Definition of the Post-COVID syndrome using a symptom-based Post-COVID score in a prospective, multi-center, cross-sectoral cohort of the German National Pandemic Cohort Network (NAPKON).

PURPOSE: The objective examination of the Post-COVID syndrome (PCS) remains difficult due to heterogeneous definitions and clinical phenotypes. The aim of the study was to verify the functionality and correlates of a recently developed PCS score. METHODS: The PCS score was applied to the prospective, multi-center cross-sectoral cohort (in- and outpatients with SARS-CoV-2 infection) of the "National Pandemic Cohort Network (NAPKON, Germany)". Symptom assessment and patient-reported outcome measure questionnaires were analyzed at 3 and 12 months (3/12MFU) after diagnosis. Scores indicative of PCS severity were compared and correlated to demographic and clinical characteristics as well as quality of life (QoL, EQ-5D-5L). RESULTS: Six hundred three patients (mean 54.0 years, 60.6% male, 82.0% hospitalized) were included. Among those, 35.7% (215) had no and 64.3% (388) had mild, moderate, or severe PCS. PCS severity groups differed considering sex and pre-existing respiratory diseases. 3MFU PCS worsened with clinical severity of acute infection (p = .011), and number of comorbidities (p = .004). PCS severity was associated with poor QoL at the 3MFU and 12MFU (p < .001). CONCLUSION: The PCS score correlated with patients' QoL and demonstrated to be instructive for clinical characterization and stratification across health care settings. Further studies should critically address the high prevalence, clinical relevance, and the role of comorbidities. TRAIL REGISTRATION NUMBER: The cohort is registered at www. CLINICALTRIALS: gov under NCT04768998.

Inferring Causalities of Environmental and Genetic Factors for Differential Somatic Cell Count and Mastitis Pathogens in Dairy Cows Using Structural Equation Modelling.

The aim of this study was to establish and evaluate a structural equation model to infer causal relationships among environmental and genetic factors on udder health. For this purpose, 537 Holstein Friesian cows were genotyped, and milk samples were analyzed for novel traits including differential somatic cell counts and specific mastitis pathogens. In the structural model, four latent variables (intramammary infection (IMI), production, time and genetics) were defined, which were explained using manifest measurable variables. The measurable variables included udder pathogens and somatic differential cell counts, milk composition, as well as significant SNP markers from previous genome-wide associations for major and minor pathogens. The housing system effect (i.e., compost-bedded pack barns versus cubicle barns) indicated a small influence on IMI with a path coefficient of -0.05. However, housing system significantly affected production (0.37), with ongoing causal effects on IMI (0.17). Thus, indirect associations between housing and udder health could be inferred via structural equation modeling. Furthermore, genotype by environment interactions on IMI can be represented, i.e., the detection of specific latent variables such as significant SNP markers only for specific housing systems. For the latent variable genetics, especially one SNP is of primary interest. This SNP is located in the EVA1A gene, which plays a fundamental role in the MAPK1 signaling pathway. Other identified genes (e.g., CTNNA3 and CHL1) support results from previous studies, and this gene also contributes to mechanisms of the MAPK1 signaling pathway.

Impact of Clinical Study Implementation on Data Quality Assessments - Using Contradictions within Interdependent Health Data Items as a Pilot Indicator.

INTRODUCTION: Contradiction is a relevant data quality indicator to evaluate the plausibility of interdependent health data items. However, while contradiction assessment is achieved using domain-established contradictory dependencies, recent studies have shown the necessity for additional requirements to reach conclusive contradiction findings. For example, the oral or rectal methods used in measuring the body temperature will influence the thresholds of fever definition. The availability of this required information as explicit data items must be guaranteed during study design. In this work, we investigate the impact of activities related to study database implementation on contradiction assessment from two perspectives including: 1) additionally required metadata and 2) implementation of checks within electronic case report forms to prevent contradictory data entries. METHODS: Relevant information (timestamps, measurement methods, units, and interdependency rules) required for contradiction checks are identified. Scores are assigned to these parameters and two different studies are evaluated based on the fulfillment of the requirements by two selected interdependent data item sets. RESULTS: None of the studies have fulfilled all requirements. While timestamps and measurement units are found, missing information about measurement methods may impede conclusive contradiction assessment. Implemented checks are only found if data are directly entered. DISCUSSION: Conclusive contradiction assessment typically requires metadata in the context of captured data items. Consideration during study design and implementation of data capture systems may support better data quality in studies and could be further adopted in primary health information systems to enhance clinical anamnestic documentation.

