Reports Grants Research Articles

Community pharmacists' perceptions of acceptability, appropriateness, and feasibility of a value-based care model for comprehensive medication management.

BACKGROUND: HealthPartners is an integrated health plan offering comprehensive medication management (CMM) under a value-based care model called Partners in Excellence (PIE). In PIE, participating organizations are incentivized to conduct CMM visits and are eligible for bonus payments if they achieve quality and engagement metrics. Engagement in PIE from community pharmacies has been lacking. Implementation science, specifically the assessment of implementation outcomes, provides key insights into the uptake of patient care services, such as CMM, into practice. OBJECTIVE: To evaluate the acceptability, appropriateness, and feasibility of the PIE program from the perspective of community pharmacists and pharmacy managers. METHODS: Semi-structured, one-on-one qualitative interviews were conducted with a group of 14 pharmacists and pharmacy managers participating in the PIE program. Interviews were coded inductively, and then codes were mapped to the implementation outcomes of acceptability, appropriateness, and feasibility. RESULTS: Twelve codes emerged from the interviews. Four codes (targeted conditions of PIE, achieving PIE metrics, comprehensiveness of PIE, and confusion and barriers) were mapped to acceptability; 3 codes (CMM documentation and billing, fitting CMM into limited time with patients, and community pharmacy's role in patient care) were mapped to appropriateness; and 1 code (collecting clinical patient information) was mapped to feasibility. Four codes (CMM payment model, targeting patients for CMM, personnel for CMM, and patient/provider buy-in of CMM) were considered a combination of more than 1 outcome. CONCLUSIONS: Although the acceptability, appropriateness, and feasibility of the PIE program was generally positive, participants cited a number of implementation challenges related to documentation and billing and producing a sustainable CMM model. The results shed light on how a value-based care model for CMM is perceived within community pharmacies and could inform the development and implementation of similar quality-based CMM programs. DISCLOSURES: This study was funded by the National Association of Chain Drug Stores (NACDS) Foundation and the UNC Eshelman Institute for Innovation. Pestka is affiliated with the University of Minnesota College of Pharmacy and reports grants from NACDS Foundation and UNC Eshelman Institute for Innovation for the conduct of the study; she has also received grants from UNC Eshelman Institute for Innovation and NACDS Foundation outside the submitted work. Stoa and Sorensen are also affiliated with the University of Minnesota College of Pharmacy. Blanchard is employed at the UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill. This work was presented as a virtual poster at the 2020 American College of Clinical Pharmacy Annual Meeting, October 19-30, 2020.

Web Exclusive. Annals On Call - The Importance of Clinician-Educators.

Web ExclusivesJuly 2021Annals On Call - The Importance of Clinician–EducatorsFREERobert M. Centor, MD, Kimberly D. Manning, MDRobert M. Centor, MDHuntsville Regional Medical Campus, University of Alabama Birmingham School of Medicine, Birmingham, Alabama (R.M.C.)Search for more papers by this author, Kimberly D. Manning, MDEmory University, Atlanta, Georgia (K.D.M.)Search for more papers by this authorAuthor, Article and Disclosure Informationhttps://doi.org/10.7326/A20-0016 CME/MOC SectionsAboutVisual Abstract ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail In this episode of Annals On Call, Dr. Centor discusses the important but often underappreciated role of clinician–educators in academic medicine with Dr. Kimberly Manning.Annals articles discussed include...The Death of a Clinician-Educator: https://www.acpjournals.org/doi/10.7326/0003-4819-149-4-200808190-00013About Annals On CallAnnals On Call focuses on a clinically influential article published in Annals of Internal Medicine. Dr. Robert Centor shares his own perspective on the material and interviews topic area experts to discuss, debate, and share diverse insights about patient care and health care delivery.For more information on Annals On Call and for more episodes, visit go.annals.org/OnCall. Comments0 CommentsSign In to Submit A Comment Author, Article and Disclosure InformationAffiliations: Huntsville Regional Medical Campus, University of Alabama Birmingham School of Medicine, Birmingham, Alabama (R.M.C.)Emory University, Atlanta, Georgia (K.D.M.)Disclosures: Dr. Centor has disclosed the following: Consultancy: DynaMed, MDCalc. Employment: U.S. Department of Veterans Affairs. Dr. Manning has reported no disclosures of interest.Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that her spouse has stock options/holdings with Targeted Diagnostics and Therapeutics. Stephanie Chang, MD, MPH, Deputy Editor, reports employment with the Agency for Healthcare Research and Quality, travel compensation from the Guidelines International Network, and participation in the Patient-Centered Outcomes Research Institute methodology committee. Vineet Chopra, MD, MSc, Deputy Editor, reports grants received from the Agency for Healthcare Research and Quality and royalties from UpToDate and Oxford University Press. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interests to disclose. Eliseo Guallar, MD, MPH, DrPH, Deputy Editor, Statistics, reports that he has no financial relationships or interests to disclose. Christina C. Wee, MD, MPH, Deputy Editor, reports employment with Beth Israel Deaconess Medical Center and consultancy with Boston Medical Center. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Yu-Xiao Yang, MD, MSCE, Deputy Editor, reports employment with the Perelman School of Medicine, University of Pennsylvania, and consultancies with the U.S. Food and Drug Administration and the State of Colorado.This article was published at Annals.org on 6 July 2021. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics July 2021Volume 174, Issue 7Page: OC1 ePublished: 6 July 2021 Issue Published: July 2021 CopyrightCopyright © 2021 by American College of Physicians. All Rights Reserved.Loading ...

