UW Neurological Surgery Recent PubMed Publications

Aberrant cell migration contributes to defective airway epithelial repair in childhood wheeze.

JCI Insight. 2020 Mar 24;:

Authors: Iosifidis T, Sutanto EN, Buckley A, Coleman LA, Gill EE, Lee AH, Ling KM, Hillas J, Looi K, Garratt LW, Martinovich KM, Shaw NC, Montgomery ST, Kicic-Starcevich E, Karpievitch YV, Le Souef P, Laing IA, Vijayasekaran S, Lannigan FJ, Rigby PJ, Hancock RE, Knight D, Stick SM, Kicic A, Waerp OBO, AusREC OBO

Abstract
Abnormal wound repair has been observed in the airway epithelium of patients with chronic respiratory diseases including asthma. Therapies focusing on repairing vulnerable airways, particularly in early life, present an extremely novel treatment strategy. We report defective lower airway epithelial cell repair to strongly associate with common pre-school and school-aged wheezing phenotypes, characterised by aberrant migration patterns and reduced α5β1 integrin expression. Next generation sequencing identified the PI3K/Akt pathway as the top upstream transcriptional regulator of α5β1 integrin, where Akt activation enhanced repair and α5β1 integrin expression in primary cultures from children with wheeze. Conversely, inhibition of PI3K/Akt signaling in primary cultures from children without wheeze reduced α5β1 expression and attenuated repair. Importantly, the FDA-approved drug celecoxib, and its non-COX2-inhibiting analogue dimethyl-celecoxib, stimulated the PI3K/Akt-integrin α5β1 axis and restored airway epithelial repair in cells from children with wheeze. When compared with published clinical datasets the identified transcriptomic signature was also associated with viral-induced wheeze exacerbations highlighting the clinical potential of such therapy. Collectively, these results identify airway epithelial restitution via targeting the PI3K/Akt-integrin axis as a novel therapeutic avenue for childhood wheeze and asthma. We propose that the next step in the therapeutic development process should be a proof-of-concept clinical trial since relevant animal models to test the crucial underlying premise are unavailable.

PMID: 32208383 [PubMed - as supplied by publisher]

Extrusion-Based Bioprinting: Current Standards and Relevancy for Human-Sized Tissue Fabrication.

Methods Mol Biol. 2020;2140:65-92

Authors: Willson K, Ke D, Kengla C, Atala A, Murphy SV

Abstract
The field of bioengineering has long pursued the goal of fabricating large-scale tissue constructs for use both in vitro and in vivo. Recent technological advances have indicated that bioprinting will be a key technique in manufacturing these specimens. This chapter aims to provide an overview of what has been achieved to date through the use of microextrusion bioprinters and what major challenges still impede progress. Microextrusion printer configurations will be addressed along with critical design characteristics including nozzle specifications and bioink modifications. Significant challenges within the field with regard to achieving long-term cell viability and vascularization, and current research that shows promise in mitigating these challenges in the near future are discussed. While microextrusion is a broad field with many applications, this chapter aims to provide an overview of the field with a focus on its applications toward human-sized tissue constructs.

PMID: 32207106 [PubMed - in process]

Enhanced transient striatal dopamine release and reuptake in Lphn3 KO rats.

ACS Chem Neurosci. 2020 Mar 23;:

Authors: Regan SL, Cryan MT, Williams MT, Vorhees CV, Ross AE

Abstract
Latrophilin-3 (LPHN3) is an adhesion G protein coupled receptor involved in regulating neuroplasticity. Variants of LPHN3 are associated with increased risk of attention-deficit hyperactivity disorder. Data from mouse, zebrafish, Drosophila, and rat show that disruption of LPHN3 results in hyperactivity and in the Sprague-Dawley Lphn3 knock-out rat exhibit deficits in learning and memory and changes in dopamine (DA) markers in the neostriatum. To determine the effects of Lphn3 deletion on DA neurotransmission, we compared the concentration, duration, and frequency of DA transients in KO and wildtype rats using fast-scan cyclic voltammetry in brain slices. Lphn3 KO rats showed higher release of DA and the duration and inter-event time were markedly decreased compared with wildtype rats. The data demonstrate that LPHN3 plays a heretofore unrecognized role in DA signaling and may represent a new target for small molecule regulation of DA neurotransmission with translational implications.

