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  • Embryonal Rhabdomyosarcoma with Posttherapy Cytodifferentiation and Aggressive Clinical Course

    Jeyaraju, Maniraj; Macatangay, Regina Ann; Munchel, Ashley Taylor-King; York, Teresa Anne; Montgomery, Elizabeth A; Kallen, Michael E (Elsevier Inc., 2021-11-08)
    Rhabdomyosarcoma is the most common soft tissue sarcoma in children and adolescents. Embryonal rhabdomyosarcoma (ERMS), its most common subtype, is a malignant soft tissue tumor with morphologic and immunophenotypic features of embryonic skeletal muscle. The histologic findings in ERMS typically include a range of differentiation in rhabdomyoblasts from primitive to terminally differentiated forms, and the latter become more prominent after chemotherapy-induced cytodifferentiation. Several reports have shown therapy-related cytodifferentiation to portend a good prognosis in ERMS. We discuss the case of a pediatric patient who presented with ERMS of the orbit. Although her tumor showed extensive posttreatment cytodifferentiation and several other good prognostic clinicopathologic factors, it pursued an aggressive course, resulting in early metastasis and death. This case represents an unusual course and may be instructive as to the clinicopathologic features impacting prognostication, and ultimately the biology, of this aggressive family of tumors.
  • A Phase 2a randomized, single-center, double-blind, placebo-controlled study to evaluate the safety and preliminary efficacy of oral iOWH032 against cholera diarrhea in a controlled human infection model.

    Erdem, Rahsan; Ambler, Gwen; Al-Ibrahim, Mohamed; Fraczek, Katarzyna; Dong, Steven D; Gast, Christopher; Mercer, Laina D; Raine, Michael; Tennant, Sharon M; Chen, Wilbur H; et al. (Public Library of Science, 2021-11-18)
    Cholera remains a major cause of infectious diarrhea globally. Despite the increased availability of cholera vaccines, there is still an urgent need for other effective interventions to reduce morbidity and mortality. Furthermore, increased prevalence of antibiotic-resistant Vibrio cholerae threatens the use of many drugs commonly used to treat cholera. We developed iOWH032, a synthetic small molecule inhibitor of the cystic fibrosis transmembrane conductance regulator chloride channel, as an antisecretory, host-directed therapeutic for cholera. In the study reported here, we tested iOWH032 in a Phase 2a cholera controlled human infection model. Forty-seven subjects were experimentally infected with V. cholerae El Tor Inaba strain N16961 in an inpatient setting and randomized to receive 500 mg iOWH032 or placebo by mouth every 8 hours for 3 days to determine the safety and efficacy of the compound as a potential treatment for cholera. We found that iOWH032 was generally safe and achieved a mean (± standard deviation) plasma level of 4,270 ng/mL (±2,170) after 3 days of oral dosing. However, the median (95% confidence interval) diarrheal stool output rate for the iOWH032 group was 25.4 mL/hour (8.9, 58.3), compared to 32.6 mL/hour (15.8, 48.2) for the placebo group, a reduction of 23%, which was not statistically significant. There was also no significant decrease in diarrhea severity and number or frequency of stools associated with iOWH032 treatment. We conclude that iOWH032 does not merit future development for treatment of cholera and offer lessons learned for others developing antisecretory therapeutic candidates that seek to demonstrate proof of principle in a cholera controlled human infection model study. Trial registration: This study is registered with ClinicalTrials.gov as NCT04150250.
  • Inhibition of endogenous ouabain by atrial natriuretic peptide is a guanylyl cyclase independent effect.