Soluble Dipeptidyl-Peptidase 4 (sDPP4) Serum Activity Is Associated With the Severity of COVID-19 Disease and is a Strong Prognostic Biomarker of Mortality

Background: Type 2 diabetes mellitus (T2DM) and obesity are risk factors of COVID-19 disease course. Retrospective observational analyses reported improvement in COVID-19 severe outcomes and mortality in T2DM patients using a DPP4 inhibitor. However, little is known about the prognostic value of circulating soluble DPP4 activity in patients with SARS-CoV-2 infection.Methods: We conducted an observational, retrospective cohort study with 184 Hungarian adults. Hospitalized patients with acute COVID-19 disease (n=102) and plasma donors (n=43) recovered from prior SARS-CoV-2 infection were enrolled from April to July, 2020 at two institutions in Budapest. “Non-COVID-19 controls” (n=39) were employed with serum sDPP4 activity determined from samples taken before September, 2019. Duplicate serum sDPP4 activity determinations by microplate base enzyme kinetic assay were successful in 182 individuals from different COVID-19 disease severity groups (acute COVID-19 patients were classified into 4 and plasma donors into 2 categories based on peak severity).Findings: A significant difference in sDPP4 activity was found among study groups (pInterpretation: We concluded that serum sDPP4 activity is associated with the severity and a strong biomarker of mortality in COVID-19 disease.Funding Information: Ramgen funded the sDPP4 activity measurement and related costs in the study.Declaration of Interests: Semmelweis University and Central Hospital of Southern Pest, National Institute for Infectious Diseases and Haematology has entered into a contractual partnership with Ramgen to conduct this research and they submitted a patent application (HIPO Ref: 311174000-20210226-1522-004576, inventors: GF, ZP, IVN). ÁN reports a prior fellowship at the Semmelweis University - Rácz Károly Doctoral School which ended prior to the initiation of this project for which he was contracted with Ramgen. IB reports institutional grants or contracts form Envision 2000 and EuroPN (Fresenius Kabi). BL reports payment or honoraria from GlaxoSmithKline, MSD, Fresenius-Kabi, Gilead Sciences, outside of the submitted work. MA reports an associate professor position of Eötvös Loránd University, Faculty of Science, Department of Probability Theory and Statistics, Institute of Mathematics and that he was separately contracted with Ramgen unconnected to his other employments. TM reports on a data safety monitoring board or advisory board participation at AbbVie, BMS, Janssen-Cilag, Novartis, Pfizer, Takeda. CG reports stocks in Ramgen and other interests as co-CEO in Ramgen. BM reports institutional payments from Medtronic, Boston Scientific; personal fees from Biotronik, Abbott, AstraZeneca, Boehringer Ingelheim, and Novartis, outside of the submitted work. PF reports leadership role as President of Hungarian Society for Experimental and Clinical Pharmacology; and other interests as the founder, and CEO of PharmaHungary Group, outside of the submitted work. VNI reports grants or contracts from National Research, Development and Innovation Office, National Research, Development and Innovation Office / Ministry of Innovation and Technology, and Ministry of Human Capacities, outside of the submitted work. GF reports a paid part time employment at the Semmelweis University- Eötvös Loránd Research Network (Molecular Medicine Study group, Hungarian Academy of Sciences, where his employer did not declare employee conflict of interest for this independently conducted project); support for attending meetings and personal fees from 77 Elektronika, and Diabetes and Metabolism Foundation, outside of the submitted work; stocks in Biomerieux and Ramgen and other interests as co-CEO in Ramgen. All the other authors have nothing to declare.Ethics Approval Statement: Study participants signed the informed consent for the whole project and all the sample collections as well as the subsequent study on sDPP4 activity conducted by Ramgen possessed the ethical approval of the national ethical body of Hungary (Medical Research Council Scientific and Research Committee, reference: IV/4403-4/2020/EKU; December 30, 2020). The study was conducted according to the declaration of Helsinki.

Menstrual fluid endometrial stem/progenitor cell and supernatant protein content: cyclical variation and indicative range.

Does natural variation exist in the endometrial stem/progenitor cell and protein composition of menstrual fluid across menstrual cycles in women? Limited variation exists in the percentage of some endometrial stem/progenitor cell types and abundance of selected proteins in menstrual fluid within and between a cohort of women. Menstrual fluid is a readily available biofluid that can represent the endometrial environment, containing endometrial stem/progenitor cells and protein factors. It is unknown whether there is natural variation in the cellular and protein content across menstrual cycles of individual women, which has significant implications for the use of menstrual fluid in research and clinical applications. Menstrual fluid was collected from 11 non-pregnant females with regular menstrual cycles. Participants had not used hormonal medications in the previous 3 months. Participants collected menstrual fluid samples from up to five cycles using a silicone menstrual cup worn on Day 2 of menstrual bleeding. Menstrual fluid samples were centrifuged to separate soluble proteins and cells. Cells were depleted of red blood cells and CD45+ leucocytes. Menstrual fluid-derived endometrial stem/progenitor cells were characterized using multicolour flow cytometry including markers for endometrial stem/progenitor cells N-cadherin (NCAD) and stage-specific embryonic antigen-1 (SSEA-1) (for endometrial epithelial progenitor cells; eEPC), and sushi domain containing-2 (SUSD2) (for endometrial mesenchymal stem cells; eMSC). The clonogenicity of menstrual fluid-derived endometrial cells was assessed using colony forming unit assays. Menstrual fluid supernatant was analyzed using a custom magnetic Luminex assay. Endometrial stem/progenitor cells are shed in menstrual fluid and demonstrate clonogenic properties. The intraparticipant agreement for SUSD2+ menstrual fluid-derived eMSC (MF-eMSC), SSEA-1+ and NCAD+SSEA-1+ MF-eEPC, and stromal clonogenicity were moderate-good (intraclass correlation; ICC: 0.75, 0.56, 0.54 and 0.52, respectively), indicating limited variability across menstrual cycles. Endometrial inflammatory and repair proteins were detectable in menstrual fluid supernatant, with five of eight (63%) factors demonstrating moderate intraparticipant agreement (secretory leukocyte protein inhibitor (SLPI), lipocalin-2 (NGAL), lactoferrin, follistatin-like 1 (FSTL1), human epididymis protein-4 (HE4); ICC ranges: 0.57-0.69). Interparticipant variation was limited for healthy participants, with the exception of key outliers of which some had self-reported menstrual pathologies. N/A. There are no OMICS or other data sets relevant to this study. The main limitations to this research relate to the difficulty of obtaining menstrual fluid samples across multiple menstrual cycles in a consistent manner. Several participants could only donate across <3 cycles and the duration of wearing the menstrual cup varied between 4 and 6 h within and between women. Due to the limited sample size used in this study, wider studies involving multiple consecutive menstrual cycles and a larger cohort of women will be required to fully determine the normal range of endometrial stem/progenitor cell and supernatant protein content of menstrual fluid. Possibility for selection bias and true representation of the population of women should also be considered. Menstrual fluid is a reliable source of endometrial stem/progenitor cells and related endometrial proteins with diagnostic potential. The present study indicates that a single menstrual sample may be sufficient in characterizing a variety of cellular and protein parameters across women's menstrual cycles. The results also demonstrate the potential of menstrual fluid for identifying endometrial and menstrual abnormalities in both research and clinical settings as a non-invasive method for assessing endometrial health. This study was supported by grants from the Australian National Health and Medical Research Council to C.E.G. (Senior Research Fellowship 1024298 and Investigator Fellowship 1173882) and to J.E. (project grant 1047756), the Monash IVF Research Foundation to C.E.G. and the Victorian Government's Operational Infrastructure Support Program. K.A.W., M.L.D.-T., S.G.S. and J.E. declare no conflicts of interest. C.E.G. reports grants from NHMRC, during the conduct of the study; grants from EndoFound USA, grants from Ferring Research Innovation, grants from United States Department of Defence, grants from Clue-Utopia Research Foundation, outside the submitted work. CEF reports grants from EndoFound USA, grants from Clue-Utopia Research Foundation, outside the submitted work.

