Genomic epidemiology of SARS-CoV-2 spread in Scotland highlights the role of European travel in COVID-19 emergence

AbstractSARS-CoV-2, the causative agent of COVID-19, emerged in Wuhan, China in December 2019 and spread rapidly throughout the world. Understanding the introductions of this new coronavirus in different settings may assist control efforts and the establishment of frameworks to support rapid response in future infectious disease outbreaks.We investigated the first four weeks of emergence of the SARS-CoV-2 virus in Scotland after the first case reported on the 1st March 2020. We obtained full genome sequences from 452 individuals with a laboratory-confirmed diagnosis of COVID-19, representing 20% of all cases until 1st April 2020 (n=2310). This permitted a genomic epidemiology approach to study the introductions and spread of the SARS-2 virus in Scotland.From combined phylogenetic and epidemiological analysis, we estimated at least 113 introductions of SARS-CoV-2 into Scotland during this period. Clusters containing multiple sequences suggestive of onward transmission occurred in 48/86 (56%). 42/86 (51%) clusters had no known international travel history indicating undetected introductions.The majority of viral sequences were most closely related to those circulating in other European countries, including Italy, Austria and Spain. Travel-associated introductions of SARS-CoV-2 into Scotland predated travel restrictions in the UK and other European countries. The first local transmission occurred three days after the first case. A shift from travel-associated to sustained community transmission was apparent after only 11 days. Undetected introductions occurred prior to the first known case of COVID-19. Earlier travel restrictions and quarantine measures might have resulted in fewer introductions into Scotland, thereby reducing the number of cases and the subsequent burden on health services. The high number of introductions and transmission rates were likely to have impacted on national contact tracing efforts. Our results also demonstrate that local real-time genomic epidemiology can be used to monitor transmission clusters and facilitate control efforts to restrict the spread of COVID-19.FundingMRC (MC UU 1201412), UKRI/Wellcome (COG-UK), Wellcome Trust Collaborator Award (206298/Z/17/Z – ARTIC Network; TCW Wellcome Trust Award 204802/Z/16/ZResearch in contextEvidence before this studyCoronavirus disease-2019 (COVID-19) was first diagnosed in Scotland on the 1st of March 2020 following the emergence of the causative severe acute respiratory system coronavirus 2 (SARS-CoV-2) virus in China in December 2019. During the first month of the outbreak in Scotland, 2310 positive cases of COVID-19 were detected, associated with 1832 hospital admissions, 207 intensive care admissions and 126 deaths. The number of introductions into Scotland and the source of those introductions was not known prior to this study.Added value of this studyUsing a combined phylogenetic and epidemiological approach following real-time next generation sequencing of 452 SARS-CoV-2 samples, it was estimated that the virus was introduced to Scotland on at least 113 occasions, mostly from other European countries, including Italy, Austria and Spain. Localised outbreaks occurred in the community across multiple Scottish health boards, within healthcare facilities and an international conference and community transmission was established rapidly, before local and international lockdown measures were introduced.</jats:sec

The circulating SARS-CoV-2 spike variant N439K maintains fitness while evading antibody-mediated immunity

SARS-CoV-2 can mutate to evade immunity, with consequences for the efficacy of emerging vaccines and antibody therapeutics. Herein we demonstrate that the immunodominant SARS-CoV-2 spike (S) receptor binding motif (RBM) is the most divergent region of S, and provide epidemiological, clinical, and molecular characterization of a prevalent RBM variant, N439K. We demonstrate that N439K S protein has enhanced binding affinity to the hACE2 receptor, and that N439K virus has similar clinical outcomes and in vitro replication fitness as compared to wild- type. We observed that the N439K mutation resulted in immune escape from a panel of neutralizing monoclonal antibodies, including one in clinical trials, as well as from polyclonal sera from a sizeable fraction of persons recovered from infection. Immune evasion mutations that maintain virulence and fitness such as N439K can emerge within SARS-CoV-2 S, highlighting the need for ongoing molecular surveillance to guide development and usage of vaccines and therapeutics

Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition)

