Covid19-Sources

Seit Beginn der Pandemie entwickeln wir Lösungen zur Bewertung der Corona-Lage und sammeln hierzu auch viele Daten. Diese Daten wurden bisher hauptsächlich von uns verwendet. In letzter Zeit erreichen uns … „Corona OpenData bei Rainer Gerhards“ weiterlesen

After the global spread of SARS-CoV-2 Omicron BA.2 lineage, some BA.2-related variants that acquire mutations in the L452 residue of spike protein, such as BA.2.9.1 and BA.2.13 (L452M), BA.2.12.1 (L452Q), and BA.2.11, BA.4 and BA.5 (L452R), emerged in multiple countries. Our statistical analysis showed that the effective reproduction numbers of these L452R/M/Q-bearing BA.2-related Omicron variants are greater than that of the original BA.2. Neutralization experiments revealed that the immunity induced by BA.1 and BA.2 infections is less effective against BA.4/5. Cell culture experiments showed that BA.2.12.1 and BA.4/5 replicate more efficiently in human alveolar epithelial cells than BA.2, and particularly, BA.4/5 is more fusogenic than BA.2. Furthermore, infection experiments using hamsters indicated that BA.4/5 is more pathogenic than BA.2. Altogether, our multiscale investigations suggest that the risk of L452R/M/Q-bearing BA.2-related Omicron variants, particularly BA.4 and BA.5, to global health is potentially greater than that of original BA.2. ### Competing Interest Statement Yuki Yamamoto and Tetsuharu Nagamoto are founders and shareholders of HiLung, Inc. Jun Kanamune is an employee of HiLung, Inc. Yuki Yamamoto is a co-inventor of patents (PCT/JP2016/057254; "Method for inducing differentiation of alveolar epithelial cells", PCT/JP2016/059786, "Method of producing airway epithelial cells"). The other authors declare that no competing interests exist.

Infection with SARS-CoV-2 virus is associated with a wide range of symptoms. The REal-time Assessment of Community Transmission -1 (REACT-1) study has been monitoring the spread and clinical manifestation of SARS-CoV-2 among random samples of the population in England from 1 May 2020 to 31 March 2022. We show changing symptom profiles associated with the different variants over that period, with lower reporting of loss of sense of smell and taste for Omicron compared to previous variants, and higher reporting of cold-like and influenza-like symptoms, controlling for vaccination status. Contrary to the perception that recent variants have become successively milder, Omicron BA.2 was associated with reporting more symptoms, with greater disruption to daily activities, than BA.1. With restrictions lifted and routine testing limited in many countries, monitoring the changing symptom profiles associated with SARS-CoV-2 infection and induced changes in daily activities will become increasingly important. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The study was funded by the Department of Health and Social Care in England. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of this manuscript. PE is Director of the Medical Research Council (MRC) Centre for Environment and Health (MR/L01341X/1, MR/S019669/1). PE acknowledges support from Health Data Research UK (HDR UK); the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre; NIHR Health Protection Research Units in Chemical and Radiation Threats and Hazards, and Environmental Exposures and Health; the British Heart Foundation Centre for Research Excellence at Imperial College London (RE/18/4/34215); and the UK Dementia Research Institute at Imperial College London (MC\_PC\_17114). HW acknowledges support from an NIHR Senior Investigator Award, the Wellcome Trust (205456/Z/16/Z), and the NIHR Applied Research Collaboration (ARC) North West London. JE is an NIHR academic clinical fellow in infectious diseases. GC is supported by an NIHR Professorship. CAD acknowledges support from the MRC Centre for Global Infectious Disease Analysis, the NIHR Health Protection Research Unit in Emerging and Zoonotic Infections and the NIHR-funded Vaccine Efficacy Evaluation for Priority Emerging Diseases (PR-OD-1017-20007). MC-H and BB acknowledge support from Cancer Research UK, Population Research Committee Project grant 'Mechanomics' (grant No 22184 to MC-H). MC-H acknowledges support from the H2020-EXPANSE (Horizon 2020 grant No 874627) and H2020-LongITools (Horizon 2020 grant No 874739). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: We obtained research ethics approval from the South Central-Berkshire B Research Ethics Committee (IRAS ID: 283787). Notification of favorable opinion and brief summary of the protocol are available here: https://www.hra.nhs.uk/planning-and-improving-research/application-summaries/research-summaries/react1-covid-19-uph/ I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Access to REACT-1 individual-level data is restricted to protect participants' anonymity. Summary statistics, descriptive tables, and code from the current REACT-1 study are available at https://github.com/mrc-ide/reactidd (doi 10.5281/zenodo.6550327). REACT-1 study materials are available for each round at https://www.imperial.ac.uk/medicine/research-and-impact/groups/react-study/react-1-study-materials/ Sequence read data are available without restriction from the European Nucleotide Archive at https://www.ebi.ac.uk/ena/browser/view/PRJEB37886, and consensus genome sequences are available from the Global initiative on sharing all influenza data (GISAID).

