Publications by authors named "Richard Harvey"

568 Publications

Conserved Role of the Large Conductance Calcium-Activated Potassium Channel, K1.1, in Sinus Node Function and Arrhythmia Risk.

Circ Genom Precis Med 2021 Feb 25. Epub 2021 Feb 25.

Victor Chang Cardiac Research Institute, Darlinghurst & Faculty of Medicine, UNSW Sydney, Kensington & Cardiology Department, St Vincent's Hospital, Darlinghurst, New South Wales, Australia.

- encodes the α-subunit of the large-conductance Ca-activated K channel, K1.1, and lies within a linkage interval for atrial fibrillation (AF). Insights into the cardiac functions of K1.1 are limited and has not been investigated as an AF candidate gene. - The gene was sequenced in 118 patients with familial AF. The role of K1.1 in normal cardiac structure and function was evaluated in humans, mice, zebrafish, and fly. A novel variant was functionally characterized. - A complex variant was identified in one kindred with AF. To evaluate potential disease mechanisms, we first evaluated the distribution of K1.1 in normal hearts using immunostaining and immunogold electron microscopy. K1.1 was seen throughout the atria and ventricles in humans and mice, with strong expression in the sinus node. In an ex vivo murine sinoatrial node preparation, addition of the K1.1 antagonist, paxilline, blunted the increase in beating rate induced by adrenergic receptor stimulation. Knockdown of the K1.1 ortholog, , in zebrafish embryos resulted in sinus bradycardia with dilatation and reduced contraction of the atrium and ventricle. Genetic inactivation of the K1.1 ortholog, , systemically or in adult stages, also slowed the heartbeat and produced fibrillatory cardiac contractions. Electrophysiological characterization of -deficient flies revealed bursts of action potentials, reflecting increased events of fibrillatory arrhythmias. Flies with cardiac-specific overexpression of the human mutant also showed increased heart period and bursts of action potentials, similar to the K1.1 loss-of-function models. - Our data point to a highly conserved role of K1.1 in sinus node function in humans, mice, zebrafish and fly and suggest that K1.1 loss of function may predispose to AF.
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http://dx.doi.org/10.1161/CIRCGEN.120.003144DOI Listing
February 2021

Lipid domain formation and non-lamellar structures associated with varied lysylphosphatidylglycerol analogue content in a model Staphylococcal plasma membrane.

Biochim Biophys Acta Biomembr 2021 May 6;1863(5):183571. Epub 2021 Feb 6.

Department of Pharmaceutical Chemistry, University of Vienna, Althanstraße 14, A-1090 Vienna, Austria. Electronic address:

Dipalmitoyl-3-aza-dehydroxy-lysylphosphatidylglycerol (DP3adLPG), is a chemically stable synthetic analogue of the bacterial lipid lysylphosphatidylglycerol (LPG), designed as a substitute for the notoriously labile native lipid in biophysical investigations. In Staphylococcus aureus, LPG is known to play a role in resistance to antibiotics by altering membrane charge properties in response to environmental stress, but little is known about how LPG influences other bilayer physicochemical properties or lateral organisation, through the formation of complexes with lipids such as phosphatidylglycerol (PG). In this study we have investigated the different phases formed by biomimetic mixtures of 3adLPG and PG in different thermotropic states, using neutron diffraction and electron microscopy. In a DPPG/DP3adLPG 70:30 mol% mixture, two distinct lamellar phases were observed below the lipid melting transition: L 1 and L 2 with respective periodicities of 82 and 62 Å. Increasing the proportion of DP3adLPG to mimic the effects of environmental stress led to the disappearance of the L 1 phase and the formation of an inverse hexagonal phase. The compositions of these different phases were identified by investigating the thermotropic properties of the two mixtures, and probing their interaction with the antimicrobial peptide magainin 2 F5W. We propose that the observed polymorphism results from the preferential formation of either triplet PG-3adLPG-PG, or paired PG-3adLPG complexes, dependent upon the mixing proportions of the two lipids. The relevance of these findings to the role native LPG in S. aureus, are discussed with respect to their influence on antibiotic resistance and lateral membrane organisation.
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http://dx.doi.org/10.1016/j.bbamem.2021.183571DOI Listing
May 2021

Intracanalicular Vestibular Schwannoma: A Systematic Review and Meta-analysis of Therapeutics Outcomes.

Otol Neurotol 2021 Mar;42(3):351-362

Department of Otolaryngology, Head and Neck Surgery, Faculty of Medicine and Health Sciences, Macquarie University.

Objective: To perform a systematic review and meta-analysis summarizing the current evidence on the management of intracanalicular vestibular schwannoma.

Data Sources: Embase (1947-), Medline (1946-), Cochrane library (1947-), Scopus (2010-), and CINAHL (1961-) were searched from 1969 to October 5, 2019 (50 years).

Study Selection: A search strategy was performed to identify patients with vestibular schwannoma confined to the internal auditory canal without extension to the cerebellopontine angle. Studies with patients aged less than 18, Neurofibromatosis type 2, revision cases, and non-English language were excluded.

Data Extraction: A standardized collection sheet was used for the extracted data and a quality assessment was performed using the Newcastle-Ottawa Scale with the comparability criterion omitted.

Data Synthesis: Seventy-one studies were included with 24 on observation, 14 on radiotherapy, and 34 on surgery. The primary outcome was serviceable hearing preservation. Secondary outcomes were preservation of facial nerve function, growth, involution, and dizziness. Sub-analysis on the type of surgery and type of radiotherapy were performed. Excel 2016 with MIX 2.0 Pro add-on package was used to analyze the data and create forest plots. Data were presented in proportion with a 95% confidence interval.

Conclusions: Serviceable hearing was observed in 31% of patients after observation, 56% after radiotherapy, and 51% after surgical treatment with mean follow-up time of 4.04 years, 4.92 years, and 2.23 years, respectively. Facial nerve function was found to be best preserved in both observation and radiotherapy groups. Vestibular schwannoma growth occurred in 33% of patients under observation. Involution occurred in 2% of patients under observation and in 38% after radiotherapy.
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http://dx.doi.org/10.1097/MAO.0000000000002979DOI Listing
March 2021

Evaluation of Diffuse Type 2 Dominant or Eosinophilic Chronic Rhinosinusitis With Corticosteroid Irrigation After Surgical Neosinus Cavity Formation.

JAMA Otolaryngol Head Neck Surg 2021 Feb 4. Epub 2021 Feb 4.

Rhinology and Skull Base Research Group, St Vincent's Centre for Applied Medical Research, University of New South Wales, Sydney, Australia.

Importance: Eosinophilic chronic rhinosinusitis (eCRS), contemporarily classified as diffuse type 2 dominant chronic rhinosinusitis (CRS), is characterized by eosinophil-dominant mucosal inflammation. Contemporary management of eCRS as an inflammatory airway condition is multimodal with corticosteroid irrigations after the surgical creation of a neosinus cavity.