The third edition of Flow Cytometry Guidelines provides the key aspects to consider when performing flow cytometry experiments and includes comprehensive sections describing phenotypes and functional assays of all major human and murine immune cell subsets. Notably, the Guidelines contain helpful tables highlighting phenotypes and key differences between human and murine cells. Another useful feature of this edition is the flow cytometry analysis of clinical samples with examples of flow cytometry applications in the context of autoimmune diseases, cancers as well as acute and chronic infectious diseases. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid. All sections are written and peer‐reviewed by leading flow cytometry experts and immunologists, making this edition an essential and state‐of‐the‐art handbook for basic and clinical researchers.DFG, 389687267, Kompartimentalisierung, Aufrechterhaltung und Reaktivierung humaner Gedächtnis-T-Lymphozyten aus Knochenmark und peripherem BlutDFG, 80750187, SFB 841: Leberentzündungen: Infektion, Immunregulation und KonsequenzenEC/H2020/800924/EU/International Cancer Research Fellowships - 2/iCARE-2DFG, 252623821, Die Rolle von follikulären T-Helferzellen in T-Helferzell-Differenzierung, Funktion und PlastizitätDFG, 390873048, EXC 2151: ImmunoSensation2 - the immune sensory syste

Correlation between liver volume and liver weight in a cohort with chronic liver disease: a semiautomated CT-volumetry study

BACKGROUND: To estimate the optimal density coefficient for conversion of liver volume into liver weight in patients with chronic liver disease based on semiautomated CT-liver volumetry data and the histologic Ishak score of explanted liver. METHODS: A total of 114 patients (39 female; age, 46±20 years) with chronic liver diseases who underwent liver transplantation between January 2010 and September 2020 were identified over a patient chart search at our institution and subsequently analyzed in retrospect. All patients had contrast-enhanced CT-examinations (mean, 24 days) to liver transplantation. Liver volume was calculated by a semiautomated software and results compared with the liver weight registered by the pathologist. Each explanted liver was histologically scored into six classes according to the Ishak classification where the categories were subgrouped based on recommendation of the pathologists into the following categories 0–3, 4–5 and 6. RESULTS: Mean liver volume was 1,870±1,195, 1,162±679 and 1,278±510 mL for the categories 0–3, 4–5 and 6, respectively. Mean liver weight was 1,624±999, 1,082±669 and 1,346±559 g for the categories 0–3, 4–5 and 6, respectively. A coefficient of 0.92±0.22, 0.98±0.28 and 1.06±0.20 g/mL was found at best for conversion of liver volume into liver weight in these subgroups. Differences between Ishak-subgroups proved significant (0.002). In 4 patients with cystic liver disease, density coefficients varied significantly and were found generally lower compared to the other liver disorders. CONCLUSIONS: Our results yielded significant differences between the density coefficients calculated along with the Ishak score and also for the subgroup with cystic liver disease

Patterns of Signal Intensity in CISS MRI of the Inner Ear and Eye

Background: Constructive interference in steady state (CISS) is a gradient echo magnetic resonance imaging (MRI) pulse sequence that provides excellent contrast between cerebrospinal fluid and adjacent structures but is prone to banding artifacts due to magnetic field inhomogeneities. We aimed to characterize artifacts in the inner ear and eye. Methods: In 30 patients (60 ears/eyes) undergoing CISS sequence MRI, nine low-signal intensity regions were identified in the inner ear and compared to temporal bone histopathology. The number and angle of bands across the eye were examined. Results: In the cochlea, all ears had regions of low signal corresponding to anatomy (modiolus (all), spiral lamina (n = 59, 98.3%), and interscalar septa (n = 50, 83.3%)). In the labyrinth, the lateral semicircular canal crista (n = 42, 70%) and utricular macula (n = 47, 78.3%) were seen. Areas of low signal in the vestibule seen in all ears may represent the walls of the membranous utricle. Zero to three banding artifacts were seen in both eyes (right: 96.7%, mean 1.5; left: 93.3%, mean 1.3). Conclusion: Low signal regions in the inner ear on CISS sequences are common and have consistent patterns; most in the inner ear represent anatomy, appearing blurred due to partial volume averaging. Banding artifacts in the eye are more variable

Fully automated whole-liver volume quantification on CT-image data: Comparison with manual volumetry using enhanced and unenhanced images as well as two different radiation dose levels and two reconstruction kernels

