Publications by authors named "Peter Andrews"

390 Publications

Olfactory and Gustatory Function before and after Laparoscopic Sleeve Gastrectomy.

Medicina (Kaunas) 2021 Aug 31;57(9). Epub 2021 Aug 31.

Department of Neurosciences, Otolaryngology Section, University of Padova, 35128 Padova, Italy.

: Bariatric surgery is the gold standard for the treatment of morbid obesity, and current evidence suggests that patients undergoing surgery can show changes in their sense of taste and smell. However, no definitive conclusions can be drawn given the heterogeneity of the studies and the contrasting results reported in the literature. : We enrolled 18 obese patients undergoing laparoscopic sleeve gastrectomy (LSG) and 15 obese controls. At baseline (T0) and 6 months after enrollment/surgery (T1), both groups underwent Sniffin' Sticks and whole mouth test. Post-operative qualitative taste variations were also analyzed and SNOT-22, VAS for taste and smell, and MMSE were administered. : An improvement in the olfactory threshold was observed in the treatment group ( = 0.03) at 6 months. At multivariate analysis, the olfactory threshold differences observed correlated with MMSE ( = 0.03) and T0 gustatory identification ( = 0.01). No changes in sense of taste were observed between the two groups at 6 months, even though nine subjects in the treatment group reported a worsening of taste. This negatively correlated with age ( < 0.001), but a positive marginal correlation was observed with the olfactory threshold difference between T0 and T1 ( = 0.06). : Olfaction can improve after LSG, and this seems to be the consequence of an improved olfactory threshold. Although we did not observe any change in gustatory identification, food's pleasantness worsened after bariatric surgery.
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http://dx.doi.org/10.3390/medicina57090913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8466191PMC
August 2021

Brief report: The uricase mutation in humans increases our risk for cancer growth.

Cancer Metab 2021 Sep 15;9(1):32. Epub 2021 Sep 15.

Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Center, Aurora, CO, USA.

Background: Recent studies suggest that fructose, as well as its metabolite, uric acid, have been associated with increased risk for both cancer incidence and growth. Both substances are known to cause oxidative stress to mitochondria and to reduce adenosine triphosphate (ATP) production by blocking aconitase in the Krebs cycle. The uricase mutation that occurred in the Miocene has been reported to increase serum uric acid and to amplify the effects of fructose to stimulate fat accumulation. Here we tested whether the uricase mutation can also stimulate tumor growth.

Methods: Experiments were performed in mice in which uricase was inactivated by either knocking out the gene or by inhibiting uricase with oxonic acid. We also studied mice transgenic for uricase. These mice were injected with breast cancer cells and followed for 4 weeks.

Results: The inhibition or knockout of uricase was associated with a remarkable increase in tumor growth and metastases. In contrast, transgenic uricase mice showed reduced tumor growth.

Conclusion: A loss of uricase increases the risk for tumor growth. Prior studies have shown that the loss of the mutation facilitated the ability of fructose to increase fat which provided a survival advantage for our ancestors that came close to extinction from starvation in the mid Miocene. Today, however, excessive fructose intake is rampant and increasing our risk not only for obesity and metabolic syndrome, but also cancer. Obesity-associated cancer may be due, in part, to a mutation 15 million years ago that acted as a thrifty gene.
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http://dx.doi.org/10.1186/s40170-021-00268-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8444362PMC
September 2021

A retrospective study on long-term efficacy of intranasal lysine-aspirin in controlling NSAID-exacerbated respiratory disease.

Eur Arch Otorhinolaryngol 2021 Sep 4. Epub 2021 Sep 4.

Department of ENT, Royal National ENT & Eastman Dental Hospitals, 47-49 Huntley St, Bloomsbury, London, WC1E 6DG, UK.

Purpose: Aspirin treatment after desensitization (ATAD) represents an effective therapeutic option suitable for NSAID-exacerbated respiratory disease (N-ERD) patients with recalcitrant disease. Intranasal administration of lysine-aspirin (LAS) has been suggested as a safer and faster route than oral ATAD but evidence for its use is less strong. We investigated nasal LAS therapy long-term efficacy based on objective outcomes, smell function, polyp recurrence and need for surgery or rescue therapy. Clinical biomarkers predicting response to intranasal LAS, long-term side effects and consequences of discontinuing treatment have been evaluated.

Methods: A retrospective analysis of a database of 60 N-ERD patients seen between 2012 and 2020 was performed in March 2021. They were followed up at 3-months, 1-, 2- and 3-years with upper and lower airway functions assessed at each follow-up.

Results: Higher nasal airflow and smell scores were found at each follow-up in patients taking LAS (p < 0.001 and p = 0.048 respectively). No influence of LAS on pulmonary function measurements was observed. Patient on intranasal LAS showed a lower rate of revision sinus surgery when compared to those who discontinued the treatment (p < 0.001). None of the variables studied was found to influence LAS treatment response.

Conclusion: Our study demonstrates the clinical effectiveness of long-term intranasal LAS in the management of N-ERD in terms of improved nasal airflow and olfaction and a reduced need for revision sinus surgery. Intranasal LAS is safe, being associated with a lower rate of side effects when compared to oral ATAD. However, discontinuation of the treatment at any stage is associated with a loss of clinical benefit.
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http://dx.doi.org/10.1007/s00405-021-07063-2DOI Listing
September 2021

Rates of contributory de novo mutation in high and low-risk autism families.

