The Evolving Dilemma of Factor XI in Pregnancy: Suggestions for Management

A case of a patient with severe factor XI (FXI) deficiency who presented for her seventh labor and delivery is presented. The nature of FXI deficiency, its prevalence, and issues related to genetic screening are discussed. Published literature on the topic is reviewed, including criteria that were developed to assess bleeding, laboratory tools used to estimate bleeding risk, and available treatments. Within the context of this challenging clinical dilemma, specific recommendations are provided for the antepartum, intrapartum, and postpartum stages of pregnancy. These include recommendations that take into account both FXI levels and history of any abnormal bleeding. While there are effective treatments available, it is important to consider that institutional multidisciplinary protocols are needed to manage this complex disorder. More work is needed to define the best management protocols. Accepted for publication December 19, 2017. Funding: None. Conflicts of Interest: See Disclosures at the end of the article. Reprints will not be available from the authors. Address correspondence to Aryeh Shander, MD, Department of Anesthesiology, Englewood Hospital and Medical Center, 350 Engle St, Englewood, NJ 07631. Address e-mail to aryeh.shander@ehmchealth.org. © 2018 International Anesthesia Research Society

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Sex Difference of Angiotensin IV–, LVV-Hemorphin 7–, and Oxytocin-Induced Antiallodynia at the Spinal Level in Mice With Neuropathic Pain

Background: We demonstrated previously that angiotensin IV (Ang IV) and LVV-hemorphin 7 (LVV-H7) act through the blockade of insulin-regulated aminopeptidase to decrease oxytocin degradation, thereby causing antihyperalgesia at the spinal level in rats. We determined that intrathecal oxytocin can induce significant antihyperalgesia in male rats with inflammation but not in female rats. Thus, we speculate that Ang IV, LVV-H7, and oxytocin can induce antiallodynia, which could be of great therapeutic potential. Because the antihyperalgesia by using these peptides was with sex difference, their possible antiallodynia was examined in male and female mice for comparison. We investigated whether Ang IV, LVV-H7, and oxytocin produce antiallodynia at the spinal level in mice and whether this antiallodynia differs between the sexes. METHODS: Partial sciatic nerve ligation surgery was performed on adult male and female C57BL/6 mice from the same litter (25–30 g). The effects of intrathecal injections of Ang IV (25.8 nmol), LVV-H7 (27.2 nmol), and oxytocin (0.125 or 1.25 nmol) were assessed through the von Frey test 3 days after partial sciatic nerve ligation. RESULTS: Intrathecal injection of Ang IV, LVV-H7, and oxytocin all produced a potent antiallodynia in male mice. However, these antiallodynia effects were either extremely weak or absent in female mice at the same dose. CONCLUSIONS: Intrathecal Ang IV, LVV-H7, and oxytocin can all cause significant antiallodynia in male mice. The Ang IV-, LVV-H7-, and oxytocin-induced antiallodynia effects differed between the sexes at the spinal level in mice. Accepted for publication November 28, 2017. Funding: The study was supported by National Defense Medical Center, Taipei, Taiwan, and was funded by the Tri-Service General Hospital Songshan Branch, Taipei, Taiwan (TSGH-SSB-10407), and the Ministry of Science and Technology, Taiwan (103-2320-B-016-016-MY3). This manuscript was edited by Wallace Academic Editing The authors E. Y.-K. Huang and J.-H. Kao have contributed equal to this study. The authors declare no conflicts of interest. Reprints will not be available from the authors. Address correspondence to Eagle Yi-Kung Huang, PhD and Jen-Hsin Kao, PhD, Department of Pharmacology, National Defense Medical Center, Taipei, Taiwan. Address e-mail to eyh58@mail.ndmctsgh.edu.tw and cindykao1128@gmail.com. © 2018 International Anesthesia Research Society

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A Systematic Review of Outcomes Associated With Withholding or Continuing Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers Before Noncardiac Surgery