Genome-Wide Associations for Microscopic Differential Somatic Cell Count and Specific Mastitis Pathogens in Holstein Cows in Compost-Bedded Pack and Cubicle Farming Systems.

The aim of the present study was to detect significant SNP (single-nucleotide polymorphism) effects and to annotate potential candidate genes for novel udder health traits in two different farming systems. We focused on specific mastitis pathogens and differential somatic cell fractions from 2198 udder quarters of 537 genotyped Holstein Friesian cows. The farming systems comprised compost-bedded pack and conventional cubicle barns. We developed a computer algorithm for genome-wide association studies allowing the estimation of main SNP effects plus consideration of SNPs by farming system interactions. With regard to the main effect, 35 significant SNPs were detected on 14 different chromosomes for the cell fractions and the pathogens. Six SNPs were significant for the interaction effect with the farming system for most of the udder health traits. We inferred two possible candidate genes based on significant SNP interactions. HEMK1 plays a role in the development of the immune system, depending on environmental stressors. CHL1 is regulated in relation to stress level and influences immune system mechanisms. The significant interactions indicate that gene activity can fluctuate depending on environmental stressors. Phenotypically, the prevalence of mastitis indicators differed between systems, with a notably lower prevalence of minor bacterial indicators in compost systems.

Microscopic differential cell count and specific mastitis pathogens in cow milk from compost-bedded pack barns and cubicle barns.

Compost bedded pack barns (compost) as a new free walk housing system favorably influence udder health due to improved animal welfare and lying comfort. On the other hand, unfavorable effects on udder health are possible, due to the open bedded pack and the associated larger bacterial content in moisture. For in-depth farming system comparisons, the present study aimed to evaluate the specific cell fractions and mastitis pathogens in milk from cows kept in compost and in conventional cubical barns (cubicle). For milk sample collection we used a repeated measurement data structure of 2,198 udder quarters from 537 Holstein cows kept in six herds (3 in compost and 3 in cubicle). Differential cell counting was conducted including lymphocytes, macrophages and polymorphonuclear leukocytes (PMN). Specific mastitis pathogens comprised major and minor pathogens. Mixed models were applied to infer environmental and cow associated effects on cell fractions and on prevalences for pathogen infections, with specific focus on system × lactation stage, system × milk yield and system × somatic cell count effects. The interaction between system and lactation stage showed significant differences (P < 0.01) between the systems. A significantly smaller number of bacteriologically positive quarters and lower prevalences for minor pathogens were detected in compost compared to cubicle. Least squares means for pathogen prevalences indicated a quite constant proportion of bacteriologically negative udder quarters across milk yield levels in compost, but a slight increase with increasing milk yield in cubicle. Cell fraction responses in both systems differed in relation to the overall bacteriological infection status and farming system particularities. In conclusion, different cell fractions and specific mastitis pathogens should be considered as an indicator for udder health in different production systems, taking into account cow associated factors (lactation stage, milk yield).

Diaphragmatic excursion measurement in emergency patients with acute dyspnea: toward a new diagnostic tool?

INTRODUCTION: During acute dyspnea (AD), respiratory exhaustion is mainly due to diaphragm fatigue. The primary objective was to validate interobserver reproducibility of diaphragmatic excursion (DE) in emergency department (ED) patients admitted for AD. The secondary objectives were to assess the feasibility of DE measurement and intraobserver reproducibility. Finally, we examined whether the DE value was associated with a need for noninvasive ventilation (NIV). MATERIALS: This was a monocentric, prospective, technical reproducibility study. Adult patients in spontaneous ventilation admitted for AD were included. Two operators carried out 2 consecutive diaphragm excursion measurements each on the right and left hemidiaphragms. RESULTS: Twenty-four patients were analyzed. The feasibility was 96% on the right and 67% on the left. The interobserver concordance between the 2 measures was 0.80 (95% confidence interval [CI], 0.59-0.91) (average difference, -0.07±0.48 cm) on the right and 0.59 (95% CI, 0.19-0.82) (average difference, 0.30±0.91 cm) on the left. For right DE values inferior to 2.3 cm, the interobserver concordance between measures was 0.92 (95% CI, 0.78-0.97). The intraobserver concordance was 0.89 (95% CI, 0.81-0.94) (average difference, 0.02±0.35 cm) on the right and 0.90 (95% CI, 0.82-0.95) (average difference,-0.06±0.45 cm) on the left. When the DE was greater than 2 cm, no patient required NIV. CONCLUSION: Diaphragmatic excursion measurement of the right diaphragm is feasible, with good interobserver and intraobserver reproducibility in ED patients admitted for AD. When the DE value is greater than 2 cm at admission, no subsequent NIV is required.