Endothelial dysfunction and its critical role in COVID-19-associated coagulopathy: Defibrotide as an endothelium-protective, targeted therapy.

To the Editor: Recent publications emphasize that patients with COVID-19 commonly present with lethal disseminated intravascular coagulopathy (DIC) characterized by increased levels of D-dimer, fibrinogen, and elevated prothrombin time and activated partial thromboplastin time [1]. These abnormalities are associated with increased rates of thromboembolism and a profound prothrombotic state. However, other authors have found that both severe and mild COVID-19 patients show similar levels of endogenous anticoagulants and similar anti-thrombin, protein C, protein S, α2-antiplasmin and plasminogen activator inhibitor-1 (PAI-1) activities [2], suggesting that we need new diagnostic criteria since the COVID-19 coagulopathy is different to the usual forms of disseminated intravascular coagulopathy [3]. These authors conclude that preventive measures for thromboprophylaxis are key and diverse antithrombotic therapies may be especially helpful in COVID-19 patients. It has been also reported that other markers of endothelial stress, including von Willebrand factor (VWF) and thrombomodulin, may predict mortality in COVID-19 patients, suggesting therapeutic strategies to normalize endothelial cell function and protect vascular integrity are indeed vital [2]. The crucial role of endotheliitis in COVID-19 has been substantiated by pathological findings from autopsies [4]. We wish to also highlight the possible role of heparan sulfate and heparanase in the endothelial dysfunction of COVID-19, via the heparan sulfate-heparanase pathway that triggers increased serum levels of inflammatory cytokines as part of disease pathobiology and additional targeted therapies derived thereon. Specifically, SARS-CoV-2 damage to endothelial cells (EC), and subsequent endotheliitis [4] leads to upregulation of heparanase, an endo-β-glucuronidase that degrades the heparan sulfate scaffold of the glycocalyx and subendothelial basement membrane, increasing endothelial dysfunction and allowing extravasation of activated immune cells into the extravascular compartment [5, 6]. Heparan sulfate is an extracellular matrix sulfated glycosaminoglycan that protects mucosal epithelia and a co-receptor for growth factors, cytokines, selectins, and viruses, including SARS-CoV-2. Additionally, heparanase is upregulated by pro-inflammatory molecules and promotes expression of TNF-α, IL-6, MIP-2, and IL-1 in a pro-inflammatory loop, which contributes further to inflammatory cytokines elevations [5]. Defibrotide is a complex mixture of poly-deoxyribonucleotides extracted from porcine gut mucosa with pleiotropic properties, including anti-thrombotic, pro-fibrinolytic, anti-inflammatory, and protective effects on small vessel endothelia [7]. Defibrotide increases tissue plasminogen activator and thrombomodulin expression, enhancing the activity of plasmin to hydrolyze fibrin clots, decreasing VWF, and PAI-1. Platelet adhesion is inhibited via increased nitric oxide and prostaglandin E2 and I2 release. Conversely, defibrotide decreases inflammatory mediators including IL-6, TNF-α, VEGF, thromboxane A2, leukotriene B4, and reactive oxygen species. Defibrotide downregulates endothelial adhesion molecules such as P-selectin, E-selectin, ICAM-1, VCAM-1, and has been shown to inhibit leukocyte-endothelial interactions [8]. Most importantly, defibrotide potently inhibits heparanase activity and its cell surface expression in variety of settings [7, 9]. Moreover, it blocks the heparanase-heparan sulfate axis, by competing with heparan sulfate, and so may in turn inhibit both heparanase-mediated viral release and spread, as well as heparanase-mediated activation of immune cells and elevated inflammatory cytokines [5]. Defibrotide is approved for the treatment of severe veno-occlusive disease/sinusoidal obstruction syndrome and has efficacy in patients with endothelial dysfunction and multiorgan failure, with activity in clinical studies and animal models of graft-versus-host disease incorporating lung injury [7, 8]. Its multitargeted endothelial-based therapeutic properties make it a potentially ideal candidate to treat vascular complications of COVID-19. Clinical studies are either planned or already underway in various countries, including Spain, Italy, and the United States, with the leading Spanish phase 2 study (ClinicalTrials.gov Identifier: NCT04348383) showing promising early results. This study has been financed in part by the Instituto de Salud Carlos III (ISCIII) project COV20/00399. US National Library of Medicine. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT04348383 (2020). All authors have contributed equally to this work. Dr. David Garcia Bernal, Dr. Israel Vlodavsky, and Dr. Massimo Iacobelli have no conflict of interest to declare. Dr. Carmelo Carlo-Stella has received research support from ADC Therapeutics and Rhizen Pharmaceuticals; has served as consultant or advisor for Servier, Novartis, Genenta Science srl, ADC Therapeutics, Roche, Sanofi, Karyopharm and Jazz Pharmaceuticals; and has received honoraria for speaker engagements from Bristol-Myers Squibb, Merck Sharp & Dohme, Janssen Oncology, and Astra-Zeneca. Dr. Ruben Jara declares honorarium from Edwards Lifesciences and Getinge. Dr. Paul Richardson serves on advisory committees for Jazz Pharmaceuticals. Dr. Jose M. Moraleda reports grants from Jazz Pharmaceuticals, during the conduct of the study; consulting honoraria and travel expenses from Gilead, consulting honoraria from Novartis, Sandoz, and Takeda, outside the submitted work.