Objectives To evaluate the accuracy of fully automated liver volume quantification vs. manual quantification using unenhanced as well as enhanced CT-image data as well as two different radiation dose levels and also two image reconstruction kernels. Material and methods The local ethics board gave its approval for retrospective data analysis. Automated liver volume quantification in 300 consecutive livers in 164 male and 103 female oncologic patients (64±12y) performed at our institution (between January 2020 and May 2020) using two different dual-energy helicals: portal-venous phase enhanced, ref. tube current 300mAs (CARE Dose4D) for tube A (100 kV) and ref. 232mAs tube current for tube B (Sn140kV), slice collimation 0.6mm, reconstruction kernel I30f/1, recon. thickness of 0.6mm and 5mm, 80–100 mL iodine contrast agent 350 mg/mL, (flow 2mL/s) and unenhanced ref. tube current 100mAs (CARE Dose4D) for tube A (100 kV) and ref. 77mAs tube current for tube B (Sn140kV), slice collimation 0.6mm (kernel Q40f) were analyzed. The post-processing tool (syngo.CT Liver Analysis) is already FDA-approved. Two resident radiologists with no and 1-year CT-experience performed both the automated measurements independently from each other. Results were compared with those of manual liver volume quantification using the same software which was supervised by a senior radiologist with 30-year CT-experience (ground truth). Results In total, a correlation of 98% was obtained for liver volumetry based on enhanced and unenhanced data sets compared to the manual liver quantification. Radiologist #1 and #2 achieved an inter-reader agreement of 99.8% for manual liver segmentation (p5% deviation) of 3.7% for unenhanced CT-image data and 4.0% for contrast-enhanced CT-images. Underestimation ( 0.05). Conclusion Results of fully automated liver volume quantification are accurate and comparable with those of manual liver volume quantification and the technique seems to be confident even if unenhanced lower-dose CT image data is used

Dual-Energy Computed Tomography-Based Quantitative Bone Marrow Imaging in Non-Hematooncological Subjects: Associations with Age, Gender and Other Variables

Background: Our aim is to assess the utility and associations of quantitative bone marrow attenuation (BMA) values measured on clinical dual-energy computed tomography (DECT) exams in non-hematooncologic subjects with skeletal regions, patient age, gender, and other clinical variables. Methods: Our local ethics committee approved this retrospective image data analysis. Between July 2019 and July 2021, 332 eligible patients (mean age, 64 &plusmn; 18 years; female, 135) were identified. Inclusion criteria were the availability of a standardized abdominopelvic DECT data set acquired on the same scanner with identical protocol. Eleven regions-of-interest were placed in the T11-L5 vertebral bodies, dorsal iliac crests, and femur necks. Patient age, gender, weight, clinical, habitual variables, inflammation markers, and anemia were documented in all cases. Results: Multi-regression analyses (all, p &lt; 0.05) identified age as the strongest predictor of lumbar BMA (standardized coefficient: &beta; = &minus;0.74), followed by CRP (&beta; = 0.11), LDH (&beta; = 0.11), and gender (&beta; = &minus;0.10). In the lower thoracic spine, age was the strongest predictor (&beta; = &minus;0.58) of BMA, followed by gender (&beta; = &minus;0.09) and LDH (&beta; = 0.12). In femoral bones, age was negatively predictive of BMA (&beta; = &minus;0.12), whereas LDH and anemia were positively predictive (&beta; = 0.16 both). Heart insufficiency significantly decreased (&beta; = 0.12, p = 0.034) a BMA value gradient from higher to lower HU values along the vertebrae T11 and L5, whereas age significantly increased this gradient (&beta; = &minus;0.2, p &le; 0.001). Conclusions: DECT-based BMA measurements can be obtained from clinical CT exams. BMA values are negatively associated with patient age and influenced by gender, anemia, and inflammatory markers