Does physician experience influence the interpretability of focused echocardiography images performed by a pocket device?

INTRODUCTION: The use of focused cardiac ultrasound (FoCUS) in a prehospital setting is recommended. Pocket ultrasound devices (PUDs) appear to be well suited to prehospital FoCUS. The main aim of our study was to evaluate the interpretability of echocardiography performed in a prehospital setting using a PUD based on the experience of the emergency physician (EP). METHODS: This was a monocentric prospective observational study. We defined experienced emergency physicians (EEPs) and novice emergency physicians (NEPs) as echocardiographers if they had performed 50 echocardiographies since their initial university training (theoretical training and at least 25 echocardiographies performed with a mentor). Each patient undergoing prehospital echocardiography with a PUD was included. Four diagnostic items based on FoCUS were analyzed: pericardial effusions (PE), right ventricular dilation (RVD), qualitative left ventricular function assessment (LVEF), and inferior vena cava compliance (IVCC). Two independent experts blindly evaluated the interpretability of each item by examining recorded video loops. If their opinions were divided, then a third expert concluded. RESULTS: Fourteen EPs participated: eight (57 %) EEPs and six (43 %) NEPs. Eighty-five patients were included: 34 (40 %) had an echocardiography by an NEP and 51 (60 %) by an EEP. The mean number of interpretable items by echocardiography was three [1; 4]; one [0; 2.25] in the NEP group, four [3; 4] in EEP (p < .01). The patient position was also associated with interpretable items: supine three [2; 4], "45°" three [1; 4], sitting two [1; 4] (p = .02). In multivariate analysis, only EP experience was associated with the number of interpretable items (p = .02). Interpretability by NEPs and EEPs was: 56 % vs. 96 % for LVF, 29 % vs. 98 % for PE, 26 % vs. 92 % for RVD, and 21 % vs. 67 % for IVCC (p < .01 for all). CONCLUSION: FoCUS with PUD in prehospital conditions was possible for EEPs, It is difficult and the diagnostic yield is poor for NEPs.

The aptamer ARC1779 blocks von Willebrand factor-dependent platelet function in patients with thrombotic thrombocytopenic purpura ex vivo.

BACKGROUND: In thrombotic thrombocytopenic purpura (TTP), ultralarge von Willebrand factor (VWF) multimers bind platelet (PLT) glycoprotein Ib and lead to the formation of disseminated fibrin-poor, VWF-rich PLT thrombi. The aptamer ARC1779 blocks binding of the VWF A1 domain to PLT glycoprotein Ib. We evaluated whether ARC1779 inhibits the excessive VWF activity and VWF-mediated PLT function in patients with TTP. STUDY DESIGN AND METHODS: We studied the ex vivo concentration response curves for ARC1779 on PLT function analyzer (PFA-100, Dade Behring) and cone-and-plate analyzer (CPA, Impact-R) PLT function tests, agonist-induced PLT aggregation, and VWF activity of TTP patients (n = 11, three in acute phase and eight in remission) and healthy controls (n = 44). RESULTS: VWF activity and VWF-dependent PLT plug formation were increased in TTP patients relative to healthy controls, but agonist-induced PLT aggregation was not. ARC1779 blocked collagen/adenosine 5'-diphosphate (ADP)-induced PLT plug formation as measured by PFA-100 with an inhibitory concentration (IC)(100) of approximately 1 microg/mL in citrate-anticoagulated samples and approximately 3 to 4 microg/mL in hirudin-anticoagulated samples. A similar concentration of ARC1779 was necessary to block shear-dependent PLT adhesion in both TTP patients and healthy controls using the CPA assay (IC(100) of approx. 1 microg/mL for both). ARC1779 blocked VWF activity with an IC(90) of approximately 3 to 4 microg/mL in all subjects, but did not inhibit PLT aggregation by ADP, collagen, or arachidonic acid even at concentrations much greater than those that fully inhibited VWF-dependent PLT function. CONCLUSIONS: ARC1779 potently and specifically inhibits VWF activity and VWF-dependent PLT function. ARC1779 may be a promising novel therapeutic for the treatment of TTP.