Fatal COVID-19 is Characterized by Distinct Vasculopathic Features and Increased Congestion of the Alveolar Capillary-Bed

Background: Clinical and radiologic studies investigating Coronavirus disease 2019 (COVID-19) indicate that a possible cause of severe hypoxia is marked ventilation-perfusion (VA/Q) mismatch. Published histopathology reports diffuse alveolar damage (DAD) in fatal COVID-19 is indistinguishable from other causes of DAD. We compared lung parenchymal and vascular alterations between COVID-19 and DAD of other etiologies using a multidimensional approach. Methods: This autopsy cohort consisted of consecutive COVID-19 patients (n=20) and patients with clinical acute respiratory distress syndrome and histologic DAD (n=21; non-COVID-19 viral and non-viral etiologies). Premortem chest CTs were evaluated for mosaic attenuation and vascular changes. Postmortem lung tissues were compared using histopathological, immunohistochemical, transcriptomics and computational analyses. Machine-learning-derived morphometric analysis of microvasculature was performed, with a random forest classifier quantifying vascular congestion (VSCong), in different microscopic compartments. Findings: On premortem CT, COVID-19 patients showed more mosaic attenuation (p<0·020), and subsegmental dilated vasculature (p=0·003) compared to controls. Histopathology revealed vasculopathic changes including: capillary-congestion and hemangiomatosis-like changes (p=0·043), microthrombi (p=0·026), thromboemboli (p=0·0036), infarcts (p=0·048), and perivascular inflammation(p <0·001). Immunohistochemistry revealed increased CD4+ T-cells(p=0·023), TIM3+ lymphocytes/macrophages (p=0·037/0·019), and PD-1+ cells(p=0·008). Morphometric analysis in COVID-19 revealed significantly higher bronchiolar VS Cong (p <0·0001) and alveolar-septal VSCong (p<0·0001), with larger overall VSCong range (p=0·002). Septal-congestion was associated with a significantly shorter time-to-death from symptom onset (p=0·02). Interpretation: Severe COVID-19 is characterized by significant vasculopathy and aberrant alveolar septal-congestion, which may be associated with shorter time-to-death. Dilated sublobar vessels and heterogeneously increased septal-congestion may translate to VA/Q mismatch in COVID-19. These findings warrant further investigation in larger multi-institutional autopsy cohorts. Funding Information: Supported by Internal Sundry, and Vickery-Colvin Award from the Department of Pathology, Massachusetts General Hospital. Declaration of Interests: LPH reports grants from Boehringer Ingelheim and has received personal consulting fees from Boehringer Ingelheim, Pliant Therapeutics, and Biogen Idec, all of which are not related to this study. SET have received CDC funding for other COVID-related work which are not related to this study. JAB has received grant support from Zeus Scientific, bioMerieux, Immunetics, the Bay Area Lyme Foundation and the Lyme Disease Biobank Foundation for work not related to this study, and has been a consultant for T2 Biosystems, DiaSorin and Roche Diagnostics, not related to this study. BPL reports royalties from Elsevier, Inc. for his work as an associate textbook editor, not related to this study. MMK has served as a compensated consultant for H3 Biomedicine and AstraZeneca and has received research (institutional) funding from Novartis and loyalty from Elsevier, all of which are not related to this study. The other authors declare no competing interests. Ethics Approval Statement: Analysis of patient autopsy material was reviewed and approved by the Partners Human Research IRB (Protocol #: 2020P001146).

Does diagnostic delay impact on the outcome of epilepsy?