    Tegin, Gulay; Gao, Yonglin; Hamlyn, John M; Clark, Barbara J; El-Mallakh, Rif S (Public Library of Science, 2021-11-18)
    BACKGROUND: Endogenous ouabain (EO) and atrial natriuretic peptide (ANP) are important in regulation of sodium and fluid balance. There is indirect evidence that ANP may be involved in the regulation of endogenous cardenolides. METHODS: H295R are human adrenocortical cells known to release EO. Cells were treated with ANP at physiologic concentrations or vehicle (0.1% DMSO), with or without guanylyl cyclase inhibitor 1,2,4 oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). Cyclic guanosine monophosphate (cGMP), the intracellular second messenger of ANP, was measured by a chemiluminescent immunoassay and EO was measured by radioimmunoassay of C18 extracted samples. RESULTS: EO secretion is inhibited by ANP treatment, with the most prolonged inhibition (90 min vs ≤ 60 min) occurring at physiologic ANP concentrations (50 pg/mL). Inhibition of guanylyl cyclase with ODQ, also reduces EO secretion. The inhibitory effects on EO release in response to cotreatment with ANP and ODQ appeared to be additive. CONCLUSIONS: ANP inhibits basal EO secretion, and it is unlikely that this is mediated through ANP-A or ANP-B receptors (the most common natriuretic peptide receptors) or their cGMP second messenger; the underlying mechanisms involved are not revealed in the current studies. The role of ANP in the control of EO synthesis and secretion in vivo requires further investigation.
  • Willingness to Get a COVID-19 Vaccine and Its Potential Predictors in Costa Rica: A Cross-Sectional Study

    Faerron Guzmán, Carlos A; Montero-Zamora, Pablo; Bolaños-Palmieri, Carolina; Araya-Amador, Juliana; Benavides-Rawson, Jorge; Ávila-Agüero, María L (Cureus, Inc., 2021-10-15)
    Since 2020, the COVID-19 pandemic has had a significant impact on morbidity and mortality around the world. As one of the most successful and cost-effective health interventions for preventing infectious diseases, immunization against SARS-CoV-2, is at the moment the most effective strategy for controlling the current pandemic. Despite the high vaccine acceptance rates that countries such as Costa Rica have shown in the past, the public acceptance of the COVID-19 vaccine is still uncertain. The purpose of this study was to examine adults' willingness to get a novel COVID-19 vaccine and its potential predictors in Costa Rica. We conducted a cross-sectional study comprising a sample of 4717 adult participants living in Costa Rica who participated in a voluntary electronic survey regarding their intent to get a future COVID-19 vaccine. Results suggest that a high percentage (86.1%) of Costa Ricans aged 18 or more would be willing to be vaccinated once a safe and effective vaccine is approved and distributed in the country. Some relevant significant predictors of willingness to get a COVID-19 vaccine in Costa Rica were higher income, being male, work in the health care sector, and having a relative or a close acquaintance diagnosed with COVID-19. Our findings suggest that it is essential to concentrate efforts on the immediate development of culturally appropriate communication, dissemination, and implementation strategies to maximize immunization against SARS-CoV-2 in Costa Rica.
  • Lofty goals and strategic plans are not enough to achieve and maintain a diverse workforce: an American Association for the Surgery of Trauma Diversity, Equity, and Inclusion Committee conversation

    Brasel, Karen; Berry, Cherisse; Williams, Brian H; Henry, Sharon M; Upperman, Jeffrey; West, Michaela A (BMJ Publishing Group, 2021-11-08)
    The American Association for the Surgery of Trauma Diversity, Equity, and Inclusion (DEI) Ad Hoc Committee organized a luncheon symposium with a distinguished panel of experts to discuss how to ensure a diverse surgical workforce. The panelists discussed the current state of DEI efforts within surgical departments and societal demographic changes that inform and necessitate surgical workforce adaptations. Concrete recommendations included the following: obtain internal data, establish DEI committee, include bias training, review hiring and compensation practices, support the department members doing the DEI work, commit adequate funding, be intentional with DEI efforts, and develop and support alternate pathways for promotion and tenure.
  • Focused Ultrasound Mediated Opening of the Blood-Brain Barrier for Neurodegenerative Diseases

    Fishman, Paul S; Fischell, Johnathan M (Frontiers Media S.A., 2021-11-04)
    The blood brain barrier (BBB) is an obstacle for the delivery of potential molecular therapies for neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). Although there has been a proliferation of potential disease modifying therapies for these progressive conditions, strategies to deliver these large agents remain limited. High intensity MRI guided focused ultrasound has already been FDA approved to lesion brain targets to treat movement disorders, while lower intensity pulsed ultrasound coupled with microbubbles commonly used as contrast agents can create transient safe opening of the BBB. Pre-clinical studies have successfully delivered growth factors, antibodies, genes, viral vectors, and nanoparticles in rodent models of AD and PD. Recent small clinical trials support the safety and feasibility of this strategy in these vulnerable patients. Further study is needed to establish safety as MRI guided BBB opening is used to enhance the delivery of newly developed molecular therapies.
  • Evaluation of mouse urinary bladder smooth muscle for diurnal differences in contractile properties