BACKGROUND: The global rate of major noncardiac surgical procedures is increasing annually, and of those patients presenting for surgery, increasing numbers are taking either an angiotensin-converting enzyme inhibitor (ACE-I) or an angiotensin receptor blocker (ARB). The current recommendations of whether to continue or withhold ACE-I and ARB in the perioperative period are conflicting. Previous meta-analyses have linked preoperative ACE-I/ARB therapy to the increased incidence of postinduction hypotension; however, they have failed to correlate this with adverse patient outcomes. The aim of this meta-analysis was to determine whether continuation or withholding ACE-I or ARB therapy in the perioperative period is associated with mortality and major morbidity. METHODS: This meta-analysis was prospectively registered on PROSPERO (CRD42017055291). A comprehensive search of MEDLINE (PubMed), CINAHL (EBSCO host), ProQuest, Cochrane database, Scopus, and Web of Science was conducted on December 6, 2016. We included adult patients >18 years of age on chronic ACE-I or ARB therapy who underwent noncardiac surgery in which ACE-I or ARB was either withheld or continued on the morning of surgery. Primary outcomes included all-cause mortality and major cardiac events (MACE). Secondary outcomes included the risk of congestive heart failure, acute kidney injury, stroke, intraoperative/postoperative hypotension, and the length of hospital stay. RESULTS: After abstract review, the full text of 25 studies was retrieved, of which 9 fulfilled the inclusion criteria: 5 were randomized control trials, and 4 were cohort studies. These studies included a total of 6022 patients on chronic ACE-I/ARB therapy before noncardiac surgery. A total of 1816 patients withheld treatment the morning of surgery and 4206 continued their ACE-I/ARB. Preoperative demographics were similar between the 2 groups. Withholding ACE-I/ARB therapy was not associated with a difference in mortality (odds ratio [OR], 0.97; 95% confidence interval [CI], 0.62–1.52; I2 = 0%) or MACE (OR, 1.12; 95% CI, 0.82–1.52; I2 = 0%). However, withholding therapy was associated with significantly less intraoperative hypotension (OR, 0.63; 95% CI, 0.47–0.85; I2 = 71%). No effect estimate could be pooled concerning length of hospital stay and congestive heart failure. CONCLUSIONS: This meta-analysis did not demonstrate an association between perioperative administration of ACE-I/ARB and mortality or MACE. It did, however, confirm the current observation that perioperative continuation of ACE-I/ARBs is associated with an increased incidence of intraoperative hypotension. A large randomized control trial is necessary to determine the appropriate perioperative management of ACE-I and ARBs. Accepted for publication December 19, 2017. Funding: No outside funding was utilized in the search and retrieval of all articles. All funding was from departmental resources. 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). PROSPERO registry: CRD42017055291. Reprints will not be available from the authors. Address correspondence to Caryl Hollmann, MBChB, DA (SA), Department of Anaesthesia and Perioperative Medicine, D23, Groote Schuur Hospital, University of Cape Town, Observatory, Cape Town 7925, South Africa. Address e-mail to carylhollmann@gmail.com. © 2018 International Anesthesia Research Society

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Activation of Melatonin Receptors by Ramelteon Induces Cardioprotection by Postconditioning in the Rat Heart

Activation of melatonin receptors protects the heart against ischemia-reperfusion injury. Ramelteon, a clinically used drug for insomnia, acts via activation of melatonin receptors. We investigated whether ramelteon induces acute infarct size reduction by postconditioning. Male Wistar rats were randomized to 6 groups. Hearts were treated with melatonin and ramelteon at the beginning of reperfusion. The melatonin receptor inhibitor luzindole was administered with and without melatonin and ramelteon, respectively. Ramelteon reduced infarct size to the same extent as melatonin. Both effects were completely abolished by luzindole. The results show for the first time that ramelteon induces cardioprotection by postconditioning. Accepted for publication September 27, 2017. Funding: This work was supported by departmental funding only. 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 Ragnar Huhn, MD, PhD, Department of Anesthesiology, University Hospital Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany. Address e-mail to Ragnar.Huhn@med.uni-duesseldorf.de. © 2018 International Anesthesia Research Society