Commun Biol 2021 09 1;4(1):1026. Epub 2021 Sep 1.

Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, NY, USA.

Autism arises in high and low-risk families. De novo mutation contributes to autism incidence in low-risk families as there is a higher incidence in the affected of the simplex families than in their unaffected siblings. But the extent of contribution in low-risk families cannot be determined solely from simplex families as they are a mixture of low and high-risk. The rate of de novo mutation in nearly pure populations of high-risk families, the multiplex families, has not previously been rigorously determined. Moreover, rates of de novo mutation have been underestimated from studies based on low resolution microarrays and whole exome sequencing. Here we report on findings from whole genome sequence (WGS) of both simplex families from the Simons Simplex Collection (SSC) and multiplex families from the Autism Genetic Resource Exchange (AGRE). After removing the multiplex samples with excessive cell-line genetic drift, we find that the contribution of de novo mutation in multiplex is significantly smaller than the contribution in simplex. We use WGS to provide high resolution CNV profiles and to analyze more than coding regions, and revise upward the rate in simplex autism due to an excess of de novo events targeting introns. Based on this study, we now estimate that de novo events contribute to 52-67% of cases of autism arising from low risk families, and 30-39% of cases of all autism.
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http://dx.doi.org/10.1038/s42003-021-02533-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8410909PMC
September 2021

Awake Rhinology Surgery in Response to the COVID-19 Pandemic in Europe.

ORL J Otorhinolaryngol Relat Spec 2021 Aug 31:1-10. Epub 2021 Aug 31.

Department of Rhinology, Royal National Throat, Nose and Ear Hospital, London, United Kingdom.

Background: European health-care systems are faced with a backlog of surgical procedures following the suspension of routine surgery during the COVID-19 crisis. Routine rhinology surgery under general anaesthetic (GA) is now faced with significant challenges which include limited theatre capacity, the negative ramifications of surgical prioritization, reduced patient throughput in secondary care, and additional personal protective equipment requirements. Delayed surgery in rhinology, particularly with regards to chronic rhinosinusitis, has previously been shown to have poorer surgical outcomes, a detrimental effect on quality of life and long-term negative health socio-economic effects. Awake rhinology surgery under local anaesthetic (LA) provides an ideal alternative to GA. It provides a means of operating on patients in a setting alternative to currently oversubscribed main theatres, by utilizing satellite facilities, while ensuring identical surgical outcomes for patients who may otherwise have been forced to wait a long time for their procedure. It also confers additional benefits in terms of shorter recovery time and hospital stay for patients.

Objectives: We have developed a set of recommendations that are intended to help support clinicians and managers to better adopt LA rhinology protocols and minimize the risk to the patient and health-care professionals involved.

Methodology: International roundtable forums were conducted and supplemented by individual interviews. The international board consisted of 12 rhinologists experienced in awake rhinology surgery. Feedback was analysed and shared to develop a consensus of best practice.

Recommendations: Local and national guidelines need to be adhered to with specific focus on patient and clinician safety. When performing awake rhinology procedures in the COVID-19 recovery process, consider implementing specific safety measures and workflow practices to safeguard patients and staff and minimize the risk of infection.

Conclusion: Awake surgery potentially provides quicker access to routine rhinology surgery in the post-COVID-19 recovery phase, ensuring patients are treated in a timely matter, thereby avoiding higher downstream costs, and improving outcomes.
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http://dx.doi.org/10.1159/000517155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8450852PMC
August 2021

In Vivo Wireless Brain Stimulation via Non-invasive and Targeted Delivery of Magnetoelectric Nanoparticles.

Neurotherapeutics 2021 Jun 15. Epub 2021 Jun 15.

Indiana Spinal Cord and Brain Injury Research Group, Stark Neuroscience Research Institute & Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN, USA.

Wireless and precise stimulation of deep brain structures could have important applications to study intact brain circuits and treat neurological disorders. Herein, we report that magnetoelectric nanoparticles (MENs) can be guided to a targeted brain region to stimulate brain activity with a magnetic field. We demonstrated the nanoparticles' capability to reliably evoke fast neuronal responses in cortical slices ex vivo. After fluorescently labeled MENs were intravenously injected and delivered to a targeted brain region by applying a magnetic field gradient, a magnetic field of low intensity (350-450 Oe) applied to the mouse head reliably evoked cortical activities, as revealed by two-photon and mesoscopic imaging of calcium signals and by an increased number of c-Fos expressing cells after stimulation. Neither brain delivery of MENs nor the magnetic stimulation caused significant increases in astrocytes and microglia. Thus, MENs could enable a non-invasive and contactless deep brain stimulation without the need of genetic manipulation.
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http://dx.doi.org/10.1007/s13311-021-01071-0DOI Listing
June 2021

The role of thrifty genes in the origin of alcoholism: A narrative review and hypothesis.

Alcohol Clin Exp Res 2021 08 16;45(8):1519-1526. Epub 2021 Jul 16.

Division of Nephrology, University of Colorado Anschutz Medical Center, Aurora, CO, USA.

