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

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

No abstract available

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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

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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

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Retrospective Review of Universal Preoperative Pregnancy Testing: Results and Perspectives

Unrecognized pregnancy in patients presenting for elective surgery is of particular concern due to the potential for significant complications. Accurate and inexpensive urine pregnancy tests are widely available in the developed world. As a result, universal preoperative pregnancy screening is commonly implemented. However, the utility of such routine testing is controversial. We retrospectively studied 8245 immediate presurgery pregnancy tests at Mayo Clinic Hospital, Phoenix, AZ, and found 11 positive tests of which 6 were false positives. We constructed a census-based approximation for unrecognized pregnancies, which shows significantly low pretest probability in this patient population. Taken together, the utility of immediate universal presurgical pregnancy testing is questionable. Accepted for publication October 30, 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. from the authors., Address correspondence to Karl A. Poterack, MD, Mayo Clinic Hospital, 5777 E Mayo Blvd, Phoenix, AZ 85054. Address e-mail to poterack.karl@mayo.edu. © 2017 International Anesthesia Research Society

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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

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In Response

No abstract available

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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

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Oxford Textbook of Anaesthesia, 1st Edition

No abstract available

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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

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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

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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

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In Response

No abstract available

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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

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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

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Response to Improving the Success Rate of Chest Compression-Only CPR by Untrained Bystanders in Adult Out-of-Hospital Cardiac Arrest: Maintaining Airway Patency May Be the Way Forward

No abstract available

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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

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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

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Nerve Blockade and Chronic Opiate Use After Orthopedic Surgery

No abstract available

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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

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Activation of astrocytic PAR1 receptors in the rat nucleus of the solitary tract regulates breathing through modulation of presynaptic TRPV1

Abstract

Many of the cellular and molecular mechanisms underlying astrocytic modulation of synaptic function remain poorly understood. Recent studies show that G-protein coupled receptor-mediated astrocyte activation modulates synaptic transmission in the nucleus of the solitary tract (NTS), a brainstem nucleus that regulates crucial physiological processes including cardiorespiratory activity. By using calcium imaging and patch clamp recordings in acute brain slices of wild-type and TRPV1^−/− rats, we show that activation of proteinase-activated receptor 1 (PAR-1) in NTS astrocytes potentiates presynaptic glutamate release on NTS neurons. This potentiation is mediated by both a TRPV1-dependent and a TRPV1-independent mechanism. The TRPV1-dependent mechanism appears to require release of endovanilloid-like molecules from astrocytes which leads to subsequent potentiation of presynaptic glutamate release via activation of presynaptic TRPV1 channels. Activation of NTS astrocytic PAR-1 receptors elicits cFOS expression in neurons that project to respiratory premotor neurons and inhibits respiratory activity in control, but not in TRPV1^−/− rats. Thus, activation of astrocytic PAR-1 receptor in the NTS leads to a TRPV1-dependent excitation of NTS neurons causing a potent modulation of respiratory motor output.

This article is protected by copyright. All rights reserved

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Tigecycline Susceptibility of Klebsiella pneumoniae Complex and Escherichia coli Isolates from Companion Animals: The Prevalence of Tigecycline-Nonsusceptible K. pneumoniae Complex, Including Internationally Expanding Human Pathogenic Lineages

Microbial Drug Resistance , Vol. 0, No. 0.


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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.

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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.

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Editorial Board

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Table of Contents

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Table of Contents

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Meetings Calendar

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Table of Contents

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Table of Contents

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Reducible complexity

It is my pleasure to be here. Last year, when standing up here, Chris Bono said he was absolutely blown away by the honor and the opportunity. I can do nothing but echo that. The title of my talk is "Reducible Complexity." This presidential address is going to be a little bit unorthodox. I am going to blame it on my background. Prior to pursuing a career in medicine, I was involved in evolutionary biology and paleontology and those two loves have never left me. I have stayed involved as a dilettante and am going to be getting a little bit more involved I hope as I get older.

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Postnatal effects of intrauterine treatment of the growth-restricted ovine fetus with intra-amniotic insulin-like growth factor-1

Abstract

Placental insufficiency-mediated fetal growth restriction (FGR) is associated with altered postnatal growth and metabolism, which are, in turn, associated with increased risk of adult disease. Intra-amniotic insulin-like growth factor-1 (IGF1) treatment of ovine FGR increases growth rate in late gestation, but the effects on postnatal growth and metabolism are unknown. We investigated the effects of intra-amniotic IGF1 administration to ovine fetuses with uteroplacental embolisation-induced FGR on phenotypic and physiologic characteristics in the two weeks after birth. We measured early postnatal growth velocity, amino-terminal propeptide of C-type natriuretic peptide (NTproCNP), body composition, tissue-specific mRNA expression, and milk intake in singleton lambs treated weekly with 360 μg intra-amniotic IGF1 (FGRI; n = 13 females, 19 males) or saline (FGRS; n = 18 females, 12 males) during gestation, and in controls (CON; n = 15 females, 22 males). There was a strong positive correlation between maternal NTproCNP and fetal oxygenation, and size at birth in FGR lambs. FGR lambs were ∼20% lighter at birth and demonstrated accelerated postnatal growth velocity. IGF1 treatment did not alter perinatal mortality, partially abrogated the reduction in newborn size in females, but not males, and reduced accelerated growth in both sexes. IGF1-mediated upregulation of somatotrophic genes in males during the early postnatal period could suggest that treatment effects are associated with delayed axis maturation, whilst treatment outcomes in females may rely on the reprogramming of nutrient-dependent mechanisms of growth. These data suggest that the growth-restricted fetus is responsive to intra-amniotic intervention with IGF1, and that sex-specific somatotrophic effects persist in the early postnatal period.