Seizure recurrence in epilepsy poses the patient at risk of self-harm and can have a negative impact on his/her personal and social life. For this reason, the disease, when suspected, should be promptly diagnosed and treated. Unfortunately, this is not the case for several patients. Diagnostic delay in people with epilepsy has been the object of a number of studies that, even with differing results, showed that the disease might go undiagnosed for several years.1-4 A delay in the diagnosis of epilepsy may occur preferably when the first seizures are focal or, if generalized, they present with inhibitory features or only mild motor signs. In those cases, the patient might seek medical advice even after several years.2 Along with seizure type, diagnostic delay can be explained by other factors, including patient's own poor awareness of the nature of his/her symptoms, doctor's misdiagnosis, and, not least, the rarity of some events and their modest impact on patient's daily life. However, seizure recurrence with strong impact on one's health and quality of life cannot be excluded even after mild events, particularly in untreated patients, and one cannot exclude that future seizures have a greater impact on patient's and public safety. For these reasons, Laura Parviainen and co-workers5 are commended for having addressed this issue in the intent to verify the impact of diagnostic delay on seizure outcome in patients with newly diagnosed focal epilepsy. The authors examined 176 adult patients who were eligible for inclusion in randomized trials of antiseizure medications. The choice of that sample was motivated by the accuracy of the medical records with specific reference to the history of seizures while untreated. Patients were followed for five years, and seizure recurrence was noted and classified in three categories: (1) Complete seizure freedom after treatment start; (2) Seizure freedom achieved after treatment changes; (3) No seizure freedom despite medication changes. The authors found that diagnostic delay alone did not correlate with treatment response at five years. However, seizure outcome was worse in patients with a higher number of seizures before diagnosis. The results of this study confirm previous reports6 in showing that diagnostic delay per se does not affect treatment outcome. However, the association between the number of seizures while untreated and treatment response during follow-up is at variance with previous studies that showed that the long-term prognosis of epilepsy (in terms of prolonged seizure remission during follow-up) is not affected by early treatment of seizures (in those studies, treatment of the first seizure).7 The differences might be explained by the differing populations at risk (patients seen at the first seizure vs. patients with two or more seizures, the latter perhaps with more severe disease varieties) and by the length of follow-up (as poor treatment response proves to be a dynamic process when long-term follow-up is considered).8, 9 Then, having several seizures before treatment might be not only the result of diagnostic delay but also of an intrinsic greater severity of the disease at first manifestation. This study brings to our attention another important problem, that is, if epilepsy should be diagnosed only after seizure relapse or even after the first seizure. The International League Against Epilepsy addressed this issue and concluded that in specific circumstances epilepsy can be diagnosed at the first seizure.10 This definition helps reducing the diagnostic gap but requires that a comprehensive evaluation of the patient is performed and, for this reason, the diagnosis of epilepsy should be made by specialists who are well aware of the risk factors for seizure recurrence in a patient with a first seizure. As the diagnosis of epilepsy is mostly based on an accurate history taken from the patient and, where present, from a witness, the diagnostic process is not easy and requires patient's awareness of the nature of his/her symptoms and skillness of the caring physician. We agree with the authors that public and healthcare workers should be made aware of the diversity of seizure types and the negative reflections of the recurrence of undiagnosed seizures. Ettore Beghi reports grants from Italian Ministry of Health, grants from Swedish Orphan Biovitrum, personal fees from Arvelle Therapeutics, and grants from American ALS Association, outside the submitted work. The author confirms that he has read the Journal's position on issues involved in ethical publication and affirms that this editorial is consistent with those guidelines. Read the winning article - https://onlinelibrary.wiley.com/doi/10.1002/epi4.12443

NTCP Modeling of Late Effects for Head and Neck Cancer: A Systematic Review.

NTCP Modeling of Late Effects for Head and Neck Cancer: A Systematic Review.

Prolonged Effects of the COVID-19 Pandemic on Sleep Medicine Services-Longitudinal Data from the Swedish Sleep Apnea Registry.

The worldwide COVID-19 pandemic has affected the operation of health care systems. The direct impact of obstructive sleep apnea (OSA) on COVID-19 infection outcome remains to be elucidated. However, the coincidence of common risk factors for OSA and severe COVID-19 suggests that patients with OSA receiving positive airway pressure therapy may have an advantage relative to those untreated when confronted with a COVID-19 infection. The ongoing COVID-19 pandemic has led to a substantial reduction of sleep medicine services, and the long-term consequences may be considerable. New strategies for the management of sleep disorders are needed to overcome the current underdiagnosis and delay of treatment.

A randomised controlled trial to assess the clinical effectiveness and safety of the endometrial scratch procedure prior to first-time IVF, with or without ICSI.

STUDY QUESTIONWhat is the clinical-effectiveness and safety of the endometrial scratch (ES) procedure compared to no ES, prior to usual first time in vitro fertilisation (IVF) treatment?SUMMARY ANSWERES was safe but did not improve pregnancy outcomes when performed in the mid-luteal phase prior to the first IVF cycle, with or without intracytoplasmic sperm injection (ICSI).WHAT IS KNOWN ALREADYES is an ‘add-on’ treatment that is available to women undergoing a first cycle of IVF, with or without ICSI, despite a lack of evidence to support its use.STUDY DESIGN, SIZE, DURATIONThis pragmatic, superiority, open-label, multi-centre, parallel-group randomised controlled trial involving 1048 women assessed the clinical effectiveness and safety of the ES procedure prior to first time IVF, with or without ICSI, between July 2016 and October 2019.PARTICIPANTS/MATERIALS, SETTING, METHODSParticipants aged 18–37 years undergoing their first cycle of IVF, with or without ICSI, were recruited from 16 UK fertility clinics and randomised (1:1) by a web-based system with restricted access rights that concealed allocation. Stratified block randomisation was used to allocate participants to TAU or ES in the mid-luteal phase followed by usual IVF with or without ICSI treatment. The primary outcome was live birth after completing 24 weeks gestation within 10.5 months of egg collection.MAIN RESULTS AND THE ROLE OF CHANCEIn total, 1048 women randomised to TAU (n = 525) and ES (n = 523) were available for intention to treat analysis. In the ES group, 453 (86.6%) received the ES procedure. IVF, with or without ICSI, was received in 494 (94.1%) and 497 (95.0%) of ES and TAU participants respectively. Live birth rate was 37.1% (195/525) in the TAU and 38.6% (202/523) in the ES: an unadjusted absolute difference of 1.5% (95% CI −4.4% to 7.4%, P = 0.621). There were no statistical differences in secondary outcomes. Adverse events were comparable across groups.LIMITATIONS, REASONS FOR CAUTIONA sham ES procedure was not undertaken in the control group, however, we do not believe this would have influenced the results as objective fertility outcomes were used.WIDER IMPLICATIONS OF THE FINDINGSThis is the largest trial that is adequately powered to assess the impact of ES on women undergoing their first cycle of IVF. ES was safe, but did not significantly improve pregnancy outcomes when performed in the mid-luteal phase prior to the first IVF or ICSI cycle. We recommend that ES is not undertaken in this population.STUDY FUNDING/COMPETING INTEREST(S)Funded by the National Institute of Health Research. Stephen Walters is an National Institute for Health Research (NIHR) Senior Investigator (2018 to present) and was a member of the following during the project: National Institute for Health Research (NIHR) Health Technology Assessment (HTA) Clinical Trials and Evaluation Committee (2011–2017), NIHR HTA Commissioning Strategy Group (2012 to 2017); NIHR Programme Grants for Applied Research Committee (2020 to present); NIHR Pre doctoral Fellowship Committee (2019 to present). Dr. Martins da Silva reports grants from AstraZeneca, during the conduct of the study; and is Associate editor of Human Reproduction and Editorial Board member of Reproduction and Fertility. Dr. Bhide reports grants from Bart's Charity and grants and non-financial support from Pharmasure Pharmaceuticals outside the submitted work.TRIAL REGISTRATION NUMBERISRCTN number: ISRCTN23800982.TRIAL REGISTRATION DATE31 May 2016DATE OF FIRST PATIENT’S ENROLMENT04 July 2016

