Showing papers by "University of Zurich published in 2022"

From cohorts to molecules: Adverse impacts of endocrine disrupting mixtures

Abstract: Convergent evidence associates exposure to endocrine disrupting chemicals (EDCs) with major human diseases, even at regulation-compliant concentrations. This might be because humans are exposed to EDC mixtures, whereas chemical regulation is based on a risk assessment of individual compounds. Here, we developed a mixture-centered risk assessment strategy that integrates epidemiological and experimental evidence. We identified that exposure to an EDC mixture in early pregnancy is associated with language delay in offspring. At human-relevant concentrations, this mixture disrupted hormone-regulated and disease-relevant regulatory networks in human brain organoids and in the model organisms Xenopus leavis and Danio rerio, as well as behavioral responses. Reinterrogating epidemiological data, we found that up to 54% of the children had prenatal exposures above experimentally derived levels of concern, reaching, for the upper decile compared with the lowest decile of exposure, a 3.3 times higher risk of language delay.

Interleukin-6 Receptor Blockade in Treatment-Refractory MOG-IgG-Associated Disease and Neuromyelitis Optica Spectrum Disorders.

Abstract: BACKGROUND AND OBJECTIVES To evaluate the long-term safety and efficacy of tocilizumab (TCZ), a humanized anti-interleukin-6 receptor antibody in myelin oligodendrocyte glycoprotein-IgG-associated disease (MOGAD) and neuromyelitis optica spectrum disorders (NMOSD). METHODS Annualized relapse rate (ARR), Expanded Disability Status Scale score, MRI, autoantibody titers, pain, and adverse events were retrospectively evaluated in 57 patients with MOGAD (n = 14), aquaporin-4 (AQP4)-IgG seropositive (n = 36), and seronegative NMOSD (n = 7; 12%), switched to TCZ from previous immunotherapies, particularly rituximab. RESULTS Patients received TCZ for 23.8 months (median; interquartile range 13.0-51.1 months), with an IV dose of 8.0 mg/kg (median; range 6-12 mg/kg) every 31.6 days (mean; range 26-44 days). For MOGAD, the median ARR decreased from 1.75 (range 0.5-5) to 0 (range 0-0.9; p = 0.0011) under TCZ. A similar effect was seen for AQP4-IgG+ (ARR reduction from 1.5 [range 0-5] to 0 [range 0-4.2]; p < 0.001) and for seronegative NMOSD (from 3.0 [range 1.0-3.0] to 0.2 [range 0-2.0]; p = 0.031). During TCZ, 60% of all patients were relapse free (79% for MOGAD, 56% for AQP4-IgG+, and 43% for seronegative NMOSD). Disability follow-up indicated stabilization. MRI inflammatory activity decreased in MOGAD (p = 0.04; for the brain) and in AQP4-IgG+ NMOSD (p < 0.001; for the spinal cord). Chronic pain was unchanged. Regarding only patients treated with TCZ for at least 12 months (n = 44), ARR reductions were confirmed, including the subgroups of MOGAD (n = 11) and AQP4-IgG+ patients (n = 28). Similarly, in the group of patients treated with TCZ for at least 12 months, 59% of them were relapse free, with 73% for MOGAD, 57% for AQP4-IgG+, and 40% for patients with seronegative NMOSD. No severe or unexpected safety signals were observed. Add-on therapy showed no advantage compared with TCZ monotherapy. DISCUSSION This study provides Class III evidence that long-term TCZ therapy is safe and reduces relapse probability in MOGAD and AQP4-IgG+ NMOSD.

Radical right parties and their welfare state stances - not so blurry after all?

Abstract: Recent literature shows that radical right parties (RRPs) present moderate or blurry economic stances. However, this paper argues that this blurriness is restricted to only one of the two main conf...