This article is protected by copyright. All rights reserved

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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.

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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.

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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.

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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

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Statistical models to predict adverse perioperative outcomes: A case for longer follow up time frames

Large datasets have become available and widely adopted by perioperative medicine researchers in the last decade [1–3]. The use of electronic medical records has facilitated massive data collection not only by single institutions, but also by multicenter initiatives [4–6]. Large datasets enabled the evaluation of infrequent (but important) perioperative outcome with the expectation that interventions could have been implemented to improve the care of patients undergoing surgical procedures.

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Individuals with lumbar spinal stenosis seek education and care focused on self-management – results of focus groups among participants enrolled in a randomized controlled trial

The effectiveness of treatments for chronic, degenerative conditions of the lumbar spine can be influenced by patient perceptions and expectations regarding treatment.

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The association between tobacco smoking and surgical intervention for lumbar spinal stenosis cohort study of 331,941 workers

Tobacco smoking is an injurious habit associated with a number of chronic disorders. Its influence on disc metabolism and degeneration including LSS has been investigated in the literature.

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Can tranexamic acid conserve blood and save operative time in spinal surgeries? a meta-analysis

It is widely accepted that tranexamic acid (TXA) effectively reduces blood losses and transfusions in major surgeries. However, limited studies investigated the role of TXA in conserving blood and saving operative time in spine surgeries. Purpose This meta-analysis was conducted to gather scientific evidences for TXA efficacy on conserving blood and saving operative time in spine surgeries.

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Does reduction in sciatica symptoms precede improvement in disability and physical health among those treated surgically for intervertebral disc herniation? analysis of temporal patterns in data from the spine patient outcomes research trial

Pain, pain-related disability, and functional limitations are common consequences of intervertebral disc herniation (IDH). We hypothesized that surgical treatment reduces pain, leading to improvement in pain-related disabilty and, ultimately, better physical health.

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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.

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Enhanced recovery care versus traditional care after laparoscopic liver resections: a randomized controlled trial

Abstract

Background

Enhanced recovery after surgery (ERAS), with several evidence-based elements, has been shown to shorten length of hospital stay and reduce perioperative hospital costs in many operations. This randomized clinical trial was performed to compare complications and hospital stay of laparoscopic liver resection between ERAS and traditional care.

Methods

A randomized controlled trial was performed for laparoscopic liver resection from August 2015 to August 2016. Patients were randomly divided into ERAS group and traditional care group. The primary outcome was length of hospital stay (LOS) after surgery. Second outcomes included postoperative complications, hospital cost, and 30-day readmissions. Elements used in ERAS group included more perioperative education, nurse navigators, nutrition support for liver diseases, respiratory therapy, oral carbohydrate 2 h before operation, early mobilization and oral intake, goal-directed fluid therapy, less drainages, postoperative nausea and vomiting (PONV) prophylaxis and multimodal analgesia.

Results

The study included 58 (two conversion to laparotomy) patients in ERAS group and 61 (three conversion to laparotomy) patients in the traditional care group. Postoperative LOS was significantly shorter in the ERAS group than traditional care group (5 vs. 8 days; p < 0.001). ERAS program significantly reduced the hospital costs (CNY 45413.1 vs. 55794.1; p = 0.006) and complications (36.2 vs. 55.7%; p = 0.033). Duration till first flatus and PONV were significantly reduced in ERAS group. Pain control was better in ERAS (Visual analogue scale (VAS) POD1 (≥ 4) 19.0 vs. 39.3%, p = 0.017; VAS POD1 2.5 vs. 3.1, p = 0.010). There was no difference in the rate of 30-day readmissions (6.9 vs. 8.2%; p = 1.000).

Conclusion

ERAS protocol is feasible and safe for laparoscopic liver resection. Patients in ERAS group have less pain and complications.

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The role of preoperative high resolution manometry in predicting dysphagia after laparoscopic Nissen fundoplication

Abstract

Background

Laparoscopic fundoplication is an accepted surgical management of refractory gastro-esophageal reflux disease (GERD). The use of high resolution esophageal manometry (HRM) in preoperative evaluation is often applied to determine the degree of fundoplication to optimize reflux control while minimizing adverse sequela of postoperative dysphagia.

Objective

Assess the role of preoperative HRM in predicting surgical outcomes, specifically risk assessment of postoperative dysphagia and quality of life, among patients receiving laparoscopic Nissen fundoplication for GERD with immediate postoperative (< 4 weeks clinic), short-term (3-month clinic), and long-term (34 ± 10.4 months of telephone) follow-up.

Methods

Retrospective analysis of 146 patients over the age of 18 who received laparoscopic Nissen fundoplication at University of Vermont Medical Center from July 1, 2011 through December 31, 2014 was completed, of which 52 patients with preoperative HRM met inclusion criteria. Exclusion criteria included history of: (a) named esophageal motility disorder or aperistalsis; (b) esophageal cancer; (c) paraesophageal hernia noted intraoperatively.