Nature Communications - Here, Tan et al. find that the rapid spread of SARS-CoV-2 in mink and deer required minimal adaptation, has only caused moderate changes to the evolutionary trajectory of...

ImportanceGovernments have introduced non-pharmaceutical interventions (NPIs) in response to the pandemic outbreak of Coronavirus disease (COVID-19). While NPIs aim at preventing fatalities related to COVID-19, the previous literature on their efficacy has focused on infections and on data of the first half of 2020. Still, findings of early NPI studies may be subject to underreporting and missing timeliness of reporting of cases. Moreover, the low variation in treatment timing during the first wave makes identification of robust treatment effects difficult.ObjectiveWe enhance the literature on the effectiveness of NPIs with respect to the period, the number of countries, and the analytical approach.Design, Setting, and ParticipantsTo circumvent problems of reporting and treatment variation, we analyse data on daily confirmed COVID-19-related deaths per capita from Our World in Data, and on 10 different NPIs from the Oxford COVID-19 Government Response Tracker (OxCGRT) for 169 countries from 1st July 2020 to 1st September 2021. To identify the causal effects of introducing NPIs on COVID-19-related fatalities, we apply the generalized synthetic control (GSC) method to each NPI, while controlling for the remaining NPIs, weather conditions, vaccinations, and NPI-residualized COVID-19 cases. This mitigates the influence of selection into treatment and allows to model flexible post-treatment trajectories.ResultsWe do not find substantial and consistent COVID-19-related fatality-...

BREAKING🔔 The 10th preprint from G2P-Japan🇯🇵 is out at @biorxivpreprint. #Omicron BA.4 & BA.5 variants seem to be more contagious and pathogenic than BA.2 variant. Please RT. 1/7https://t.co/UjNFtAAADW— The Sato Lab (Kei Sato) (@SystemsVirology) May 26, 2022

BackgroundEmerging evidence shows that both adults and children may develop post-acute sequelae of SARS-CoV-2 infection (PASC). The aim of this study is to characterise and compare long-term post-SARS-CoV-2 infection outcomes in adults and children in a defined region in Italy.MethodsA prospective cohort study including children (≤18 years old) with PCR-confirmed SARS-CoV-2 infection and their household members. Participants were assessed via telephone and face-to-face visits up to 12 months post-SARS-CoV-2 diagnosis of household index case, using the ISARIC COVID-19 follow-up survey.ResultsOf 507 participants from 201 households, 56.4% (286/507) were children, 43.6% (221/507) adults. SARS-CoV-2 positivity was 87% (249/286) in children, and 78% (172/221) in adults. The mean age of PCR positive children was 10.4 (SD = 4.5) and of PCR positive adults was 44.5 years (SD = 9.5), similar to the PCR negative control groups [children 10.5 years (SD = 3.24), adults 42.3 years (SD = 9.06)]. Median follow-up post-SARS-CoV-2 diagnosis was 77 days (IQR 47–169). A significantly higher proportion of adults compared to children reported at least one persistent symptom (67%, 68/101 vs. 32%, 57/179, p 0.001) at the first follow up. Adults had more frequently coexistence of several symptom categories at both follow-up time-points. Female gender was identified as a risk factor for PASC in adults (p 0.02 at 1–3 months and p 0.01 at 6–9 months follow up), but not in children. We found no sig...