Cell-based and stem-cell-based treatments for spinal cord injury: evidence from clinical trials

Abstract: Spinal cord injury is a severely disabling neurological condition leading to impaired mobility, pain, and autonomic dysfunction. Most often, a single traumatic event, such as a traffic or recreational accident, leads to primary spinal cord damage through compression and laceration, followed by secondary damage consisting of inflammation and ischaemia, and culminating in substantial tissue loss. Patients need appropriate timely surgical and critical care, followed by neurorehabilitation to facilitate neuronal reorganisation and functional compensation. Although some neurological function might be regained, most patients with initially complete lesions have severe, irreversible neurological impairment. Cell-based and stem-cell-based therapies are recognised as promising candidates to promote functional recovery. However, no trials of these therapies in patients have yet provided reproducible evidence for clinical efficacy, challenged by small effect sizes, low immune suppression, and low sensitivity study designs. Nevertheless, in the past decade, clinical trials have shown the feasibility and long-term safety of cell transplantation into the injured spinal cord. This crucial milestone has paved the way to consider refinements and combined therapies, such as the use of biomaterials to augment the effects of cell transplantation. In the future, emerging cell types, scaffolding, and cell engineering might improve cell survival, integration, and therapeutic efficiency. Spinal cord injury is a severely disabling neurological condition leading to impaired mobility, pain, and autonomic dysfunction. Most often, a single traumatic event, such as a traffic or recreational accident, leads to primary spinal cord damage through compression and laceration, followed by secondary damage consisting of inflammation and ischaemia, and culminating in substantial tissue loss. Patients need appropriate timely surgical and critical care, followed by neurorehabilitation to facilitate neuronal reorganisation and functional compensation. Although some neurological function might be regained, most patients with initially complete lesions have severe, irreversible neurological impairment. Cell-based and stem-cell-based therapies are recognised as promising candidates to promote functional recovery. However, no trials of these therapies in patients have yet provided reproducible evidence for clinical efficacy, challenged by small effect sizes, low immune suppression, and low sensitivity study designs. Nevertheless, in the past decade, clinical trials have shown the feasibility and long-term safety of cell transplantation into the injured spinal cord. This crucial milestone has paved the way to consider refinements and combined therapies, such as the use of biomaterials to augment the effects of cell transplantation. In the future, emerging cell types, scaffolding, and cell engineering might improve cell survival, integration, and therapeutic efficiency.

Ultra-High-Resolution Coronary CT Angiography With Photon-Counting Detector CT

Abstract: The aim of this study was to evaluate the feasibility and quality of ultra-high-resolution coronary computed tomography angiography (CCTA) with dual-source photon-counting detector CT (PCD-CT) in patients with a high coronary calcium load, including an analysis of the optimal reconstruction kernel and matrix size.In this institutional review board-approved study, 20 patients (6 women; mean age, 79 ± 10 years; mean body mass index, 25.6 ± 4.3 kg/m 2 ) undergoing PCD-CCTA in the ultra-high-resolution mode were included. Ultra-high-resolution CCTA was acquired in an electrocardiography-gated dual-source spiral mode at a tube voltage of 120 kV and collimation of 120 × 0.2 mm. The field of view (FOV) and matrix sizes were adjusted to the resolution properties of the individual reconstruction kernels using a FOV of 200 × 200 mm 2 or 150 × 150 mm 2 and a matrix size of 512 × 512 pixels or 1024 × 1024 pixels, respectively. Images were reconstructed using vascular kernels of 8 sharpness levels (Bv40, Bv44, Bv56, Bv60, Bv64, Bv72, Bv80, and Bv89), using quantum iterative reconstruction (QIR) at a strength level of 4, and a slice thickness of 0.2 mm. Images with the Bv40 kernel, QIR at a strength level of 4, and a slice thickness of 0.6 mm served as the reference. Image noise, signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), vessel sharpness, and blooming artifacts were quantified. For subjective image quality, 2 blinded readers evaluated image noise and delineation of coronary artery plaques and the adjacent vessel lumen using a 5-point discrete visual scale. A phantom scan served to characterize image noise texture by calculating the noise power spectrum for every reconstruction kernel.Maximum spatial frequency (f peak ) gradually shifted to higher values for reconstructions with the Bv40 to Bv64 kernel (0.15 to 0.56 mm -1 ), but not for reconstructions with the Bv72 to Bv89 kernel. Ultra-high-resolution CCTA was feasible in all patients (median calcium score, 479). In patients, reconstructions with the Bv40 kernel and a slice thickness of 0.6 mm showed largest blooming artifacts (55.2% ± 9.8%) and lowest vessel sharpness (477.1 ± 73.6 ΔHU/mm) while achieving highest SNR (27.4 ± 5.6) and CNR (32.9 ± 6.6) and lowest noise (17.1 ± 2.2 HU). Considering reconstructions with a slice thickness of 0.2 mm, image noise, SNR, CNR, vessel sharpness, and blooming artifacts significantly differed across kernels (all P 's < 0.001). With higher kernel sharpness, SNR and CNR continuously decreased, whereas image noise and vessel sharpness increased, with highest sharpness for the Bv89 kernel (2383.4 ± 787.1 ΔHU/mm). Blooming artifacts continuously decreased for reconstructions with the Bv40 (slice thickness, 0.2 mm; 52.8% ± 9.2%) to the Bv72 kernel (39.7% ± 9.1%). Subjective noise was perceived by both readers in agreement with the objective measurements. Considering delineation of coronary artery plaques and the adjacent vessel lumen, reconstructions with the Bv64 and Bv72 kernel (for both, median score of 5) were favored by the readers providing an excellent anatomic delineation of plaque characteristics and vessel lumen.Ultra-high-resolution CCTA with PCD-CT is feasible and enables the visualization of calcified coronaries with an excellent image quality, high sharpness, and reduced blooming. Coronary plaque characterization and delineation of the adjacent vessel lumen are possible with an optimal quality using Bv64 kernel, a FOV of 200 × 200 mm 2 , and a matrix size of 512 × 512 pixels.