Results

Elevated basal integrated relaxation pressure (IRP), which is the mean of 4 s of maximal lower esophageal sphincter (LES) relaxation within 10 s of swallowing, was significantly correlated with worsened severity of post-fundoplication dysphagia (r = 0.572, p < 0.0001 with sensitivity and NPV of 100%) and poorer quality of life (r = 0.348, p = 0.018) at up to 3-years follow-up. The presence of preoperative dysphagia was independently related to post-fundoplication dysphagia at short-term (r = 0.403, p = 0.018) and long-term follow-up (r = 0.415, p = 0.005). Also, both elevated mean wave amplitude (r=-0.397, p = 0.006) and distal contractile integral (DCI) (r = − 0.294, p = 0.047) were significantly, inversely correlated to post-Nissen dysphagia. No significant association was demonstrated between other preoperative HRM parameters and surgical outcomes.

Conclusions

Inadequacy of lower esophageal sphincter (LES) relaxation with swallowing as delineated by elevated IRP is significantly predictive of worse long-term postoperative outcomes including dysphagia and quality of life scores. Further assessment of tailoring anti-reflux surgical approach with partial vs. total fundoplication to functionally resistant LES is required.

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Short-term surgical outcomes of a randomized controlled trial comparing laparoscopic versus open gastrectomy with D2 lymph node dissection for advanced gastric cancer

Abstract

Background

Laparoscopy-assisted gastrectomy (LAG) has gained acceptance as one of the best treatments for early gastric cancer. However, the application of LAG with D2 lymph node dissection in patients with locally advanced gastric cancer (AGC) remains controversial.

Methods

We launched a prospective randomized controlled trial comparing laparoscopic and open gastrectomy with D2 lymph node dissection for locally AGC to evaluate technical safety and oncologic feasibility. The postoperative morbidity and mortality rates were based on the modified intention-to-treat analysis.

Results

Between January 2010 and June 2012, a total of 328 patients with preoperative clinical stage T_2–3N_0–3M₀ gastric cancer were enrolled in the trial. Six patients with unresected AGC were excluded, and the remaining 322 patients were randomized to the laparoscopic group (162 patients) or the open group (160 patients) for radical surgery. All patients underwent D2 lymph node dissection including 18 (5.59%) proximal gastrectomies, 196 (60.87%) distal gastrectomies, and 108 (33.54%) total gastrectomies. Six patients (3.70%) in the LAG group were converted to open procedures. The overall complication rate was 11.72% in the LAG group and 14.38% in the open group (P = 0.512). No mortality occurred in either group.

Conclusions

The short-term results of the current study suggest that LAG with D2 lymph node dissection is a safe and feasible procedure in treating patients with locally AGC in experienced centers.

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St.Gallen consensus on safe implementation of transanal total mesorectal excision

Abstract

Background

The management of rectal cancer has evolved over the years, including the recent rise of Transanal Total Mesorectal Excision (TaTME). TaTME addresses the limitations created by the bony confines of the pelvis, bulky tumours, and fatty mesorectum, particularly for low rectal cancers. However, guidance is required to ensure safe implementation and to avoid the pitfalls and potential major morbidity encountered by the early adopters of TaTME. We report a broad international consensus statement, which provides a basis for optimal clinical practice.

Methods

Forty international experts were invited to participate based on clinical and academic achievements. The consensus statements were developed using Delphi methodology incorporating three successive rounds. Consensus was defined as agreement by 80% or more of the experts.

Results

A total of 37 colorectal surgeons from 20 countries and 5 continents (Europe, Asia, North and South America, Australasia) contributed to the consensus. Participation to the iterative Delphi rounds was 100%. An expert radiologist, pathologist, and medical oncologist provided recommendations to maximize relevance to current practice. Consensus was obtained on all seven different chapters: patient selection and surgical indication, perioperative management, patient positioning and operating room set up, surgical technique, devices and instruments, pelvic anatomy, TaTME training, and outcomes analysis.

Conclusions

This multidisciplinary consensus statement achieved more than 80% approval and can thus be graded as strong recommendation, yet acknowledging the current lack of high level evidence. It provides the best possible guidance for safe implementation and practice of Transanal Total Mesorectal Excision.

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Does hiatal repair affect gastroesophageal reflux symptoms in patients undergoing laparoscopic sleeve gastrectomy?

Abstract

Background

Laparoscopic sleeve gastrectomy (LSG) has gained popularity as a treatment of choice for morbid obesity and associated comorbidities. There has been a concern about new onset or worsening of gastroesophageal reflux (GERD) following LSG.

Objective

The objective of the study was to evaluate the effect of surgically treating hiatal weakness on GERD symptoms in patients undergoing LSG.

Setting

Single tertiary referral institution, Sydney, Australia.

Methods

A prospective observational cohort study was conducted with consecutive patients undergoing LSG. Hiatal findings, patient demographics, medications and reflux score were recorded prospectively. Patients were followed up post-operatively for a minimum of 12 months and assessed using GERD-HRQL score to quantify reflux symptoms.

Results

Data from 100 patients with a minimum of 1-year follow-up were analysed. Mean follow-up was 18.9 months. Overall, GERD-HRQL improved from mean 4.5 ± 5.8 pre-operatively to 0.76 ± 1.5 after 18.9 months (p = 0.0001). For those with pre-operative reflux, GERD-HRQL improved from mean (SD) 8.43 ± 6.26 pre-operatively to 0.94 ± 1.55 (p = 0.0001). All the nine patients with troublesome daily reflux significantly improved. For those without pre-operative reflux, GERD-HRQL improved from 0.88 ± 1.37 to 0.47 ± 1.25 (p-ns) post-operatively. On multivariate analysis, higher pre-operative reflux and dysphagia/bloat scores, younger age and lower percentage excess weight loss after 18.9 months were associated with GERD-HRQL improvement.