Neurological complications of cancer immunotherapy

Immunotherapy has emerged as a powerful therapeutic approach in many areas of clinical oncology and hematology. The approval of ipilimumab, a monoclonal antibody targeting the immune cell receptor CTLA-4, has marked the beginning of the era of immune checkpoint inhibitors. In the meantime, numerous antibodies targeting the PD-1 pathway have expanded the class of clinically approved immune checkpoint inhibitors. Furthermore, novel antibodies directed against other immune checkpoints are currently in clinical evaluation. More recently, bispecific antibodies, which link T cells directly to tumor cells as well as adoptive T cell transfer with immune cells engineered to express a chimeric antigen receptor, have been approved in certain indications. Neurological complications associated with the use of these novel immunotherapeutic concepts have been recognized more and more frequently. Immune checkpoint inhibitors may cause various neurological deficits mainly by alterations of the peripheral nervous system's integrity. These include radiculopathies, neuropathies, myopathies as well as myasthenic syndromes. Side effects involving the central nervous system are less frequent but may result in severe clinical symptoms and syndromes. The administration of chimeric antigen receptor (CAR) T cell is subject to rigorous patient selection and their use is frequently associated with neurological complications including encephalopathy and seizures, which require immediate action and appropriate therapeutic measures. Close clinical monitoring for neurological symptoms is key for early recognition of immunotherapy-related side effects. Comprehensive diagnostic work-up and adequate therapeutic measures are essential to avoid further clinical deterioration and residual neurological deficits

The Tregiovo area and related volcanics in the Tregiovo section. Excursion 2: from the Giudicarie area to the Dolomites.

Academic excellence and its social construction is far from being a classical issue in sociological research and debate. To be sure, the sociology of science has for long studied how intellectual reputations rise and are established, and how they impact on both intellectual production and the working of academic and scientific organizations. Based on the measurement of citations, bibliometrics is possibly the most renown and used research strategy for empirically assessing intellectual prestige and studying its correlates, its possible causes and its consequences. However, social scientists have not paid any special attention to the actual working of procedures and practices of evaluation as well as to its cognitive underpinning and its impact on the final assessment. This international symposium debates peer review method starting from the work of Michele Lamont "How professors think" with contribution of scholars from different sociological perspecitives: sociology of science (Collins, Brian), cultural sociology (Inglis), the sociology of ideas and intellectuals (Angermuller), and behavioral economic sociology (Squazzoni)

Is a single portal venous phase in contrast-enhanced CT sufficient to detect metastases or recurrence in clear cell renal cell carcinoma? - a single-center retrospective study

BACKGROUND: This study aims at describing the imaging features of the metastatic presentation of clear cell renal cell carcinoma (ccRCC) in arterial (AP) and portal venous phase (PVP) of contrast-enhanced-computed-tomography (CECT) during clinical follow-up (FU) and to evaluate the necessity of a dual phase approach for metastasis detection. METHODS: We identified a total of 584 patients that were diagnosed with ccRCC between January 2016 and April 2020. Inclusion criteria were histologically proven ccRCC with metastatic spread, proven by histology or interim follow-up of at least 2 years and follow-up CT examination with AP and PVP CECT including thorax/abdomen and pelvis. Exclusion criteria were defined by missing or incomplete CT-scans or lack of sufficient follow-up. CT studies of 43 patients with histologically proven ccRCCs were analyzed in retrospect. AP and PVP images were analyzed by two radiologists for metastases, two additional independent radiologists analyzed PVP images only. A 5-point Likert scale was used to evaluate the likelihood off the presence of metastasis. Imaging patterns of the metastases were analyzed visually. RESULTS: 43 patients (16 female; mean age: 67±10 years) with recurrent ccRCC and metastatic disease were included. Three imaging patterns were observed (solid, heterogeneous or cystic metastases), which rarely exhibited calcifications (2%). All metastases showed hyperenhancement in AP and PVP. Inter-reader agreement was substantial (Fleiss’ κ 0.6–0.8, p<0.001). No significant differences in sensitivity or specificity between readers (AP and PVP images vs. PVP images only) were present (79.4-85.2%, 97.1-99.6%, p ≥ 0.05). The area under the receiver-operating-characteristic (ROC) curve was between 0.901and 0.922 for all four radiologists. CONCLUSIONS: Similar rates for detection, sensitivity and specificity of metastasis and local recurrence in ccRCC were observed irrespective of using a dual-phase protocol with AP and PVP or a single PVP protocol only. Thus, a single-phase examination of PVP can be sufficient for experienced radiologists to detect metastatic disease in the follow-up of ccRCC patients