It's really striking how well trained scent dogs can detect Covid (and #LongCovid): a randomized controlled, triple-blinded validation trial and real life study at in airport. They need to get retrained for diff't variants https://t.co/gge2ZLMxfk @GlobalHealthBMJ @HelsinkiUniMed pic.twitter.com/9QbE3tzt6Q— Eric Topol (@EricTopol) May 16, 2022

We describe relapse of COVID-19 symptoms and SARS-CoV-2 viral load following nirmatrelvir/ritonavir (NM/R) in 10 non-immunocompromised patients aged 31 to 71-years-old. Most patients improved rapidly after treatment with NM/R and had negative antigen or PCR tests prior to relapse on Days 9-12 ...

This cohort study compares the secondary attack rate and infectious viral shedding kinetics of SARS-CoV-2 in fully vaccinated vs partially vaccinated and unvaccinated individuals.

Research suggests that vaccination against COVID via mRNA vaccines may reduce body's ability to produce key type of antibody.

Could prior COVID-19 infection play a role? Perhaps, health officials say.

The World Health Organization have recently announced outbreak news of acute, severe hepatitis of unknown cause in children under a Covid-19 pandemic. Whether it is associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is still under debating. Here, we performed genomic sequence alignment analysis of the genome of SARS-Cov-2 (Wuhan-hu-1) to the human genome reference. Sequence analysis revealed that the SARS-CoV-2 ORF1ab1056-1173 presented high identities with the human protein PAPR1453-176(3Q6Z_A). After searching the fully sequenced SARS-CoV-2 genomes deposited in GISAID (https://www.gisaid.org/), we detected 170 SARS-CoV-2 variants with mutation in ORF1ab1061, where alanine (A) was substituted by serine (S). This alteration made a 7-amino acid peptide (VVVNASN) in ORF1ab1056-1062 identical to its counterpart in PARP1453-59(3Q6Z_A). HLA prediction suggested that the peptides with high identities in PARP14 and ORF1ab could be presented by a same globally prevalent HLA-A*11:01 molecule. And in consistent with the first reported case of hepatitis of unknown, SARS-CoV-2 ORF1abVVVNASN variants were mostly identified as Delta lineages in UK by the late 2021, with an overall frequency of 0.00161%. Thus, our preliminary results raised a possibility that infection by SARS-CoV-2 ORF1abVVVNASN variant might elicit an autoimmune T cell response via epitope mimicry and is associated with the outbreak of unknown hepatitis. We anticipated that these findings will alert the human societies to pay more attention to rare mutations beyond the spike proteins. ### Competing Interest Statement The authors have declared no competing interest.

