B Surface Antigen

Patients with chronic hepatitis B virus infection after clearance of hepatitis B surface antigen have a small yet persistent risk of hepatocellular carcinoma; diabetes mellitus was identified as an independent risk factor. Controlling glycemia might further reduce the risk.

http://ift.tt/2Axgtqy

Double pylorus. A rare complication of peptic ulcer disease

http://ift.tt/2yj0ZAn

A Rare Cause of Progressive Constipation, Abdominal Distension, and Weight Loss

http://ift.tt/2Axglay

Stool Donor Body Mass Index Does Not Affect Recipient Weight After a Single Fecal Microbiota Transplantation for C. difficile Infection

http://ift.tt/2yjakZc

Helping first responders recover after Las Vegas shooting

As the country struggles to make sense of the massacre in Las Vegas, it's important that those who responded are not overlooked

http://ift.tt/2C9HBsW

Customized care can help first responders in the aftermath of trauma

First responders witness some of the most difficult moments in the lives of the men and women in their communities, and are charged to keep us safe at all costs

http://ift.tt/2BIweLm

The Role of the Surgical Pathologist in the Diagnosis of Gastrointestinal Polyposis Syndromes

Polyps of the gastrointestinal tract are very common lesions and most frequently sporadic in nature. Some polyp subtypes are associated with rare hereditary polyposis syndromes, including juvenile polyposis syndrome, Peutz-Jeghers syndrome, and Cowden syndrome. However, many sporadic benign lesions of the gastrointestinal tract can mimic some of these syndromic hamartomatous polyps. The role of the surgical pathologist is to raise the possibility of a hereditary condition in case of suggestive polyp histology and to look for clinical information to support the suspected diagnosis. In this review, the clinical presentation and the pathology associated with these rare hamartomatous polyposis syndromes are discussed in an attempt to provide pathologists clues in suggesting one such syndrome on the basis of histologic findings and clinical context. Identification of affected individuals is important because of the increased gastrointestinal and other malignancies. Recently, new adenomatous polyposis syndromes have been discovered, expanding the genetic causes of patient diagnosed with multiple colonic adenomas. By being aware of the clinical phenotype and the tumor spectrum associated with gastrointestinal polyposis syndromes, surgical pathologists can play a critical role in recommending genetic counseling when suspicious of such a diagnosis. This may lead to the identification of a genetic cause and appropriate surveillance of affected family members to screen for associated malignancies.

http://ift.tt/2krlWUQ

An Update on the Diagnosis, Grading, and Staging of Appendiceal Mucinous Neoplasms

Despite advances in our understanding of appendiceal mucinous neoplasms and their relationship to the pseudomyxoma peritonei syndrome, the classification of mucinous tumors of the appendix is still confusing. This review will provide an update on the various classification systems that have been recently proposed for appendiceal mucinous neoplasia, with a particular emphasis on how to handle and report the histologic findings for these tumors using the newly published Peritoneal Surface Oncology Group International (PSOGI) and American Joint Committee on Cancer (AJCC) eighth edition guidelines. A simplified approach to diagnostic reporting of appendiceal mucinous neoplasms based on the 3-tier AJCC grading scheme is detailed and specific criteria for assessing grade in appendiceal mucinous neoplasia will be outlined. In addition, histologic mimics of appendiceal mucinous neoplasia and how to distinguish these mimics from mucinous neoplasia will be discussed. Finally, despite improvements in diagnostic terminology, significant challenges in classifying appendiceal mucinous neoplasia persist and diagnostic strategies will be detailed to assist practicing pathologists in these challenging scenarios.

http://ift.tt/2kqn9fb

There Are No Magic Bullets in Hematopathology: Even Immunostains for CD20 and CD3 Can Get You Into Trouble

