Background: Patients with inborn errors of immunity (IEI) are at increased risk of severe coronavirus disease-2019 (COVID-19). Effective vaccination against COVID-19 is therefore of great... Show moreBackground: Patients with inborn errors of immunity (IEI) are at increased risk of severe coronavirus disease-2019 (COVID-19). Effective vaccination against COVID-19 is therefore of great importance in this group, but little is known about the immunogenicity of COVID-19 vaccines in these patients.Objectives: We sought to study humoral and cellular immune responses after mRNA-1273 COVID-19 vaccination in adult patients with IEI.Methods: In a prospective, controlled, multicenter study, 505 patients with IEI (common variable immunodeficiency [CVID], isolated or undefined antibody deficiencies, X-linked agammaglobulinemia, combined B- and T-cell immunodeficiency, phagocyte defects) and 192 controls were included. All participants received 2 doses of the mRNA-1273 COVID-19 vaccine. Levels of severe acute respiratory syndrome coronavirus-2-specific binding antibodies, neutralizing antibodies, and T-cell responses were assessed at baseline, 28 days after first vaccination, and 28 days after second vaccination.Results: Seroconversion rates in patients with clinically mild antibody deficiencies and phagocyte defects were similar to those in healthy controls, but seroconversion rates in patients with more severe IEI, such as CVID and combined B- and T-cell immunodeficiency, were lower. Binding antibody titers correlated well to the presence of neutralizing antibodies. T-cell responses were comparable to those in controls in all IEI cohorts, with the exception of patients with CVID. The presence of noninfectious complications and the use of immunosuppressive drugs in patients with CVID were negatively correlated with the antibody response.Conclusions: COVID-19 vaccination with mRNA-1273 was immunogenic in mild antibody deficiencies and phagocyte defects and in most patients with combined B- and T-cell immunodeficiency and CVID. Lowest response was detected in patients with X-linked agammaglobulinemia and in patients with CVID with noninfectious complications. The assessment of longevity of immune responses in these vulnerable patient groups will guide decision making for additional vaccinations. Show less
Langerak, T.; Bakker, G.J.; Porcelijn, L.; Lauw, M.N.; Laar, R.J. van de; Eefting, M. 2022
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes mild symptoms in the majority of infected individuals, yet in some cases it leads to a life-threatening condition.... Show moreThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes mild symptoms in the majority of infected individuals, yet in some cases it leads to a life-threatening condition. Determination of early predictive biomarkers enabling risk stratification for coronavirus disease 2019 (COVID-19) patients can inform treatment and intervention strategies. Herein, we analyzed whole blood samples obtained from individuals infected with SARS-CoV-2, varying from mild to critical symptoms, approximately one week after symptom onset. In order to identify blood-specific markers of disease severity status, a targeted expression analysis of 143 immune-related genes was carried out by dual-color reverse transcriptase multiplex ligation-dependent probe amplification (dcRT-MLPA). The clinically well-defined subgroups of COVID-19 patients were compared with healthy controls. The transcriptional profile of the critically ill patients clearly separated from that of healthy individuals. Moreover, the number of differentially expressed genes increased by severity of COVID-19. It was also found that critically ill patients can be distinguished by reduced peripheral blood expression of several genes, which most likely reflects the lower lymphocyte counts. There was a notable predominance of IFN-associated gene expression in all subgroups of COVID-19, which was most profound in critically ill patients. Interestingly, the gene encoding one of the main TNF-receptors, TNFRS1A, had selectively lower expression in mild COVID-19 cases. This report provides added value in understanding COVID-19 disease, and shows potential of determining early immune transcript signatures in the blood of patients with different disease severity. These results can guide further explorations to uncover mechanisms underlying immunity and immunopathology in COVID-19. Show less
Adamina, M.; Ademuyiwa, A.; Adisa, A.; Bhangu, A.A.; Bravo, A.M.; Cunha, M.F.; ... ; Gill, R. 2022