Background The safety of SARS-CoV-2 vaccines is unknown in children aged

The Omicron lineage of SARS-CoV-2, first described in November 2021, spread rapidly to become globally dominant and has split into a number of sub-lineages. BA.1 dominated the initial wave but has been replaced by BA.2 in many countries. Recent sequencing from South Africa's Gauteng region uncovered two new sub-lineages, BA.4 and BA.5 which are taking over locally, driving a new wave. BA.4 and BA.5 contain identical spike sequences and, although closely related to BA.2, contain further mutations in the receptor binding domain of spike. Here, we study the neutralization of BA.4/5 using a range of vaccine and naturally immune serum and panels of monoclonal antibodies. BA.4/5 shows reduced neutralization by serum from triple AstraZeneca or Pfizer vaccinated individuals compared to BA.1 and BA.2. Furthermore, using serum from BA.1 vaccine breakthrough infections there are likewise, significant reductions in the neutralization of BA.4/5, raising the possibility of repeat Omicron infections. ### Competing Interest Statement G.R.S. sits on the GSK Vaccines Scientific Advisory Board and is a founder member of RQ Biotechnology. Oxford University holds intellectual property related to the Oxford-Astra Zeneca vaccine and SARS-CoV-2 mAb discovered in G.R.S laboratory. A.J.P. is Chair of UK Dept. Health and Social Care (DHSC) Joint Committee on Vaccination & Immunisation (JCVI) but does not participate in the JCVI COVID-19 committee, and is a member of the WHO SAGE. The views expressed in this article do not necessarily represent the views of DHSC, JCVI, or WHO. The University of Oxford has entered into a partnership with AstraZeneca on coronavirus vaccine development. T.L. is named as an inventor on a patent application covering this SARS-CoV-2 vaccine and was a consultant to Vaccitech for an unrelated project whilst the study was conducted. S.J.D. is a Scientific Advisor to the Scottish Parliament on COVID-19.

This report describes how survivors of COVID-19 were at higher risk for developing many other health conditions.

Background: A substantial proportion of persons who develop COVID-19 report persistent symptoms after acute illness. Various pathophysiologic mechanisms have been implicated in the pathogenesis of postacute sequelae of SARS-CoV-2 infection (PASC). Objective: To characterize medical sequelae and persistent symptoms after recovery from COVID-19 in a cohort of disease survivors and controls. Design: Cohort study. (ClinicalTrials.gov: NCT04411147) Setting: National Institutes of Health Clinical Center, Bethesda, Maryland. Participants: Self-referred adults with laboratory-documented SARS-CoV-2 infection who were at least 6 weeks from symptom onset were enrolled regardless of presence of PASC. A control group comprised persons with no history of COVID-19 or serologic evidence of SARS-CoV-2 infection, recruited regardless of their current health status. Both groups were enrolled over the same period and from the same geographic area. Measurements: All participants had the same evaluations regardless of presence of symptoms, including physical examination, laboratory tests and questionnaires, cognitive function testing, and cardiopulmonary evaluation. A subset also underwent exploratory immunologic and virologic evaluations. Results: 189 persons with laboratory-documented COVID-19 (12% of whom were hospitalized during acute illness) and 120 antibody-negative control participants were enrolled. At enrollment, symptoms consistent with PASC were reported by 55% of the COVID-19 cohort and 13% of control participants. Increased risk for PASC was noted in women and those with a history of anxiety disorder. Participants with findings meeting the definition of PASC reported lower quality of life on standardized testing. Abnormal findings on physical examination and diagnostic testing were uncommon. Neutralizing antibody levels to spike protein were negative in 27% of the unvaccinated COVID-19 cohort and none of the vaccinated COVID-19 cohort. Exploratory studies found no evidence of persistent viral infection, autoimmunity, or abnormal immune activation in participants with PASC. Limitations: Most participants with COVID-19 had mild to moderate acute illness that did not require hospitalization. The prevalence of reported PASC was likely overestimated in this cohort because persons with PASC may have been more motivated to enroll. The study did not capture PASC that resolved before enrollment. Conclusion: A high burden of persistent symptoms was observed in persons after COVID-19. Extensive diagnostic evaluation revealed no specific cause of reported symptoms in most cases. Antibody levels were highly variable after COVID-19. Primary Funding Source: Division of Intramural Research, National Institute of Allergy and Infectious Diseases.