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In Response

No abstract available

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Flupirtine: A Less-Explored, Neglected Nonopioid Analgesic

No abstract available

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Misguided by INR in Liver Disease Patients? Implications for Clinicians Including Pain Proceduralists

No abstract available

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ABC of Clinical Leadership, 2nd ed

No abstract available

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Summative Objective Structured Clinical Examination Assessment at the End of Anesthesia Residency for Perioperative Ultrasound

While standardized examinations and data from simulators and phantom models can assess knowledge and manual skills for ultrasound, an Objective Structured Clinical Examination (OSCE) could assess workflow understanding. We recruited 8 experts to develop an OSCE to assess workflow understanding in perioperative ultrasound. The experts used a binary grading system to score 19 graduating anesthesia residents at 6 stations. Overall average performance was 86.2%, and 3 stations had an acceptable internal reliability (Kuder–Richardson formula 20 coefficient >0.5). After refinement, this OSCE can be combined with standardized examinations and data from simulators and phantom models to assess proficiency in ultrasound. Accepted for publication December 11, 2017. Funding: This study was funded by the Foundation for Anesthesia Research and Education (FAER) as part of a grant awarded to Robina Matyal. 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). J. D. Mitchell and R. Amir contributed equally to this work. Reprints will not be available from the authors. Address correspondence to John D. Mitchell, MD, Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 1 Deaconess Rd, RB-470, Boston, MA 02215. Address e-mail to jdmitche@bidmc.harvard.edu. © 2018 International Anesthesia Research Society

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The Lateral Femoral Cutaneous Nerve: Description of the Sensory Territory and a Novel Ultrasound-Guided Nerve Block Technique

Background and Objectives Nerve blockade of the lateral femoral cutaneous (LFC) nerve provides some analgesia after hip surgery. However, knowledge is lacking about the extent of the cutaneous area anesthetized by established LFC nerve block techniques, as well as the success rate of anesthetic coverage of various surgical incisions. Nerve block techniques that rely on ultrasonographic identification of the LFC nerve distal to the inguinal ligament can be technically challenging. Furthermore, the branching of the LFC nerve is variable, and it is unknown if proximal LFC nerve branches are anesthetized using the current techniques. The primary aim of this study was to investigate a novel ultrasound-guided LFC nerve block technique based on injection into the fat-filled flat tunnel (FFFT), which is a duplicature of the fascia lata between the sartorius and the tensor fasciae latae muscle, in order to assess the success rate of anesthetizing the proximal LFC nerve branches and covering of the different surgical incisions used for hip surgery. Methods First, a cadaveric study was conducted in order to identify an FFFT injection technique that would provide adequate injectate spread to the proximal LFC nerve branches. Second, a clinical study was conducted in a group of 20 healthy volunteers over 2 consecutive days. On trial day 1, successful complete anesthesia of the LFC nerve was defined by performing a suprainguinal fascia iliaca block bilaterally in each subject. On trial day 2, a triple-blind randomized controlled trial compared the effect of the novel ultrasound-guided LFC nerve block technique for bupivacaine versus placebo. The primary end point was the success rate of anesthesia of the proximal cutaneous area innervated by the LFC nerve for the FFFT injection with bupivacaine versus placebo. Results Adequate spread of injectate to the proximal LFC nerve branches in cadavers was obtained by injecting 10 mL with dynamic needle-tip tracking in the FFFT. Application of this technique in the randomized controlled trial provided anesthesia of the lateral thigh with a success rate of 95% (95% confidence interval, 73.9%–99.8%) for the active side and 0% for placebo (P

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Efficacy and Safety of Lidocaine Infusion Treatment for Neuropathic Pain: A Randomized, Double-Blind, and Placebo-Controlled Study