In this narrative review, we present the hypothesis that key mutations in two genes, occurring 15 and 10 million years ago (MYA), were individually and then collectively adaptive for ancestral humans during periods of starvation, but are maladaptive in modern civilization (i.e., "thrifty genes"), with the consequence that these genes not only increase our risk today for obesity, but also for alcoholism. Both mutations occurred when ancestral apes were experiencing loss of fruit availability during periods of profound climate change or environmental upheaval. The silencing of uricase (urate oxidase) activity 15 MYA enhanced survival by increasing the ability for fructose present in dwindling fruit to be stored as fat, a consequence of enhanced uric acid production during fructose metabolism that stimulated lipogenesis and blocked fatty acid oxidation. Likewise, a mutation in class IV alcohol dehydrogenase ~10 MYA resulted in a remarkable 40-fold increase in the capacity to oxidize ethanol (EtOH), which allowed our ancestors to ingest fallen, fermenting fruit. In turn, the EtOH ingested could activate aldose reductase that stimulates the conversion of glucose to fructose, while uric acid produced during EtOH metabolism could further enhance fructose production and metabolism. By aiding survival, these mutations would have allowed our ancestors to generate more fat, primarily from fructose, to survive changing habitats due to the Middle Miocene disruption and also during the late-Miocene aridification of East Africa. Unfortunately, the enhanced ability to metabolize and utilize EtOH may now be acting to increase our risk for alcoholism, which may be yet another consequence of once-adaptive thrifty genes.
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http://dx.doi.org/10.1111/acer.14655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8429132PMC
August 2021

Sinonasal surgery alters brain structure and function: Neuroanatomical correlates of olfactory dysfunction.

J Neurosci Res 2021 Sep 10;99(9):2156-2171. Epub 2021 Jun 10.

Department of Otorhinolaryngology, TU Dresden, Dresden, Germany.

Olfactory dysfunction (OD) is more common than hearing loss, partial blindness, or blindness and can have a significant impact on the quality of life. Moreover, unexplained OD is an early biomarker in neurodegenerative diseases and increases 5-year mortality risk. Structural alterations in olfactory eloquent brain regions may represent the neuroanatomical correlates of OD. Previous studies have demonstrated reduced gray matter (GM) volume in areas of presumed olfactory relevance in patients with OD. However, being cross-sectional in nature, these studies do not provide evidence of causality, for which longitudinal work is required. At present, however, longitudinal studies addressing olfactory structural plasticity are limited, both in number and methodological approach: to our knowledge, such work has not included parallel functional imaging to confirm the relevance of structural change. We therefore performed a longitudinal multimodal neuroimaging study investigating structural and functional plasticity in 24 patients undergoing surgical treatment for chronic rhinosinusitis, compared with 17 healthy controls. We demonstrated functionally significant structural plasticity within the orbitofrontal, anterior cingulate and insular cortices, and temporal poles in patients 3 months after surgery. Of interest, GM volume decreased in these regions, in association with increased psychophysical scores and BOLD signal. To our knowledge, this is the first study to demonstrate both structural and functional plasticity of the central olfactory networks, thereby confirming these areas as neuroanatomical correlates of olfactory function/dysfunction.
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http://dx.doi.org/10.1002/jnr.24897DOI Listing
September 2021

The Nasal Obstruction Balance Index: A Novel Approach to Improving Correlation Between Unilateral Nasal Airway Measurements and Evaluating Nasal Airway Asymmetry.

Laryngoscope 2021 May 5. Epub 2021 May 5.

Department of Medical Physics and Biomedical Engineering, University College London, London, United Kingdom.

Objectives/hypothesis: Demonstrate that the Nasal Obstruction Balance Index (NOBI) model fulfils the unmet need of improving unilateral correlation between subjective and objective nasal obstruction outcome measures and identifying the more obstructed side. Improve correlation between unilateral objective nasal airway measurements (nasal inspiratory peak flow [NIPF] and acoustic rhinometry [AR]) and subjective Visual Analogue Scale for nasal obstruction (VAS-NO) scores. Improve assessment of nasal airway asymmetry by evaluating unilateral measurements both before and after the application of nasal decongestant; which the patient could better understand. NOBI represents a ratio calculated by taking the difference between left and right nasal airway measurements and divided by the maximum unilateral measurement. It is based on Poiseuille's law and aims to reduce the confounding variables which challenge nasal airway measurement.

Study Design: Prospective cohort study.

Methods: Forty-three controls and 34 patients with nasal obstruction underwent both unilateral and bilateral NIPF, AR and VAS-NO measurements; these were repeated after the application of nasal decongestant. The NOBI values for unilateral NIPF, AR, and VAS-NO were calculated both before and after decongestant.

Results: The correlation between unilateral NIPF and AR measurements was enhanced considerably (r = 0.57, P < .01) when NOBI was applied. The NOBI metric significantly increased the correlation between unilateral NIPF, AR, and VAS-NO scores. Postdecongestant NOBI for NIPF and AR measurements correctly identified the more obstructed side in 82.4% and 94.1% of the deviated nasal septum (DNS) cases, respectively.

Conclusion: The NOBI model provides a better correlation between unilateral subjective and objective measurements and identifies the more obstructed side.

Level Of Evidence: Prospective cohort study (level III) Laryngoscope, 2021.
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http://dx.doi.org/10.1002/lary.29597DOI Listing
May 2021

A Single-Center 5-Year Experience Using the Triple-Layer Technique for Surgical Repair of Nasal Septal Perforations.

Facial Plast Surg Aesthet Med 2021 Apr 13. Epub 2021 Apr 13.