PMID: 32203648 [PubMed - as supplied by publisher]

MetaBridge: An Integrative Multi-Omics Tool for Metabolite-Enzyme Mapping.

Curr Protoc Bioinformatics. 2020 Jun;70(1):e98

Authors: Blimkie T, Lee AH, Hancock REW

Abstract
MetaBridge is a web-based tool designed to facilitate the integration of metabolomics with other "omics" data types such as transcriptomics and proteomics. It uses data from the MetaCyc metabolic pathway database and the Kyoto Encyclopedia of Genes and Genomes (KEGG) to map metabolite compounds to directly interacting upstream or downstream enzymes in enzymatic reactions and metabolic pathways. The resulting list of enzymes can then be integrated with transcriptomics or proteomics data via protein-protein interaction networks to perform integrative multi-omics analyses. MetaBridge was developed to be intuitive and easy to use, requiring little to no prior computational experience. The protocols described here detail all steps involved in the use of MetaBridge, from preparing input data and performing metabolite mapping to utilizing the results to build a protein-protein interaction network. © 2020 by John Wiley & Sons, Inc. Basic Protocol 1: Mapping metabolite data using MetaCyc identifiers Basic Protocol 2: Mapping metabolite data using KEGG identifiers Support Protocol 1: Converting compound names to HMDB IDs Support Protocol 2: Submitting mapped genes produced by MetaBridge for protein-protein interaction (PPI) network construction.

PMID: 32199034 [PubMed - as supplied by publisher]

Inflammation in Heart Failure: JACC State-of-the-Art Review.

J Am Coll Cardiol. 2020 03 24;75(11):1324-1340

Authors: Murphy SP, Kakkar R, McCarthy CP, Januzzi JL

Abstract
It has long been observed that heart failure (HF) is associated with measures of systemic inflammation. In recent years, there have been significant advancements in our understanding of how inflammation contributes to the pathogenesis and progression of HF. However, although numerous studies have validated the association between measures of inflammation and HF severity and prognosis, clinical trials of anti-inflammatory therapies have proven mostly unsuccessful. On this backdrop emerges the yet unmet goal of targeting precise phenotypes within the syndrome of HF; if such precise definitions can be realized, and with better understanding of the roles played by specific inflammatory mediators, the expectation is that targeted anti-inflammatory therapies may improve prognosis in patients whose HF is driven by inflammatory pathobiology. Here, the authors describe mechanistic links between inflammation and HF, discuss traditional and novel inflammatory biomarkers, and summarize the latest evidence from clinical trials of anti-inflammatory therapies.

PMID: 32192660 [PubMed - indexed for MEDLINE]

Slow release oral morphine versus methadone for opioid use disorder in the fentanyl era (pRESTO): Protocol for a non-inferiority randomized clinical trial.

Contemp Clin Trials. 2020 Mar 16;:105993

Authors: Socias ME, Wood E, Dong H, Brar R, Bach P, Murphy SM, Fairbairn N

Abstract
BACKGROUND: North America is facing an unprecedented public health crisis of opioid-related morbidity and mortality, increasingly as a result of the introduction of illicitly manufactured fentanyl into the street drug market. Although the treatment of opioid use disorder (OUD) is a key element in the response to the opioid overdose epidemic, currently available pharmacotherapies (e.g., methadone, buprenorphine) may not be acceptable to or effective in all patients. Available evidence suggests that slow-release oral morphine (SROM) has similar efficacy rates as methadone with respect to promoting abstinence, and with improvements in a number of patient-reported outcomes among persons using heroin. However, little is known about the relative effectiveness and acceptability of SROM compared to methadone in the context of fentanyl use. This study aims to address this research gap.
METHODS: pRESTO is a 24-week, open-label, two arm, non-inferiority, randomized controlled trial comparing SROM versus methadone for the treatment of OUD. Participants will be 298 clinically stable, non-pregnant adults with OUD, recruited from outpatient clinics in Vancouver, Canada, where the majority of the illicit opioids are contaminated with fentanyl. The primary outcome is suppression of illicit opioid use, measured by bi-weekly urine drug screens. Secondary outcomes include: treatment retention, medication safety, overdose events, treatment satisfaction, psychological functioning, changes in drug-related problems, changes in quality of life, opioid cravings, other substance use, and cost-effectiveness.
DISCUSSION: pRESTO will be among the first studies to evaluate treatment options for individuals primarily using synthetic street opioids, providing important evidence to guide treatment strategies for this population.