Objectives: To assess long-term treatment outcomes in patients with primary diffuse type 2 CRS or eCRS receiving multimodal treatment.

Design, Setting, And Participants: A prospective cohort study of patients seen in a tertiary rhinology practice recruited from May 2010 to November 2018 was conducted. Follow-up duration was 12 months or more following endoscopic sinus surgery (ESS) with a neosinus cavity formed. Data analysis was performed from August to November 2020. Consecutive adult (≥18 years) patients diagnosed with primary diffuse type 2 dominant CRS or eCRS based on the European Position Paper on Rhinosinusitis and Nasal Polyps 2020 criteria were included. Type 2 inflammation was defined as more than 10 eosinophils per high-power field obtained from sinus mucosal biopsy and managed with neosinus cavity ESS and ongoing corticosteroid irrigations. Exclusion criteria were less than 12 months of follow-up and secondary CRS.

Interventions: Endoscopic sinus surgery with complete removal of intersinus bony partitions to create a neosinus cavity. Nasal irrigation (240 mL) with betamethasone, 1 mg, or budesonide, 1 mg, daily for 3 to 6 months after ESS and tapered to an as-needed basis (minimum, 2-3 per week).

Main Outcomes And Measures: Poor control was defined as polyp recurrence (polyp growth in >1 sinus area on a single side), use of long-term systemic therapy (biologic therapy or ≥3 consecutive months of oral corticosteroids), and revision surgery involving polypectomy. The disease in patients with no poor control criteria was defined as well controlled, and the disease in those with 1 or more criteria was considered poorly controlled. Maintenance medical therapy use and patient-reported outcomes based on the 22-item Sinonasal Outcomes Test for preoperative and last follow-up were collected.

Results: Of the 222 participants recruited with primary diffuse type 2 dominant CRS or eCRS and minimum of year of follow-up, 126 were men (56.8%). Mean (SD) age was 54.8 (13.6) years, and median (SD) follow-up was 2.2 (2.2) years. Of the 222 patients, 195 (87.8%) had well-controlled disease, 16 (7.2%) had polyp recurrence, 7 (3.2%) continued to receive long-term oral corticosteroid therapy, 5 (2.3%) received biologic therapy, and 8 (3.6%) underwent a revision polypectomy. Clinically meaningful change on the 22-item Sinonasal Outcomes Test and the nasal subdomain score was maintained at the last follow-up in 134 patients (67.0%). Poor disease control was not associated with poor adherence to irrigation use.

Conclusions And Relevance: The findings of this cohort study suggest that long-term disease control and reduction in symptom burden in patients with primary diffuse type 2 CRS or eCRS might be achieved when managed as an inflammatory disorder. Maintenance corticosteroid irrigations in the population examined appeared to be successfully self-tapered to disease activity.
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http://dx.doi.org/10.1001/jamaoto.2020.5286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863015PMC
February 2021

Single cell sequencing reveals endothelial plasticity with transient mesenchymal activation after myocardial infarction.

Nat Commun 2021 01 29;12(1):681. Epub 2021 Jan 29.

Institute for Cardiovascular Regeneration, Goethe University Frankfurt, Frankfurt am Main, Germany.

Endothelial cells play a critical role in the adaptation of tissues to injury. Tissue ischemia induced by infarction leads to profound changes in endothelial cell functions and can induce transition to a mesenchymal state. Here we explore the kinetics and individual cellular responses of endothelial cells after myocardial infarction by using single cell RNA sequencing. This study demonstrates a time dependent switch in endothelial cell proliferation and inflammation associated with transient changes in metabolic gene signatures. Trajectory analysis reveals that the majority of endothelial cells 3 to 7 days after myocardial infarction acquire a transient state, characterized by mesenchymal gene expression, which returns to baseline 14 days after injury. Lineage tracing, using the Cdh5-CreERT2;mT/mG mice followed by single cell RNA sequencing, confirms the transient mesenchymal transition and reveals additional hypoxic and inflammatory signatures of endothelial cells during early and late states after injury. These data suggest that endothelial cells undergo a transient mes-enchymal activation concomitant with a metabolic adaptation within the first days after myocardial infarction but do not acquire a long-term mesenchymal fate. This mesenchymal activation may facilitate endothelial cell migration and clonal expansion to regenerate the vascular network.
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http://dx.doi.org/10.1038/s41467-021-20905-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846794PMC
January 2021

Locked-In Syndrome: Practical Rehabilitation Management.

PM R 2021 Jan 19. Epub 2021 Jan 19.

Shirley Ryan AbilityLab, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

Locked-in syndrome is a rare and devastating condition that results in tetraplegia, lower cranial nerve paralysis, and anarthria with preserved cognition, vertical gaze, and upper eyelid movements. Although acute management is much like that of any severe stroke, rehabilitation and recovery of these patients have not been previously described. Challenges relevant to this population include blood pressure management and orthostasis, timing and appropriateness of reinstating oral feeding, ventilatory support, decannulation after tracheostomy, bowel and bladder management, vestibular dysfunction, and eye care. Targeted rehabilitation of head, neck, and trunk stability to improve function, and proper fit in an appropriate wheelchair are essential to assist with mobility. Rehabilitation interventions should include a focus on distal motor control and upright tolerance training followed by balance and mobility exercises. In addition, special considerations must be given to developing early methods of communication through use of augmentative systems to call for help and express needs. These systems along with additional technology provide the basis to promote connectivity to family and friends through the use of social media and the internet. Establishment of communication, mobility, and connectivity is essential in promoting independence, autonomy, and improving quality of life. Overall, with specialized rehabilitative care and access to the proper equipment, long-term outcomes and quality of life in these patients can be favorable.
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http://dx.doi.org/10.1002/pmrj.12555DOI Listing
January 2021

Eosinophilic chronic rhinosinusitis and concurrent Kimura's disease treated with mepolizumab.

BMJ Case Rep 2021 Jan 18;14(1). Epub 2021 Jan 18.

Rhinology and Skull Base Research Group, St Vincent's Centre for Applied Medical Research, University of New South Wales, Sydney, New South Wales, Australia.

Kimura's disease is a rare, benign, chronic inflammatory disorder characterised by its eosinophilic infiltrate. Patients often present with one or more progressively enlarging subcutaneous lymph nodes in the head and neck region or enlarging salivary glands. We describe the case of a 26-year-old man presenting with severe peripheral eosinophilia and upper airway inflammatory symptoms, who later developed cervical lymphadenopathy and formally diagnosed with Kimura's disease. Based on our English-language MEDLINE literature search, to our knowledge this is the first case report describing treatment of Kimura's disease with mepolizumab.
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http://dx.doi.org/10.1136/bcr-2019-232627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7813409PMC
January 2021

How close are we to anterior robotic skull base surgery?

Curr Opin Otolaryngol Head Neck Surg 2021 Feb;29(1):44-52

Faculty of Medicine, Health and Human Sciences, Macquarie University.