Department of ENT, Royal National ENT and Eastman Dental Hospitals, London, United Kingdom.

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http://dx.doi.org/10.1089/fpsam.2020.0623DOI Listing
April 2021

Olfactory dysfunction in antineutrophil cytoplasmic antibody-associated vasculitides: A review of the literature.

World J Methodol 2021 Mar 20;11(2):15-22. Epub 2021 Mar 20.

Department of Ear, Nose and Throat, Royal National ENT and Eastman Dental Hospitals, London WC1E 6DG, United Kingdom.

Olfactory dysfunction (OD) has been described in patients with antineutrophil cytoplasmic antibody-associated vasculitides (AAV), but the underlying mechanisms are not completely understood. The causes of altered smell function can generally be divided into conductive, sensorineural or others. To date no specific treatment is available for AAV-related OD and the efficacy of currently available options has not been explored. The aim of this review is to provide an overview of the causes that may lead to OD in patients with AAV. Current available treatments for OD and possible options in patients with AAV presenting with smell impairment are also mentioned.
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http://dx.doi.org/10.5662/wjm.v11.i2.15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7970017PMC
March 2021

Nanopore Sequencing Indicates That Tandem Amplification of Chromosome 20q11.21 in Human Pluripotent Stem Cells Is Driven by Break-Induced Replication.

Stem Cells Dev 2021 Jun 30;30(11):578-586. Epub 2021 Apr 30.

Department of Biomedical Science, University of Sheffield, Sheffield, United Kingdom.

Copy number variants (CNVs) are genomic rearrangements implicated in numerous congenital and acquired diseases, including cancer. The appearance of culture-acquired CNVs in human pluripotent stem cells (PSCs) has prompted concerns for their use in regenerative medicine. A particular problem in PSC is the frequent occurrence of CNVs in the q11.21 region of chromosome 20. However, the exact mechanism of origin of this amplicon remains elusive due to the difficulty in delineating its sequence and breakpoints. Here, we have addressed this problem using long-read Nanopore sequencing of two examples of this CNV, present as duplication and as triplication. In both cases, the CNVs were arranged in a head-to-tail orientation, with microhomology sequences flanking or overlapping the proximal and distal breakpoints. These breakpoint signatures point to a mechanism of microhomology-mediated break-induced replication in CNV formation, with surrounding sequences likely contributing to the instability of this genomic region.
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http://dx.doi.org/10.1089/scd.2021.0013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165465PMC
June 2021

Characteristics of taste dysfunction in COVID-19 subjects coming from two different countries.

J Neurovirol 2021 06 22;27(3):482-485. Epub 2021 Mar 22.

Department of Ear, Nose and Throat, Royal National ENT & Eastman Dental Hospitals, London, UK.

Taste dysfunction (TD) has been recognised, together with olfactory dysfunction, as a key presenting symptom of COVID-19. The capability to recognise flavours, flavour intensities and aroma characteristics can be highly variable within the same population, as well as potentially diverse between culturally different populations. The aims of this study are to evaluate whether a difference in the types of TD presentation amongst COVID-19 positive subjects can be demonstrated and whether a difference exists between populations of different cultures.
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http://dx.doi.org/10.1007/s13365-021-00942-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983960PMC
June 2021

The Evidence Base for the Benefits of Functional Septorhinoplasty and its Future Post COVID-19.

Facial Plast Surg 2021 Oct 6;37(5):625-631. Epub 2021 Mar 6.

Department of Otolaryngology, Charing Cross Hospital, London, United Kingdom.

Ever since the introduction of the concept of Procedures of Limited Clinical Value (PoLCV), procedures such as functional septorhinoplasty have been subject to additional funding restrictions within the British National Health Service. Recent publications have suggested that 10% of Clinical Commissioning Groups in the United Kingdom no longer fund septorhinoplasty surgery irrespective of the indications, including congenital malformations or post-trauma, and despite the strong evidence available in the literature in treating a range of health conditions. Thus, inequity exists across the country. At present functional septorhinoplasty surgery is frequently but incorrectly grouped together with aesthetic rhinoplasty, both of which are deemed to be cosmetic interventions. Moreover, as we exit the peak of the current coronavirus disease 2019 (COVID-19) pandemic, procedures deemed to be of lower clinical priority will potentially be at risk throughout Europe. The purpose of this review is twofold; the first is to put forward the evidence to commissioners in favor of functional septorhinoplasty surgery on patient well-being and mental health; the second is to demonstrate why functional septorhinoplasty surgery is a distinct procedure from aesthetic rhinoplasty and why it ought not to be classified as a procedure of limited clinical value.
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http://dx.doi.org/10.1055/s-0041-1725162DOI Listing
October 2021

Defining the signalling determinants of a posterior ventral spinal cord identity in human neuromesodermal progenitor derivatives.

Development 2021 03 23;148(6). Epub 2021 Mar 23.