    White, Rachel S; Zemen, Betsir G; Khan, Zulqarnain; Montgomery, Jenna R; Herrera, Gerald M; Meredith, Andrea L (Frontiers Media S.A., 2015-01-09)
    Most physiological systems show daily variations in functional output, entrained to the day–night cycle. Humans exhibit a daily rhythm in urinary voiding (micturition), and disruption of this rhythm (nocturia) has significant clinical impact. However, the underlying mechanisms are not well-understood. Recently, a circadian rhythm in micturition was demonstrated in rodents, correlated with functional changes in urodynamics, providing the opportunity to address this issue in an animal model. Smooth muscle cells from mouse bladder have been proposed to express a functional and autonomous circadian clock at the molecular level. In this study, we addressed whether a semi-intact preparation of mouse urinary bladder smooth muscle (UBSM) exhibited measurable differences in contractility between day and night. UBSM tissue strips were harvested at four time points over the diurnal cycle, and spontaneous (phasic) and nerve-evoked contractions were assessed using isometric tension recordings. During the active period (ZT12-24) when micturition frequency is higher in rodents, UBSM strips had no significant differences in maximal- (high K+) or nerve-evoked contractions compared to strips harvested from the resting period (ZT0-12). However, a diurnal rhythm in phasic contraction was observed, with higher amplitudes at ZT10. Consistent with the enhanced phasic amplitudes, expression of the BK K+ channel, a key suppressor of UBSM excitability, was lower at ZT8. Higher expression of BK at ZT20 was correlated with an enhanced effect of the BK antagonist paxilline (PAX) on phasic amplitude, but PAX had no significant time-of-day dependent effect on phasic frequency or nerve-evoked contractions. Overall, these results identify a diurnal difference for one contractile parameter of bladder muscle. Taken together, the results suggest that autonomous clocks in UBSM make only a limited contribution to the integrated control of diurnal micturition patterns. Copyright © 2015 White, Zemen, Khan, Montgomery, Herrera and Meredith.
  • New Medical Device and Therapeutic Approvals in Otolaryngology: State of the Art Review 2020

    Brenner, Michael J.; Shenson, Jared A.; Rose, Austin S.; Valdez, Tulio A.; Takashima, Masayoshi; Ahmed, Omar G.; Weissbrod, Philip A.; Hong, Robert S.; Djalilian, Hamid; Wolf, Jeffrey S.; et al. (SAGE Publications Inc., 2021-11-10)
    Objectives: To evaluate new drugs and devices relevant to otolaryngology–head and neck surgery that were approved by the US Food and Drug Administration (FDA) in 2020. Data Sources: Publicly available device and therapeutic approvals from ENT (ear, nose, and throat), anesthesia, neurology (neurosurgery), and plastic and general surgery FDA committees. Review Methods: Members of the American Academy of Otolaryngology–Head and Neck Surgery’s Medical Devices and Drugs Committee reviewed new therapeutics and medical devices from a query of the FDA’s device and therapeutic approvals. Two independent reviewers assessed the drug’s or device’s relevance to otolaryngology, classified to subspecialty field, with a critical review of available scientific literature. Conclusions: The Medical Devices and Drugs Committee reviewed 53 new therapeutics and 1094 devices (89 ENT, 140 anesthesia, 511 plastic and general surgery, and 354 neurology) approved in 2020. Ten drugs and 17 devices were considered relevant to the otolaryngology community. Rhinology saw significant improvements around image guidance systems; indications for cochlear implantation expanded; several new monoclonal therapeutics were added to head and neck oncology’s armamentarium; and several new approvals appeared for facial plastics surgery, pediatric otolaryngology, and comprehensive otolaryngology. Implications for Practice: New technologies and pharmaceuticals offer the promise of improving how we care for otolaryngology patients. However, judicious introduction of innovations into practice requires a nuanced understanding of safety, advantages, and limitations. Working knowledge of new drugs and medical devices approved for the market helps clinicians tailor patient care accordingly. © The Authors 2021.
  • Determinants of the type of health care sought for symptoms of Acute respiratory infection in children: analysis of Ghana demographic and health surveys