PMID: 32194251 [PubMed - as supplied by publisher]

Repeated Application of Transcranial Diagnostic Ultrasound Towards the Visual Cortex Induced Illusory Visual Percepts in Healthy Participants.

Front Hum Neurosci. 2020;14:66

Authors: Schimek N, Burke-Conte Z, Abernethy J, Schimek M, Burke-Conte C, Bobola M, Stocco A, Mourad PD

Abstract
Transcranial magnetic stimulation (TMS) of the visual cortex can induce phosphenes as participants look at a visual target. So can non-diagnostic ultrasound (nDU), delivered in a transcranial fashion, while participants have closed their eyes during stimulation. Here, we sought to determine if DU, aimed at the visual cortex, could alter the perception of a visual target. We applied a randomized series of actual or sham DU, transcranially and towards the visual cortex of healthy participants while they stared at a visual target (a white crosshair on a light-blue background), with the ultrasound device placed where TMS elicited phosphenes. These participants observed percepts seven out of ten times, which consisted of extra or extensions of lines relative to the original crosshair, and additional colors, an average of 53.7 ± 2.6% of the time over the course of the experiment. Seven out of ten different participants exposed to sham-only DU observed comparable percepts, but only an average of 36.3 ± 1.9% of the time, a statistically significant difference (p < 0.00001). Moreover, on average, participants exposed to a combination of sham and actual ultrasound reported a net increase of 47.9 percentage points in the likelihood that they would report a percept by the end of the experiment. Our results are consistent with the hypothesis that a random combination of sham-only and actual DU, applied directly over the visual cortex of participants, increased the likelihood that they would observe visual effects, but not the type of effects, with that likelihood increasing over the course of the experiment. From this, we conclude that repeated exposures by DU may make the visual cortex more responsive to stimulation of their visual cortex by the visual target itself. Future studies should identify the biophysical mechanism(s) and neural pathways by which DU, in our hands and others, can generate its observed effects on brain function. These observations, consistent with other's observation of effects of DU stimulation of the human motor cortex and amygdala, as well as the FDA approved nature of DU, may lead to increased use of DU as a means of altering brain function.

PMID: 32194387 [PubMed]

CCAP regulates feeding behavior via the NPF pathway in Drosophila adults.

Proc Natl Acad Sci U S A. 2020 03 31;117(13):7401-7408

Authors: Williams MJ, Akram M, Barkauskaite D, Patil S, Kotsidou E, Kheder S, Vitale G, Filaferro M, Blemings SW, Maestri G, Hazim N, Vergoni AV, Schiöth HB

Abstract
The intake of macronutrients is crucial for the fitness of any animal and is mainly regulated by peripheral signals to the brain. How the brain receives and translates these peripheral signals or how these interactions lead to changes in feeding behavior is not well-understood. We discovered that 2 crustacean cardioactive peptide (CCAP)-expressing neurons in Drosophila adults regulate feeding behavior and metabolism. Notably, loss of CCAP, or knocking down the CCAP receptor (CCAP-R) in 2 dorsal median neurons, inhibits the release of neuropeptide F (NPF), which regulates feeding behavior. Furthermore, under starvation conditions, flies normally have an increased sensitivity to sugar; however, loss of CCAP, or CCAP-R in 2 dorsal median NPF neurons, inhibited sugar sensitivity in satiated and starved flies. Separate from its regulation of NPF signaling, the CCAP peptide also regulates triglyceride levels. Additionally, genetic and optogenetic studies demonstrate that CCAP signaling is necessary and sufficient to stimulate a reflexive feeding behavior, the proboscis extension reflex (PER), elicited when external food cues are interpreted as palatable. Dopaminergic signaling was also sufficient to induce a PER. On the other hand, although necessary, NPF neurons were not able to induce a PER. These data illustrate that the CCAP peptide is a central regulator of feeding behavior and metabolism in adult flies, and that NPF neurons have an important regulatory role within this system.

PMID: 32179671 [PubMed - indexed for MEDLINE]

In defense of the AAN position on lawful physician-hastened death.