Conclusion

In the medium term, GERD-HRQL improves following sleeve gastrectomy with meticulous hiatal assessment and repair of hiatal laxity and herniation.

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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

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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

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Impact of incisional hernia development following abdominal operations on total healthcare cost

Abstract

Background

Introduction of the category III CPT code (0437T) for prophylactic mesh augmentation (PMA) highlights efforts to reduce incisional hernia (IH). PMA's value in the context of value-based care requires understanding both the cost of IH development and the savings from prevention. We hypothesized large healthcare costs with IH development. Appreciating which subsets of patients are at highest risk for IH, and the subsets who have the costliest care is essential in targeting interventions for hernia prevention.

Methods

Retrospective cohort study utilizing data from Truven Health Analytic MarketScan Commercial Claims and Encounters Database from calendar years 2011–2014. Adults undergoing open abdominal operations with continued enrollment 3-year post-surgery were included. Inpatient and outpatient claims were tracked over 3 years to identify IH. Quantile regression estimated the association between conditional distribution of total cost and IH. A generalized linear model with gamma distribution estimated the association of conditional mean of total cost and IH. Models were adjusted for confounding cost covariates (e.g., age, gender, obesity, smoking, cancer).

Results

14,290 patients were identified, 1294 (9.1%) developed IH, 48% within 1-year, 33% at 1–2 years, and 19% at 2–3 years post-surgery. 515 underwent stoma creation, 4579 colon resection, 2263 liver/kidney, 3890 peritoneal, 3043 other (foregut, appendectomy, cholecystectomy). Rate of IH formation was 25, 13, 5.9, 6.3, and 6.3%, respectively. The difference in median expenditures for IH development versus no IH was ostomies: $26,098, colorectal: $21,211, liver/kidney: $23,811, peritoneal: $25,554, others: $28,870 (p < 0.0.01). IH within 1 year was more expensive than within 3 years in the following categories: colorectal ($16,034, p = 0.0385), liver/kidney ($27,145, p = 0.0004), and ostomy ($18,992, p = 0.0035).

Conclusion

IH is a common occurrence imposing significant healthcare burden. Higher costs occur when IH occurs within 1 year versus 3 years from the index-procedure. This highlights the importance of hernia prevention techniques and the question of whether temporizing closure adjuncts  are appropriate in high-risk patients.

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High-resolution mapping of cis-regulatory variation in budding yeast [Genetics]

Genetic variants affecting gene-expression levels are a major source of phenotypic variation. The approximate locations of these variants can be mapped as expression quantitative trait loci (eQTLs); however, a major limitation of eQTLs is their low resolution, which precludes investigation of the causal variants and their molecular mechanisms. Here we...

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Precision genome editing using synthesis-dependent repair of Cas9-induced DNA breaks [Genetics]

The RNA-guided DNA endonuclease Cas9 has emerged as a powerful tool for genome engineering. Cas9 creates targeted double-stranded breaks (DSBs) in the genome. Knockin of specific mutations (precision genome editing) requires homology-directed repair (HDR) of the DSB by synthetic donor DNAs containing the desired edits, but HDR has been reported...

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Improved detection of synthetic lethal interactions in Drosophila cells using variable dose analysis (VDA) [Genetics]

Synthetic sick or synthetic lethal (SS/L) screens are a powerful way to identify candidate drug targets to specifically kill tumor cells, but this approach generally suffers from low consistency between screens. We found that many SS/L interactions involve essential genes and are therefore detectable within a limited range of knockdown...

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Def1 interacts with TFIIH and modulates RNA polymerase II transcription [Genetics]

The DNA damage response is an essential process for the survival of living cells. In a subset of stress-responsive genes in humans, Elongin controls transcription in response to multiple stimuli, such as DNA damage, oxidative stress, and heat shock. Yeast Elongin (Ela1-Elc1), along with Def1, is known to facilitate ubiquitylation...

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Synchronizing Gait with Cardiac Cycle Phase Alters Heart Rate Response during Running

ABSTRACT Timing foot strike to occur in synchrony with cardiac diastole may reduce left ventricular afterload and promote coronary and skeletal muscle perfusion. Purpose To assess heart rate (HR) and metabolic responses to running when foot strikes are timed to occur exclusively during 1) the systolic phase of the cardiac cycle, or 2) the diastolic phase. Methods Ten elite male distance runners performed a testing session on a treadmill at 4.72 m[BULLET OPERATOR]s-1 while matching their steps to an auditory tone and wearing a chest strap that transmitted accelerometer and ECG signals. Testing comprised eight prompted three-minute stages, where a real-time adaptive auditory tone guided subjects to step with each ECG R-wave (systolic stepping) or alternatively, at 45% of each R-R interval (diastolic stepping), followed by a three-minute unprompted control stage. Metabolic variables were measured continuously. Results HR (p

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Iowa city planning to charge patients for on-scene care

The $186 to $327 charge is a way to cut down on taxpayers' cost for the new EMS division that Sioux City Fire Rescue will soon implement

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Predictors for incidence of increased time spent in hospital after ambulatory surgery in children: a retrospective cohort study

Abstract

Purpose

Recently, pediatric ambulatory surgery has become common. However, for some of these patients, unplanned admission or prolonged hospital stay is also necessary, which can increase the mental burden on these patients. The aim of this study was to identify the predictors of the incidence of increased time spent in hospitals associated with pediatric ambulatory surgery.