Remdesivir for the Treatment of Hospitalised Patients with COVID-19 (DisCoVeRy): A Randomised, Controlled, Open-Label Trial

Remdesivir for the Treatment of Hospitalised Patients with COVID-19 (DisCoVeRy): A Randomised, Controlled, Open-Label Trial

Changes in Neonatal Admissions, Care Processes and Outcomes in England and Wales During the COVID-19 Pandemic

Background: The COVID-19 pandemic instigated multiple societal and healthcare interventions with potential to affect perinatal practice. We evaluated population-level changes in preterm and full-term admissions to neonatal units, care processes, and outcomes.Methods: We obtained information from the National Neonatal Research Database on all admissions to National Health Service neonatal units in England and Wales from 2012-2020. We evaluated admissions by gestational age, ethnicity, and Index of Multiple Deprivation, and key care processes and outcomes. We calculated the differences in numbers and rates between April-June 2020 (spring), the first three months of national lockdown and December 2019-February 2020 (winter), prior to introduction of mitigation measures (COVID period), and compared them with the corresponding differences in the seven previous years. We considered the COVID period highly unusual if the difference was smaller or larger than all previous corresponding differences, and calculated the level of confidence in this conclusion.Findings: Marked fluctuations occurred in all measures over the eight years with several highly unusual changes during the COVID period. Total admissions fell, having risen over all previous years (COVID difference: -1492; previous seven-year difference range: +100, +1617; pInterpretation: Our findings indicate substantial changes occurred in care pathways and clinical thresholds, with disproportionate effects on Black ethnic groups, during the immediate COVID-19 period, and raise the intriguing possibility that non-healthcare interventions may reduce extremely preterm births.Funding Information: Medical Research Council; Health Data Research UK.Declaration of Interests: NM reports grants outside the submitted work from the Medical Research Council, National Institute of Health Research, March of Dimes, British Heart Foundation, HCA International, Health Data Research UK, Shire Pharmaceuticals, Chiesi Pharmaceuticals, Prolacta Life Sciences, and Westminster Children’s Research Fund; NM is a member of the Nestle Scientific Advisory Board and accepts no personal remuneration for this role. NM reports travel and accommodation reimbursements from Chiesi, Nestle and Shire. All other authors report no declarations of interest.Ethics Approval Statement: The study was undertaken under approval from the Health Research Authority and Health and Care Research Wales, and with the agreement of all NHS neonatal units in England and Wales.

Decompressive Craniectomy Following Traumatic Brain Injury; Does International Practice Align with Evidence? Harmonised, Multi-Centre Cohort Studies in Europe, the United Kingdom and Australia

Background: Clinical practice guidelines recommend both for and against use of decompressive craniectomy (DC) for treatment of intracranial hypertension following traumatic brain injury (TBI). The contemporary use of DC internationally, and the alignment of practice, evidence, and clinical practice guidelines, are unknown. Methods: We analysed the harmonised CENTER-TBI and OzENTER-TBI Core study datasets, which include patients of any age with TBI of any severity admitted to participating ICUs in Europe, the UK and Australia between 2015 and 2017. Patients were compared between different regions and by injury characteristics. Outcomes of interest were treatment with DC, and alignment with evidence and the Brain Trauma Foundation guidelines. Findings: Of 2336 people admitted to ICUs following TBI, DC was performed in 320 (13·7%): in 64/1422 (4·5%) patients with diffuse TBI, and 195/640 (30·5%) patients with traumatic mass lesions. Secondary DC (used for treatment of measured intracranial hypertension) was used infrequently in patients whose characteristics matched the enrolment criteria of the two randomised clinical trials informing the guidelines: in 11/124 (8·9%) of those matching DECRA eligibility, and in 30/224 (13·4%) of those matching RESCUEicp eligibility. Of the patients who underwent DC 258/320 (80·6%) were ineligible for either trial: 149/320 (46·6%) underwent primary DC, 62/320 (19·4%) were outside the trials’ age criteria, and 126/320 (39·4%) did not develop intracranial hypertension refractory to medical therapies prior to DC. Interpretation: Decompressive craniectomy remains in widespread use following TBI. Secondary DC was used infrequently in patients in whom it has been shown to be potentially harmful, indicating satisfactory alignment between evidence and practice. However, most patients who underwent DC were ineligible for the key trials; whether they benefitted from DC remains unknown. Funding: European Commission 7th Framework programme, Australian National Health and Medical Research Council, and Victorian Transport Accident Commission. Declaration of Interest: AIRM declares consulting fees from PresSura Neuro, Integra Life Sciences, and NeuroTrauma Sciences. DJC is an Australian NHMRC Practitioner Fellow and reports grants from the NHMRC and consulting fees to Monash University from PresSura Neuro; additionally, he is the Chief Investigator for the DECRA trial. All other authors declare no competing interests. Ethical Approval: Human research ethics approvals were granted with waivers of consent by the ethics committees of all individual participating hospitals, and additionally of Monash University for OzENTER.