Background and Objectives Lidocaine infusion therapy (LIT) is an effective treatment for relieving neuropathic pain (NeP). However, it remains unclear whether pain relief can be sustained through repeated lidocaine infusions. This study aimed to determine whether repeated intravenous administration of low-dose lidocaine could provide prolonged pain relief in patients with specific NeP conditions. Methods This is a prospective, randomized, double-blind, placebo-controlled, parallel study. We compared the efficacy and safety of lidocaine infusions (3 mg/kg) in the LIT group and normal saline infusions in the control group once a week for 4 consecutive weeks in patients with postherpetic neuralgia or complex regional pain syndrome type II. The primary outcome was the difference in the percentage change in the 11-point numerical rating scale (NRS) pain score from baseline to after the final infusion. Secondary outcomes included pain scores during 4 weeks of follow-up and any complications. Results Forty-two patients completed this study protocol. The percentage reduction in NRS pain scores after the final infusion was significantly greater in the LIT group compared with the control group (P = 0.011). However, this pain reduction was not detectable at the 4-week follow-up. The difference in the percentage change in NRS pain scores was especially prominent in the LIT group after the third and fourth infusions. None of the study participants experienced serious complications from the treatment. Conclusions Lidocaine infusion therapy (3 mg/kg of lidocaine administered over 1 hour) provided effective short-term pain relief, which was substantially prominent after repeated infusions were administered to patients with refractory NeP. Clinical Trial Registration This study was registered at ClinicalTrials.gov, identifier NCT02597257. Accepted for publication September 2, 2017. Address correspondence to: Jee Youn Moon, MD, PhD, FIPP, CIPS, Department of Anesthesiology and Pain Medicine, Seoul National University Hospital College of Medicine, 110 Daehang-ro, Jongno-gu, Seoul 110-744, Korea (e-mail: jymoon0901@gmail.com). This research was supported by a grant (14172MFDS178) from Korean Ministry of Food and Drug Safety in 2014. The agency was not involved in conduct of this study or its submission. The authors declare no conflict of interest. Y.-C.K., A.M.C., and C.-S.L. contributed equally to this study. Copyright © 2018 by American Society of Regional Anesthesia and Pain Medicine.

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Dexamethasone as an Adjuvant to Femoral Nerve Block in Children and Adolescents Undergoing Knee Arthroscopy: A Prospective, Randomized, Double-Blind, Placebo-Controlled Trial