Myocarditis following<scp>COVID</scp>‐19 vaccine: incidence, presentation, diagnosis, pathophysiology, therapy, and outcomes put into perspective. A clinical consensus document supported by the Heart Failure Association of the European Society of Cardiology (ESC) and the ESC Working Group on Myocardial and Pericardial Diseases

Abstract: Over 10 million doses of COVID-19 vaccines based on RNA technology, viral vectors, recombinant protein, and inactivated virus have been administered worldwide. Although generally very safe, post-vaccine myocarditis can result from adaptive humoral and cellular, cardiac-specific inflammation within days and weeks of vaccination. Rates of vaccine-associated myocarditis vary by age and sex with the highest rates in males between 12 and 39 years. The clinical course is generally mild with rare cases of left ventricular dysfunction, heart failure and arrhythmias. Mild cases are likely underdiagnosed as cardiac magnetic resonance imaging (CMR) is not commonly performed even in suspected cases and not at all in asymptomatic and mildly symptomatic patients. Hospitalization of symptomatic patients with electrocardiographic changes and increased plasma troponin levels is considered necessary in the acute phase to monitor for arrhythmias and potential decline in left ventricular function. In addition to evaluation for symptoms, electrocardiographic changes and elevated troponin levels, CMR is the best non-invasive diagnostic tool with endomyocardial biopsy being restricted to severe cases with heart failure and/or arrhythmias. The management beyond guideline-directed treatment of heart failure and arrhythmias includes non-specific measures to control pain. Anti-inflammatory drugs such as non-steroidal anti-inflammatory drugs, and corticosteroids have been used in more severe cases, with only anecdotal evidence for their effectiveness. In all age groups studied, the overall risks of SARS-CoV-2 infection-related hospitalization and death are hugely greater than the risks from post-vaccine myocarditis. This consensus statement serves as a practical resource for physicians in their clinical practice, to understand, diagnose, and manage affected patients. Furthermore, it is intended to stimulate research in this area.

How digitalised are vocational teachers? Assessing digital competence in vocational education and looking at its underlying factors

Abstract: Teachers' digital competence (TDC) is an important condition for the effective integration of technologies in education, and it depends on personal and context-related factors. Different frameworks and instruments have been developed to measure TDC. However, research on digital competence in vocational education and training (VET) is still scarce. Therefore, this study aims: (a) to provide a snapshot of the status quo of digital competence on a sample of 1692 Swiss VET teachers, both using an assessment instrument that relies on previous validated questionnaires, and at the same time accounting for VET-related specificities; (b) to examine possible differences in digital competence depending on the VET teachers' profiles (i.e. professional baccalaureate, professional subject and general education teachers); and (c) to investigate whether personal and context-related factors play a similar role in VET like in other educational settings. The results confirm the validity of the 10-dimensional structure of the TDC assessment instrument. Compared with previous results in other educational domains, our findings indicate that VET teachers place themselves at a similar degree of digital competence, with a few differences across profiles in some of the sub-competences. Moreover, multiple regression analysis highlights the main role of attitude towards technology and digital tool use frequency among the personal factors that contribute to TDC development. The teachers’ workload, rarely considered in previous studies, is also a relevant factor. For the context-related factors, curriculum support is the element with the largest effect on TDC, although it has a smaller impact than the personal factors.