Purpose Of Review: The application of robotic surgery to anterior skull base disease has yet to be defined despite the potential for improved tumour resection with less morbidity in this region. Complex anatomy and restricted access have limited the development of robotic anterior skull base surgery.

Recent Findings: A limited number of transoral robotic surgical anterior skull base procedures have been undertaken; however, there are significant limitations to the utilization of this technology in the anterior skull base. In this article, the advantages, disadvantages and limitations of robotic anterior skull base surgery are discussed. Currently, the major limitation is the size of the robotic endoscope and of the available instrumentation. Technological advancements that provide promise for the future development of robotic anterior skull base surgery are in development, such as single-port robots, flexible instrument systems and miniaturization and growth of minimally invasive platforms.

Summary: Although transnasal access to the skull base is not possible with the currently available robotic systems, promising technology does exist and is in development. Robotic anterior skull base surgery promises to provide greater access to skull base disease, improve oncologic results, reduce morbidity and to reduce the ergonomic burden on the surgeon.
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http://dx.doi.org/10.1097/MOO.0000000000000683DOI Listing
February 2021

Overall survival and prognostic factors in diabetic patients with invasive fungal rhinosinusitis.

Asian Pac J Allergy Immunol 2020 Dec 2. Epub 2020 Dec 2.

Department of Otolaryngology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.

Background: Patients with diabetes mellitus (DM) are susceptible to invasive fungal rhinosinusitis (IFRS). The mortality rate of IFRS varies greatly among the patients with DM.

Objective: To identify the prognostic factors for the overall survival of patients with DM and IFRS.

Methods: A retrospective study was conducted in four tertiary hospitals in Thailand, Malaysia and Myanmar. Patients diagnosed with IFRS and DM from 2008 to 2019 were identified. The outcome was the overall survival. Variables analyzed for risk factors were age, HbA1C level, ketoacidosis, white blood cell count, hyperglycemia, duration of DM, current use of diabetic medications, serum creatinine level, and the extensions of IFRS to the orbit, the cavernous sinus and intracranial cavity.

Results: Sixty-five diabetic patients with IFRS (age 57.9 ± 13.4 years, male 60%) were identified. The mortality rate was 21.5%. The extensions of IFRS to the cavernous sinus (hazard ratio 5.1, 95% CI [1.4-18.2], p = 0.01) and intracranial cavity (hazard ratio 3.4, 95% CI [1.1-11.3, p = 0.05) predicted mortality. Current use of diabetic medications decreased the mortality risk (hazard ratio 0.2, 95% CI [0.1-0.9], p = 0.03). The 6-month overall survival of the patients with and without the cavernous sinus extension were 51.4% and 83.6%, (p = 0.001), with and without intracranial extension 53.3% and 88.9%, (p = 0.001), and with and without current diabetic medications 82.3% and 57.5%, respectively (p = 0.045).

Conclusions: The extensions of IFRS to the cavernous sinus and intracranial cavity increased the risk of death in patients with DM. Survival was primarily related to current use of diabetic medications.
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http://dx.doi.org/10.12932/AP-310720-0934DOI Listing
December 2020

Ambient PM exposure and rapid spread of COVID-19 in the United States.

Sci Total Environ 2021 Mar 9;760:143391. Epub 2020 Nov 9.

Center for Aerosol Science and Engineering, Department of Energy, Environmental and Chemical Engineering, Washington University in St. Louis, St. Louis, MO 63130, USA.

It has been posited that populations being exposed to long-term air pollution are more susceptible to COVID-19. Evidence is emerging that long-term exposure to ambient PM (particulate matter with aerodynamic diameter 2.5 μm or less) associates with higher COVID-19 mortality rates, but whether it also associates with the speed at which the disease is capable of spreading in a population is unknown. Here, we establish the association between long-term exposure to ambient PM in the United States (US) and COVID-19 basic reproduction ratio R- a dimensionless epidemic measure of the rapidity of disease spread through a population. We inferred state-level R values using a state-of-the-art susceptible, exposed, infected, and recovered (SEIR) model initialized with COVID-19 epidemiological data corresponding to the period March 2-April 30. This period was characterized by a rapid surge in COVID-19 cases across the US states, implementation of strict social distancing measures, and a significant drop in outdoor air pollution. We find that an increase of 1 μg/m in PM levels below current national ambient air quality standards associates with an increase of 0.25 in R (95% CI: 0.048-0.447). A 10% increase in secondary inorganic composition, sulfate-nitrate-ammonium, in PM associates with ≈10% increase in R by 0.22 (95% CI: 0.083-0.352), and presence of black carbon (soot) in the ambient environment moderates this relationship. We considered several potential confounding factors in our analysis, including gaseous air pollutants and socio-economical and meteorological conditions. Our results underscore two policy implications - first, regulatory standards need to be better guided by exploring the concentration-response relationships near the lower end of the PM air quality distribution; and second, pollution regulations need to be continually enforced for combustion emissions that largely determine secondary inorganic aerosol formation.
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http://dx.doi.org/10.1016/j.scitotenv.2020.143391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7651233PMC
March 2021

International Consensus Statement on Rhinology and Allergy: Rhinosinusitis.

Int Forum Allergy Rhinol 2020 Nov 24. Epub 2020 Nov 24.

Capital Medical University.

Background: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR-RS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICAR-RS-2021 as well as updates to the original 140 topics. This executive summary consolidates the evidence-based findings of the document.

Methods: ICAR-RS presents over 180 topics in the forms of evidence-based reviews with recommendations (EBRRs), evidence-based reviews, and literature reviews. The highest grade structured recommendations of the EBRR sections are summarized in this executive summary.

Results: ICAR-RS-2021 covers 22 topics regarding the medical management of RS, which are grade A/B and are presented in the executive summary. Additionally, 4 topics regarding the surgical management of RS are grade A/B and are presented in the executive summary. Finally, a comprehensive evidence-based management algorithm is provided.

Conclusion: This ICAR-RS-2021 executive summary provides a compilation of the evidence-based recommendations for medical and surgical treatment of the most common forms of RS. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/alr.22741DOI Listing
November 2020

Morphology of bile salts micelles and mixed micelles with lipolysis products, from scattering techniques and atomistic simulations.

J Colloid Interface Sci 2021 Apr 27;587:522-537. Epub 2020 Oct 27.

Institute of Pharmaceutical Science, King's College London, London SE1 9NH, United Kingdom. Electronic address:

Hypotheses: Bile salts (BS) are biosurfactants released into the small intestine, which play key and contrasting roles in lipid digestion: they adsorb at interfaces and promote the adsorption of digestive enzymes onto fat droplets, while they also remove lipolysis products from that interface, solubilising them into mixed micelles. Small architectural variations on their chemical structure, specifically their bile acid moiety, are hypothesised to underlie these conflicting functionalities, which should be reflected in different aggregation and solubilisation behaviour.