Centre for Stem Cell Biology, Department of Biomedical Science, The University of Sheffield, Sheffield S10 2TN, UK

The anteroposterior axial identity of motor neurons (MNs) determines their functionality and vulnerability to neurodegeneration. Thus, it is a crucial parameter in the design of strategies aiming to produce MNs from human pluripotent stem cells (hPSCs) for regenerative medicine/disease modelling applications. However, the generation of posterior MNs corresponding to the thoracic/lumbosacral spinal cord has been challenging. Although the induction of cells resembling neuromesodermal progenitors (NMPs), the bona fide precursors of the spinal cord, offers a promising solution, the progressive specification of posterior MNs from these cells is not well defined. Here, we determine the signals guiding the transition of human NMP-like cells toward thoracic ventral spinal cord neurectoderm. We show that combined WNT-FGF activities drive a posterior dorsal pre-/early neural state, whereas suppression of TGFβ-BMP signalling pathways promotes a ventral identity and neural commitment. Based on these results, we define an optimised protocol for the generation of thoracic MNs that can efficiently integrate within the neural tube of chick embryos. We expect that our findings will facilitate the comparison of hPSC-derived spinal cord cells of distinct axial identities.
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http://dx.doi.org/10.1242/dev.194415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015249PMC
March 2021

Human pluripotent stem cells: genetic instability or stability?

Authors:
Peter W Andrews

Regen Med 2021 02 2;16(2):113-115. Epub 2021 Mar 2.

Department of Biomedical Science, Centre for Stem Cell Biology, The University of Sheffield, Sheffield S10 2TN, United Kingdom.

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http://dx.doi.org/10.2217/rme-2021-0013DOI Listing
February 2021

Reducing the risks of endoscopic sinonasal surgery in the Covid-19 era.

Clin Otolaryngol 2021 07 10;46(4):809-815. Epub 2021 Mar 10.

Spire Regency Hospital, Macclesfield, UK.

Objectives: Many routine sinonasal procedures utilising powered instruments are regarded as aerosol-generating. This study aimed to assess how different instrument settings affect detectable droplet spread and patterns of aerosolised droplet spread during simulated sinonasal surgery in order to identify mitigation strategies.

Design: Simulation series using three-dimensional (3-D) printed sinonasal model. Fluorescein droplet spread was assessed following microdebriding and drilling of fluorescein-soaked grapes and bones, respectively.

Setting: University dry lab.

Participants: 3-D printed sinonasal model.

Main Outcome Measures: Patterns of aerosolised droplet spread.

Results And Conclusion: There were no observed fluorescein droplets or splatter in the measured surgical field after microdebridement of nasal polyps at aspecific irrigation rate and suction pressure. Activation of the microdebrider in the presence of excess fluid in the nasal cavity (reduced or blocked suction pressure, excessive irrigation fluid or bleeding) resulted in detectable droplet spread. Drilling with either coarse diamond or cutting burs resulted in detectable droplets and greater spread was observed when drilling within the anterior nasal cavity. High-speed drilling is a high-risk AGP but the addition of suction using a third hand technique reduces detectable droplet spread outside the nasal cavity. Using the instrument outside the nasal cavity inadvertently, or when unblocking, produces greater droplet spread and requires more caution.
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http://dx.doi.org/10.1111/coa.13743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8013456PMC
July 2021

Diagnostic Yield of Whole Genome Sequencing After Nondiagnostic Exome Sequencing or Gene Panel in Developmental and Epileptic Encephalopathies.

Neurology 2021 03 10;96(13):e1770-e1782. Epub 2021 Feb 10.

From the School of Women's and Children's Health (E.E.P., R.S., S.R., T.K., H.S., P.I.A., J.L., M.C., D.M., M.J.C., A.B., E.K.), The School of Biotechnology and Biomolecular Sciences (M.E.D.), Childrens Cancer Institute (M.J.C.), and NeuRA (T.R.), University of New South Wales; Sydney Childrens Hospital Randwick (E.E.P., R.S., R.M., S.R., T.K., H.S., P.I.A., J.L., M.C., D.M., A.B., E.K.), Sydney Childrens Hospital Network; GOLD Service (E.E.P.), Hunter Genetics; Kinghorn Centre for Clinical Genomics (E.E.P., A.E.M., C.P., V.G., L.H., S.I., R.L.D., A.P.D., S.K., M.J.C.), Garvan Institute of Medical Research, Sydney, Australia; RG Development & Disease (U.S.M., S.M.), Max Planck Institute for Molecular Genetics; Institute for Medical Genetics and Human Genetics (U.S.M., S.M.), Charité-Universitätsmedizin, Berlin, Germany; Faculty of Medicine, Prince of Wales Clinical School (L.H.), and Faculty of Medicine, St Vincents Clinical School (S.K.), UNSW Sydney, Randwick; Adelaide Medical School (C.S., M.H.N.T.), University of Adelaide; Kolling Institute (R.L.D.), University of Sydney; SWSLHD Liverpool Hospital (A.C.), Liverpool; and New South Wales Health Pathology Randwick Genomics Laboratory (T.R., E.K.), Australia.

Objective: To assess the benefits and limitations of whole genome sequencing (WGS) compared to exome sequencing (ES) or multigene panel (MGP) in the molecular diagnosis of developmental and epileptic encephalopathies (DEE).

Methods: We performed WGS of 30 comprehensively phenotyped DEE patient trios that were undiagnosed after first-tier testing, including chromosomal microarray and either research ES (n = 15) or diagnostic MGP (n = 15).