Design choices for next-generation IIoT-connected MES/MOM: An empirical study on smart factories

Abstract: The role of enterprise information systems is becoming increasingly crucial for improving customer responsiveness in the manufacturing industry. However, manufacturers engaged in mass customization are currently facing challenges related to implementing Industrial Internet of Things (IIoT) concepts of Industry 4.0 in order to increase responsiveness. In this article, we apply the findings from a two-year design science study to establish the role of manufacturing execution systems/manufacturing operations management (MES/MOM) in an IIoT-enabled brownfield manufacturing enterprise. We also present design recommendations for developing next-generation MES/MOM as a strong core to make factories smart and responsive. First, we analyze the architectural design challenges of MES/MOM in IIoT through a selective literature review. We then present an exploratory case study in which we implement our homegrown MES/MOM data model design based on ISA 95 in Aalborg University's Smart Production Lab, which is a reconfigurable cyber-physical production system. This was achieved through the use of a custom module for the open-source Odoo ERP platform (mainly version 14). Finally, we enrich our case study with three industrial design demonstrators and combine the findings with a quality function deployment (QFD) method to determine design requirements for next-generation IIoT-connected MES/MOM. The results from our QFD analysis indicate that interoperability is the most important characteristic when designing a responsive smart factory, with the highest relative importance of 31% of the eight characteristics we studied.

Defining and Measuring News Media Quality: Comparing the Content Perspective and the Audience Perspective:

Abstract: High-quality news is important, not only for its own sake but also for its political implications However, defining, operationalizing, and measuring news media quality is difficult, because evalua

Global Structure of the Intrinsically Disordered Protein Tau Emerges from Its Local Structure

Abstract: The paradigmatic disordered protein tau plays an important role in neuronal function and neurodegenerative diseases. To disentangle the factors controlling the balance between functional and disease-associated conformational states, we build a structural ensemble of the tau K18 fragment containing the four pseudorepeat domains involved in both microtubule binding and amyloid fibril formation. We assemble 129-residue-long tau K18 chains with atomic detail from an extensive fragment library constructed with molecular dynamics simulations. We introduce a reweighted hierarchical chain growth (RHCG) algorithm that integrates experimental data reporting on the local structure into the assembly process in a systematic manner. By combining Bayesian ensemble refinement with importance sampling, we obtain well-defined ensembles and overcome the problem of exponentially varying weights in the integrative modeling of long-chain polymeric molecules. The resulting tau K18 ensembles capture nuclear magnetic resonance (NMR) chemical shift and J-coupling measurements. Without further fitting, we achieve very good agreement with measurements of NMR residual dipolar couplings. The good agreement with experimental measures of global structure such as single-molecule Förster resonance energy transfer (FRET) efficiencies is improved further by ensemble refinement. By comparing wild-type and mutant ensembles, we show that pathogenic single-point P301L, P301S, and P301T mutations shift the population from the turn-like conformations of the functional microtubule-bound state to the extended conformations of disease-associated tau fibrils. RHCG thus provides us with an atomically detailed view of the population equilibrium between functional and aggregation-prone states of tau K18, and demonstrates that global structural characteristics of this intrinsically disordered protein emerge from its local structure.

Dose- and Volume-Limiting Late Toxicity of FLASH Radiotherapy in Cats with Squamous Cell Carcinoma of the Nasal Planum and in Mini Pigs