Experiments: The micellisation of two BS, sodium taurocholate (NaTC) and sodium taurodeoxycholate (NaTDC), which differ by one hydroxyl group on the bile acid moiety, was assessed by pyrene fluorescence spectroscopy, and the morphology of aggregates formed in the absence and presence of fatty acids (FA) and monoacylglycerols (MAG) - typical lipolysis products - was resolved by small-angle X-ray/neutron scattering (SAXS, SANS) and molecular dynamics simulations. The solubilisation by BS of triacylglycerol-incorporating liposomes - mimicking ingested lipids - was studied by neutron reflectometry and SANS.

Findings: Our results demonstrate that BS micelles exhibit an ellipsoidal shape. NaTDC displays a lower critical micellar concentration and forms larger and more spherical aggregates than NaTC. Similar observations were made for BS micelles mixed with FA and MAG. Structural studies with liposomes show that the addition of BS induces their solubilisation into mixed micelles, with NaTDC displaying a higher solubilising capacity.
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http://dx.doi.org/10.1016/j.jcis.2020.10.101DOI Listing
April 2021

Nanomaterials fusing with the skin: Alpha-tocopherol phosphate delivery into the viable epidermis to protect against ultraviolet radiation damage.

Int J Pharm 2021 Feb 6;594:120000. Epub 2020 Nov 6.

Institute of Pharmaceutical Science, Faculty of Life Sciences & Medicine, Franklin-Wilkins Building, King's College London, 150 Stamford Street, London SE1 9NH, UK. Electronic address:

Vitamin E (alpha tocopherol, α-T) is an important skin antioxidant, but its penetration into the viable epidermis, where it acts, is very limited. This study investigated if phosphorylating α-tocopherol (α-TP) to form a provitamin, improved its interactions with skin, its passage into the tissue, and thus its ability to protect the skin from ultraviolet radiation (UVR) damage. At pH 7.4, when the α-TPO microspecies predominated in solution, dynamic light scattering measurements showed that α-TP formed nanoaggregates with a median hydrodynamic diameter of 9 nm (Critical aggregation constant, CAC, - 4.2 mM). At 9.0 when the α-TPO microspecies predominated there was no aggregation. The passage of α-TP nanoaggregates through regenerated cellulose membranes was significantly slower than the α-TP monomers (at pH 9) suggesting that aggregation slowed diffusion. However, a lotion formulation containing the nanoaggregates delivered more α-TP into the skin compared to the formulation containing the monomers. In addition, the nanosized α-TP aggregates delivered 8-fold more active into the stratum corneum (SC) (252.2 μg/cm vs 29.5 μg/cm) and 4 fold more active into the epidermis (85.1 μg/cm vs 19 μg/cm, respectively, p < 0.05) compared to α-T. Langmuir subphase injection studies at pH 7.4 (surface pressure 10 mN m) showed that the α-TP nanoaggregates more readily fused with the SC compared to the monomers and the membrane compression studies demonstrated that α-TP fluidised the SC lipids. Together the fusion with the SC and its fluidisation were proposed as the causes of the better α-TP penetration into the skin, which enhanced potential of α-TP to protect from UVR-induced skin damage compared to α-T.
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http://dx.doi.org/10.1016/j.ijpharm.2020.120000DOI Listing
February 2021

International Consensus Statement: Spontaneous Cerebrospinal Fluid Rhinorrhea.

Int Forum Allergy Rhinol 2020 Oct 25. Epub 2020 Oct 25.

Department of Otolaryngology, University of Alabama at Birmingham, Birmingham, AL.

Background: The association between spontaneous cerebrospinal fluid (CSF) leak/rhinorrhea and idiopathic intracranial hypertension (IIH) has been increasingly recognized over the last years. However, considerable variability of opinion regarding the assessment, investigations, and management of patients with spontaneous CSF rhinorrhea remains.

Methods: A consensus group was formed from experts from Europe, Asia, Australia, South and North America. Following literature review and open discussions with members of the panel, a set of 61 statements was produced. A modified Delphi method was used to refine expert opinion with 3 rounds of questionnaires and a consensus group meeting in Santo-Rhino meeting in September 2019.

Results: Fifty statements (82% of total) on spontaneous CSF leak and IIH reached consensus. In 38 of 50 statements, the median response was 7 (strongly agree) and in the 12 remaining statements the median response was 6 (agree). Eleven statements were excluded because they did not reach consensus and one new statement was added during SantoRhino meeting. The final statements refer to patient history and clinical examination ("History taking should include presence of headache, tinnitus and visual defects"), investigations (role of Thin Slice Computed Tomography and CISS/FLAIR sequences in Magnetic Resonance Imaging), principles of management (watchful waiting or measures to reduce ICP are supplementary but cannot subsitute surgical closure), surgical technique, intraoperative, early postoperative and long term management.

Conclusion: We present fifty consensus statements on the diagnosis, investigation, and management of spontaneous CSF rhinorrhea based on the currently available evidence and expert opinion. Although by no means comprehensive and final, we believe they can contribute to the standardization of clinical practice. Early diagnosis, prompt surgical closure of the defect, assesment for and treatment of potentially co-existing idiopathic intracranial hypertension in a comprehensive multidisciplinary approach are essential in order to successfully manage spontaneous CSF rhinorrhea, reduce associated morbidity and prevent recurrence.
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http://dx.doi.org/10.1002/alr.22704DOI Listing
October 2020

Evolution of the Epigenetic Landscape in Childhood B Acute Lymphoblastic Leukemia and Its Role in Drug Resistance.

Cancer Res 2020 12 16;80(23):5189-5202. Epub 2020 Oct 16.

Perlmutter Cancer Center, NYU Langone Health, New York, New York.

Although B-cell acute lymphoblastic leukemia (B-ALL) is the most common malignancy in children and while highly curable, it remains a leading cause of cancer-related mortality. The outgrowth of tumor subclones carrying mutations in genes responsible for resistance to therapy has led to a Darwinian model of clonal selection. Previous work has indicated that alterations in the epigenome might contribute to clonal selection, yet the extent to which the chromatin state is altered under the selective pressures of therapy is unknown. To address this, we performed chromatin immunoprecipitation, gene expression analysis, and enhanced reduced representation bisulfite sequencing on a cohort of paired diagnosis and relapse samples from individual patients who all but one relapsed within 36 months of initial diagnosis. The chromatin state at diagnosis varied widely among patients, while the majority of peaks remained stable between diagnosis and relapse. Yet a significant fraction was either lost or newly gained, with some patients showing few differences and others showing massive changes of the epigenetic state. Evolution of the epigenome was associated with pathways previously linked to therapy resistance as well as novel candidate pathways through alterations in pyrimidine biosynthesis and downregulation of polycomb repressive complex 2 targets. Three novel, relapse-specific superenhancers were shared by a majority of patients including one associated with S100A8, the top upregulated gene seen at relapse in childhood B-ALL. Overall, our results support a role of the epigenome in clonal evolution and uncover new candidate pathways associated with relapse. SIGNIFICANCE: This study suggests a major role for epigenetic mechanisms in driving clonal evolution in B-ALL and identifies novel pathways associated with drug resistance.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-1145DOI Listing
December 2020

Retargeting azithromycin analogues to have dual-modality antimalarial activity.