Results: Eight diagnoses were made in the 15 individuals who received prior ES (53%): 3 individuals had complex structural variants; 5 had ES-detectable variants, which now had additional evidence for pathogenicity. Eleven diagnoses were made in the 15 MGP-negative individuals (68%); the majority (n = 10) involved genes not included in the panel, particularly in individuals with postneonatal onset of seizures and those with more complex presentations including movement disorders, dysmorphic features, or multiorgan involvement. A total of 42% of diagnoses were autosomal recessive or X-chromosome linked.

Conclusion: WGS was able to improve diagnostic yield over ES primarily through the detection of complex structural variants (n = 3). The higher diagnostic yield was otherwise better attributed to the power of re-analysis rather than inherent advantages of the WGS platform. Additional research is required to assist in the assessment of pathogenicity of novel noncoding and complex structural variants and further improve diagnostic yield for patients with DEE and other neurogenetic disorders.
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http://dx.doi.org/10.1212/WNL.0000000000011655DOI Listing
March 2021

Monitoring Re-Growth of Invasive Plants Using an Autonomous Surface Vessel.

Front Robot AI 2020 22;7:583416. Epub 2021 Jan 22.

Farlain Lake Community Association, Tiny, ON, Canada.

Invasive aquatic plant species, and in particular Eurasian Water-Milfoil (EWM), pose a major threat to domestic flora and fauna and can in turn negatively impact local economies. Numerous strategies have been developed to harvest and remove these plant species from the environment. However it is still an open question as to which method is best suited to removing a particular invasive species and the impact of different lake conditions on the choice. One problem common to all harvesting methods is the need to assess the location and degree of infestation on an ongoing manner. This is a difficult and error prone problem given that the plants grow underwater and significant infestation at depth may not be visible at the surface. Here we detail efforts to monitor EWM infestation and evaluate harvesting methods using an autonomous surface vessel (ASV). This novel ASV is based around a mono-hull design with two outriggers. Powered by a differential pair of underwater thrusters, the ASV is outfitted with RTK GPS for position estimation and a set of submerged environmental sensors that are used to capture imagery and depth information including the presence of material suspended in the water column. The ASV is capable of both autonomous and tele-operation.
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http://dx.doi.org/10.3389/frobt.2020.583416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862761PMC
January 2021

The human origin recognition complex is essential for pre-RC assembly, mitosis, and maintenance of nuclear structure.

Elife 2021 Feb 1;10. Epub 2021 Feb 1.

Cold Spring Harbor Laboratory, Cold Spring Harbor, United States.

The origin recognition complex (ORC) cooperates with CDC6, MCM2-7, and CDT1 to form pre-RC complexes at origins of DNA replication. Here, using tiling-sgRNA CRISPR screens, we report that each subunit of ORC and CDC6 is essential in human cells. Using an auxin-inducible degradation system, we created stable cell lines capable of ablating ORC2 rapidly, revealing multiple cell division cycle phenotypes. The primary defects in the absence of ORC2 were cells encountering difficulty in initiating DNA replication or progressing through the cell division cycle due to reduced MCM2-7 loading onto chromatin in G1 phase. The nuclei of ORC2-deficient cells were also large, with decompacted heterochromatin. Some ORC2-deficient cells that completed DNA replication entered into, but never exited mitosis. ORC1 knockout cells also demonstrated extremely slow cell proliferation and abnormal cell and nuclear morphology. Thus, ORC proteins and CDC6 are indispensable for normal cellular proliferation and contribute to nuclear organization.
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http://dx.doi.org/10.7554/eLife.61797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877914PMC
February 2021

Olfactory and taste dysfunction among mild-to-moderate symptomatic COVID-19 positive health care workers: An international survey.

Laryngoscope Investig Otolaryngol 2020 Dec 2;5(6):1019-1028. Epub 2020 Dec 2.

Department of Microbiology Whittington Health London UK.

Objectives: To determine the prevalence of olfactory and taste dysfunction (OD; TD) among COVID-19 positive health care workers (HCWs), their associated risk factors and prognosis.

Methods: Between May and June 2020, a longitudinal multicenter study was conducted on symptomatic COVID-19 PCR confirmed HCWs (COVID-19 positive) in London and Padua.

Results: Hundred and fourteen COVID-19 positive HCWs were surveyed with a response rate of 70.6% over a median follow-up period of 52 days. UK prevalence of OD and TD was 73.1% and 69.2%, respectively. There was a male to female ratio of 1:3 with 81.6% being white, 43.7% being nurses/health care assistants (HCAs), and 39.3% being doctors. In addition, 53.2% of them worked on COVID-19 wards. Complete recovery was reported in 31.8% for OD and 47.1% for TD with a 52 days follow-up. The job role of doctors and nurses negatively influenced smell ( = .04 and = .02) and taste recovery ( = .02 and = .01). Ethnicity (being white) showed to positively influence only taste recovery ( = .04). Sex (being female) negatively influenced OD and TD recovery only in Paduan HCWs ( = .02 and = .011, respectively). Working on a COVID-19 ward did not influence prognosis.

Conclusions: The prevalence of OD and TD was considerably higher in HCWs. The prognosis for OD and TD recovery was worse for nurses/HCAs and doctors but working on a COVID-19 ward did not influence prognosis. Sixty-eight percent of surveyed HCWs at 52 days continued to experience OD or TD requiring additional future medical management capacity.

Level Of Evidence: 4.
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http://dx.doi.org/10.1002/lio2.507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752034PMC
December 2020

Germline AGO2 mutations impair RNA interference and human neurological development.