Eyelid myotonia and face stiffness in skeletal muscle sodium channelopathy

Title Eyelid myotonia and face stiffness in skeletal muscle sodium channelopathy&#x0D; Video Legend Video 1. Notice the delayed relaxation of the eyelids after forced eye closure (eyelid myotonia). Also, notice the full facial hair to prevent facial muscle stiffening exacerbation with cold weather.&#x0D; AuthorsSrijan Adhikari, MBBS, Jeffrey Statland, MD, Constantine Farmakidis, MD&#x0D; Authors information:&#x0D; Srijan Adhikari, MBBS, ORCID ID: 0000-0001-9653-3079, University of Kansas Medical Center, Department of Neurology, Kansas City, Kansas, USAJeffrey Statland, MD, ORCID ID: 0000-0003-0790-5315 University of Kansas Medical Center, Department of Neurology, Kansas City, Kansas, USAConstantine Farmakidis, MD, ORCID ID: 0000-0002-4688-9224, University of Kansas Medical Center, Department of Neurology, Kansas City, Kansas, USA&#x0D; Corresponding Author &#x0D; Srijan Adhikari, MBBS,Department of Neurology,University of Kansas Medical Center,3901 Rainbow Boulevard., MS 2012,Kansas City, KS 66160sadhikari@kumc.edu&#x0D; Author Conflict of Interests &#x0D; Dr Adhikari has nothing to disclose.Dr. Statland reports grants from NIH, grants from MDA, grants from FSHD Society, grants from Friends of FSH Research, personal fees from Dyne, personal fees from Fulcrum, personal fees from Avidity, personal fees from MT Pharma, personal fees from Acceleron, personal fees from Sarepta, personal fees from Strongbridge, outside the submitted work. Dr. Farmakidis reports personal fees from Argnex, personal fees from Momenta, personal fees from Terumo BCT, outside the submitted work.

The Role of Mobility Endpoints in Marketing Authorisation of Drugs:&amp;nbsp;What Gets the EMA Moving?

Background: Mobility is defined as the ability to independently move around the environment and is a key contributor to quality of life. The aim of this study was to evaluate the use of mobility as a decisive outcome for the marketing authorisation of drugs by the European Medicines Agency (EMA). Methods: Fifteen therapeutic areas which commonly lead to mobility impairments and alter the quantity and/or the quality of walking were selected: two systemic neurological diseases, four conditions primarily affecting exercise capacity, seven musculoskeletal diseases, and two conditions representing sensory impairments. European Public Assessment Reports (EPARs) published by the EMA up to September 2020 were examined for mobility endpoints included in their ‘main studies’, defined as those which were decisive for EU approval. Clinical study registries and primary scientific publications for these studies were also reviewed. Findings: 484 EPARs yielded 186 relevant documents with 402 ‘main studies’. The EPARs reported 153 primary and 584 secondary endpoints which considered mobility; 70 different assessment tools (38 patient-reported outcomes, 13 clinician-reported outcomes, 8 performance outcomes, and 13 composite endpoints) were used. Importantly, only 15·7% of those tools distinctly informed on patients’ mobility status. 105/402 (26·1%) of the ‘main studies’ did not have any mobility assessment and none of these studies included a digital mobility outcome. The supplementary review of study registries and primary publications revealed only five uses of mobility assessments not reported by EPARs. Interpretation: For conditions with a high impact on mobility, distinct mobility assessment was given little consideration in the marketing authorisation of drugs by the EMA. Where mobility impairment was considered to be a relevant outcome, questionnaires or composite scores were predominantly used. Reporting biases for such outcomes presents challenges for the interpretation of study results. Funding: Mobilise-D (Innovative Medicines Initiative) and Robert Bosch Stiftung, Germany. Declaration of Interest: SJ is partly supported by the Robert Bosch Stiftung Stuttgart. MW reports grants from HORIZON2020 IMI No. 820820, during the conduct of the study. DS reports grants from HORIZON2020 IMI No. 820820, during the conduct of the study. MC reports personal fees from Takeda Pharmaceuticals, during the conduct of the study; personal fees from Takeda Pharmaceuticals, outside the submitted work. JK reports grants from HORIZON2020 IMI No. 820820, during the conduct of the study. JGA reports grants from HORIZON2020 IMI No. 820820, and from AstraZeneca, Chiesi, Esteve, outside the submitted work. WM receives or received funding from the European Union, the German Federal Ministry of Education of Research, Michael J. Fox Foundation, Robert Bosch Foundation, Neuroalliance, Lundbeck and Janssen. He received speaker honoraria from Abbvie, Bayer, GlaxoSmithKline, Licher MT, Rolke Pharma and UCB, was invited to Advisory Boards of Abbvie, Biogen, Lundbeck and Market Access & Pricing Strategy GmbH, and is an advisory board member of the Critical Path for Parkinson's Consortium. He serves as the co-chair of the MDS Technology Task Force. MP reports grants from HORIZON2020 IMI No. 820820, outside the submitted work. MS is supported by the Robert Bosch Stiftung Stuttgart and reports grants from HORIZON2020 IMI 2 Mobilise D, during the conduct of the study, and grants and non-financial support from Green Cross WellBeing Co. Ltd., Gilead Sciences Inc., Robert Bosch GmbH, and CORAT Therapeutics GmbH , as well as other from Agena Bioscience GmbH, outside the submitted work. CB disclosed consultation from E. Lilly and speaker fees from Amgen, Nutricia and Pfizer reports grants from HORIZON2020 IMI No. 820820, during the conduct of the study. RT, BS, LL, LR, SCR declare no competing interests.

The challenges and opportunities of mental health data sharing in the UK

The challenges and opportunities of mental health data sharing in the UK

Urgent needs to accelerate the race for COVID-19 therapeutics.

Urgent needs to accelerate the race for COVID-19 therapeutics.