BMC Biol 2020 09 29;18(1):133. Epub 2020 Sep 29.

Research Centre for Infectious Diseases, School of Biological Sciences, The University of Adelaide, Adelaide, 5005, Australia.

Background: Resistance to front-line antimalarials (artemisinin combination therapies) is spreading, and development of new drug treatment strategies to rapidly kill Plasmodium spp. malaria parasites is urgently needed. Azithromycin is a clinically used macrolide antibiotic proposed as a partner drug for combination therapy in malaria, which has also been tested as monotherapy. However, its slow-killing 'delayed-death' activity against the parasite's apicoplast organelle and suboptimal activity as monotherapy limit its application as a potential malaria treatment. Here, we explore a panel of azithromycin analogues and demonstrate that chemical modifications can be used to greatly improve the speed and potency of antimalarial action.

Results: Investigation of 84 azithromycin analogues revealed nanomolar quick-killing potency directed against the very earliest stage of parasite development within red blood cells. Indeed, the best analogue exhibited 1600-fold higher potency than azithromycin with less than 48 hrs treatment in vitro. Analogues were effective against zoonotic Plasmodium knowlesi malaria parasites and against both multi-drug and artemisinin-resistant Plasmodium falciparum lines. Metabolomic profiles of azithromycin analogue-treated parasites suggested activity in the parasite food vacuole and mitochondria were disrupted. Moreover, unlike the food vacuole-targeting drug chloroquine, azithromycin and analogues were active across blood-stage development, including merozoite invasion, suggesting that these macrolides have a multi-factorial mechanism of quick-killing activity. The positioning of functional groups added to azithromycin and its quick-killing analogues altered their activity against bacterial-like ribosomes but had minimal change on 'quick-killing' activity. Apicoplast minus parasites remained susceptible to both azithromycin and its analogues, further demonstrating that quick-killing is independent of apicoplast-targeting, delayed-death activity.

Conclusion: We show that azithromycin and analogues can rapidly kill malaria parasite asexual blood stages via a fast action mechanism. Development of azithromycin and analogues as antimalarials offers the possibility of targeting parasites through both a quick-killing and delayed-death mechanism of action in a single, multifactorial chemotype.
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http://dx.doi.org/10.1186/s12915-020-00859-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526119PMC
September 2020

Central pain syndromes.

NeuroRehabilitation 2020 ;47(3):285-297

Department of Physical Medicine and Rehabilitation, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

The management of pain in persons with neurological injuries is challenging and complex. A holistic view and clinical approach are necessary when addressing pain in patients with neurological impairment because interpreting signs and symptoms and deciphering sources of pain is never a straightforward process. This problem is further magnified with the management of central pain syndromes. The best approach is to have a good understanding of the clinical characteristics commonly found in this patient population, in particular for patients with stroke, multiple sclerosis (MS), or spinal cord injury (SCI), as central pain manifests differently between these groups. This paper will focus on the history, clinical presentation, pathophysiology, assessment, and treatment of central pain in patients with these types of neurological conditions. In addition to being at risk for a decline in quality of life, patients with pain syndromes are also prone to adverse responses to treatments (e.g., opioid addiction). It is therefore important to methodically analyze the similarities and differences between patients with different pain syndromes.
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http://dx.doi.org/10.3233/NRE-208003DOI Listing
February 2021

Effect of monoclonal antibody drug therapy on mucosal biomarkers in airway disease: A systematic review.

Clin Exp Allergy 2020 11 9;50(11):1212-1222. Epub 2020 Sep 9.

Rhinology and Skull Base Research Group, St Vincent's Centre for Applied Medical Research, University of New South Wales, Sydney, New South Wales, Australia.

Background: Monoclonal antibody therapies have a growing role in treating refractory airway disease.

Objective: The review aimed to summarize the response of respiratory mucosa to monoclonal antibody treatments in inflammatory airway conditions.

Design: We conducted a systematic review including risk of bias assessment.

Data Sources: MEDLINE, EMBASE and PubMed from 1 January 2000 to 16 November 2019 were searched.

Eligibility Criteria: Eligible studies assessed the immunological and histological response of airway mucosa to monoclonal antibody therapy compared with baseline or a comparison group in patients with respiratory diseases (asthma, chronic rhinosinusitis and allergic rhinitis). Any prospective interventional studies, including randomized controlled trials (RCTs) and single-arm trials, were eligible.

Results: There were 4195 articles screened, and full-text analysis produced n = 11 studies with extractable data. Nine were RCTs, and two were single-arm trials. These studies focused on asthma (n = 9 articles), chronic rhinosinusitis (n = 1) and allergic rhinitis (n = 1). Five monoclonal antibody drugs were assessed (omalizumab, mepolizumab, dupilumab, benralizumab and tralokinumab). Risk of bias was low (n = 6) or unclear (n = 3) in the RCTs and moderate in the single-arm trials. Omalizumab reduced the mucosal concentration of its target, IgE. Dupilumab reduced the concentration of one of its targets, IL-13, but not IL-4. Omalizumab, mepolizumab and benralizumab reduced tissue eosinophil cell density. Dupilumab decreased mucosal eosinophil granule proteins. Tralokinumab did not affect airway mucosa.

Conclusions: Knowledge of the expected biological response of monoclonal antibody therapy on biomarkers in disease tissue provides an important supplement to data about clinical outcomes. An understanding of the biological effect is essential to identify likely responders, reasons for treatment failure and necessary adjustments to monoclonal antibody treatment. Further investigation into the effect of monoclonal antibody therapy on disease mucosa and more precise endotyping are required to move closer to achieving personalized medicine.
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http://dx.doi.org/10.1111/cea.13721DOI Listing
November 2020

Uterine artery pulsatility index and serum BMP-9 predict resistance to methotrexate therapy in gestational trophoblastic neoplasia: A cohort study.

Curr Probl Cancer 2021 Feb 4;45(1):100622. Epub 2020 Aug 4.

Charing Cross Gestational Trophoblastic Disease Centre, Charing Cross Campus of Imperial College Healthcare NHS Trust, London, UK; Molecular Oncology, Department of Surgery and Cancer, Hammersmith Hospital Campus of Imperial College London, London, UK.

Background: Methotrexate is the most common first-line chemotherapy for low-risk gestational trophoblastic neoplasia (GTN). Uterine artery pulsatility index (UAPI) is an ultrasound marker for tumor vascularity that has been associated with an increased risk of methotrexate resistance. The combination of circulating angiogenic factor levels with UAPI data may improve the capacity of this model to predict chemoresistance.