Abstract: The FLASH effect is characterized by normal tissue sparing without compromising tumor control. Although demonstrated in various preclinical models, safe translation of FLASH-radiotherapy stands to benefit from larger vertebrate animal models. Based on prior results, we designed a randomized phase III trial to investigate the FLASH effect in cat patients with spontaneous tumors. In parallel, the sparing capacity of FLASH-radiotherapy was studied on mini pigs by using large field irradiation.Cats with T1-T2, N0 carcinomas of the nasal planum were randomly assigned to two arms of electron irradiation: arm 1 was the standard of care (SoC) and used 10 × 4.8 Gy (90% isodose); arm 2 used 1 × 30 Gy (90% isodose) FLASH. Mini pigs were irradiated using applicators of increasing size and a single surface dose of 31 Gy FLASH.In cats, acute side effects were mild and similar in both arms. The trial was prematurely interrupted due to maxillary bone necrosis, which occurred 9 to 15 months after radiotherapy in 3 of 7 cats treated with FLASH-radiotherapy (43%), as compared with 0 of 9 cats treated with SoC. All cats were tumor-free at 1 year in both arms, with one cat progressing later in each arm. In pigs, no acute toxicity was recorded, but severe late skin necrosis occurred in a volume-dependent manner (7-9 months), which later resolved.The reported outcomes point to the caveats of translating single-high-dose FLASH-radiotherapy and emphasizes the need for caution and further investigations. See related commentary by Maity and Koumenis, p. 3636.

Simulating hyperbolic space on a circuit board

Abstract: The Laplace operator encodes the behavior of physical systems at vastly different scales, describing heat flow, fluids, as well as electric, gravitational, and quantum fields. A key input for the Laplace equation is the curvature of space. Here we discuss and experimentally demonstrate that the spectral ordering of Laplacian eigenstates for hyperbolic (negatively curved) and flat two-dimensional spaces has a universally different structure. We use a lattice regularization of hyperbolic space in an electric-circuit network to measure the eigenstates of a 'hyperbolic drum', and in a time-resolved experiment we verify signal propagation along the curved geodesics. Our experiments showcase both a versatile platform to emulate hyperbolic lattices in tabletop experiments, and a set of methods to verify the effective hyperbolic metric in this and other platforms. The presented techniques can be utilized to explore novel aspects of both classical and quantum dynamics in negatively curved spaces, and to realise the emerging models of topological hyperbolic matter.

Extracellular Volume Quantification With Cardiac Late Enhancement Scanning Using Dual-Source Photon-Counting Detector CT

Abstract: The aim of this study was to evaluate the feasibility and accuracy of cardiac late enhancement (LE) scanning for extracellular volume (ECV) quantification with dual-source photon-counting detector computed tomography (PCD-CT).In this institutional review board-approved study, 30 patients (mean age, 79 years; 12 women; mean body mass index, 28 kg/m2) with severe aortic stenosis undergoing PCD-CT as part of their preprocedural workup for transcatheter aortic valve replacement were included. The scan protocol consisted of a nonenhanced calcium-scoring scan, coronary CT angiography (CTA) followed by CTA of the thoracoabdominal aorta, and a low-dose LE scan 5 minutes after the administration of 100 mL contrast media (all scans electrocardiogram-gated). Virtual monoenergetic (65 keV) and dual-energy (DE) iodine images were reconstructed from the LE scan. Extracellular volume was calculated using the iodine ratios of myocardium and blood-pool of the LE scan, and additionally based on single-energy (SE) subtraction of the nonenhanced scan from the LE scan. Three-dimensional analysis was performed automatically for the whole-heart myocardial volume by matching a heart model generated from the respective coronary CTA data. Bland-Altman and correlation analysis were used to compare the ECV values determined by both methods.The median dose length product for the LE scan was 84 mGy·cm (interquartile range, 69; 125 mGy·cm). Extracellular volume quantification was feasible in all patients. The median ECV value was 30.5% (interquartile range, 28.4%-33.6%). Two focal ECV elevations matched known prior myocardial infarction. The DE- and SE-based ECV quantification correlated well (r = 0.87, P < 0.001). Bland-Altman analysis showed small mean errors between DE- and SE-based ECV quantification (0.9%; 95% confidence interval, 0.1%-1.6%) with narrow limits of agreement (-3.3% to 5.0%).Dual-source PCD-CT enables accurate ECV quantification using an LE cardiac DE scan at low radiation dose. Extracellular volume calculation from iodine ratios of the LE scan obviates the need for acquisition of a true nonenhanced scan and is not affected by potential misregistration between 2 separate scans.