Background and Objectives Perineural dexamethasone has been demonstrated to extend postsurgical analgesia after peripheral nerve blockade in adults. The mechanism of action of dexamethasone as a regional anesthetic adjuvant is unclear as intravenous dexamethasone has been shown to have similar analgesic efficacy as perineural dexamethasone. The efficacy of perineural dexamethasone has not been previously explored in the pediatric population. Methods After obtaining informed consent, children (aged 10–18 years) presenting for arthroscopic knee surgery with a femoral nerve block were randomized to 1 of 3 groups: ropivacaine 0.5% and intramuscular saline (group R), ropivacaine 0.5% plus perineural dexamethasone 0.1 mg/kg (maximum 4 mg) and intramuscular saline (group D), and ropivacaine 0.5% and intramuscular dexamethasone 0.1 mg/kg (maximum 4 mg) (group M). The primary outcome was the number of doses of analgesic agents in the first 48 hours after hospital discharge. The number of doses was compared across study groups using Wilcoxon rank sum tests. Results Seventy-seven patients were enrolled in the study, of whom 4 were withdrawn because of additional surgical repair being performed, emergence delirium requiring unblinding, or loss to follow-up. The remaining 36 boys and 37 girls (aged 15 ± 2 years) included 23 patients randomized to group D, 23 patients randomized to group M, and 27 patients randomized to group R. The median number of pain medication doses within 48 hours of discharge was 2, 3, and 2 in groups D, M, and R, respectively. There were no significant differences in this outcome between groups D and M (difference in medians, 1; 95% confidence interval [CI] of difference in medians, −1 to 2; P = 0.475), groups D and R (difference in medians, 0; 95% CI of difference, −2 to 1; P = 0.821), or groups M and R (difference in medians, −1; 95% CI of difference, −2 to 1; P = 0.594). Other secondary outcomes, including time to first analgesic consumption after discharge, visual analog scale pain score, and subjective intensity of motor block, did not evince statistically significant differences among the study groups. Conclusions In the pediatric population, perineural or intramuscular dexamethasone did not improve analgesia after femoral nerve blockade for knee arthroscopy. Whether the observed lack of benefit reflects a true adult-pediatric difference or a limitation of the study could not be determined. Future pediatric studies are needed to evaluate dexamethasone for other block types and other types of surgery. Clinical Trial Registration This study was registered at ClinicalTrials.gov, identifier NCT01971645. Accepted for publication October 4, 2017. Address correspondence to: Giorgio Veneziano, MD, Department of Anesthesiology & Pain Medicine, Nationwide Children's Hospital, 700 Children's Dr, Columbus, OH 43205 (e-mail: Giorgio.Veneziano@Nationwidechildrens.org). This project was supported by The Clinical and Translational Intramural Funding Program (award grant number UL1TR001070), through the Research Institute at Nationwide Children's Hospital (Columbus, OH). The content is solely the responsibility of the authors and does not necessarily represent the official views of Nationwide Children's Hospital. This work was presented in part at moderated abstract presentations at the Society of Pediatric Pain Medicine's CCAS 2017 Annual Meeting on March 2 and the SPA-AAP Pediatric Anesthesiology 2017, on March 3, 2017, both in Austin, TX. The authors declare no conflict of interest. This study was registered with the Food and Drug Administration as an investigational new drug (IND 120188). Copyright © 2018 by American Society of Regional Anesthesia and Pain Medicine.

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Plant genetics: Parasites plant microRNAs in the host

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Cloud computing for genomic data analysis and collaboration

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The detection of higher-order acoustic transitions is reflected in the N1 ERP

Abstract

The auditory system features various types of dedicated change detectors enabling the rapid parsing of auditory stimulation into distinct events. The activity of such detectors is reflected by the N1 ERP. Interestingly, certain acoustic transitions show an asymmetric N1 elicitation pattern: whereas first-order transitions (e.g., a change from a segment of constant frequency to a frequency glide [c-to-g change]) elicit N1, higher-order transitions (e.g., glide-to-constant [g-to-c] changes) do not. Consensus attributes this asymmetry to the absence of any available sensory mechanism that is able to rapidly detect higher-order changes. In contrast, our study provides compelling evidence for such a mechanism. We collected electrophysiological and behavioral data in a transient-detection paradigm. In each condition, a random (50%–50%) sequence of two types of tones occurred, which did or did not contain a transition (e.g., c-to-g and constant stimuli or g-to-c and glide tones). Additionally, the rate of pitch change of the glide varied (i.e., 10 vs. 40 semitones per second) in order to increase the number of responding neural assemblies. The rate manipulation modulated transient ERPs and behavioral detection performance for g-to-c transitions much stronger than for c-to-g transitions. The topographic and tomographic analyses suggest that the N1 response to c-to-g and also to g-to-c transitions emerged from the superior temporal gyrus. This strongly supports a sensory mechanism that allows the fast detection of higher-order changes.