Methods: This was a single-center cohort study of women newly diagnosed between January 2008 and June 2012 with low-risk GTN during postmolar surveillance and treated with single-agent methotrexate at Charing Cross Hospital, a UK national center for treatment of gestational trophoblastic disease. Two hundred seventeen women underwent an ultrasound for UAPI measurement prior to initiation of chemotherapy. To examine serologic markers of methotrexate resistance among this cohort, we performed a case-control study using archived serum from 76 patients who could be matched based on prognostic risk score. Serum samples were examined by immunoassay to measure 8 different angiogenic factors (VEGF-A, FGF-basic, PLGF-1, PDGF-BB, EGF, ANGPT2, BMP-9, and ENG). Receiver-operator characteristic area under the curve (AUC) values were calculated for the ability of each analyte to correctly classify patients as methotrexate sensitive (MTX-S) or resistant (MTX-R).

Results: Total human chorionic gonadotropin levels were similar between the MTX-S and MTX-R groups. UAPI values were significantly higher in MTX-S (median 1.30 [interquartile range {IQR} = 0.80-1.90]) compared to MTX-R patients (median 0.875 [IQR = 0.60-1.30]; P < 0.0001) with AUC 0.68 (95% confidence interval 0.61-0.76; P < 0.0001). In univariate analysis, only BMP-9 concentrations were significantly different between groups, lower among MTX-S (median of 225 ng/L, IQR = 170-287) compared to MTX-R patients (median 280 ng/L [IQR = 200-339]; P= 0.03). Combining UAPI with BMP-9 concentration improved prediction for chemoresistance with AUC 0.77 (95% confidence interval 0.66-0.88; P < 0.0001).

Conclusion: Circulating levels of BMP-9 are elevated in newly diagnosed women with low-risk GTN destined to fail primary methotrexate therapy. A combined test using serum BMP-9 plus UAPI might improve prediction of MTX-R in low-risk GTN.
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http://dx.doi.org/10.1016/j.currproblcancer.2020.100622DOI Listing
February 2021

Outcomes of pituitary surgery for Cushing's disease: a systematic review and meta-analysis.

Pituitary 2020 Oct;23(5):595-609

St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW, Australia.

Purpose: Transsphenoidal surgery (TSS) is the first-line treatment for Cushing's disease (CD). This review aimed to synthesize the remission and recurrence rates following TSS for CD and identify predictors of these outcomes.

Methods: Medline (1946-) and Embase (1947-) were searched until 23rd January 2019 for original studies. A meta-analysis was performed of remission and recurrence rates. Studies were excluded if patients had prior radiosurgery/radiotherapy, mixed pathologies or interventions without separated data, follow-up not reported or population size < 20. For recurrence rate syntheses, studies with follow-up < 6 months were excluded.

Results: The search produced 2663 studies, of which n = 68 were included, involving 5664 patients. Remission rates after primary and revision TSS were 80% [77-82] and 58% [50-66] at last follow-up. After primary TSS, predictors of remission were micro- v macroadenomas (83% v 68%, p < 0.01), imaging-visible adenomas (81% v 69%, p < 0.01), adenomas confirmed on histopathology (87% v 45%, p < 0.01), absence of cavernous sinus invasion (80% v 30%, p < 0.01), postoperative serum cortisol (MSeC) nadir < 2 μg/dL (< 55 nmol/L; 95% v 46%, p < 0.01) and lower preoperative 24-h urine free cortisol (1250 nmol v 1726 nmol, p < 0.01). For revision TSS, predictors of remission were postoperative MSeC nadir < 2 μg/dL (< 55 nmol/L; 100% v 38%, p < 0.01) and operations for recurrence v persistence (80% v 54%, p < 0.01). Recurrence rates after primary and revision TSS were 18% [14-22] and 28% [16-42].

Conclusions: TSS is most effective in primary microadenomas, visible on preoperative imaging and without CS invasion, lower preoperative 24-h urine free cortisol and postoperative MSeC nadir < 2 μg/dL (< 55 nmol/L).
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http://dx.doi.org/10.1007/s11102-020-01066-8DOI Listing
October 2020

Following chemotherapy for gestational trophoblastic neoplasia, do residual lung lesions increase the risk of relapse?

Gynecol Oncol 2020 Sep 9;158(3):698-701. Epub 2020 Jul 9.

Department of Medical Oncology, Charing Cross Gestational Trophoblastic Disease Centre, Hammersmith Hospitals Campus of Imperial College, London W6 8RF, UK.

Background: There remains uncertainty about the prognostic significance of residual lung lesion on imaging after completion of treatment of low- or high-risk gestational trophoblastic neoplasia (GTN). Here, we determine if such residual lung lesions are associated with an increased risk of relapse.

Methods: We retrospectively screened our electronic database to identify patients with low- or high-risk GTN and lung metastases between 2004 and 18. Recurrences among patients with or without residual lung lesions on imaging were compared. Chi square analysis and Kaplan-Meier survival curves were constructed. As the numbers of cases were low, we combined this data with our previously published and non-overlapping patient cohort (1995-2004).

Results: Of 1304 GTN patients treated at our centre between 2004 and 18, 99 had lung metastases without other distant sites. There were 40 patients (40.4%) with residual lung lesions. Whilst an increased rate of relapse was observed among patients with residual lung lesions (4/40; 10.0%) compared to without such lesions (3/59; 5.1%), this difference was not statistically significant (p = .35). By combining the data with our previous cohort, there was an increase in relapse rate of patients with residual lung lesions (5/63; 7.9%) compared to those without such lesions (4/112; 3.6%). However, this difference was also not statistically significant (p = .21).

Conclusion: Residual lung lesions on imaging after completion of GTN treatment are common. However, this finding did not statistically increase relapse rate. Due to low number of recurrent events, a multi-centre, larger dataset would be needed to provide more definitive evidence.
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http://dx.doi.org/10.1016/j.ygyno.2020.06.483DOI Listing
September 2020

Contemporary Classification of Chronic Rhinosinusitis Beyond Polyps vs No Polyps: A Review.

JAMA Otolaryngol Head Neck Surg 2020 09;146(9):831-838

Rhinology and Skull Base Research Group, St Vincent's Centre for Applied Medical Research, University of New South Wales, Sydney, New South Wales, Australia.

Importance: Chronic rhinosinusitis (CRS) is a broadly defined process that has previously been used to describe many different sinonasal pathologic conditions from odontogenic sinusitis and allergic fungal sinusitis to the more contemporary definition of broad inflammatory airway conditions. Previous classification systems have dichotomized these conditions into CRS with nasal polyps and CRS without nasal polyps. However, clinicians are learning more about the inflammatory subtypes of CRS, which can lead to improved delivery and effectiveness of treatment.