Aim The SARS-CoV-2 pandemic has provided a unique opportunity to explore the impact of surgical delays on cancer resectability. This study aimed to compare resectability for colorectal cancer... Show moreAim The SARS-CoV-2 pandemic has provided a unique opportunity to explore the impact of surgical delays on cancer resectability. This study aimed to compare resectability for colorectal cancer patients undergoing delayed versus non-delayed surgery. Methods This was an international prospective cohort study of consecutive colorectal cancer patients with a decision for curative surgery (January-April 2020). Surgical delay was defined as an operation taking place more than 4 weeks after treatment decision, in a patient who did not receive neoadjuvant therapy. A subgroup analysis explored the effects of delay in elective patients only. The impact of longer delays was explored in a sensitivity analysis. The primary outcome was complete resection, defined as curative resection with an R0 margin. Results Overall, 5453 patients from 304 hospitals in 47 countries were included, of whom 6.6% (358/5453) did not receive their planned operation. Of the 4304 operated patients without neoadjuvant therapy, 40.5% (1744/4304) were delayed beyond 4 weeks. Delayed patients were more likely to be older, men, more comorbid, have higher body mass index and have rectal cancer and early stage disease. Delayed patients had higher unadjusted rates of complete resection (93.7% vs. 91.9%, P = 0.032) and lower rates of emergency surgery (4.5% vs. 22.5%, P < 0.001). After adjustment, delay was not associated with a lower rate of complete resection (OR 1.18, 95% CI 0.90-1.55, P = 0.224), which was consistent in elective patients only (OR 0.94, 95% CI 0.69-1.27, P = 0.672). Longer delays were not associated with poorer outcomes. Conclusion One in 15 colorectal cancer patients did not receive their planned operation during the first wave of COVID-19. Surgical delay did not appear to compromise resectability, raising the hypothesis that any reduction in long-term survival attributable to delays is likely to be due to micro-metastatic disease. Show less
Lith, T.J. van; Sluis, W.M.; Wijers, N.T.; Meijer, F.J.A.; Kamphuis-van Ulzen, K.; Bresser, J. de; ... ; Leeuw, F.E. de 2022
Background: COVID-19 is often complicated by thrombo-embolic events including ischemic stroke. The underlying mechanisms of COVID-19-associated ischemic stroke, the incidence and risk factors of... Show moreBackground: COVID-19 is often complicated by thrombo-embolic events including ischemic stroke. The underlying mechanisms of COVID-19-associated ischemic stroke, the incidence and risk factors of silent cerebral ischemia, and the long-term functional outcome in these patients are currently unknown. Patients and methods: CORONavirus and Ischemic Stroke (CORONIS) is a multicentre prospective cohort study investigating the prevalence, risk factors and long-term incidence of (silent) cerebral ischemia, and the long-term functional outcome among patients with COVID-19. We aim to include 200 adult patients hospitalized with COVID-19 without symptomatic ischemic stroke to investigate the prevalence of silent cerebral ischemia compared with 60 (matched) controls with MRI. In addition, we will identify potential risk factors and/or causes of cerebral ischemia in COVID-19 patients with (n = 70) or without symptomatic stroke (n = 200) by means of blood sampling, cardiac workup and brain MRI. We will measure functional outcome and cognitive function after 3 and 12 months with standardized questionnaires in all patients with COVID-19. Finally, the long-term incidence of (new) silent cerebral ischemia in patients with COVID-19 will be assessed with follow up MRI (n = 120). The CORONIS study is designed to add further insight into the prevalence, long-term incidence and risk factors of cerebral ischemia, and the long-term functional outcome in hospitalized adult patients with COVID-19. Show less
Background: Immunoglobulin G1 (IgG1) effector functions are impacted by the structure of fragment crystallizable (Fc) tail-linked N-glycans. Low fucosylation levels on severe acute respiratory... Show moreBackground: Immunoglobulin G1 (IgG1) effector functions are impacted by the structure of fragment crystallizable (Fc) tail-linked N-glycans. Low fucosylation levels on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein-specific IgG1 has been described as a hallmark of severe coronavirus disease 2019 (COVID-19) and may lead to activation of macrophages via immune complexes thereby promoting inflammatory responses, altogether suggesting involvement of IgG1 Fc glycosylation modulated immune mechanisms in COVID-19. Methods: In this prospective, observational single center cohort study, IgG1 Fc glycosylation was analyzed