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Hypothalamic and liver transcriptome from two critical life-history stages in a migratory songbird

Abstract

Very little is understood about genetic mechanisms underlying the onset of spring migration in latitudinal avian migrants. To gain insight into genetic architecture of the hypothalamus and liver tissues of a long-distance migrant, we examined and compared the transcriptome profile of captive night-migratory blackheaded buntings (Emberiza melanocephala) between photoperiodically-induced winter non-migratory (WnM) and spring migratory (SM) life-history states (LHSs) under short and long days, respectively. High-throughput 454 pyrosequenced transcripts were mapped initially with reference to the genome of two phylogenetically close species, Taeniopygia guttata and Ficedula albicollis. The F. albicollis genome gave higher annotation results, and was used for further analysis. A total of 216 (78 in hypothalamus; 138 in liver) genes were found to be differentially expressed between the WnM and SM LHSs. These genes were enriched for physiological pathways, which may be involved in regulating seasonal migrations in birds. For example, genes that enriched for ATP binding pathway in the hypothalamus were expressed at a significantly higher level in SM than in the WnM LHS. Similarly, upregulated genes associated with myelin sheath and focal adhesion were enriched in the hypothalamus, and those with cell-to-cell junction, intracellular protein transport, calcium ion transport and small GTPase-mediated signal transduction were enriched in the liver. Many of these genes are a part of physiological pathways potentially involved in regulating seasonal migration in birds. These results show molecular changes at the regulatory and metabolic levels associated with seasonal transitions in a long-distance migrant, and provide bases for future studies aimed at unravelling the genetic control of migration in birds.

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Anterior Pituitary Transcriptome Suggests Differences in ACTH Release in Tame and Aggressive Foxes

Domesticated species exhibit a suite of behavioral, endocrinological, and morphological changes referred to as "domestication syndrome." These changes may include a reduction in reactivity of the hypothalamic-pituitary-adrenal (HPA) axis, specifically reduced adrenocorticotropic hormone release from the anterior pituitary. To investigate the biological mechanisms targeted during domestication, we investigated gene expression in the pituitaries of experimentally domesticated foxes (Vulpes vulpes). RNA was sequenced from the anterior pituitary of six foxes selectively bred for tameness ("tame foxes") and six foxes selectively bred for aggression ("aggressive foxes"). Expression, splicing, and network differences identified between the two lines indicated the importance of genes related to regulation of exocytosis, specifically mediated by cAMP, organization of pseudopodia, and cell motility.  These findings provide new insights into biological mechanisms that may have been targeted when these lines of foxes were selected for behavior, and suggest new directions for research into HPA axis regulation and the biological underpinnings of domestication.

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Genetic Loci Controlling Carotenoid Biosynthesis in Diverse Tropical Maize Lines

The discovery and use of genetic markers associated with carotenoid levels can help to more effectively exploit the genetic potential of maize for provitamin A accumulation. Provitamin A carotenoids are classes of carotenoids that are precursors of vitamin A, an essential micronutrient in humans. Vitamin A deficiency is a global public health problem affecting millions of people, especially in developing countries. Maize is one of the most important staple crops targeted for provitamin A biofortification to help alleviate vitamin A deficiency in developing countries. A genome-wide association study (GWAS) of maize endosperm carotenoids was conducted using a panel of 130 diverse yellow maize tropical inbred lines genotyped with Genotyping by Sequencing (GBS) SNP markers. Numerous significant association signals co-localizing with the known carotenoid biosynthesis genes crtRB1, lcyE and ZEP1 were identified. The GWAS confirmed previously reported large effects of the two major carotenoid biosynthesis genes lcyE and crtRB1. In addition, significant novel associations were detected for several transcription factors (e.g. RING zinc finger domain and HLH DNA-binding domain super family proteins) that may be involved in regulation of carotenoid biosynthesis in maize. When the GWAS was re-conducted by including the major effects of lcyE and crtRB1 genes as covariates, a SNP in a gene coding for an auxin response factor 20 transcription factor was identified which displayed an association with β-carotene and provitamin A levels. Our study provides a foundation for design and implementation of genomics-assisted selection strategies for provitamin A maize breeding in tropical regions. Our results advance efforts towards identification of additional genes (and allelic variants) involved in the regulation of carotenoid biosynthesis in plants.