Early Oscillatory Mechanics Predict Surfactant Need and Respiratory Outcomes in Preterm Infants

Background: Current criteria for surfactant administration assume that hypoxia is a direct marker of lung-volume de-recruitment. Objectives: To evaluate whether lung reactance (Xrs) assessment by FOT within 2h of birth identifies infants who would need surfactant within 24h; to eventually determine Xrs performance and a cut-off value for early detection of infants requiring surfactant. Methods: We conducted a prospective, observational, non-randomized study in our tertiary NICU in Milan. Eligible infants were born between 27+0 and 34+6 weeks' gestation presenting respiratory distress after birth. Exclusion criteria: endotracheal intubation at birth, major malformations. We assessed Xrs during nasal CPAP at 5cmH2O at 10Hz within 2h of life, recording flow and pressure tracing through a Fabian Ventilator for off-line analysis. Clinicians were blinded to FOT results. Results: We enrolled 61 infants, with a median[IQR] gestational age of 31.9[30.3; 32.9]weeks and birth weight 1490[1230; 1816]g. 14/59 infants received surfactant within 24h. Xrs predicted surfactant need with a cut-off -33.4 cmH2O*s/L and AUC-ROC=0.86 (0.76-0.96), with sensitivity 0.85 and specificity 0.83. An Xrs cut-off value of -23.3 cmH2O*s/L identified infants needing surfactant or respiratory support >28 days with AUC-ROC=0.89 (0.81-0.97), sensitivity 0.86 and specificity 0.77. Interestingly, 12 infants with Xrs <-23.3 cmH2O*s/L (i.e. de-recruited lungs) did not receive surfactant and subsequently required prolonged respiratory support. Interpretation: Xrs assessed within 2 h of life predicts surfactant need and respiratory support duration in preterm infants. Xrs possible role for improving the individualization preterm infants' respiratory management deserves further investigation. Funding: None Declaration of Interest: RD reports grants and other from Restech, personal fees from Philips Healthcare, outside the submitted work; Dr Dellaca' has a patent on the detection of EFL by Forced Oscillation technique (FOT) with royalties paid to Philips Respironics and Restech Srl, a patent on monitoring lung volume recruitment by FOT with royalties paid to Vyaire, and a patent on early detection of exacerbations by home monitoring of FOT with royalties paid to Restech and is co-founder and shareholder of Restech Srl, a spin-off company of the Politecnico di Milano University producing medical devices for lung function testing based on FOT. AL was consultant for Getinge and Chiesi S.p.A and received travel grants from Vapotherm and Fischer&Pykel. The other authors have no financial interest to declare. Ethical Approval: Our ethical committee approved the research protocol in April 2016. Between December 2016 and February 2020, we recruited the study participants, whose follow-up lasted until discharge home.

POS0594 MEANINGFUL IMPROVEMENT AND WORSENING IN PATIENTS WHO DO NOT ACHIEVE LDA AND SWITCH THERAPY TO A NEW BIOLOGIC OR TARGETED THERAPY: RESULTS FROM THE CORRONA REGISTRY

POS0594 MEANINGFUL IMPROVEMENT AND WORSENING IN PATIENTS WHO DO NOT ACHIEVE LDA AND SWITCH THERAPY TO A NEW BIOLOGIC OR TARGETED THERAPY: RESULTS FROM THE CORRONA REGISTRY

Older Age and Frailty Are Associated With Higher Mortality but Lower Intensive Care Unit Admission Among Adults Admitted to Canadian Hospitals With COVID-19: A Report From the Canadian Immunization Research Network (CIRN) Serious Outcomes Surveillance Network

Background: We report characteristics and outcomes of adults admitted to Canadian Immunization Research Network (CIRN) Serious Outcomes Surveillance (SOS) Network hospitals with COVID-19 in 2020. Methods: Adult patients with laboratory-confirmed COVID-19 admitted to eleven sites in Ontario, Quebec, Alberta and Nova Scotia up to December 31, 2020 were enrolled in this prospective observational cohort study. Age, sex, demographics, housing, exposure characteristics, Clinical Frailty Scale, comorbidities, and outcomes including length of stay, intensive care unit (ICU) admission, mechanical ventilation, and survival were conducted. Descriptive analyses and multivariable logistic regressions were conducted. Findings: Among 2011 patients, mean age was 71·0 (range 19-105) years. 45·7% were women and 74·0% were white. 21·5% were admitted from Assisted Living facilities, 8·2% from long term care, and 2·1% from homeless shelters. The full spectrum of frailty was represented in both younger and older age groups. The majority (61·7% of adults =65) had at least one underlying comorbidity and 27·2% had obesity. Mortality was 14·3% among those not admitted to ICU, and 24·6% for those admitted to ICU. Older age and higher frailty were associated with reduced ICU admission but increased mortality. Obesity was independently associated with ICU admission but not with death. Associations between underlying comorbidities and adverse outcomes were attenuated but persisted when adjusting for frailty.Interpretation: Frailty and age were independent predictors of lower ICU use and higher mortality; when accounting for frailty, obesity was not an independent predictor of mortality, and associations of comorbidities with mortality were weakened.Funding Statement: Funding was provided by the Public Health Agency of Canada and the Canadian Institutes of Health Research.Declaration of Interests: MKA reports grant funding from the Public Health Association of Canada, CIHR, Canadian Frailty Network, Sanofi Pasteur and GSK group of companies, and payments from Pfizer, Sanofi Pasteur and Seqirus outside the submitted work. AM reports payments from GSK, Seqirus and Sanofi Pasteur, outside the submitted work. JEM reports payments from RestorBio, Sanofi, GSK, Merck and Medicago outside of the submitted work. TFH reports grants from Pfizer and GSK. ML reports payments from Sanofi, Medicago, Sequirus, and Pfizer outside the submitted work. SAM reports grants and payments from Pfizer, GSK, Merck, Novartis and Sanofi, outside the submitted work. JG, JJL, GB, LV, ME, DM-C, AA, KW, ST, SS, AMc and KK report no conflicts of interest.Ethics Approval Statement: The protocol for active COVID-19 surveillance has been approved by each local site’s Research Ethics Board.