Reciprocal Developmental Relations Between ADHD and Anxiety in Adolescence: A Within-Person Longitudinal Analysis of Commonly Co-Occurring Symptoms

Abstract: Objective: Significant anxiety often occurs in the presence of ADHD symptoms; however, the reasons are not well understood. We aimed to establish whether the relations between ADHD symptons and anx...

Media Systems in the Digital Age: An Empirical Comparison of 30 Countries

Abstract: Abstract Media systems have changed significantly as a result of the development of information technologies. However, typologies of media systems that incorporate aspects of digitalization are rare. This study fills this gap by identifying, operationalizing, and measuring indicators of media systems in the digital age. We build on previous work, extend it with new indicators that reflect changing conditions (such as online news use), and include media freedom indicators. We include 30 countries in our study and use cluster analysis to identify three clusters of media systems. Two of these clusters correspond to the media system models described by Hallin and Mancini, namely the democratic-corporatist and the polarized-pluralist model. However, the liberal model as described by Hallin and Mancini has vanished; instead, we find empirical evidence of a new cluster that we call “hybrid”: it is positioned in between the poles of the media-supportive democratic-corporatist and the polarized-pluralist clusters.

Impact of Contrast Enhancement and Virtual Monoenergetic Image Energy Levels on Emphysema Quantification

Abstract: Purpose The aim of this study was to evaluate the impact of contrast enhancement and different virtual monoenergetic image energies on automatized emphysema quantification with photon-counting detector computed tomography (PCD-CT). Material and Methods Sixty patients who underwent contrast-enhanced chest CT on a first-generation, clinical dual-source PCD-CT were retrospectively included. Scans were performed in the multienergy (QuantumPlus) mode at 120 kV with weight-adjusted intravenous contrast agent. Virtual noncontrast (VNC) images as well as virtual monoenergetic images (VMIs) from 40 to 80 keV obtained in 10-keV intervals were reconstructed. Computed tomography attenuation was measured in the aorta. Noise was measured in subcutaneous fat and defined as the standard deviation of attenuation. Contrast-to-noise with region of interest in the ascending aorta and signal-to-noise ratio in the subcutaneous fat were calculated. Subjective image quality (and emphysema assessment, lung parenchyma evaluation, and vessel evaluation) was rated by 2 blinded radiologists. Emphysema quantification (with a threshold of −950 HU) was performed by a commercially available software. Virtual noncontrast images served as reference standard for emphysema quantification. Results Noise and contrast-to-noise ratio showed a strong negative correlation (r = −0.98; P < 0.01) to VMI energies. The score of subjective assessment was highest at 70 keV for lung parenchyma and 50 keV for pulmonary vessel evaluation (P < 0.001). The best trade-off for the assessment of emphysema while maintaining reasonable contrast for pulmonary vessel evaluation was determined between 60 and 70 keV. Overall, contrast-enhanced imaging led to significant and systematic underestimation of emphysema as compared with VNC (P < 0.001). This underestimation decreased with increasing VMI-energy (r = 0.98; P = 0.003). Emphysema quantification showed significantly (P < 0.05) increased emphysema volumes with increasing VMI energies, except between 60–70 keV and 70–80 keV. The least difference in emphysema quantification between contrast-enhanced scans and VNC was found at 80 keV. Conclusion Computed tomography emphysema quantification was significantly affected by intravenous contrast administration and VMI-energy level. Virtual monoenergetic image at 80 keV yielded most comparable results to VNC. The best trade-off in qualitative as well as in quantitative image quality evaluation was determined at 60/70 keV.

Do elections accelerate the COVID-19 pandemic?: Evidence from a natural experiment.

Abstract: Elections define representative democracies but also produce spikes in physical mobility if voters need to travel to polling places. In this paper, we examine whether large-scale, in-person elections propagate the spread of COVID-19. We exploit a natural experiment from the Czech Republic, which biannually renews mandates in one-third of Senate constituencies that rotate according to the 1995 election law. We show that in the second and third weeks after the 2020 elections (held on October 9-10), new COVID-19 infections grew significantly faster in voting compared to non-voting constituencies. A temporarily related peak in hospital admissions and essentially no changes in test positivity rates suggest that the acceleration was not merely due to increased testing. The acceleration did not occur in the population above 65, consistently with strategic risk-avoidance by older voters. Our results have implications for postal voting reforms or postponing of large-scale, in-person (electoral) events during viral outbreaks.