Observations: In clinical practice, treatment decisions are often based on observable findings, clinical history, presumed disease, and molecular pathophysiologic characteristics. A proposed classification system is simple and practical. It proposes that the functional anatomical compartments involved create the first level of separation into local and diffuse CRS, which are usually unilateral or bilateral in distribution. Diffuse does not imply "pansinusitis" but simply that the disease is not confined to a known functional anatomical unit. This classification takes into account whether local anatomical factors are associated with pathogenesis. Then the inflammatory endotype dominance is separated into a type 2 skewed inflammation, as this has both causal and treatment implications. The non-type 2 CRS encompasses everything else that is not yet known about inflammation and may change over time. The phenotypes or clinical examples are CRS entities that have been described and how they align with this system.

Conclusions And Relevance: Although research continues to further define the subtypes of CRS into phenotypes and endotypes, the proposed classification system of primary CRS by anatomical distribution and endotype dominance allows for a pathway forward.
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http://dx.doi.org/10.1001/jamaoto.2020.1453DOI Listing
September 2020

Sierra: discovery of differential transcript usage from polyA-captured single-cell RNA-seq data.

Genome Biol 2020 07 8;21(1):167. Epub 2020 Jul 8.

School of Mathematics and Statistics, Faculty of Science, The University of Sydney, Camperdown, 2006, Australia.

High-throughput single-cell RNA-seq (scRNA-seq) is a powerful tool for studying gene expression in single cells. Most current scRNA-seq bioinformatics tools focus on analysing overall expression levels, largely ignoring alternative mRNA isoform expression. We present a computational pipeline, Sierra, that readily detects differential transcript usage from data generated by commonly used polyA-captured scRNA-seq technology. We validate Sierra by comparing cardiac scRNA-seq cell types to bulk RNA-seq of matched populations, finding significant overlap in differential transcripts. Sierra detects differential transcript usage across human peripheral blood mononuclear cells and the Tabula Muris, and 3 UTR shortening in cardiac fibroblasts. Sierra is available at https://github.com/VCCRI/Sierra .
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http://dx.doi.org/10.1186/s13059-020-02071-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341584PMC
July 2020

Should Oral Corticosteroids be Used in Medical Therapy for Chronic Rhinosinusitis? A Risk Analysis.

Laryngoscope 2021 03 7;131(3):473-481. Epub 2020 Jul 7.

Department of Otolaryngology-Head & Neck Surgery, University of Toronto, Toronto, Ontario, Canada.

Objectives: Oral corticosteroid (OCS) as a part of appropriate medical therapy (AMT) (formerly maximal medical therapy) in chronic rhinosinusitis remains controversial. While the risks of OCS are well known, the benefit remains unclear due the absence of a standardized prescribing regimen. Consequently, it is difficult to characterize whether the risks of OCS and its ability to avert endoscopic sinus surgery (ESS) are helpful in AMT. When OCS is highly effective at averting surgery, the lesser risks of OCS would be justified because it can avoid the greater risks of ESS. When OCS is poorly effective at averting ESS, the risks of OCS would not be justified because many patients will be exposed to both risks. This study seeks to identify the threshold effectiveness of OCS at averting ESS that would minimize risk exposure to patients.

Methods: A probabilistic risks-based decision analysis was constructed from literature reported incidences and impacts of adverse events of OCS and ESS. Monte Carlo analysis was performed to identify the minimum effectiveness required to avoid further intervention (MERAFI) for chronic sinusitis without nasal polyp (CRSsNP) and chronic sinusitis with nasal polyp (CRSwNP).

Results: The analysis showed MERAFI results of 20.8% (95% CI 20.7-20.9%) for CRSsNP and 16.8% (95% CI 16.7-16.9%) for CRSwNP.

Conclusions: Given reported OCS effectiveness in the range of 34-71% in CRSsNP and 46-63% in CRSwNP, this analysis suggests that the inclusion of OCS in AMT may be the lower risk strategy.

Level Of Evidence: N/A Laryngoscope, 131:473-481, 2021.
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http://dx.doi.org/10.1002/lary.28843DOI Listing
March 2021

The potential use of urinary hCG measurements in the management of pregnancies of unknown location.

Hum Fertil (Camb) 2020 Jun 16:1-8. Epub 2020 Jun 16.

Tommy's National Centre for Miscarriage Research, Queen Charlotte's & Chelsea Hospital, Imperial College, London, UK.

Multiple measurements of serum human chorionic gonadotropin (hCG) are used to predict the final pregnancy outcome for women with a pregnancy of unknown location (PUL) and monitor the management of ectopic pregnancy (EP). Urine-based testing would be more convenient and economical. This prospective cohort study involving 80 women assessed the degree of correlation between serum and urine hCG levels and whether urine hCG levels have the potential to impact clinical decision making in the management of women with a PUL. Paired urine and serum hCG measurements differed quite widely but were well correlated and the degree of correlation improved after creatinine correction. Although serial serum hCG measurements appear to be better for the overall prediction of pregnancy outcome in PUL (AUC 0.77-0.94 compared to corrected urine AUC 0.69-0.84), serial urine hCG measurements may have a role in identifying subtypes of low-risk PUL (AUC 0.83-0.84).
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http://dx.doi.org/10.1080/14647273.2020.1777590DOI Listing
June 2020

Smell Preservation following Unilateral Endoscopic Transnasal Approach to Resection of Olfactory Groove Meningioma: A Multi-institutional Experience.

J Neurol Surg B Skull Base 2020 Jun 28;81(3):263-267. Epub 2019 May 28.

Rhinology and Skull Base Research Group, Applied Medical Research Centre, University of New South Wales, Sydney, New South Wales, Australia.

 Olfactory groove meningiomas (OGMs) are often associated with loss of smell following resection. Loss of smell has a measurable impact on quality of life. Smell preservation has been previously described in open approaches for early stage or unilateral OGMs. Evidence of smell preservation in endoscopic approaches is lacking.  A multi-institutional retrospective review was performed on consecutive patients who underwent unilateral endoscopic endonasal resection of OGM. A gross total resection was achieved with preservation of the contralateral olfactory cleft and bulb. Olfactory function was assessed with a six-point olfactory symptom score and the Sniffin' Sticks 12-item smell identification test (SS-12). Contralateral olfactory bulb volume was measured on postoperative magnetic resonance imaging.  Four patients (age 42.0 ± 7.5, 75% female) were assessed. Olfactory function was assessed at 21.8 ± 5.6 months following surgery. All patients reported some degree of smell preservation (75% described a slight/mild impairment in smell or better). Olfactory identification was preserved with an SS-12 score of 9 ± 1.4 (anosmia defined as ≤6). The olfactory bulb volume was calculated to be 47.4 ± 15.9 mm (normal >40 mm ).  Smell preservation is possible following unilateral endoscopic endonasal resection of carefully selected OGM.
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http://dx.doi.org/10.1055/s-0039-1688794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7253307PMC
June 2020

Fungal ball of the maxillary sinus and the risk of persistent sinus dysfunction after simple antrostomy.

Am J Otolaryngol 2020 Jul - Aug;41(4):102541. Epub 2020 May 8.