by liquid chromatography-mass spectrometry following affinity capturing from serial plasma samples of 159 SARS-CoV-2 infected hospitalized patients. Findings: At baseline close to disease onset, anti-S IgG1 glycosylation was highly skewed when compared to total plasma IgG1. A rapid, general reduction in glycosylation skewing was observed during the disease course. Low anti S IgG1 galactosylation and sialylation as well as high bisection were early hallmarks of disease severity, whilst high galactosylation and sialylation and low bisection were found in patients with low disease severity. In line with these observations, anti-S IgG1 glycosylation correlated with various inflammatory markers. Interpretation: Association of low galactosylation, sialylation as well as high bisection with disease severity and inflammatory markers suggests that further studies are needed to understand how anti-S IgG1 glycosylation may contribute to disease mechanism and to evaluate its biomarker potential. Copyright (c) 2022 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) Show less
Driessen, M.L.S.; Ditshuizen, J.C. van; Waalwijk, J.F.; Bunt, G. van den; IJpma, F.F.A.; Reininga, I.H.F.; ... ; Jongh, M.A.C. de 2022
Purpose The SARS-CoV-2 pandemic severely disrupted society and the health care system. In addition to epidemiological changes, little is known about the pandemic's effects on the trauma care chain.... Show morePurpose The SARS-CoV-2 pandemic severely disrupted society and the health care system. In addition to epidemiological changes, little is known about the pandemic's effects on the trauma care chain. Therefore, in addition to epidemiology and aetiology, this study aims to describe the impact of the SARS-CoV-2 pandemic on prehospital times, resource use and outcome. Methods A multicentre observational cohort study based on the Dutch Nationwide Trauma Registry was performed. Characteristics, resource usage, and outcomes of trauma patients treated at all trauma-receiving hospitals during the first (W1, March 12 through May 11) and second waves (W2, May 12 through September 23), as well as the interbellum period in between (INT, September 23 through December 31), were compared with those treated from the same periods in 2018 and 2019. Results The trauma caseload was reduced by 20% during the W1 period and 11% during the W2 period. The median length of stay was significantly shortened for hip fracture and major trauma patients (ISS >= 16). A 33% and 66% increase in the prevalence of minor self-harm-related injuries was recorded during the W1 and W2 periods, respectively, and a 36% increase in violence-related injuries was recorded during the INT. Mortality was significantly higher in the W1 (2.9% vs. 2.2%) and W2 (3.2% vs. 2.7%) periods. Conclusion The imposed restrictions in response to the SARS-CoV-2 pandemic led to diminished numbers of acute trauma admissions in the Netherlands. The long-lasting pressing demand for resources, including ICU services, has negatively affected trauma care. Further caution is warranted regarding the increased incidence of injuries related to violence and self-harm. Show less
Background: COVID-19 is associated with increased morbidity and mortality in patients with chronic kidney disease (CKD) stages G4-G5, on dialysis or after kidney transplantation (kidney replacement... Show moreBackground: COVID-19 is associated with increased morbidity and mortality in patients with chronic kidney disease (CKD) stages G4-G5, on dialysis or after kidney transplantation (kidney replacement therapy, KRT). SARS-CoV-2 vaccine trials do not elucidate if SARS-CoV-2 vaccination is effective in these patients. Vaccination against other viruses is known to be less effective in kidney patients. Our objective is to assess the efficacy and safety of various types of SARS-CoV-2 vaccinations in patients with CKD stages G4-G5 or on KRT. Methods: In this national prospective observational cohort study we will follow patients with CKD stages G4-G5 or on KRT (n = 12,000) after SARS-CoV-2 vaccination according to the Dutch vaccination program. Blood will be drawn for antibody response measurements at day 28 and month 6 after completion of vaccination. Patient characteristics and outcomes will be extracted from registration data and questionnaires during 2 years of follow-up. Results will be compared with a control group of non-vaccinated patients. The level of antibody response to vaccination will be assessed in subgroups to predict protection against COVID-19 breakthrough infection. Results: The primary endpoint is efficacy of SARS-CoV-2 vaccination determined as the incidence of COVID-19 after vaccination. Secondary