The aptamer ARC1779 is a potent and specific inhibitor of von Willebrand Factor mediated ex vivo platelet function in acute myocardial infarction.

ARC1779 is an aptamer, which blocks binding of the von Willebrand Factor (VWF) A1 domain to platelet GPIb receptors. VWF is increased in the elderly an in the setting of acute myocardial infarction (AMI), as reflected by increased shear-dependent platelet function. We hypothesized that ARC1779 concentration-dependently inhibits ex vivo platelet function, and that this concentration effect relationship may be shifted in patients with AMI. We studied ex vivo dose response curves for ARC1779 on VWF activity, shear-dependent platelet function, and agonist-induced platelet aggregation. We included patients with AMI on standard treatment (n = 40), young (n = 20) and elderly controls (n = 20) in this ex vivo dosing study. AMI patients displayed approximately 2-fold increased plasma levels of VWF activity as compared to controls. ARC1779 inhibited VWF activity (IC90: approximately 3-4 microg/mL) and shear dependent platelet function (Platelet Function Analyzer (PFA-100), IC50: approximately 0.5-0.9 microg/mL and Cone and Plate Analyzer (CPA), IC50: approximately 0.1-0.4 microg/mL in citrated blood) at comparable concentrations in all groups. In contrast to GPIIb/IIIa antagonists, ARC1779 did not inhibit platelet aggregation induced by ADP, collagen or arachidonic acid at concentrations (10 microg/mL) that fully inhibited VWF dependent platelet function. ARC1779 potently and specifically inhibits VWF activity and VWF dependent platelet function, even in the setting of AMI where VWF activity is increased.

Anti-von Willebrand factor aptamer ARC1779 for refractory thrombotic thrombocytopenic purpura.

BACKGROUND: Plasma exchange is the main therapy for thrombotic thrombocytopenic purpura (TTP). No treatments other than plasma exchange have been documented to be effective nor are approved for treatment of TTP. The anti-von Willebrand factor (VWF) aptamer ARC1779 effectively inhibits VWF activity in plasma samples of TTP patients and thus shear-dependent platelet (PLT) function as measured by the PLT function analyzer PFA-100 (Dade Behring). It was hypothesized that ARC1779 would offer a potentially effective treatment option for a critically ill patient, refractory to standard care. CASE REPORT: A 39-year-old male patient with idiopathic TTP, refractory to daily plasma exchange, rituximab, steroids, and splenectomy, was additionally treated with a continuous infusion of the anti-von Willebrand factor (VWF) aptamer ARC1779 for 3 weeks. RESULTS: Plasma concentrations of approximately 10 microg/mL ARC1779 decreased VWF activity by more than 96%. Plasma exchange treatment acutely decreased the plasma concentrations of ARC1779 by a mean of 47% (range, 40%-61%). Thus, additional minibolus infusions of ARC1779 were given after each plasma exchange to rapidly restore steady-state concentrations. ARC1779 resulted in an increase of PLT counts as long as ARC1779 was given. On three occasions the infusion was stopped, each accompanied by a decrease in PLT counts and worsening of microangiopathy. No serious adverse effects were observed during the treatment with ARC1779. CONCLUSION: ARC1779 caused a clear and reproducible increase in PLT counts in an otherwise refractory TTP case. These clinical, pharmacokinetic, and pharmacodynamic data provide a rational basis for clinical trials with ARC1779 in TTP.

Dagher redux: searching for the missing pieces.

The most relevant question for any joint venture is, when does the relationship become a jointventure and not simply a price-fixing cartel? With respect to this question, this Article juxtaposes Texaco, Inc. v. Dagher, 126 S. Ct. 1276 (2006), against years of contrary precedent. In Dagher, the Court altered the seemingly settled foundation of antitrust law by changing its view on past holdings and abandoning the ancillary effects doctrine. The Article provides an outline of key holdings prior to Dagher, as well as a discussion of the issues that can arise as joint ventures are formed. Additionally, the authors examine how the decision altered the foundation of joint venture law in the United States. In particular, the Article exposes several important antitrust concerns relating to joint ventures that the Supreme Court did not address in Dagher. Perhaps the most perplexing issue of Dagher is whether the venture at issue would have survived analysis under the Federal Trade Commission's "continuum" approach.