Methods

Data were obtained from the medical and anesthetic records of 1087 consecutive patients aged < 18 years who underwent ambulatory surgery under general anesthesia. We defined the incidence of increased time spent in a hospital as a composite outcome of unplanned admission and prolonged hospital stay. Multivariate logistic regression analysis was used to examine the associations between the incidence of increased time spent in a hospital and 14 parameters including patient characteristics, anesthesia, and operative factors.

Results

Multivariate analysis identified American Society of Anesthesiologist Physical Status (ASA-PS), type of regional block, intraoperative fluid volume, and type of surgery as predictors for the incidence of increased time spent in a hospital. Specifically, caudal block compared to no regional block [odds ratio (OR) (95% confidence interval (CI)) = 0.44 (0.22–0.90)]; increasing intraoperative fluid volume [OR (95% CI) = 0.71 (0.55–0.92) in every increment of 5 ml/kg/h); and ear, nose, and throat (ENT) and urology surgery compared to other types of surgery [OR (95% CI) = 0.13 (0.03–0.64), and 3.93 (1.99–7.77), respectively] were identified as strong predictors.

Conclusions

This study found that the incidence of increased time spent in a hospital in pediatric ambulatory surgery was affected by the type of regional block, intraoperative fluid volume, type of surgery. Potentially modifiable factors, such as intraoperative fluid volume or type of regional block, should be further investigated in future prospective studies.

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Causal somatic mutations in urine DNA from persons with the CLOVES subgroup of the PIK3CA Related Overgrowth Spectrum (PROS)

Abstract

Congenital Lipomatous Overgrowth with Vascular, Epidermal, and Skeletal anomalies (CLOVES) and Klippel-Trenaunay (KTS) syndromes are caused by somatic gain-of-function mutations in PIK3CA, encoding a catalytic subunit of phosphoinositide 3-kinase. Affected tissue is needed to find mutations, since mutant alleles are not detectable in blood. Because some patients with CLOVES develop Wilms tumor, we tested urine as a source of DNA for mutation detection. We extracted DNA from the urine of 17 and 24 individuals with CLOVES and KTS, respectively, and screened 5 common PIK3CA mutation hotspots using droplet digital PCR. Six of 17 CLOVES participants (35%) had mutant PIK3CA alleles in urine. Among 8 individuals in whom a mutation had been previously identified in affected tissue, 4 had the same mutant allele in the urine. One study participant with CLOVES had been treated for Wilms tumor. We detected the same PIK3CA mutation in her affected tissue, urine, and tumor, indicating Wilms tumors likely arise from PIK3CA mutant cells in patients with CLOVES. No urine sample from a participant with KTS had detectable PIK3CA mutations. We suggest that urine, which has the advantage of being collected non-invasively, is useful when searching for mutations in individuals with CLOVES syndrome.

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A Randomized, Two-Way Crossover Study to Evaluate the Pharmacokinetics of Caffeine Delivered Using Caffeinated Chewing Gum Versus a Marketed Caffeinated Beverage in Healthy Adult Volunteers

Journal of Caffeine Research Dec 2017, Vol. 7, No. 4: 125-132.


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Exome sequencing helps diagnose infants in the ICU

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In this issue

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Table of Contents, Volume 176A, Number 1, January 2018

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Publication schedule for 2017

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Cover Image, Volume 176A, Number 1, January 2018

The cover image, by Satoru Ikenoue et al., is based on the Clinical Report Discordant fetal phenotype of hypophosphatasia in two siblings, DOI: 10.1002/ajmg.a.38531.

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Testing scenario for intellectual disability, developmental delay, and autism challenged

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Associations between laterality of orofacial clefts and medical and academic outcomes

Patients with oral clefts have an increased risk of other malformations, syndromes, and lower academic performance in school. Few studies have investigated if laterality of clefts is associated with medical and academic outcomes. Oral clefts have nonrandom laterality, with left-sided clefts occurring approximately twice as often as right-sided clefts. Using a retrospective study design, we examined potential associations of cleft attributes and outcomes in patients with cleft lip with or without cleft palate (CL/P) born in 2003–2010 who were treated at the Seattle Children's Craniofacial Center. The following variables were extracted from medical records: cleft type, medical history, maternal hyperglycemia, other malformations, and the need for academic support at school. We used logistic regression to examine risk of associations with outcomes of interest. Relative to patients with left-sided clefts, patients with bilateral CL/P were more likely to have a syndrome. Patients with nonsyndromic right-sided CL/P had a higher risk (OR and 95%CI: 3.5, 1.3–9.5, and 5.5, 1.9–16.0, respectively) of having other malformations and requiring academic support at school, when compared to patients with left-sided CL/P. Understanding the etiology of oral clefts is complicated, in part because both genetic and environmental factors contribute to the risk of developing a cleft. However, the different outcomes associated with cleft laterality suggest that right-sided clefts may have a distinct etiology. Using laterality to study cleft subgroups may advance our understanding of the etiology of this common birth defect.