Correspondence from The New England Journal of Medicine — Neutralization Profile after Recovery from SARS-CoV-2 Omicron Infection

Objectives: Establishing the rate of post-vaccination cardiac myocarditis in the 12-15 and 16-17-year-old population in the context of their COVID-19 hospitalization risk is critical for developing a vaccination recommendation framework that balances harms with benefits for this patient demographic. Design, Setting and Participants: Using the Vaccine Adverse Event Reporting System (VAERS), this retrospective epidemiological assessment reviewed reports filed between January 1, 2021, and June 18, 2021, among adolescents ages 12-17 who received mRNA vaccination against COVID-19. Symptom search criteria included the words myocarditis, pericarditis, and myopericarditis to identify children with evidence of cardiac injury. The word troponin was a required element in the laboratory findings. Inclusion criteria were aligned with the CDC working case definition for probable myocarditis. Stratified cardiac adverse event (CAE) rates were reported for age, sex and vaccination dose number. A harm-benefit analysis was conducted using existing literature on COVID-19-related hospitalization risks in this demographic. Main outcome measures: 1) Stratified rates of mRNA vaccine-related myocarditis in adolescents age 12-15 and 16-17; and 2) harm-benefit analysis of vaccine-related CAEs in relation to COVID-19 hospitalization risk. Results: A total of 257 CAEs were identified. Rates per million following dose 2 among males were 162.2 (ages 12-15) and 94.0 (ages 16-17); among females, rates were 13.0 and 13.4 per million, respectively. For boys 12-15 without medical comorbidities receiving their second mRNA vaccination dose, the rate of CAE is 3.7-6.1 times higher than their 120-day COVID-19 hospitalization risk as of August 21, 2021 (7-day hospitalizations 1.5/100k population) and 2.6-4.3-fold higher at times of high weekly hospitalization risk (2.1/100k), such as during January 2021. For boys 16-17 without medical comorbidities, the rate of CAE is currently 2.1-3.5 times higher than their 120-day COVID-19 hospitalization risk, and 1.5-2.5 times higher at times of high weekly COVID-19 hospitalization. Conclusions: Post-vaccination CAE rate was highest in young boys aged 12-15 following dose two. For boys 12-17 without medical comorbidities, the likelihood of post vaccination dose two CAE is 162.2 and 94.0/million respectively. This incidence exceeds their expected 120-day COVID-19 hospitalization rate at both moderate (August 21, 2021 rates) and high COVID-19 hospitalization incidence. Further research into the severity and long-term sequelae of post-vaccination CAE is warranted. Quantification of the benefits of the second vaccination dose and vaccination in addition to natural immunity in this demographic may be indicated to minimize harm. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement There was no funding received for this study. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: NA All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Data used in this analysis are available at the link listed below.

Summary Background Vaccination against COVID-19 is the cornerstone to control and mitigate the ongoing pandemic. Thrombotic adverse events linked to Moderna, Pfizer and the Oxford-AstraZeneca vaccine have been documented and described as extremely rare. While the Oxford-AstraZeneca vaccine has received much of the attention, the other vaccines should not go unchallenged. This study aimed to determine the frequency of reported thrombotic adverse events and clinical outcomes for these three COVID-19 vaccines, namely, Moderna, Pfizer and Oxford-AstraZeneca Methods A retrospective descriptive analysis was conducted of spontaneous reports for Moderna, Pfizer and Oxford-AstraZeneca COVID-19 vaccines submitted to the EudraVigilance database in the period from 17 February to 14 June 2021. Findings There were 729,496 adverse events for the three vaccines, of which 3,420 were thrombotic, mainly Oxford-AstraZeneca (n=1,988; 58.1%) followed by Pfizer (n=1,096; 32.0%) and Moderna (n=336; 9.8%). As serious adverse events, there were 705 reports of pulmonary embolism for the three vaccines, of which 130 reports (18.4%) were for Moderna, 226 reports (32.1%) for Pfizer and 349 (49.5%) for Oxford-AstraZeneca vaccines. The occurrence of pulmonary embolism is significantly associated with a fatal outcome (P=

Inherited genetic factors can influence the severity of COVID-19, but the molecular explanation underpinning a genetic association is often unclear. Intracellular antiviral defenses can inhibit the...