Faculty of Medicine and Health Sciences, Macquarie University, Sydney, Australia; Rhinology and Skull Base Research Group, Applied Medical Research Centre, University of New South Wales, Sydney, Australia.

Background: Maxillary sinus fungal ball is a common cause of unilateral maxillary sinusitis. Fungal balls or mycetomas are primarily treated with surgery to remove the fungus. However, this assumes the pre-fungal ball sinus cavity was normal and post-surgery patients may suffer from mucostasis in the sinus cavity with persistent symptoms. It is proposed that fungal balls are potentially a feature of impaired mucus clearance as they are a pathology in their own right.

Methods: A case series of consecutive patients undergoing antrostomy for maxillary sinus fungal ball was performed. Patient factors including age, gender, smoking status, comorbidities (allergy, asthma, and reflux), disease specific factors including duration of symptoms, microbiology (bacterial co-infection, Gram-positive and/or Gram-negative) and preoperative radiologic findings (extent of sinus development, and neo-osteogenesis/bone thickness) were collected. The primary outcome was sinus function defined by evidence of a normal functioning maxillary sinus, with the absence of mucostasis or pooling, on endoscopic exam at three months, six months and last follow-up. Endoscopic evaluation of inflammation was also collected.

Results: 28 patients (age 58.5 ± 15.5 years, 64.3% female) were assessed. Mucostasis was present at three months in 39.3%, at six months in 32.1%, and 17.9% at last follow-up. There was no comorbidity or radiologic finding that was associated with failure to normalize. Those patients with mucostasis had a higher modified Lund-Mackay endoscopic score at last follow-up (5.0 ± 0.7 v 0.2 ± 0.6, p < 0.01).

Conclusions: Long term post-operative mucostasis occurred in 17.9% of patients following an adequate maxillary antrostomy for treatment of a fungal ball. Patients with mucostasis had persistent mucosal inflammation and a greater need for further surgery (modified medial maxillectomy).
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http://dx.doi.org/10.1016/j.amjoto.2020.102541DOI Listing
November 2020

Gait Measures at Admission to Inpatient Rehabilitation after Ischemic Stroke Predict 3-Month Quality of Life and Function.

PM R 2020 May 9. Epub 2020 May 9.

Department of Physical Medicine and Rehabilitation, Northwestern University, Chicago, IL, USA.

Background: Ischemic stroke can impact a patient's quality of life, but the extent is unknown.

Objective: To evaluate the association between gait measures during inpatient rehabilitation with quality-of-life scores and function at 3 months in patients with stroke.

Setting: Single-Center inpatient rehabilitation facility.

Participants: Eight five patients with ischemic stroke.

Methods: A 6-Minute Walk Test and a 10-Meter Walk Test were recorded on admission to rehabilitation. We analyzed the association between gait function at rehabilitation and 3-month quality of life and poor functional outcome (modified Rankin Scale score >2) using multivariable logistic regression.

Main Outcome: Measures 3-month health related quality of life.

Results: Eighty-five patients (mean age 68.3 14.9 years; 54.3% male) were enrolled. In adjusted analyses, an increase of 0.31 m/s (ie, 1 SD) on the 10-meter walk test was linked with a decreased odds of impaired lower extremity quality of life by 94% (odds ratio [OR] 0.06, 95% confidence interval [CI] 0.01-0.52; P =.01), and decreased odds of poor functional outcome by 98% (OR 0.02, 95% CI <0.01-0.47; P =.01). For the 6-minute walk test, an increase of 109.5 meters (ie, 1 SD) was linked with decreased odds of having impaired lower extremity quality of life by 1% (OR 0.99, 95% CI 0.98-1.00; P < .01) and poor functional outcome by 1% (OR 0.99, 95% CI 0.99-1.00; P = .04).

Conclusion: Gait measurements at rehabilitation can predict 3-month lower extremity quality of life and function.
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http://dx.doi.org/10.1002/pmrj.12402DOI Listing
May 2020

Nasal Peak Inspiratory Flow in Healthy and Obstructed Patients: Systematic Review and Meta-Analysis.

Laryngoscope 2021 02 9;131(2):260-267. Epub 2020 May 9.

Rhinology and Skull Base Research Group, St. Vincent's Centre for Applied Medical Research, University of New South Wales, Sydney, New South Wales, Australia.

Objectives: Nasal peak inspiratory flow (NPIF) is a practical and affordable tool that measures maximum inspiratory flow rate through both nostrils. Although NPIF values for healthy controls and patients appear to differ considerably, a generally expected value for populations with and without nasal obstruction has yet to be established. The aim of this systematic review and meta-analysis was to determine the mean NPIF value in populations with and without nasal obstruction.

Methods: Medline (1946-) and Embase (1947-) were searched until July 1, 2017. A search strategy was used to identify studies that reported NPIF values for defined healthy or disease states. All studies providing original data were included. The study population was defined as having either normal nasal breathing or nasal obstruction. A meta-analysis of the mean data was presented in forest plots, and data were presented as mean (95% confidence interval [CI]).

Results: The search yielded 1,526 studies, of which 29 were included. The included studies involved 1,634 subjects with normal nasal breathing and 817 subjects with nasal obstruction. The mean NPIF value for populations with normal nasal breathing was 138.4 (95% CI: 127.9-148.8) L/min. The mean value for populations with nasal obstruction was 97.5 (95% CI: 86.1-108.8) L/min.

Conclusions: Current evidence confirms a difference between mean NPIF values of populations with and without nasal obstruction. The mean value of subjects with no nasal obstruction is 138.4 L/min, and the mean value of nasally obstructed populations is 97.5 L/min. Prospective studies adopting a standardized procedure are required to further assess normative NPIF values. Laryngoscope, 131:260-267, 2021.
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http://dx.doi.org/10.1002/lary.28682DOI Listing
February 2021

Basic Biology of Extracellular Matrix in the Cardiovascular System, Part 1/4: JACC Focus Seminar.

J Am Coll Cardiol 2020 05;75(17):2169-2188

Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia; St. Vincent's Clinical School, University of New South Wales, Darlinghurst, New South Wales, Australia; The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address:

The extracellular matrix (ECM) is the noncellular component of tissues in the cardiovascular system and other organs throughout the body. It is formed of filamentous proteins, proteoglycans, and glycosaminoglycans, which extensively interact and whose structure and dynamics are modified by cross-linking, bridging proteins, and cleavage by matrix degrading enzymes. The ECM serves important structural and regulatory roles in establishing tissue architecture and cellular function. The ECM of the developing heart has unique properties created by its emerging contractile nature; similarly, ECM lining blood vessels is highly elastic in order to sustain the basal and pulsatile forces imposed on their walls throughout life. In this part 1 of a 4-part JACC Focus Seminar, we focus on the role, function, and basic biology of the ECM in both heart development and in the adult.
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http://dx.doi.org/10.1016/j.jacc.2020.03.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7324287PMC
May 2020