    Danquah, Leslie; Amegbor, Prince Michael; Ayele, Dawit Getnet (Springer Nature, 2021-11-17)
    Background: Globally, acute respiratory infection (ARI) is a leading cause of infant and childhood morbidity and mortality. Currently, it is estimated that 50 million cases of childhood ARI are untreated. In this study, we identified determinants of the type of treatment sought for symptoms of childhood acute respiratory infection (ARI), including non-treatment, amongst a nationally representative sample of children under five years in Ghana. Methods: In total, 1 544 children were studied by a secondary analysis of pooled survey data from the 1993, 1998, 2003, 2008, and 2014 Ghana Demographic and Health Surveys (GDHS). Cross-tabulations, chi-square, multinomial logistic regression, and Bayesian hierarchical spatial logistic regression analyses were used to identify relationships between the type of treatment sought and maternal socio-economic and household characteristics. Results: Seeking medical care was significantly associated with child age (RRR= 1.928, 95 % CI 1.276 – 2.915), maternal employment status (RRR = 1.815, 95 % CI 1.202 – 2.740), maternal health insurance status, (RRR = 2.618, 95 % CI 1.801 – 3.989), children belonging to middle (RRR = 2.186, 95 % CI 1.473 – 3.243), richer (RRR = 1.908, 95 % CI 1.145 – 3.180) and richest households (RRR = 2.456, 95 % CI 1.363 – 4.424) and the 1998 survey period (RRR = 0.426, 95 % CI 0.240 – 7.58). Seeking self-care or visiting a traditional healer was significantly associated with maternal educational status (RRR = 0.000, 95 % CI 0.000 – 0.000), and the 1998 (RRR= 0.330, 95 % CI 0.142 – 0.765), 2003 (RRR= 0.195, 95 % CI 0.071 – 0.535), 2008 (RRR= 0.216, 95 % CI 0.068 – 0.685) and 2014 (RRR= 0.230, 95 % CI 0.081 – 0.657) GDHS periods. The probability that the odds ratio of using medical care exceeded 1 was higher for mothers/caregivers in the Western, Ashanti, Upper West, and Volta regions. Conclusions: Government policies that are aimed at encouraging medical care-seeking for children with ARI may yield positive results by focusing on improving maternal incomes, maternal NHIS enrolment, and maternal household characteristics. Improving maternal education could be a positive step towards addressing challenges with self-care or traditional healing amongst children with ARI. © 2021, The Author(s).
  • Potential Role for Combined Subtype-Selective Targeting of M and M Muscarinic Receptors in Gastrointestinal and Liver Diseases

    Tolaymat, Mazen; Sundel, Margaret H; Alizadeh, Madeline; Xie, Guofeng; Raufman, Jean-Pierre (Frontiers Media S.A., 2021-11-04)
    Despite structural similarity, the five subtypes comprising the cholinergic muscarinic family of G protein-coupled receptors regulate remarkably diverse biological functions. This mini review focuses on the closely related and commonly co-expressed M1R and M3R muscarinic acetylcholine receptor subtypes encoded respectively by CHRM1 and CHRM3. Activated M1R and M3R signal via Gq and downstream initiate phospholipid turnover, changes in cell calcium levels, and activation of protein kinases that alter gene transcription and ultimately cell function. The unexpectedly divergent effects of M1R and M3R activation, despite similar receptor structure, distribution, and signaling, are puzzling. To explore this conundrum, we focus on the gastrointestinal (GI) tract and liver because abundant data identify opposing effects of M1R and M3R activation on the progression of gastric, pancreatic, and colon cancer, and liver injury and fibrosis. Whereas M3R activation promotes GI neoplasia, M1R activation appears protective. In contrast, in murine liver injury models, M3R activation promotes and M1R activation mitigates liver fibrosis. We analyze these findings critically, consider their therapeutic implications, and review the pharmacology and availability for research and therapeutics of M1R and M3R-selective agonists and antagonists. We conclude by considering gaps in knowledge and other factors that hinder the application of these drugs and the development of new agents to treat GI and liver diseases.
  • Ensuring High and Equitable COVID-19 Vaccine Uptake Among Patients With IBD