endpoints are the antibody based immune response at 28 days after vaccination, the durability of this response at 6 months after vaccination, mortality and (serious) adverse events. Conclusion: This study will fulfil the lack of knowledge on efficacy and safety of SARS-CoV-2 vaccination in patients with CKD stages G4-G5 or on KRT. Current knowledge about this subject. COVID-19 has devastating impact on patients with CKD stages G4-G5, on dialysis or after kidney transplantation.. Effective SARS-CoV-2 vaccination is very important in these vulnerable patient groups.. Recent studies on vaccination in these patient groups are small short-term studies with surrogate endpoints. Contribution of this study. Assessment of incidence and course of COVID-19 after various types of SARS-CoV-2 vaccination during a twoyear follow-up period in not only patients on dialysis or kidney transplant recipients, but also in patients with CKD stages G4-G5.. Quantitative analysis of antibody response after SARS-CoV-2 vaccination and its relationship with incidence and course of COVID-19 in patients with CKD stages G4-G5, on dialysis or after kidney transplantation compared with a control group.. Monitoring of (serious) adverse events and development of anti-HLA antibodies. Impact on practice or policy. Publication of the study design contributes to harmonization of SARS-CoV-2 vaccine study methodology in kidney patients at high-risk for severe COVID-19.. Data on efficacy of SARS-CoV-2 vaccination in patients with CKD will provide guidance for future vaccination policy. Show less
Bardiot, D.; Vangeel, L.; Koukni, M.; Arzel, P.; Zwaagstra, M.; Lyoo, H.; ... ; Marchand, A. 2022
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, has led to a pandemic, that continues to be a huge public health burden. Despite the availability... Show moreThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, has led to a pandemic, that continues to be a huge public health burden. Despite the availability of vaccines, there is still a need for small-molecule antiviral drugs. In an effort to identify novel and drug-like hit matter that can be used for subsequent hit-to-lead optimization campaigns, we conducted a high-throughput screening of a 160 K compound library against SARS-CoV-2, yielding a 1-heteroaryl-2-alkoxyphenyl analog as a promising hit. Antiviral profiling revealed this compound was active against various beta-coronaviruses and preliminary mode-of-action experiments demonstrated that it interfered with viral entry. A systematic structure-activity relationship (SAR) study demonstrated that a 3- or 4-pyridyl moiety on the oxadiazole moiety is optimal, whereas the oxadiazole can be replaced by various other heteroaromatic cycles. In addition, the alkoxy group tolerates some structural diversity. Show less
The COVID-19 pandemic has caused the destruction of routine hospital services globally, leading to an increase in the backlog of elective surgery cases. The aim of the study was to retrospectively... Show moreThe COVID-19 pandemic has caused the destruction of routine hospital services globally, leading to an increase in the backlog of elective surgery cases. The aim of the study was to retrospectively investigate the pandemic's impact on the urologic oncology surgical activity of a high-volume center located in Milan, Italy. The number and type of procedures performed in 2020 during the COVID-19 pandemic was evaluated using 2019 data as control. Waiting times for each surgical procedure were compared, on a bimonthly basis, between the two different years. Overall, a 26.7% reduction in the number of urologic oncology surgeries between 2019 and 2020 was observed (2019: 720, 2020: 528). Both the main indication for surgery and the type of procedure performed significantly differed between 2019 and 2020 (all p < 0.0001), with a decrease in the number of radical prostatectomies and an increase in the number of radical cystectomies and radical nephrectomies/nephroureterectomies performed in 2020. Waiting time decreased by 20% between 2019 and 2020, with the most significant reduction seen after the first wave of the COVID-19 pandemic (July-October 2020), in particular for partial nephrectomy and radical prostatectomy, possibly due to the underdiagnosis of cases. In conclusion, in accordance with recommendations by international urological societies on prioritization strategies for oncological procedures, a higher proportion of surgeries for high-risk tumors was performed in 2020 at our center at the expense of procedures for lower risk diseases; however, future implications for patients' prognosis still need to be determined. Show less