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Association of functional markers with flowering time in lentil

Abstract

In the present study, a diverse panel of 96 accessions of lentil germplasm was used to study flowering time over environments and to identify simple sequence repeat markers associated with flowering time through association mapping. The study showed high broad sense heritability estimate (h ² bs=0.93) for flowering time in lentil. Screening of 534 SSR markers resulted in an identification of 75 SSR polymorphic markers (13.9%) across studied genotypes. These markers amplified 266 loci and generated 697 alleles ranging from two to 16 alleles per locus. Model-based cluster analysis used for the determination of population structure resulted in the identification of two distinct subpopulations. Distribution of flowering time was ranged from 40 to 70 days in subpopulation I and from 54 to 69 days in subpopulation II and did not skew either late or early flowering time within a subpopulation. No admixture was observed within the subpopulations. Use of the most accepted maximum likelihood model (P3D mixed linear model with optimum compression) of MTA analysis showed significant association of 26 SSR markers with flowering time at <0.05 probability. The percent of phenotypic explained by each associated marker with flowering time ranged from 2.1 to 21.8% and identified QTLs for flowering time explaining high phenotypic variation across the environments (10.7-21.8%) or in a particular environment (10.2-21.4%). In the present study, 13 EST-SSR showed significant association with flowering time and explained large phenotypic variation (2.3-21.8%) compared to genomic SSR markers (2.1-10.2%). Hence, these markers can be used as functional markers in the lentil breeding program to develop short duration cultivars.

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Cardiovascular and metabolic responses during indoor climbing and laboratory cycling exercise in advanced and élite climbers

Abstract

Purpose

To validate heart rate (f _H) as an effective indicator of the aerobic demands of climbing, the f _H vs oxygen uptake ( \(\dot {V}_{\text{2}}}\) ) relationship determined during cycling exercise and climbing on a circular climbing treadwall was compared. Possible differences in maximum aerobic characteristics between advanced and élite climbers were also assessed.

Methods

Seven advanced and six élite climbers performed a discontinuous incremental test on a cycle ergometer and a similar test on a climbing treadwall. Cardiorespiratory and gas exchange parameters were collected at rest and during exercise.

Results

The f _H vs \(\dot {V}_{\text{2}}}\) relationship was steeper during cycling than climbing at submaximal exercise for both groups and during climbing in the élite climbers as compared to the advanced. At peak exercise, \(\dot {V}_{\text{2}}}\) was similar during both cycling and climbing (3332 ± 115 and 3193 ± 129 ml/min, respectively). Despite similar \(\dot {V}__}}}}\) , the élite climbers had a higher peak workload during climbing (11.8 ± 0.8 vs 9.2 ± 0.3 m/min in élite and advanced climbers, respectively; P = .024) but not during cycling (291 ± 13 and 270 ± 12 W in élite and advanced climbers, respectively).

Conclusions

Our findings indicate that care should be taken when energy expenditure during climbing is estimated from the f _H vs \(\dot {V}_{\text{2}}}\) relationship determined in the laboratory. The level of climbing experience significantly affects the energy cost of exercise. Last, the similar aerobic demands of cycling and climbing at peak exercise, suggest that maximum \(\dot {V}_{\text{2}}}\) may play an important role in climbing performance. Specific training methodologies should be implemented to improve aerobic power in climbers.

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Transient cardiac dysfunction but elevated cardiac and kidney biomarkers 24 h following an ultra-distance running event in Mexican Tarahumara

The Mexican Tarahumara are accustomed to running ultra-distance races. No data exist on the acute physiological changes following ultra-distance running and physiological-biomarker associations in this populat...

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Visual cortical activity before and after cochlear implantation: A follow up ERP prospective study in deaf children

Publication date: Available online 3 November 2017
Source:International Journal of Psychophysiology
Author(s): Scania de Schonen, Josiane Bertoncini, Nathalie Petroff, Vincent Couloigner, Thierry Van Den Abbeele
ERPs were recorded in response to presentation of static colored patterned stimuli in 25 children (19 to 80months of age at cochlear implantation, CI) with very early prelingual profound deafness (PreLD), 21 postlingual profoundly deaf children (PostLD) (34 to 180months of age at CI) and gender- and age-matched control hearing children. Recording sessions were performed before CI, then 6 and 24months after CI.Results showed that prelingual and, at a lesser degree, postlingual auditory deprivation altered cortical visual neural activity associated to colored shapes from both P1 and N1 cortical processing stages. The P1 and N1 amplitude modifications vanished about 24months after CI in both PreLD and PostLD deaf children. In PreLD the visual processing pattern becomes similar to the typical one essentially by an amplitude decrease of P1 on the left hemisphere together with an amplitude increase of the N1 on the right hemisphere. Finally, in PreLD, increased LH advantage over the RH in N1 amplitude on the cerebellar-occipito-parietal region before CI showed a significant inverse relationship with speech perception outcomes 3years after CI.Investigating early visual processing development and its neural substrates in deaf children would help to understand the variability of CI outcome, because their cortical visual organization diverged from the one of typically developing hearing children, and cannot be predicted from what is observed in deaf adults.