Potential of Photon-Counting Detector CT for Radiation Dose Reduction for the Assessment of Interstitial Lung Disease in Patients With Systemic Sclerosis

Abstract: The aim of this study was to determine the potential of photon-counting detector computed tomography (PCD-CT) for radiation dose reduction compared with conventional energy-integrated detector CT (EID-CT) in the assessment of interstitial lung disease (ILD) in systemic sclerosis (SSc) patients.In this retrospective study, SSc patients receiving a follow-up noncontrast chest examination on a PCD-CT were included between May 2021 and December 2021. Baseline scans were generated on a dual-source EID-CT by selecting the tube current-time product for each of the 2 x-ray tubes to obtain a 100% (D 100 ), a 66% (D 66 ), and a 33% dose image (D 33 ) from the same data set. Slice thickness and kernel were adjusted between the 2 scans. Image noise was assessed by placing a fixed region of interest in the subcutaneous fat. Two independent readers rated subjective image quality (5-point Likert scale), presence, extent, diagnostic confidence, and accuracy of SSc-ILD. D 100 interpreted by a radiologist with 22 years of experience served as reference standard. Interobserver agreement was calculated with Cohen κ, and mean variables were compared by a paired t test.Eighty patients (mean 56 ± 14; 64 women) were included. Although CTDI vol of PCD-CT was comparable to D 33 (0.72 vs 0.76 mGy, P = 0.091), mean image noise of PCD-CT was comparable to D 100 (131 ± 15 vs 113 ± 12, P > 0.05). Overall subjective image quality of PCD-CT was comparable to D 100 (4.72 vs 4.71; P = 0.874). Diagnostic accuracy was higher in PCD-CT compared with D 33 /D 66 (97.6% and 92.5%/96.3%, respectively) and comparable to D 100 (98.1%).With PCD-CT, a radiation dose reduction of 66% compared with EID-CT is feasible, without penalty in image quality and diagnostic performance for the evaluation of ILD.

Non-invasive imaging of tau-targeted probe uptake by whole brain multi-spectral optoacoustic tomography

Abstract: Abnormal tau accumulation within the brain plays an important role in tauopathies such as Alzheimer's disease and frontotemporal dementia. High-resolution imaging of tau deposits at the whole-brain scale in animal disease models is highly desired.We approached this challenge by non-invasively imaging the brains of P301L mice of 4-repeat tau with concurrent volumetric multi-spectral optoacoustic tomography (vMSOT) at ~ 115 μm spatial resolution using the tau-targeted pyridinyl-butadienyl-benzothiazole derivative PBB5 (i.v.). In vitro probe characterization, concurrent vMSOT and epi-fluorescence imaging of in vivo PBB5 targeting (i.v.) was performed in P301L and wild-type mice, followed by ex vivo validation using AT-8 antibody for phosphorylated tau.PBB5 showed specific binding to recombinant K18 tau fibrils by fluorescence assay, to post-mortem Alzheimer's disease brain tissue homogenate by competitive binding against [11C]PBB3 and to tau deposits (AT-8 positive) in post-mortem corticobasal degeneration and progressive supranuclear palsy brains. Dose-dependent optoacoustic and fluorescence signal intensities were observed in the mouse brains following i.v. administration of different concentrations of PBB5. In vivo vMSOT brain imaging of P301L mice showed higher retention of PBB5 in the tau-laden cortex and hippocampus compared to wild-type mice, as confirmed by ex vivo vMSOT, epi-fluorescence, multiphoton microscopy, and immunofluorescence staining.We demonstrated non-invasive whole-brain imaging of tau in P301L mice with vMSOT system using PBB5 at a previously unachieved ~ 115 μm spatial resolution. This platform provides a new tool to study tau spreading and clearance in a tauopathy mouse model, foreseeable in monitoring tau targeting putative therapeutics.