The ongoing coronavirus (CoV) disease 2019 (COVID-19) pandemic caused by infection with severe acute respiratory syndrome CoV 2 (SARS-CoV-2) is associated with substantial morbidity and mortality.... Show moreThe ongoing coronavirus (CoV) disease 2019 (COVID-19) pandemic caused by infection with severe acute respiratory syndrome CoV 2 (SARS-CoV-2) is associated with substantial morbidity and mortality. Understanding the immunological and patho-logical processes of coronavirus diseases is crucial for the rational design of effective vaccines and therapies for COVID-19. Previous studies showed that 2'-O-methylation of the viral RNA cap structure is required to prevent the recognition of viral RNAs by intra-cellular innate sensors. Here, we demonstrate that the guanine N7-methylation of the 5' cap mediated by coronavirus nonstructural protein 14 (nsp14) contributes to viral evasion of the type I interferon (IFN-I)-mediated immune response and pathogenesis in mice. A Y414A substitution in nsp14 of the coronavirus mouse hepatitis virus (MHV) significantly decreased N7-methyltransferase activity and reduced guanine N7-methyla-tion of the 5' cap in vitro. Infection of myeloid cells with recombinant MHV harboring the nsp14-Y414A mutation (rMHV(nsp14-Y414A)) resulted in upregulated expression of IFN-I and ISG15 mainly via MDA5 signaling and in reduced viral replication compared to that of wild-type rMHV. rMHV(nsp14-Y414A) replicated to lower titers in livers and brains and exhibited an attenuated phenotype in mice. This attenuated phenotype was IFN-I de-pendent because the virulence of the rMHV(nsp14-Y414A) mutant was restored in Ifnar(-/-) mice. We further found that the comparable mutation (Y420A) in SARS-CoV-2 nsp14 (rSARS-CoV-2(nsp14-Y420A)) also significantly decreased N7-methyltransferase activity in vitro, and the mutant virus was attenuated in K18-human ACE2 transgenic mice. Moreover, infection with rSARS-CoV-2(nsp14-Y420A) conferred complete protection against subsequent and otherwise lethal SARS-CoV-2 infection in mice, indicating the vaccine potential of this mutant.IMPORTANCE Coronaviruses (CoVs), including SARS-CoV-2, the cause of COVID-19, use several strategies to evade the host innate immune responses. While the cap struc-ture of RNA, including CoV RNA, is important for translation, previous studies indi-cate that the cap also contributes to viral evasion from the host immune response. In this study, we demonstrate that the N7-methylated cap structure of CoV RNA is pivotal for virus immunoevasion. Using recombinant MHV and SARS-CoV-2 encoding an inactive N7-methyltransferase, we demonstrate that these mutant viruses are highly attenuated in vivo and that attenuation is apparent at very early times after infection. Virulence is restored in mice lacking interferon signaling. Further, we show that infection with virus defective in N7-methylation protects mice from lethal SARSCoV-2, suggesting that the N7-methylase might be a useful target in drug and vaccine development. Show less
As coronaviruses (CoVs) replicate in the host cell cytoplasm, they rely on their own capping machinery to ensure the efficient translation of their messenger RNAs (mRNAs), protect them from... Show moreAs coronaviruses (CoVs) replicate in the host cell cytoplasm, they rely on their own capping machinery to ensure the efficient translation of their messenger RNAs (mRNAs), protect them from degradation by cellular 5 ' exoribonucleases (ExoNs), and escape innate immune sensing. The CoV nonstructural protein 14 (nsp14) is a bifunctional replicase subunit harboring an N-terminal 3 '-to-5 ' ExoN domain and a C-terminal (N7-guanine)-methyltransferase (N7-MTase) domain that is presumably involved in viral mRNA capping. Here, we aimed to integrate structural, biochemical, and virological data to assess the importance of conserved N7-MTase residues for nsp14's enzymatic activities and virus viability. We revisited the crystal structure of severe acute respiratory syndrome (SARS)-CoV nsp14 to perform an in silico comparative analysis between beta-coronaviruses. We identified several residues likely involved in the formation of the N7-MTase catalytic pocket, which presents a fold distinct from the Rossmann fold observed in most known MTases. Next, for SARS-CoV andMiddle East respiratory syndrome CoV, site-directed mutagenesis of selected residues was used to assess their importance for in vitro enzymatic activity. Most of the engineered mutations abolished N7-MTase activity, while not affecting nsp14-ExoN activity. Upon reverse engineering of these mutations into different betacoronavirus genomes, we identified two substitutions (R310A and F426A in SARS-CoV nsp14) abrogating virus viability and one mutation (H424A) yielding a crippled phenotype across all viruses tested. Our results identify the N7-MTase as a critical enzyme for betacoronavirus replication and define key residues of its catalytic pocket that can be targeted to design inhibitors with a potential pan-coronaviral activity spectrum. Show less