Neurology. 2020 04 14;94(15):641-643

Authors: Russell JA, Epstein LG, Bonnie RJ, Conwit R, Graf WD, Kirschen M, Kurek JA, Larriviere DG, Pascuzzi RM, Rizzo M, Sattin JA, Simmons Z, Taylor L, Williams MA, Ethics, Law, and Humanities Committee (a joint committee of the AAN, ANA, and CNS)

PMID: 32179699 [PubMed - indexed for MEDLINE]

Metabolic and evolutionary responses of Clostridium thermocellum to genetic interventions aimed at improving ethanol production.

Biotechnol Biofuels. 2020;13:40

Authors: Holwerda EK, Olson DG, Ruppertsberger NM, Stevenson DM, Murphy SJL, Maloney MI, Lanahan AA, Amador-Noguez D, Lynd LR

Abstract
Background: Engineering efforts targeted at increasing ethanol by modifying the central fermentative metabolism of Clostridium thermocellum have been variably successful. Here, we aim to understand this variation by a multifaceted approach including genomic and transcriptomic analysis combined with chemostat cultivation and high solids cellulose fermentation. Three strain lineages comprising 16 strains total were examined. Two strain lineages in which genes involved in pathways leading to organic acids and/or sporulation had been knocked out resulted in four end-strains after adaptive laboratory evolution (ALE). A third strain lineage recapitulated mutations involving adhE that occurred spontaneously in some of the engineered strains.
Results: Contrary to lactate dehydrogenase, deleting phosphotransacetylase (pta, acetate) negatively affected steady-state biomass concentration and caused increased extracellular levels of free amino acids and pyruvate, while no increase in ethanol was detected. Adaptive laboratory evolution (ALE) improved growth and shifted elevated levels of amino acids and pyruvate towards ethanol, but not for all strain lineages. Three out of four end-strains produced ethanol at higher yield, and one did not. The occurrence of a mutation in the adhE gene, expanding its nicotinamide-cofactor compatibility, enabled two end-strains to produce more ethanol. A disruption in the hfsB hydrogenase is likely the reason why a third end-strain was able to make more ethanol. RNAseq analysis showed that the distribution of fermentation products was generally not regulated at the transcript level. At 120 g/L cellulose loadings, deletions of spo0A, ldh and pta and adaptive evolution did not negatively influence cellulose solubilization and utilization capabilities. Strains with a disruption in hfsB or a mutation in adhE produced more ethanol, isobutanol and 2,3-butanediol under these conditions and the highest isobutanol and ethanol titers reached were 5.1 and 29.9 g/L, respectively.
Conclusions: Modifications in the organic acid fermentative pathways in Clostridium thermocellum caused an increase in extracellular pyruvate and free amino acids. Adaptive laboratory evolution led to improved growth, and an increase in ethanol yield and production due a mutation in adhE or a disruption in hfsB. Strains with deletions in ldh and pta pathways and subjected to ALE demonstrated undiminished cellulolytic capabilities when cultured on high cellulose loadings.

PMID: 32175007 [PubMed]

Single pedicle advancement flap for treatment of feline stenotic nares: technique and results in five cases.

J Feline Med Surg. 2020 Mar 16;:1098612X20910539

Authors: Berns CN, Schmiedt CW, Dickerson VM, Murphy SM

Abstract
OBJECTIVES: Brachycephalic obstructive airway syndrome (BOAS) is a common cause of upper airway obstruction in dogs, but is appreciated less commonly in cats. Of the components of BOAS, stenotic nares appear to play a major role in cats. However, the axial deviation of the alar wing, a common cause of nasal obstruction in dogs, is typically not present. We report a series of brachycephalic cats with a ventral nasal obstruction resulting from redundant skin along the floor of the nares. In these cats, surgical techniques developed for dogs were felt to be suboptimal. Our aim is to describe a novel surgical procedure designed specifically to surgically correct stenotic nares in cats with an obstructive fold of skin ventral to the nostril.
METHODS: Five brachycephalic cats presenting for clinical signs of stenotic nares underwent surgical repair. In each case, a resection of the skin fold followed by a bilateral single pedicle advancement flap technique was performed. Postoperative outcomes were obtained by contacting owners by telephone.
RESULTS: All cats had positive outcomes, resulting in immediate reduction of the nasal fold and opening of the nares. Owners noted resolution of stertor and no episodes of respiratory distress. No surgical complications were reported.
CONCLUSIONS AND RELEVANCE: In brachycephalic cats, the ventral skin fold may be a significant contributor to stenotic nares, unlike dogs. Resection of the skin fold, followed by bilateral single pedicle advancement flaps is a novel technique and appeared to be successful for treating stenotic nares in this series of brachycephalic cats.