    Caldera, Freddy; Balzora, Sophie; Hayney, Mary S; Farraye, Francis A; Cross, Raymond K (Oxford University Press, 2021-05-20)
    The recent emergency use authorization of a third COVID-19 vaccine means that most patients with inflammatory bowel disease (IBD) will soon be eligible to be vaccinated. Gastroenterology clinicians should be prepared to address patients' concerns regarding safety and efficacy of vaccines. They should also strongly recommend that all their patients be vaccinated with a COVID-19 vaccine. Additionally, they should be prepared to educate patients about logistics that will result in successful vaccination completion. All these measures will be crucial to ensure high uptake among their patients with IBD. © 2021 Crohn's & Colitis Foundation.
  • Human periodontal ligament stem cell and umbilical vein endothelial cell co-culture to prevascularize scaffolds for angiogenic and osteogenic tissue engineering

    Zhao, Zeqing; Sun, Yaxi; Qiao, Qingchen; Zhang, Li; Xie, Xianju; Weir, Michael D.; Schneider, Abraham; Xu, Hockin H.K.; Zhang, Ning; Zhang, Ke; et al. (MDPI AG, 2021-11-16)
    (1) Background: Vascularization remains a critical challenge in bone tissue engineering. The objective of this study was to prevascularize calcium phosphate cement (CPC) scaffold by coculturing human periodontal ligament stem cells (hPDLSCs) and human umbilical vein endothelial cells (hUVECs) for the first time; (2) Methods: hPDLSCs and/or hUVECs were seeded on CPC scaffolds. Three groups were tested: (i) hUVEC group (hUVECs on CPC); (ii) hPDLSC group (hPDLSCs on CPC); (iii) co-culture group (hPDLSCs + hUVECs on CPC). Osteogenic differentiation, bone mineral synthesis, and microcapillary-like structures were evaluated; (3) Results: Angiogenic gene expressions of co-culture group were 6–9 fold those of monoculture. vWF expression of co-culture group was 3 times lower than hUVEC-monoculture group. Osteogenic expressions of co-culture group were 2–3 folds those of the hPDLSC-monoculture group. ALP activity and bone mineral synthesis of co-culture were much higher than hPDLSC-monoculture group. Co-culture group formed capillary-like structures at 14–21 days. Vessel length and junction numbers increased with time; (4) Conclusions: The hUVECs + hPDLSCs co-culture on CPC scaffold achieved excellent osteogenic and angiogenic capability in vitro for the first time, generating prevascularized networks. The hPDLSCs + hUVECs co-culture had much better osteogenesis and angiogenesis than monoculture. CPC scaffolds prevacularized via hPDLSCs + hUVECs are promising for dental, craniofacial, and orthopedic applications. © 2021 by the authors.
  • Mechanical ventilation and prone positioning in pregnant patients with severe COVID-19 pneumonia: experience at a quaternary referral center

    Wong, M J; Bharadwaj, S; Lankford, A S; Galey, J L; Kodali, B S (Elsevier Inc., 2021-11-08)
    Background: We present the care of 17 consecutive pregnant patients who required mechanical ventilation for Coronavirus disease 2019 (COVID-19) pneumonia at a quaternary referral center in the United States. We retrospectively describe the management of these patients, maternal and fetal outcomes, as well as the feasibility of prone positioning and delivery. Methods: Between March 2020 and June 2021, all pregnant and postpartum patients who were mechanically ventilated for COVID-19 pneumonia were identified. Details of their management including prone positioning, maternal and neonatal outcomes, and complications were noted. Results: Seventeen pregnant patients required mechanical ventilation for COVID-19. Thirteen patients received prone positioning, with a total of 49 prone sessions. One patient required extracorporeal membrane oxygenation. All patients in this series survived until at least discharge. Nine patients delivered while mechanically ventilated, and all neonates survived, subsequently testing negative for SARS-CoV-2. There was one spontaneous abortion. Four emergent cesarean deliveries were prompted by refractory maternal hypoxemia or non-reassuring fetal heart rate after maternal intubation. Conclusions: Overall, maternal and neonatal survival were favorable even in the setting of severe COVID-19 pneumonia requiring mechanical ventilation. Prone positioning was well tolerated although the impact of prone positioning or fetal delivery on maternal oxygenation and ventilation are unclear.
  • Adjunctive virtual reality pain relief following traumatic injury: protocol for a randomised within-subjects clinical trial