Machado, F.V.C.; Meys, R.; Delbressine, J.M.; Vaes, A.W.; Goertz, Y.M.J.; Herck, M. van; ... ; Spruit, M.A. 2021
Background An increasing number of subjects are recovering from COVID-19, raising the need for tools to adequately assess the course of the disease and its impact on functional status. We aimed to... Show moreBackground An increasing number of subjects are recovering from COVID-19, raising the need for tools to adequately assess the course of the disease and its impact on functional status. We aimed to assess the construct validity of the Post-COVID-19 Functional Status (PCFS) Scale among adult subjects with confirmed and presumed COVID-19. Methods Adult subjects with confirmed and presumed COVID-19, who were members of an online panel and two Facebook groups for subjects with COVID-19 with persistent symptoms, completed an online survey after the onset of infection-related symptoms. The number and intensity of symptoms were evaluated with the Utrecht Symptom Diary, health-related quality of life (HrQoL) with the 5-level EQ-5D questionnaire, impairment in work and activities with the Work Productivity and Activity Impairment questionnaire and functional status with the PCFS Scale. Results 1939 subjects were included in the analyses (85% women, 95% non-hospitalized during infection) about 3 months after the onset of infection-related symptoms. Subjects classified as experiencing 'slight', 'moderate' and 'severe' functional limitations presented a gradual increase in the number/intensity of symptoms, reduction of HrQoL and impairment in work and usual activities. No differences were found regarding the number and intensity of symptoms, HrQoL and impairment in work and usual activities between subjects classified as experiencing 'negligible' and 'no' functional limitations. We found weak-to-strong statistical associations between functional status and all domains of HrQoL (r: 0.233-0.661). Notably, the strongest association found was with the 'usual activities' domain of the 5-level EQ-5D questionnaire. Conclusion We demonstrated the construct validity of the PCFS Scale in highly-symptomatic adult subjects with confirmed and presumed COVID-19, 3 months after the onset of symptoms. Show less
The tremendous global impact of the current SARS-CoV-2 pandemic, as well as other current and recent outbreaks of (re)emerging viruses, emphasize the need for fast-track development of effective... Show moreThe tremendous global impact of the current SARS-CoV-2 pandemic, as well as other current and recent outbreaks of (re)emerging viruses, emphasize the need for fast-track development of effective vaccines. Yellow fever virus 17D (YF17D) is a live-attenuated virus vaccine with an impressive efficacy record in humans, and therefore, it is a very attractive platform for the development of novel chimeric vaccines against various pathogens. In the present study, we generated a YF17D-based replicon vaccine platform by replacing the prM and E surface proteins of YF17D with antigenic subdomains from the spike (S) proteins of three different betacoronaviruses: MERS-CoV, SARS-CoV and MHV. The prM and E proteins were provided in trans for the packaging of these RNA replicons into single-round infectious particles capable of expressing coronavirus antigens in infected cells. YF17D replicon particles expressing the S1 regions of the MERS-CoV and SARS-CoV spike proteins were immunogenic in mice and elicited (neutralizing) antibody responses against both the YF17D vector and the coronavirus inserts. Thus, YF17D replicon-based vaccines, and their potential DNA- or mRNA-based derivatives, may constitute a promising and particularly safe vaccine platform for current and future emerging coronaviruses. Show less