Nat Commun 2020 11 16;11(1):5797. Epub 2020 Nov 16.

Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada.

ARGONAUTE-2 and associated miRNAs form the RNA-induced silencing complex (RISC), which targets mRNAs for translational silencing and degradation as part of the RNA interference pathway. Despite the essential nature of this process for cellular function, there is little information on the role of RISC components in human development and organ function. We identify 13 heterozygous mutations in AGO2 in 21 patients affected by disturbances in neurological development. Each of the identified single amino acid mutations result in impaired shRNA-mediated silencing. We observe either impaired RISC formation or increased binding of AGO2 to mRNA targets as mutation specific functional consequences. The latter is supported by decreased phosphorylation of a C-terminal serine cluster involved in mRNA target release, increased formation of dendritic P-bodies in neurons and global transcriptome alterations in patient-derived primary fibroblasts. Our data emphasize the importance of gene expression regulation through the dynamic AGO2-RNA association for human neuronal development.
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http://dx.doi.org/10.1038/s41467-020-19572-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670403PMC
November 2020

The synapse in traumatic brain injury.

Brain 2021 02;144(1):18-31

Centre for Clinical Brain Sciences, Chancellor's Building, Edinburgh BioQuarter, University of Edinburgh, Edinburgh EH16 4SB, UK.

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide and is a risk factor for dementia later in life. Research into the pathophysiology of TBI has focused on the impact of injury on the neuron. However, recent advances have shown that TBI has a major impact on synapse structure and function through a combination of the immediate mechanical insult and the ensuing secondary injury processes, leading to synapse loss. In this review, we highlight the role of the synapse in TBI pathophysiology with a focus on the confluence of multiple secondary injury processes including excitotoxicity, inflammation and oxidative stress. The primary insult triggers a cascade of events in each of these secondary processes and we discuss the complex interplay that occurs at the synapse. We also examine how the synapse is impacted by traumatic axonal injury and the role it may play in the spread of tau after TBI. We propose that astrocytes play a crucial role by mediating both synapse loss and recovery. Finally, we highlight recent developments in the field including synapse molecular imaging, fluid biomarkers and therapeutics. In particular, we discuss advances in our understanding of synapse diversity and suggest that the new technology of synaptome mapping may prove useful in identifying synapses that are vulnerable or resistant to TBI.
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http://dx.doi.org/10.1093/brain/awaa321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880663PMC
February 2021

Detection of Copy Number Variants by Short Multiply Aggregated Sequence Homologies.

J Mol Diagn 2020 12 23;22(12):1476-1481. Epub 2020 Oct 23.

Cold Spring Harbor Laboratory, Cold Spring Harbor, New York. Electronic address:

Chromosomal microarray testing is indicated for patients with diagnoses including unexplained developmental delay or intellectual disability, autism spectrum disorders, and multiple congenital anomalies. The short multiply aggregated sequence homologies (SMASH) genomic assay is a novel next-generation sequencing technology that performs copy number analysis at resolution similar to high-coverage whole genome sequencing but requires far less capacity. We benchmarked the performance of SMASH on a panel of genomic DNAs containing known copy number variants (CNVs). SMASH was able to detect pathogenic copy number variants of ≥10 kb in 77 of 77 samples. No pathogenic events were seen in 32 of 32 controls, indicating 100% sensitivity and specificity for detecting pathogenic CNVs >10 kb. Repeatability (interassay precision) and reproducibility (intra-assay precision) were assessed with 13 samples and showed perfect concordance. We also established that SMASH had a limit of detection of 20% for detection of large mosaic CNVs. Finally, we analyzed seven blinded specimens by SMASH analysis and successfully identified all pathogenic events. These results establish the efficacy of the SMASH genomic assay as a clinical test for the detection of pathogenic copy number variants at a resolution comparable to chromosomal microarray analysis.
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http://dx.doi.org/10.1016/j.jmoldx.2020.09.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722526PMC
December 2020

Interventions to reduce body temperature to 35 ⁰C to 37 ⁰C in adults and children with traumatic brain injury.

Cochrane Database Syst Rev 2020 10 31;10:CD006811. Epub 2020 Oct 31.

Intensive Care Unit, St George Hospital, Sydney, Australia.

Background: Traumatic brain injury (TBI) is a major cause of death and disability, with an estimated 5.5 million people experiencing severe TBI worldwide every year. Observational clinical studies of people with TBI suggest an association between raised body temperature and unfavourable outcome, although this relationship is inconsistent. Additionally, preclinical models suggest that reducing temperature to 35 °C to 37.5 °C improves biochemical and histopathological outcomes compared to reducing temperature to a lower threshold of 33 °C to 35 °C. It is unknown whether reducing body temperature to 35 °C to 37.5 °C in people admitted to hospital with TBI is beneficial, has no effect, or causes harm. This is an update of a review last published in 2014.

Objectives: To assess the effects of pharmacological interventions or physical interventions given with the intention of reducing body temperature to 35 °C to 37.5 °C in adults and children admitted to hospital after TBI.

Search Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Web of Science, and PubMed on 28 November 2019. We searched clinical trials registers, grey literature and references lists of reviews, and we carried out forward citation searches of included studies.