    Felix, Ryan B; Rao, Aniruddha; Khalid, Mazhar; Wang, Yang; Colloca, Luana; Murthi, Sarah B; Morris, Nicholas A (BMJ Publishing Group, 2021-11-30)
    Introduction: The annual mortality and national expense of the opioid crisis continue to rise in the USA (130 deaths/day, $50 billion/year). Opioid use disorder usually starts with the prescription of opioids for a medical condition. Its risk is associated with greater pain intensity and coping strategies characterised by pain catastrophising. Non-pharmacological analgesics in the hospital setting are critical to abate the opioid epidemic. One promising intervention is virtual reality (VR) therapy. It has performed well as a distraction tool and pain modifier during medical procedures; however, little is known about VR in the acute pain setting following traumatic injury. Furthermore, no studies have investigated VR in the setting of traumatic brain injury (TBI). This study aims to establish the safety and effect of VR therapy in the inpatient setting for acute traumatic injuries, including TBI. Methods and analysis: In this randomised within-subjects clinical study, immersive VR therapy will be compared with two controls in patients with traumatic injury, including TBI. Affective measures including pain catastrophising, trait anxiety and depression will be captured prior to beginning sessions. Before and after each session, we will capture pain intensity and unpleasantness, additional affective measures and physiological measures associated with pain response, such as heart rate and variability, pupillometry and respiratory rate. The primary outcome is the change in pain intensity of the VR session compared with controls. Ethics and dissemination: Dissemination of this protocol will allow researchers and funding bodies to stay abreast in their fields through exposure to research not otherwise widely publicised. Study protocols are compliant with federal regulation and University of Maryland Baltimore's Human Research Protections and Institutional Review Board (protocol number HP-00090603). Study results will be published on completion of enrolment and analysis, and deidentified data can be shared by request to the corresponding author. Trial registration number: NCT04356963; Pre-results.
  • 73-year-old Female with Syncope and Motor Vehicle Collision

    Flanagan, Kevin; Dezman, Zachary D W; Dachroeden, Karl J; Bontempo, Laura J (eScholarship, 2021-11-01)
    Introduction: Patients with traumatic injuries can be difficult to assess, and their evaluation often evolves in the emergency department (ED). We describe how an ED attending physician member developed a differential diagnosis for this presentation, arrived at a suspected diagnosis, and what test he proposed to prove his hypothesis. Case presentation: This clinicopathological case presentation details the initial assessment and management of a 73-year-old female who presented to the ED following a motor vehicle collision precipitated by a syncopal episode. Conclusion: The final surprising diagnosis is then revealed.
  • Tangier Disease: An Unusual Cause of Chronic Diarrhea

    Ritaccio, Gabrielle; Asif, Bilal; Yfantis, Harris; Wong, Uni (Wolters Kluwer Health, 2021-11-24)
    Tangier disease is a rare autosomal recessive disease resulting in cholesterol deposition in different organs. We report a case of a 52-year-old white man who presented for chronic diarrhea without significant findings on noninvasive testing. Subsequent colonoscopy revealed endoscopically normal mucosa, with random biopsies remarkable for foamy macrophages in the lamina propria. Genetic testing showed adenosine triphosphate-binding cassette transporter gene mutation with low high-density lipoprotein and low low-density lipoprotein. To the best of our knowledge, this is the first report of chronic diarrhea in a patient with Tangier disease without any other clear etiology.
  • Two Cases of Armour Thyroid Interference in Thyroglobulin Monitoring for Thyroid Cancer

    Ponder, Michelle; Lamos, Elizabeth; Munir, Kashif (Elsevier Inc., 2021-11-17)
    Thyroglobulin (Tg) monitoring is the biochemical standard for surveillance of recurrent differentiated thyroid cancer (DTC). Several assays are available to quantify Tg levels: immunometric assay (IMA), radioimmunoassay (RIA), and the newer liquid chromatography tandem mass spectrometry (LC-MS). It is well known that a number of entities can interfere with the accuracy of testing, and at this point in time, no one assay perfectly balances high sensitivity with low risk of interference. In this case study, we present two cases in which treatment with desiccated thyroid extract (Armour thyroid) led to a sudden elevation in Tg, which resolved when Armour thyroid was discontinued. This elevation occurred when Tg was measured with both IMA and LC-MS, which suggests direct interference from porcine Tg rather than heterophilic or thyroglobulin antibody (TgAb) interference. We suggest that patients with a history of DTC not be treated with desiccated thyroid extracts consistent with guidelines. Furthermore, more advances need to be made in the area of Tg testing to improve specificity and avoid detection of nonhuman Tg and other similar proteins.
  • Imaging and Electrophysiology for Degenerative Cervical Myelopathy [AO Spine RECODE DCM Research Priority Number 9]