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Putting gene essentiality into context

Putting gene essentiality into context

Putting gene essentiality into context, Published online: 12 December 2017; doi:10.1038/nrg.2017.141

Two articles in this issue of Nature Reviews Genetics discuss our maturing understanding of gene essentiality in cells and humans

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The comparison between effectiveness of ultrasound guided corticosteroid injection above versus below the median nerve in mild to moderate carpal tunnel syndrome: A randomized controlled trial

ABSTRACT Objective In this study the clinical effectiveness of ultrasound-guided corticosteroid injection "above" versus "below" the median nerve for treatment of patients with mild to moderate carpal tunnel syndrome (CTS) was compared. Design This prospective randomized double-blind clinical trial included 44 patients with mild to moderate CTS. The subjects were randomly assigned to two groups to receive ultrasound-guided injection of 40 mg triamcinolone either "above" or "below" the involved median nerve. Outcome measures were the Boston Carpal Tunnel Questionnaire, Visual Analogue Scale, electrophysiological tests, and ultrasonographic measurement of the median nerve cross-sectional area at baseline, 6 weeks and 12 weeks after the injection Results All outcome measures improved significantly in both groups at 6 weeks after intervention, and these improvements were persevered up to 12 weeks follow up (all P-value

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Neural coding of sound envelope structure in songbirds

Abstract

Songbirds are a well-established animal model to study the neural basis of learning, perception and production of complex vocalizations. In this system, telencephalic neurons in HVC present a state-dependent, highly selective response to auditory presentations of the bird's own song (BOS). This property provides an opportunity to study the neural code behind a complex motor behavior. In this work, we explore whether changes in the temporal structure of the sound envelope can drive changes in the neural responses of highly selective HVC units. We generated an envelope-modified BOS (MOD) by reversing each syllable's envelope but leaving the overall temporal structure of syllable spectra unchanged, which resulted in a subtle modification for each song syllable. We conducted in vivo electrophysiological recordings of HVC neurons in anaesthetized zebra finches (Taeniopygia guttata). Units analyzed presented a high BOS selectivity and lower response to MOD, but preserved the profile response shape. These results show that the temporal evolution of the sound envelope is being sensed by the avian song system and suggest that the biomechanical properties of the vocal apparatus could play a role in enhancing subtle sound differences.

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Do acute effects of exercise on vascular function predict adaptation to training?

Abstract

Purpose

No previous study has explored the importance of exercise-induced changes in vascular function to prolonged adaptations. Therefore, the purpose was to explore the within-subject relationship between the acute post-exercise change in brachial artery endothelial function (flow-mediated dilation, FMD) and the change in resting FMD after a 2-week exercise training in healthy volunteers.

Methods

Twenty one healthy, young men (24 ± 5 years) underwent assessment of brachial artery FMD using high-resolution ultrasound before and after 30-min of moderate-intensity cycle exercise (80% maximal heart rate). Subsequently, subjects performed five 30-min cycle exercise bouts at 80% maximal heart rate across a 2-week period, followed by repeat assessment of resting brachial FMD post-training.

Results

Correcting for changes in diameter and shear, FMD did not change after the initial exercise bout (P = 0.26). However, a significant correlation was found between post-exercise changes in FMD and adaptation in resting FMD after training (r = 0.634, P = 0.002), where an acute decrease in post-exercise FMD resulted in a decrease in baseline FMD after 2 weeks and vice versa. We also found a positive correlation between antegrade shear rate during exercise and change in FMD% after acute exercise and after exercise training (r = 0.529 and 0.475, both P < 0.05).

Conclusion

Our findings suggest that acute post-exercise changes in vascular function are related to changes in resting FMD after a 2-week endurance exercise training period in healthy men, an effect that may be related to exercise-induced increases in antegrade shear rate. This provides further insight into the relevance of acute changes in shear and FMD for subsequent adaptation.

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The impact of exertional-heat stress on gastrointestinal integrity, gastrointestinal symptoms, systemic endotoxin and cytokine profile

Abstract

Purpose

The study aimed to determine the effects of exertional-heat stress on gastrointestinal integrity, symptoms, systemic endotoxin and inflammatory responses; and assess the relationship between changes in body temperature and gastrointestinal perturbations.

Methods

Ten endurance runners completed 2 h running at 60% \(\dot {V}\) O_2max in hot (HOT: 35 °C) and temperate (TEMP: 22 °C)-ambient conditions. Rectal temperature (T _re) and gastrointestinal symptoms were recorded every 10 min during exercise. Blood samples were collected pre- and post-exercise, and during recovery to determine plasma intestinal fatty acid binding protein (I-FABP), cortisol, bacterial endotoxin and cytokine profile. Calprotectin was determined from pre- and post-exercise faecal samples. Urinary lactulose:l-rhamnose ratio was used to measure intestinal permeability.

Results

Compared with TEMP, HOT significantly increased T _re (1.4 ± 0.5 vs 2.4 ± 0.8 °C, p < 0.001), cortisol (26 vs 82%, p < 0.001), I-FABP (127 vs 432%, p < 0.001), incidence (70 vs 90%) and severity (58 counts vs 720 counts, p = 0.008) of total gastrointestinal symptoms. Faecal calprotectin and circulating endotoxin increased post-exercise in both trials (mean increase 1.5 ± 2.5 µg/g, p = 0.032, and 6.9 ± 10.3 pg/ml, p = 0.047, respectively), while anti-endotoxin antibodies increased 28% post-exercise in TEMP and decreased 21% in HOT (p = 0.027). However, intestinal permeability did not differ between trials (p = 0.185). Inflammatory cytokines were greater on HOT compared to TEMP (p < 0.05). Increases in T _re were positively associated with I-FABP, IL-10, cortisol, nausea and urge to regurgitate (p < 0.05).