Selection Criteria: We included randomised controlled trials (RCTs) with participants of any age admitted to hospital following TBI. We included interventions that aimed to reduce body temperature to 35 °C to 37.5 °C: these included pharmacological interventions (such as paracetamol, or non-steroidal anti-inflammatory drugs), or physical interventions (such as surface cooling devices, bedside fans, or cooled intravenous fluids). Eligible comparators were placebo or usual care.

Data Collection And Analysis: Two review authors independently assessed studies for inclusion, extracted data, and assessed risks of bias. We assessed the certainty of the evidence with GRADE.

Main Results: We included one RCT with 41 participants. This study recruited adult participants admitted to two intensive care units in Australia, and evaluated a pharmacological intervention. Researchers gave participants 1 g paracetamol or a placebo intravenously at four-hourly intervals for 72 hours. We could not be certain whether intravenous paracetamol influenced mortality at 28 days (risk ratio 2.86, 95% confidence interval 0.32 to 25.24). We judged the evidence for this outcome to be very low certainty, meaning we have very little confidence in this effect estimate, and the true result may be substantially different to this effect. We downgraded the certainty for imprecision (because the evidence was from a single study with very few participants), and study limitations (because we noted a high risk of selective reporting bias). This study was otherwise at low risk of bias. The included study did not report the primary outcome for this review, which was the number of people with a poor outcome at the end of follow-up (defined as death or dependency, as measured on a scale such as the Glasgow Outcome Score), or any of our secondary outcomes, which included the number of people with further intracranial haemorrhage, extracranial haemorrhage, abnormal intracranial pressure, or pneumonia or other serious infections. The only other completed trial that we found was of a physical intervention that compared advanced fever control (using a surface cooling device) versus conventional fever control in 12 participants. The trial was published as an abstract only, with insufficient details to allow inclusion, so we have added this to the 'studies awaiting classification' section, pending further information from the study authors or publication of the full study report. We identified four ongoing studies that will contribute evidence to future updates of the review if they measure relevant outcomes and, in studies with a mixed population, report data separately for participants with TBI.

Authors' Conclusions: One small study contributed very low-certainty evidence for mortality to this review. The uncertainty is largely driven by limited research into reduction of body temperature to 35 °C to 37.5 °C in people with TBI. Further research that evaluates pharmacological or physical interventions, or both, may increase certainty in this field. We propose that future updates of the review, and ongoing and future research in this field, incorporate outcomes that are important to the people receiving the interventions, including side effects of any pharmacological agent (e.g. nausea or vomiting), and discomfort caused by physical therapies.
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http://dx.doi.org/10.1002/14651858.CD006811.pub4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8094748PMC
October 2020

Generation and trapping of a mesoderm biased state of human pluripotency.

Nat Commun 2020 10 5;11(1):4989. Epub 2020 Oct 5.

Stem Cell Laboratory, Department of Cancer Biology, University College London Cancer Institute, 72 Huntley St, London, WC1E 6AG, UK.

We postulate that exit from pluripotency involves intermediates that retain pluripotency while simultaneously exhibiting lineage-bias. Using a MIXL1 reporter, we explore mesoderm lineage-bias within the human pluripotent stem cell compartment. We identify a substate, which at the single cell level coexpresses pluripotent and mesodermal gene expression programmes. Functionally these cells initiate stem cell cultures and exhibit mesodermal bias in differentiation assays. By promoting mesodermal identity through manipulation of WNT signalling while preventing exit from pluripotency using lysophosphatidic acid, we 'trap' and maintain cells in a lineage-biased stem cell state through multiple passages. These cells correspond to a normal state on the differentiation trajectory, the plasticity of which is evidenced by their reacquisition of an unbiased state upon removal of differentiation cues. The use of 'cross-antagonistic' signalling to trap pluripotent stem cell intermediates with different lineage-bias may have general applicability in the efficient production of cells for regenerative medicine.
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http://dx.doi.org/10.1038/s41467-020-18727-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536399PMC
October 2020

Acquired genetic changes in human pluripotent stem cells: origins and consequences.

Nat Rev Mol Cell Biol 2020 12 23;21(12):715-728. Epub 2020 Sep 23.

Centre for Stem Cell Biology, Department of Biomedical Science, The University of Sheffield, Sheffield, UK.

In the 20 years since human embryonic stem cells, and subsequently induced pluripotent stem cells, were first described, it has become apparent that during long-term culture these cells (collectively referred to as 'pluripotent stem cells' (PSCs)) can acquire genetic changes, which commonly include gains or losses of particular chromosomal regions, or mutations in certain cancer-associated genes, especially TP53. Such changes raise concerns for the safety of PSC-derived cellular therapies for regenerative medicine. Although acquired genetic changes may not be present in a cell line at the start of a research programme, the low sensitivity of current detection methods means that mutations may be difficult to detect if they arise but are present in only a small proportion of the cells. In this Review, we discuss the types of mutations acquired by human PSCs and the mechanisms that lead to their accumulation. Recent work suggests that the underlying mutation rate in PSCs is low, although they also seem to be particularly susceptible to genomic damage. This apparent contradiction can be reconciled by the observations that, in contrast to somatic cells, PSCs are programmed to die in response to genomic damage, which may reflect the requirements of early embryogenesis. Thus, the common genetic variants that are observed are probably rare events that give the cells with a selective growth advantage.
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http://dx.doi.org/10.1038/s41580-020-00292-zDOI Listing
December 2020
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