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Maize Transposable Elements Ac/Ds as Insertion Mutagenesis Tools in Candida albicans

In non-model systems genetic research is often limited by the lack of techniques for the generation and identification of gene mutations. One approach to overcome this bottleneck is the application of transposons for gene tagging. We have established a two-element transposon tagging system, based on the transposable elements Activator (Ac)/Dissociation (Ds) from maize, for in vivo insertion mutagenesis in the fungal human pathogen Candida albicans. A non-autonomous Ds transposon carrying a selectable marker was constructed into the ADE2 promoter on chromosome 3 and a codon usage-adapted Ac transposase gene was inserted into the neutral NEUT5L locus on chromosome 5. In C. albicans cells expressing the transposase the Ds element efficiently excised and reintegrated elsewhere in the genome, which makes the Ac/Ds transposons promising tools for saturating insertion mutagenesis in clinical strains of C. albicans.

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Whole Genome Sequence Accuracy Is Improved by Replication in a Population of Mutagenized Sorghum

The accurate detection of induced mutations is critical for both forward and reverse genetics studies. Experimental chemical mutagenesis induces relatively few single base changes per individual. In a complex eukaryotic genome, false positive detection of mutations can occur at or above this mutagenesis rate. We demonstrate here, using a population of ethyl methanesulfonate (EMS) treated Sorghum bicolor BTx623 individuals, that using replication to detect false positive induced variants in next-generation sequencing data permits higher throughput variant detection with greater accuracy. We used a lower sequence coverage depth (average of 7X) from 586 independently mutagenized individuals and detected 5,399,493 homozygous SNPs. Of these, 76% originated from only 57,872 genomic positions prone to false positive variant calling. These positions are characterized by high copy number paralogs where the error-prone SNP positions are at copies containing a variant at the SNP position. The ability of short stretches of homology to generate these error prone positions suggests that incompletely assembled or poorly mapped repeated sequences are one driver of these error prone positions. Removal of these false positives left 1,275,872 homozygous and 477,531 heterozygous EMS-induced SNPs which, congruent with the mutagenic mechanism of EMS, were greater than 98% G:C to A:T transitions. Through this analysis we generated a collection of sequence indexed mutants of Sorghum. This collection contains 4,035 high impact homozygous mutations in 3,637 genes and 56,514 homozygous missense mutations in 23,227 genes. Each line contains, on average, 2,177 annotated homozygous SNPs per genome, including seven likely gene knockouts and 96 missense mutations. The number of mutations in a transcript was linearly correlated with the transcript length and also the G+C count, but not with the GC/AT ratio. Analysis of the detected mutagenized positions identified CG-rich patches, and flanking sequences strongly influenced EMS-induced mutation rates. This method for detecting false-positive induced mutations is generally applicable to any organism, is independent of the choice of in silico variant-calling algorithm, and is most valuable when the true mutation rate is likely to be low, such as in laboratory induced mutations or somatic mutation detection in medicine.

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Are Mothers’ Working Hours Associated with General and Abdominal Obesity in Children and Adolescents? The Korean National Health and Nutrition Examination Survey (2008–2012)

Abstract

Objectives Despite an increase in the female work force and recent increase in childhood obesity, the association between working hours of mothers and childhood obesity as well as how such association differs according to mothers' weight and intake frequency of energy-dense, nutrition-poor (EDNP) foods remain unclear. Methods Data from the Korean National Health and Nutrition Examination Survey (2008–2012) that included samples from 3914 children in 2526 households were analyzed. Two-level (household-children) mixed-effects modeling was performed to investigate the association between mothers' working hours and childhood obesity based on body mass index (BMI) and waist circumference (WC). Results Long working hours (h) of mothers were associated with both BMI (β = − 0.14; P = 0.324 for 1–20 h, β = 0.10; P = 0.334 for ≤ 21–40 h; β = 0.09; P = 0.429 for 41–68 h, β = 0.51; P = 0.015 for ≥ 69 h) and WC of the child (β = 0.06; P = 0.809 for 1–20 h; β = 0.46; P = 0.017 for ≤ 21–40 h; β = 0.59; P = 0.004 for 41–68 h, β = 1.35; P < 0.001 for ≥ 69 h), and the mean increase was greater for mothers working ≥ 69 h compared to those working 0 h. We also observed that the association between mothers' working hours and child's BMI and WC was greater for children whose mothers were either overweight or obese and frequently consumed energy-dense, nutrient-poor foods (EDNP). Conclusions for Practice Long working hours of mothers are associated with higher BMI and WC in children. Thus, it is important to improve labor welfare for mothers who work long hours, and provide interventions to promote good health behaviors in both children and working mothers.