PMID: 32175790 [PubMed - as supplied by publisher]

Another version of the truth.

J Neurointerv Surg. 2020 04;12(4):335-336

Authors: Levitt M

PMID: 32161165 [PubMed - indexed for MEDLINE]

Presynaptic calcium channels: specialized control of synaptic neurotransmitter release.

Nat Rev Neurosci. 2020 04;21(4):213-229

Authors: Dolphin AC, Lee A

Abstract
Chemical synapses are heterogeneous junctions formed between neurons that are specialized for the conversion of electrical impulses into the exocytotic release of neurotransmitters. Voltage-gated Ca2+ channels play a pivotal role in this process as they are the major conduits for the Ca2+ ions that trigger the fusion of neurotransmitter-containing vesicles with the presynaptic membrane. Alterations in the intrinsic function of these channels and their positioning within the active zone can profoundly alter the timing and strength of synaptic output. Advances in optical and electron microscopic imaging, structural biology and molecular techniques have facilitated recent breakthroughs in our understanding of the properties of voltage-gated Ca2+ channels that support their presynaptic functions. Here we examine the nature of these channels, how they are trafficked to and anchored within presynaptic boutons, and the mechanisms that allow them to function optimally in shaping the flow of information through neural circuits.

PMID: 32161339 [PubMed - indexed for MEDLINE]

Telephone-delivered cognitive behavioral therapy for veterans with chronic pain following traumatic brain injury: Rationale and study protocol for a randomized controlled trial study.

Contemp Clin Trials. 2019 01;76:112-119

Authors: Hoffman JM, Ehde DM, Dikmen S, Dillworth T, Gertz K, Kincaid C, Lucas S, Temkin N, Sawyer K, Williams R

Abstract
BACKGROUND AND OBJECTIVES: Chronic pain is a highly prevalent and potentially disabling condition in Veterans who have had a traumatic brain injury (TBI) and access to non-pharmacological pain treatments such as cognitive behavioral therapy is limited and variable. The purpose of this randomized controlled trial (RCT) is to evaluate the efficacy of a telephone-delivered cognitive behavioral therapy (T-CBT) for pain in Veterans with a history of TBI.
METHODS: Veterans with a history of TBI and chronic pain of at least six months duration (N = 160) will be randomized to either T-CBT or a telephone-delivered pain psychoeducational active control condition (T-Ed). The eight-week T-CBT intervention builds on other efficacious CBT interventions for chronic pain in the general population but is novel in that it is conducted via telephone and adapted for Veterans with a history of TBI. Outcome variables will be collected pre, mid-, and post-treatment, and 6 months following randomization (follow-up).
PROJECTED OUTCOMES: In addition to evaluating the effects of the interventions on pain intensity (primary outcome), this study will determine their effects on pain interference, sleep, depression, and life satisfaction. We will also examine potential moderators of treatment outcomes such as cognition, PTSD, and alcohol and drug use. This non-pharmacologic one-on-one therapeutic intervention has the potential to reduce pain and pain-related dysfunction, improve access to care, and reduce barriers associated with geography, finances, and stigma, without the negative effects on physical and cognitive performance and potential for addiction as seen with some pharmacologic treatments for pain. This trial is registered at ClinicalTrials.gov, protocol NCT01768650.

PMID: 30553077 [PubMed - indexed for MEDLINE]

Diurnal variation in autonomic regulation among patients with genotyped Rett syndrome.

J Med Genet. 2020 Mar 10;:

Authors: Carroll MS, Ramirez JM, Weese-Mayer DE

Abstract
BACKGROUND: Rett syndrome is a severe neurological disorder with a range of disabling autonomic and respiratory symptoms and resulting predominantly from variants in the methyl-CpG binding protein 2 gene on the long arm of the X-chromosome. As basic research begins to suggest potential treatments, sensitive measures of the dynamic phenotype are needed to evaluate the results of these research efforts. Here we test the hypothesis that the physiological fingerprint of Rett syndrome in a naturalistic environment differs from that of controls, and differs among genotypes within Rett syndrome.
METHODS: A comprehensive array of heart rate variability, cardiorespiratory coupling and cardiac repolarisation measures were evaluated from an existing database of overnight and daytime inhome ambulatory recordings in 47 cases and matched controls.
RESULTS: Differences between girls with Rett syndrome and matched controls were apparent in a range of autonomic measures, and suggest a shift towards sympathetic activation and/or parasympathetic inactivation. Daily temporal trends analysed in the context of circadian rhythms reveal alterations in amplitude and phase of diurnal patterns of autonomic balance. Further analysis by genotype class confirms a graded presentation of the Rett syndrome phenotype such that patients with early truncating mutations were most different from controls, while late truncating and missense mutations were least different from controls.
CONCLUSIONS: Comprehensive autonomic measures from extensive inhome physiological measurements can detect subtle variations in the phenotype of girls with Rett syndrome, suggesting these techniques are suitable for guiding novel therapies.