Correspondence from The New England Journal of Medicine — SARS-CoV-2 Neutralization with BNT162b2 Vaccine Dose 3

Bei insgesamt 36 291 Todesbescheinigungen war im Jahr 2020 laut vorläufigen Daten der Todesursachenstatistik COVID-19 als Erkrankung vermerkt. In 30 136 Fällen war dies die Todesursache, in den anderen 6 155 Fällen war es eine Begleiterkrankung. Nach diesen ersten vorläufigen Angaben des Statistischen Bundesamtes (Destatis) starben somit in 83 % dieser Fälle die betroffenen Personen an COVID-19 als sogenanntem Grundleiden, das heißt die Krankheit war die für den Tod verantwortliche Todesursache. In 17 % der Fälle starben die Personen mit COVID-19 als Begleiterkrankung, jedoch an einem anderen Grundleiden. Dies geht aus den vorläufigen Ergebnissen der Todesursachenstatistik hervor, die ab dem Berichtszeitraum Januar 2020 erstmals monatlich veröffentlicht werden und die bis zur vorliegenden Auswertung knapp 92 % aller Sterbefälle umfassen.

New @TheLancetInfDis Reduction in vaccine + booster effectiveness vs hospitalization for BA.2 vs BA.1 variants at 10+ weeks https://t.co/PZ6r29aba510-14 wks: 70.2 vs 85.415+ wks: 56.5 vs 80.4See table below for 95% CI and text for detailsby @freja_kirsebom and colleagues pic.twitter.com/VLEmW0t2js— Eric Topol (@EricTopol) May 24, 2022

Human coronaviruses (HCoV) cause common colds but can also infect neural cell cultures. To provide definitive experimental evidence for the neurotropism and neuroinvasion of HCoV and its possible association with multiple sclerosis (MS), we have performed ...

Marit J. van Gils and colleagues investigate antibody responses against diverse emerging SARS-CoV-2 variants induced by four different SARS-CoV-2 vaccines in health care workers in the Netherlands.

Recent studies suggest that medication that stabilizes mast cell activation may help both conditions.

Out now – our preprint "A live attenuated vaccine confers superior mucosal and systemic immunity to SARS-CoV-2 variants", comparing live attenuated/mRNA/Adeno vaccines using histopathology, serology, scRNA-seq in hamsters.https://t.co/V1rquNNbXF – summary in the thread … (1/8) pic.twitter.com/UNnR5ZMK8k— Emanuel Wyler (@ewyler) May 17, 2022

Vaccines are a cornerstone in COVID-19 pandemic management. Here, we compare immune responses to and preclinical efficacy of the mRNA vaccine BNT162b2, an adenovirus-vectored spike vaccine, and the live-attenuated-virus vaccine candidate sCPD9 after single and double vaccination in Syrian hamsters. All regimens containing sCPD9 showed superior efficacy. The robust immunity elicited by sCPD9 was evident in a wide range of immune parameters after challenge with heterologous SARS-CoV-2 including rapid viral clearance, reduced tissue damage, fast differentiation of pre-plasmablasts, strong systemic and mucosal humoral responses, and rapid recall of memory T cells from lung tissue. Our results demonstrate that use of live-attenuated vaccines may offer advantages over available COVID-19 vaccines, specifically when applied as booster, and may provide a solution for containment of the COVID-19 pandemic. ### Competing Interest Statement Related to this work, Freie Universität Berlin has filed a patent application for the use of sCPD9 as vaccine in humans. In this application, JT, NO and DK are named as inventors of sCPD9. Freie Universität Berlin is collaborating with RocketVax Inc. for further development of sCPD9 and receives funding for research. Independent of this work GN has received project funding from Biotest AG. Independent of this work MW received funding for research from Bayer Health Care, Biotest, Pantherna, Vaxxilon, and for lectures and advisory from Alexion, Aptarion, Astra Zeneca, Bayer Health Care, Berlin Chemie, Biotest, Boehringer Ingelheim, Chiesi, Glaxo Smith Kline, Insmed, Novartis, Teva and Vaxxilon. The other authors declare that they have no competing interest.