At the time SARS-CoV-2 was identified as the cause of coronavirus disease 2019 (COVID-19) no in vitro diagnostic (IVD) tests were available since it was a new virus. Very shortly after the release... Show moreAt the time SARS-CoV-2 was identified as the cause of coronavirus disease 2019 (COVID-19) no in vitro diagnostic (IVD) tests were available since it was a new virus. Very shortly after the release of the genomic sequence of SARS-CoV-2, laboratory-developed tests (LDTs) were developed, made available and implemented in several laboratories in the Netherlands and globally. In this study, the performance of an E-gene Sarbeco specific realtime reverse-transcriptase PCR (RT-PCR) was verified on the open modus of the geneLEAD VIII sample-to-answer platform. The results obtained from 134 clinical samples, of which 63 had been tested positive, showed almost complete concordance compared to the same PCR on the routine diagnostic systems and that was validated according to the national reference standard. The only discordant sample tested positive using the routine diagnostic workflow with a cycle threshold (CT) value of 37.7, while the sample tested negative using the geneLEAD VIII workflow. In addition, good performance was achieved in analyzing a blinded SARS-CoV-2 external quality assurance (EQA) panel. Implementation of the geneLEAD VIII platform as routine diagnostic tool resulted in testing 871 clinical samples with 115 positive results. In conclusion, the geneLEAD VIII SARSCoV-2 workflow presented in this study showed excellent diagnostic performance and with a rapid turnaround time of approximately two hours it proved a valuable option for STAT SARS-CoV-2 testing in the absence of (rapid, CE-IVD) point-of-care testing platforms. Show less
Perimyocarditis is a well-known acute inflammation of the pericardium and the underlying myocardium. Most commonly perimyocarditis is of viral aetiology, specifically the coxsackie B virus. However... Show morePerimyocarditis is a well-known acute inflammation of the pericardium and the underlying myocardium. Most commonly perimyocarditis is of viral aetiology, specifically the coxsackie B virus. However, nowadays SARSCoV-2 associated with COVID-19 infections has emerged as a potential rare cause of perimyocarditis. This case report will demonstrate a case of a young female with perimyocarditis as diagnosed by magnetic resonance imaging (MRI) accompanied by antigens indicating a past COVID-19 infection. Clinical status as well as Findings at MRI, echocardiography and lab results will be reviewed. Show less
The potential for zoonotic transmission and global spread demonstrated by the pandemic SARS-CoV-2, and its burden on public health, have emphasized the critical need to develop highly efficacious... Show moreThe potential for zoonotic transmission and global spread demonstrated by the pandemic SARS-CoV-2, and its burden on public health, have emphasized the critical need to develop highly efficacious strategies for prophylaxis and therapy of infections with coronavirus at large. This thesis was largely dedicated to the search of coronavirus inhibitors by phenotypic cell-based screenings using different classes of compounds including immunosuppressive and non-immunosuppressive derivatives of cyclosporin A, hits from FDA-approved drug libraries and molecules synthesized by collaborators. Although, no effective therapies were found, this work warranted the further clinical investigation of a non-immunosuppressive compound in SARS-CoV-2-infected kidney transplant recipients, which is currently in progress. The development of antiviral therapies requires a detailed understanding of CoV replication and its interplay with host cells. Here, an in-depth characterization of the viral replicase subunit non-structural protein 14 provides evidence for its importance for virus viability and fitness, while establishing that nsp14 might be a good target for drug design with a potential pan-coronaviral activity spectrum. In the discussion, the history of unsuccessful CoV-targeting antivirals is briefly summarized, together with possible new approaches in antiviral research. Lastly, some prospects for future research are outlined. Show less
Ridwan, S.; Ganau, M.; Zoia, C.; Broekman, M.; Grote, A.; Clusmann, H. 2021
Background: Since the COVID-19 outbreak several manuscripts regarding neurosurgical practice during this pandemic have been published. Qualitative studies on how the pandemic affected neurosurgeons... Show moreBackground: Since the COVID-19 outbreak several manuscripts regarding neurosurgical practice during this pandemic have been published. Qualitative studies on how the pandemic affected neurosurgeons, with additional focus on their practice, are still scarce. This study's objective was to investigate the impact of COVID-19 on various aspects of the professional and private life of a homogeneous group of international neurosurgeons affiliated to the European Association of Neurosurgical Societies (EANS).Methods: Neurosurgeons from Europe and abroad were invited to participate in an online survey endorsed by the Individual Membership Committee of the EANS. The survey captured a subjective snapshot of the