PMID: 32156713 [PubMed - as supplied by publisher]

Diagnostic coronary angiography and percutaneous coronary intervention practices in New Zealand: The All New Zealand Acute Coronary Syndrome-Quality Improvement CathPCI registry 3-year study (ANZACS-QI 37).

Int J Cardiol. 2020 Feb 29;:

Authors: Wang TKM, Kasargod C, Chan D, Cicovic S, Dimalapang E, Webster M, Nunn C, Devlin G, El-Jack S, Fisher N, Simmonds M, Kneale B, Smyth D, Williams M, Kerr A, Somaratne J

Abstract
BACKGROUND: Coronary heart disease remains one of the leading causes of mortality and morbidity in New Zealand (NZ) and globally. The All New Zealand Acute Coronary Syndrome Quality Improvement (ANZACS-QI) programme includes the CathPCI registry which records all those referred for diagnostic coronary angiography (DCA) and percutaneous coronary intervention (PCI) in NZ. We present the methods and three-years of data from the ANZACS-QI CathPCI registry.
METHODS: The data was extracted from the ANZACS QI CathPCI registry from 01/09/2014 to 24/09/2017. The ANZACS-QI data dictionary defines all the clinical, procedural and outcomes variables collected, and standard statistical analyses were applied.
RESULTS: 40,870 patients underwent cardiac catheterisation, with a mean age of 65 years, and males making up 67% of the cohort. Indications included acute coronary syndrome 55%, angina with suspected stable coronary disease 28%, valve surgery workup 8%, planned PCI 3%, heart failure/cardiomyopathy 3%, arrhythmia 1% and other 2%. For those undergoing DCA alone, radial access was used in 85% and two-thirds had at least one major artery with >50% stenosis. PCI was performed in 39% of patients. Drug-eluting stents were used in 97%.
CONCLUSION: The CathPCI registry records the characteristics and outcomes of all patients undergoing DCA and PCI in NZ hospitals. As part of the ANZACS-QI programme the registry provides an important platform for quality improvement, research and to inform clinical practice.

PMID: 32151441 [PubMed - as supplied by publisher]

Total copy number variation, somatic mutation burden, and histologic grade correlate with clinical outcome in oligodendroglioma.

Clin Neuropathol. 2020 Mar 08;:

Authors: Richardson TE, Williams M, Galbraith K, Mirchia K, Kumar A, Xing C, Walker JM

PMID: 32145756 [PubMed - as supplied by publisher]

Enhancing Medical Students' Interprofessional Teamwork Through Simulated Room of Errors Experience.

J Surg Res. 2020 07;251:137-145

Authors: Turrentine FE, Schroen AT, Hallowell PT, Quatrara BA, Smith PW, Williams MD, Haizlip JA

Abstract
BACKGROUND: Fostering medical students' appreciation for team members particularly those from other disciplines with varying levels of experience promotes a promising beginning to a health care career.
METHODS: During surgical clerkship orientation, third-year medical students completed 30-item TeamSTEPPS Teamwork Attitudes Questionnaire preintervention and postintervention, spent 7 min identifying errors in a simulated operating room, followed by recorded physician-led 30-min discussions.
RESULTS: Postintervention (67) compared with preintervention (141) mean TeamSTEPPS Teamwork Attitudes Questionnaire domain scores were statistically significantly higher for team structure (4.59, 4.70; P = 0.03) and higher but not significant for leadership (4.74, 4.75; P = 0.86), situation monitoring (4.62, 4.68; P = 0.32), communication (4.40, 4.50; P = 0.14), and decreased for mutual support (4.43, 4.36; P = 0.43). Medical students identified 2%-93% of 33 staged errors and 291 additional errors, which were placed into 14 categories. Soiled gloves in the operative field and urinary bag on the floor were the most frequently identified staged errors. Experienced nurses compared with medical students identified significantly more errors (mean, 17.7 versus 11.7, respectively; P < 0.001). Recognizing errors when lacking familiarity with the operative environment and appreciating teammates' perspectives were themes that emerged from discussions.
CONCLUSIONS: This well-received teamwork exercise enabled medical students to appreciate team members' contributions and other disciplines' perspectives, in addition to the synergy that occurs with multidisciplinary teams.