Antibodies from convalescent plasma promote SARS-CoV-2 clearance in individuals with and without endogenous antibody response

Abstract: BACKGROUNDNeutralizing antibodies are considered a key correlate of protection by current SARS-CoV-2 vaccines. The manner in which human infections respond to therapeutic SARS-CoV-2 antibodies, including convalescent plasma therapy, remains to be fully elucidated.METHODSWe conducted a proof-of-principle study of convalescent plasma therapy based on a phase I trial in 30 hospitalized COVID-19 patients with a median interval between onset of symptoms and first transfusion of 9 days (IQR, 7-11.8 days). Comprehensive longitudinal monitoring of the virological, serological, and disease status of recipients allowed deciphering of parameters on which plasma therapy efficacy depends.RESULTSIn this trial, convalescent plasma therapy was safe as evidenced by the absence of transfusion-related adverse events and low mortality (3.3%). Treatment with highly neutralizing plasma was significantly associated with faster virus clearance, as demonstrated by Kaplan-Meier analysis (P = 0.034) and confirmed in a parametric survival model including viral load and comorbidity (adjusted hazard ratio, 3.0; 95% CI, 1.1-8.1; P = 0.026). The onset of endogenous neutralization affected viral clearance, but even after adjustment for their pretransfusion endogenous neutralization status, recipients benefitted from plasma therapy with high neutralizing antibodies (hazard ratio, 3.5; 95% CI, 1.1-11; P = 0.034).CONCLUSIONOur data demonstrate a clear impact of exogenous antibody therapy on the rapid clearance of viremia before and after onset of the endogenous neutralizing response, and point beyond antibody-based interventions to critical laboratory parameters for improved evaluation of current and future SARS-CoV-2 therapies.TRIAL REGISTRATIONClinicalTrials.gov NCT04869072.FUNDINGThis study was funded via an Innovation Pool project by the University Hospital Zurich; the Swiss Red Cross Glückskette Corona Funding; Pandemiefonds of the UZH Foundation; and the Clinical Research Priority Program "Comprehensive Genomic Pathogen Detection" of the University of Zurich.

Microfluidic characterisation reveals broad range of SARS-CoV-2 antibody affinity in human plasma.

Abstract: The clinical outcome of SARS-CoV-2 infections, which can range from asymptomatic to lethal, is crucially shaped by the concentration of antiviral antibodies and by their affinity to their targets. However, the affinity of polyclonal antibody responses in plasma is difficult to measure. Here we used microfluidic antibody affinity profiling (MAAP) to determine the aggregate affinities and concentrations of anti-SARS-CoV-2 antibodies in plasma samples of 42 seropositive individuals, 19 of which were healthy donors, 20 displayed mild symptoms, and 3 were critically ill. We found that dissociation constants, Kd, of anti-receptor-binding domain antibodies spanned 2.5 orders of magnitude from sub-nanomolar to 43 nM. Using MAAP we found that antibodies of seropositive individuals induced the dissociation of pre-formed spike-ACE2 receptor complexes, which indicates that MAAP can be adapted as a complementary receptor competition assay. By comparison with cytopathic effect-based neutralisation assays, we show that MAAP can reliably predict the cellular neutralisation ability of sera, which may be an important consideration when selecting the most effective samples for therapeutic plasmapheresis and tracking the success of vaccinations.

How to Establish Benchmarks for Surgical Outcomes?

Abstract: To define a standardized methodology for establishing benchmarks for relevant outcomes in surgery.Benchmarking is an established tool to improve quality in industry and economics, and is emerging in assessing outcome values in surgery. Despite a recent 10-step approach to identify such benchmark values, a standardized and more widely agreed-on approach is still lacking.A multinational web-based Delphi survey with a focus on methodological requirements for establishing benchmarks for surgical outcomes was performed. Participants were selected among internationally renowned specialists in abdominal, vascular, and thoracic surgery. Consensus was defined as ≥70% agreement and results were used to develop a checklist to establish benchmarks in surgery.Forty-one surgical opinion leaders from 19 countries and 5 continents were involved. Experts' response rates were 98% and 80% in rounds 1 and 2, respectively. Upon completion of the final Delphi round, consensus was successfully achieved for 26 of 36 items covering the following areas: center eligibility, validation of databases, patient cohort selection, procedure selection, duration of follow-up, statistical analysis, and publication requirements regarding center-specific outcomes.This multinational Delphi survey represents the first expert-led process for developing a standardized approach for establishing benchmarks for relevant outcome measures in surgery. The provided consensual checklist customizes the methodology of outcome reporting in surgery and thus improves reproducibility and comparability of data and should ultimately serve to improve quality of care.