impact of the first wave of the COVID-19 pandemic on EANS members and was advertised through its Institutional website. In addition to departmental data, personal feeling of safety, financial security, local precautions, number of surgeries performed, changes in daily routine, and other practice-related information were inquired. Differences among practice types were closely reviewed.Results: The survey was distributed between April and May 2020: 204 neurosurgeons participated. Participants were typically active EANS members (73%), consultants (57.9%), from university hospitals (64.5%). Elective surgical practice was still ongoing only for 15% of responders, whereas 18.7% of them had already transitioned to COVID-19 and emergency medical services. While 65.7% of participants thought their institutions were adequately prepared, lack of testing for SARS-CoV-2, and scarcity of personal protective equipment were still a matter of concern for most of them. Overall surgical activity dropped by 68% (cranial by 54%, spine by 71%), and even emergencies decreased by 35%. COVID-19 prompted changes in communication in 74% of departments, 44% increased telemedicine by >50%. While most neurosurgeons had concerns about personal and families' health, financial outlook appeared to be gloomy only for private practitioners.Conclusion: The lockdown imposed in many countries by the COVID-19 outbreak called for immediate modification of working routine and resulted in a dramatic decrease of elective surgical procedures. Neurosurgeons share common concerns but were not equally exposed to the personal health and financial dangers of the ongoing pandemic. Show less
Sablerolles, R.S.G.; Goorhuis, A.; GeurtsvanKessel, C.H.; Vries, R.D. de; Huckriede, A.L.W.; Koopmans, M.P.G.; ... ; Kuy, P.H.M. van der 2021
In the wake of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, an increasing number of patients with neurological disorders, including Guillain-Barre syndrome (GBS), have... Show moreIn the wake of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, an increasing number of patients with neurological disorders, including Guillain-Barre syndrome (GBS), have been reported following this infection. It remains unclear, however, if these cases are coincidental or not, as most publications were case reports or small regional retrospective cohort studies.The International GBS Outcome Study is an ongoing prospective observational cohort study enrolling patients with GBS within 2 weeks from onset of weakness. Data from patients included in this study, between 30 January 2020 and 30 May 2020, were used to investigate clinical and laboratory signs of a preceding or concurrent SARS-CoV-2 infection and to describe the associated clinical phenotype and disease course. Patients were classified according to the SARS-CoV-2 case definitions of the European Centre for Disease Prevention and Control and laboratory recommendations of the World Health Organization.Forty-nine patients with GBS were included, of whom eight (16%) had a confirmed and three (6%) a probable SARS-CoV-2 infection. Nine of these 11 patients had no serological evidence of other recent preceding infections associated with GBS, whereas two had serological evidence of a recent Campylobacter jejuni infection. Patients with a confirmed or probable SARS-CoV-2 infection frequently had a sensorimotor variant 8/11 (73%) and facial palsy 7/11 (64%). The eight patients who underwent electrophysiological examination all had a demyelinating subtype, which was more prevalent than the other patients included in the same time window [14/30 (47%), P = 0.012] as well as historical region and age-matched control subjects included in the International GBS Outcome Study before the pandemic [23/44 (52%), P = 0.016]. The median time from the onset of infection to neurological symptoms was 16 days (interquartile range 12-22).Patients with SARS-CoV-2 infection shared uniform neurological features, similar to those previously described in other post-viral GBS patients. The frequency (22%) of a preceding SARS-CoV-2 infection in our study population was higher than estimates of the contemporaneous background prevalence of SARS-CoV-2, which may be a result of recruitment bias during the pandemic, but could also indicate that GBS may rarely follow a recent SARS-CoV-2 infection. Consistent with previous studies, we found no increase in patient recruitment during the pandemic for our ongoing International GBS Outcome Study compared to previous years, making a strong relationship of GBS with SARS-CoV-2 unlikely. A case-control study is required to determine if there is a causative link or not. Show less