PMID: 32143058 [PubMed - indexed for MEDLINE]

Interplay of Staphylococcal and Host Proteases Promotes Skin Barrier Disruption in Netherton Syndrome.

Cell Rep. 2020 Mar 03;30(9):2923-2933.e7

Authors: Williams MR, Cau L, Wang Y, Kaul D, Sanford JA, Zaramela LS, Khalil S, Butcher AM, Zengler K, Horswill AR, Dupont CL, Hovnanian A, Gallo RL

Abstract
Netherton syndrome (NS) is a monogenic skin disease resulting from loss of function of lymphoepithelial Kazal-type-related protease inhibitor (LEKTI-1). In this study we examine if bacteria residing on the skin are influenced by the loss of LEKTI-1 and if interaction between this human gene and resident bacteria contributes to skin disease. Shotgun sequencing of the skin microbiome demonstrates that lesional skin of NS subjects is dominated by Staphylococcus aureus (S. aureus) and Staphylococcus epidermidis (S. epidermidis). Isolates of either species from NS subjects are able to induce skin inflammation and barrier damage on mice. These microbes promote skin inflammation in the setting of LEKTI-1 deficiency due to excess proteolytic activity promoted by S. aureus phenol-soluble modulin α as well as increased bacterial proteases staphopain A and B from S. aureus or EcpA from S. epidermidis. These findings demonstrate the critical need for maintaining homeostasis of host and microbial proteases to prevent a human skin disease.

PMID: 32130897 [PubMed - in process]

Cytomorphologic findings of cervical Pap smears from female-to-male transgender patients on testosterone therapy.

Cancer Cytopathol. 2020 07;128(7):491-498

Authors: Williams MPA, Kukkar V, Stemmer MN, Khurana KK

Abstract
BACKGROUND: The cervical cancer screening recommendation for transgender female-to-male (FTM) patients is the same as that for cisgender females. A lack of literature on testosterone-induced changes in cervical cytology in these patients may result in interpretation errors, especially without a proper clinical history. The aim of this study was to delineate the Papanicolaou (Pap) test findings in this patient population.
METHODS: A pathology laboratory information system was used to obtain a cohort of FTM transgender patients on testosterone therapy (2009-2019). A cohort of age-matched, atrophic, control cisgender female patients (postpartum or menopausal) was selected. A retrospective review of the cytomorphologic findings on cervical Pap smears, pertinent follow-up, and human papillomavirus (HPV) test results was performed.
RESULTS: Fourteen transgender patients (age range, 21-64 years; mean age, 42.5 years) receiving testosterone therapy with 17 Pap smears were identified. One of the 5 available HPV tests was positive for HPV, and 4 were negative. A Pap smear review revealed the following: negative for intraepithelial lesion (NILM; 82.4%), unsatisfactory (5.9%), atypical squamous cells of undetermined significance (ASCUS; 5.9%), and low-grade squamous intraepithelial lesion (5.9%). The Pap smears of the atrophic cisgender cohort (102 patients) revealed the following: NILM (92.5%), unsatisfactory (0.9%), ASCUS (5.6%), and high-grade squamous intraepithelial lesion (0.9%). The difference between the rates of epithelial cell abnormality in the 2 cohorts was not statistically significant. Although atrophy was noted in both groups, cytomorphologic findings of transitional cell metaplasia (TCM; 88.2%) and "small cells" (82.4%) were characteristic of the testosterone-treated transgender cohort. Histologic correlates of TCM and small cells were noted in hysterectomy specimens from 6 patients.
CONCLUSIONS: Small cells and TCM are common cytomorphologic findings in Pap smears of testosterone-treated transgender (FTM) patients. On the basis of histologic follow-up, small cells most likely represent atrophic parabasal cells of cervical-vaginal epithelium.

PMID: 32125771 [PubMed - indexed for MEDLINE]