Conclusions

Exertional-heat stress induces a thermoregulatory strain that subsequently injures the intestinal epithelium, reduces endotoxin clearance capacity, promotes greater cytokinaemia, and development of gastrointestinal symptoms.

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Quantitative examination of isometric tongue protrusion forces in children with Orofacial dysfunctions (OFD) or myofunctional disorders

Abstract

Objectives

Orofacial dysfunctions (OFD) or orofacial myofunctional disorders in children lead to severe problems in teeth and jaw position, articulation, chewing and swallowing. The forces of the tongue, the central muscle for articulation, chewing and swallowing is focused on in several studies. In this examination, isometric tongue protrusion forces (TPF) of children with OFD and controls were compared.

Methods

30 participants with OFD and 30 controls were presented a target force level as a straight line on a monitor that they were supposed to match by generating an isometric tongue force for different target levels (0.25 N and 0.5 N). Correlations of the severity of OFD (symptom score) with the capacities of the TPF 0.25 N and 0.5 N were calculated.

Results

Statistical differences were obvious in TPF variability and the accuracy, depending on the weight. Tongue contact time, expressed as per cent (TCT, total contact: 100%), was significantly lower in children with OFD (p=0.005). Mean and median TPF was not different between groups. The predictive value of TPF for OFD revealed a level of 58.6% for TPF 0.25 N and 74.5% for TPF 0.5 N. Correlations of the severity of OFD were seen for some parameters.

Discussion

Subjects with OFD show significantly lower competencies in accuracy and endurance of tongue protrusion forces. This may have a high impact on phenotyping children with OFD and influence therapeutical approaches.

This article is protected by copyright. All rights reserved.

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A child with Myhre syndrome presenting with corectopia and tetralogy of Fallot

Myhre syndrome is a rare autosomal dominant disorder caused by a narrow spectrum of missense mutations in the SMAD4 gene. Typical features of this disorder are distinctive facial appearance, deafness, intellectual disability, cardiovascular abnormalities, short stature, short hands and feet, compact build, joint stiffness, and skeletal anomalies. The clinical features generally appear during childhood and become more evident in older patients. Therefore, the diagnosis of this syndrome in the first years of life is challenging. We report a 2-year-old girl diagnosed with Myhre syndrome by whole exome sequencing (WES) that revealed the recurrent p.Ile500Val mutation in the SMAD4 gene. Our patient presented with growth deficiency, dysmorphic features, tetralogy of Fallot, and corectopia (also known as ectopia pupillae). The girl we described is the youngest patient with Myhre syndrome. Moreover, corectopia and tetralogy of Fallot have not been previously reported in this disorder.

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Laparoscopic colectomy after self-expanding metallic stent placement through the ileocecal valve for right-sided malignant colonic obstruction: A case report

Abstract

A 78-year-old man with a history of open sigmoidectomy for sigmoid cancer presented with abdominal pain and vomiting. Abdominal multi-detector CT revealed an obstructive ileocecal tumor with distended small bowel on the oral side. We performed emergency drainage using a transnasal decompression tube, and 2 days later, we conducted a colonoscopic examination, which lead to a provisional diagnosis of obstruction with a malignant tumor invading the ileocecal valve. We then placed a self-expanding metallic stent (SEMS) through the ileocecal valve. We confirmed patency of the ileocecal valve and removed the transnasal decompression tube 2 days after SEMS placement. We then performed elective laparoscopic colectomy 8 days after SEMS placement. To the best of our knowledge, there has been only one previous report of laparoscopic colectomy after decompression with SEMS placement through the ileocecal valve for right-sided malignant colonic obstruction.

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Preventive effect of diverting stoma on anastomotic leakage after laparoscopic low anterior resection with double stapling technique reconstruction applied based on risk stratification

Abstract

Introduction

During laparoscopic low anterior resection with double stapling technique reconstruction, it is necessary to securely implement rectal transection and anastomosis to prevent anastomotic leakage (AL). However, risk factors and preventive measures for AL are not known sufficiently. Therefore, this study aimed to elucidate risk factors associated with AL and to clarify strategies to prevent it.

Methods

We analyzed a total of 296 cases with rectal cancer who had undergone laparoscopic low anterior resection with double stapling technique reconstruction at the National Cancer Center Hospital East. The relationship between AL and patient, tumor, and treatment characteristics were retrospectively investigated.

Results

There were 186 male and 110 female patients with a median age of 62. Overall, AL occurred in 24 cases (8.1%). Being a man, having an anal verge distance ≤7 cm, and undergoing neoadjuvant chemotherapy were associated with an elevated risk for AL (P = 0.0005, 0.0034, and 0.0222, respectively). Neither an anal drainage tube nor diverting stoma creation correlated with incidence of AL. Multivariate analysis demonstrated that being a man (odds ratio = 18.0; 95% confidence interval: 2.4–138) and having an anal verge distance ≤7 cm (odds ratio = 3.8; 95% confidence interval: 1.5–9.4) were significant risk factors. These two factors were present in 61 cases, including 14 who developed AL (23.0%). In this high-risk group, diverting stoma creation significantly reduced the occurrence of AL (P = 0.0363), but an anal drainage tube had no effect on incidence of AL (P = 0.3399).

Conclusion

We identified the high-risk population for AL after laparoscopic low anterior resection with double stapling technique reconstruction based on two factors. This will enable surgeons to appropriately recommend diverting stoma creation.

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