    Martin, Allan R; Tetreault, Lindsay; Davies, Benjamin M; Curt, Armin; Freund, Patrick; Rahimi-Movaghar, Vafa; Wilson, Jefferson R; Fehlings, Michael G; Kwon, Brian K; Harrop, James S; et al. (SAGE Publications Inc., 2021-11-19)
    Study Design: Narrative review. Objective: The current review aimed to describe the role of existing techniques and emerging methods of imaging and electrophysiology for the management of degenerative cervical myelopathy (DCM), a common and often progressive condition that causes spinal cord dysfunction and significant morbidity globally. Methods: A narrative review was conducted to summarize the existing literature and highlight future directions. Results: Anatomical magnetic resonance imaging (MRI) is well established in the literature as the key imaging tool to identify spinal cord compression, disc herniation/bulging, and inbuckling of the ligamentum flavum, thus facilitating surgical planning, while radiographs and computed tomography (CT) provide complimentary information. Electrophysiology techniques are primarily used to rule out competing diagnoses. However, signal change and measures of cord compression on conventional MRI have limited utility to characterize the degree of tissue injury, which may be helpful for diagnosis, prognostication, and repeated assessments to identify deterioration. Early translational studies of quantitative imaging and electrophysiology techniques show potential of these methods to more accurately reflect changes in spinal cord microstructure and function. Conclusion: Currently, clinical management of DCM relies heavily on anatomical MRI, with additional contributions from radiographs, CT, and electrophysiology. Novel quantitative assessments of microstructure, perfusion, and function have the potential to transform clinical practice, but require robust validation, automation, and standardization prior to uptake. © The Author(s) 2021.
  • Brain innate immune response via miRNA-TLR7 sensing in polymicrobial sepsis

    Zou, Lin; He, Junyun; Gu, Lili; Shahror, Rami A.; Li, Yun; Cao, Tuoxin; Wang, Sheng; Zhu, Jing; Huang, Huang; Chen, Fengqian; et al. (Academic Press Inc., 2021-11-19)
    Sepsis-associated encephalopathy (SAE) occurs in sepsis survivors and is associated with breakdown of the blood–brain barrier (BBB), brain inflammation, and neurological dysfunction. We have previously identified a group of extracellular microRNAs (ex-miRNAs), such as miR-146a-5p, that were upregulated in the plasma of septic mice and human, and capable of inducing potent pro-inflammatory cytokines and complements. Here, we established a clinically relevant mouse model of SAE and investigated the role of extracellular miRNAs and their sensor Toll-like receptor 7 (TLR7) in brain inflammation and neurological dysfunction. We observed BBB disruption and a profound neuroinflammatory responses in the brain for up to 14 days post-sepsis; these included increased pro-inflammatory cytokines production, microglial expansion, and peripheral leukocyte accumulation in the CNS. In a battery of neurobehavioral tests, septic mice displayed impairment of motor coordination and neurological function. Sepsis significantly increased plasma RNA and miRNA levels for up to 7 days, such as miR-146a-5p. Exogenously added miR-146a-5p induces innate immune responses in both cultured microglia/astrocytes and the intact brain via a TLR7-dependent manner. Moreover, mice genetically deficient of miR-146a showed reduced accumulation of monocytes and neutrophils in the brain compared to WT after sepsis. Finally, ablation of TLR7 in the TLR7-/- mice preserved BBB integrity, reduced microglial expansion and leukocyte accumulation, and attenuated GSK3β signaling in the brain, but did not improve neurobehavioral recovery following sepsis. Taken together, these data establish an important role of extracellular miRNA and TLR7 sensing in sepsis-induced brain inflammation. © 2021 The Author(s)

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