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Favorite Features of Elite for EMS & Fire

ImageTrend Elite™ offers both EMS and fire incident documentation on a single platform. Elite also has many other distinct advantages for more efficient workflow, department operations management and data analysis. In this video, Phil provides an overview of some of the favorite features of Elite for EMS and Fire. Fully NEMSIS v3 Compliant (Collect and Receive & Process), NFIRS 5.0 compliant, platform independent, cloud-based and offline/online capable ePCR and fire RMS.

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Never at rest: insights into the conformational dynamics of ion channels from cryo-electron microscopy

Abstract

The tightly regulated opening and closure of ion channels underlies the electrical signals that are vital for a wide range of physiological processes. Two decades ago the first atomic level view of ion channel structures led to a detailed understanding of ion selectivity and conduction. In recent years spectacular developments in the field of cryo-electron microscopy have resulted in cryo-EM superseding crystallography as the technique of choice for determining near atomic resolution structures of ion channels. Here, we will review the recent developments in cryo-EM and its specific application to the study of ion channel gating. We will highlight the advantages and disadvantages of the current technology and where the field is likely to head in the next few years.

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Mechanisms linking T-wave alternans to spontaneous initiation of ventricular arrhythmias in rabbit models of long QT syndrome

Abstract

T-wave alternans (TWA) and irregular beat-to-beat T-wave variability or T-wave lability (TWL), the ECG manifestations of action potential duration (APD) alternans and variability, are precursors of ventricular arrhythmias in long QT syndromes. TWA and TWL in patients tend to occur at normal heart rates and are usually potentiated by bradycardia. Whether or how TWA and TWL at normal or slow heart rates are causally linked to arrhythmogenesis remains unknown. In this study, we used computer simulations and experiments of a transgenic rabbit model of long QT syndrome to investigate the underlying mechanisms. Computer simulations showed that APD prolongation and slowed heart rates caused early afterdepolarizations mediated APD alternans and chaos, manifesting as TWA and TWL, respectively. Regional APD alternans and chaos exacerbated pre-existing APD dispersion, and APD chaos could also induce APD dispersion de novo via chaos desynchronization. Increased APD dispersion, combined with substantially enhanced I_Ca,L, resulted in a tissue-scale dynamical instability to cause spontaneous occurrence of unidirectionally propagating premature ventricular complexes (PVCs) originating from the APD gradient region. These PVCs could directly degenerate into reentrant arrhythmias without the need for an additional tissue substrate or could block the following sinus beat to result in a longer RR interval which further exacerbated the APD dispersion to cause spontaneous occurrence of ventricular arrhythmias. Slow heart rate induced PVC alternans was observed in experiments of transgenic LQT2 rabbits under isoproterenol, associated with increased APD dispersion and spontaneous occurrence of ventricular arrhythmias, agreeing with the theoretical predictions.

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Three-dimensional genome architecture in health and disease

Abstract

More than a decade of massive DNA sequencing efforts has generated a large body of genomic, transcriptomic and epigenomic information that has provided a more and more detailed view of the functional elements and transactions within the human genome. Considerable efforts have also focused on linking these elements with one another by mapping their interactions and by establishing 3D genomic landscapes in various cell and tissue types. In parallel, multiple studies have associated genomic deletions, duplications and other rearrangements with human pathologies. In this review, we explore recent progresses that have allowed connecting disease-causing alterations with perturbations of the 3D genome organization.

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