Immunohistochemistry is a powerful tool for the diagnosis and subclassification of hematolymphoid neoplasms. However, the expression of certain markers is not always as expected, and unusual patterns of staining can lead to misdiagnosis. CD20 and CD3 are our most commonly used markers for identification of B cells and T cells, respectively, and they almost always yield reliable, specific staining. This discussion focuses on diagnostic pitfalls related to the use of immunohistochemistry for CD20 and CD3 in hematopathology, and specifically on diagnostic challenges that arise when (1) CD20 is not expressed in B-cell lymphomas, when (2) CD20 is expressed in plasma cell neoplasms and T-cell lymphomas, and when (3) CD3 is expressed in B-cell lymphomas and Hodgkin lymphoma.

http://ift.tt/2krllCA

The New Realization About Cribriform Prostate Cancer

Data from the past 6 years have shown that the presence of any amount of cribriform (or more comprehensively, large acinar cribriform to papillary) pattern of invasive prostate cancer is associated with adverse pathologic features and leads to uniquely adverse outcomes. Sixteen papers and numerous abstracts have reached these conclusions concordantly. Not only does this justify removal of all cribriform cancer from Gleason grade 3, it shows that cribriform cancer has pathologic, outcome, and molecular features distinct from noncribriform Gleason grade 4. Suggestions for accommodating the presence of cribriform cancer into the 2014 Grade Group scheme are proposed.

http://ift.tt/2kqYdV6

Recent Advances in the Diagnosis of Malignant Mesothelioma: Focus on Approach in Challenging Cases and in Limited Tissue and Cytologic Samples

Mesothelial proliferations can be diagnostically challenging in small specimens, such as body fluid cytology and small tissue biopsies. A great morphologic challenge for pathologists is the separation of benign reactive mesothelial proliferations from malignant mesotheliomas. Reactive mesothelial proliferations may have histologic features that resemble malignancy including increased cellularity, cytologic atypia, and mitoses. Recent advances in mesothelioma genetics resulted in identification of BAP1 mutations and p16 deletions as features of malignant mesotheliomas. Hence, BAP1 immunohistochemistry and fluorescence in situ hybridization for p16 emerged as 2 most common diagnostically helpful ancillary studies used on limited samples when the question is whether the proliferation is malignant or benign. In contrast, separation of mesothelioma from other malignancies is relatively straight forward using morphology and immunohistochemical stains. The choice of antibody panel to be applied in an individual case is driven by morphology, either epithelioid or sarcomatoid. This brief review will focus on morphology and ancillary testing of mainly pleural mesothelial proliferations.

http://ift.tt/2kqmudH

Does a p53 “Wild-type” Immunophenotype Exclude a Diagnosis of Endometrial Serous Carcinoma?

An aberrant p53 immunophenotype may be identified in several histotypes of endometrial carcinoma, and is accordingly recognized to lack diagnostic specificity in and of itself. However, based on the high frequency with which p53 aberrations have historically been identified in endometrial serous carcinoma, a mutation-type immunophenotype is considered to be highly sensitive for the histotype. Using an illustrative case study and a review of the literature, we explore a relatively routine diagnostic question: whether the negative predictive value of a wild-type p53 immunophenotype for serous carcinoma is absolute, that is, whether a p53-wild type immunophenotype is absolutely incompatible with a diagnosis of serous carcinoma. The case is an advanced stage endometrial carcinoma that was reproducibly classified by pathologists from 3 institutions as serous carcinoma based on its morphologic features. By immunohistochemistry, the tumor was p53-wild type (DO-7 clone), diffusely positive for p16 (block positivity), and showed retained expression of PTEN, MSH2, MSH6, MLH1, and PMS2. Next generation sequencing showed that there indeed was an underlying mutation in TP53 (D393fs*78, R213*). The tumor was microsatellite stable, had a low mutational burden (4 mutations per MB), and displayed no mutations in the exonuclease domain of DNA polymerase epsilon (POLE) gene. Other genomic alterations included RB1 mutation (R46fs*19), amplifications in MYST3 and CRKL, and ARID1A deletion (splice site 5125-94_5138del108). A review of the recent literature identified 5 studies in which a total of 259 cases of serous carcinoma were whole-exome sequenced. The average TP53 mutational rate in endometrial serous carcinoma was only 75% (range, 60 to 88). A total of 12 (33%) of 36 immunohistochemical studies reported a p53-aberrant rate of

http://ift.tt/2kqmevf