Vaccine-induced immune thrombotic thrombocytopenia (VITT) is mediated by a stereotyped clonotypic antibody

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare thromboembolic complication of adenoviral-vectored SARS-CoV2 vaccines, mediated by antibodies directed against platelet factor 4 (PF4). Given their causal role in VITT, identification of the molecular composition of anti-PF4 antibodies is crucial for developing better diagnostics and treatments. Here, we utilised a novel proteomic workflow to analyse the immunoglobulin variable (IgV) region composition of anti-PF4 antibodies at the level of the secreted proteome. Serum anti-PF4 IgG antibodies from five patients with VITT triggered by ChAdOx1 nCoV-19 vaccination were affinity purified by PF4-coupled magnetic beads and sequenced by mass spectrometry. We revealed a single IgG heavy (H)-chain species paired with a single lambda light (L)-chain species in all five unrelated patients. Remarkably, all L-chains were encoded by the identical IGLV3-21*02 gene subfamily with identical L-chain third complementarity determining region (LCDR3) lengths. Moreover, striking stereotypic features were also identified in heavy-chains anti-PF4 antibodies characterised by identical HCDR3 length and homologous sequences. In summary, we unravelled the molecular signature of highly stereotyped clonotypic anti-PF4 antibodies, indicating shared pathways of antibody production in VITT patients. These discoveries are critical to understand the molecular basis of this serious condition and develop novel therapies aimed at removing pathogenic clones. KEY POINTSO_LIAnti-PF4 antibodies in VITT comprise highly stereotyped clonotype C_LIO_LIA single IGLV3-21*02 encoded light chain is found in unrelated patients C_LI

A novel computational approach to reconstruct SARS-CoV-2 infection dynamics through the inference of unsampled sources of infection

Infectious diseases such as the COVID19 pandemic cemented the importance of disease tracking. The role of asymptomatic, undiagnosed individuals in driving infection has become evident. Their unaccountability results in ineffective prevention. We developed a pipeline using genomic data to accurately predict a populations transmission network complete with the inference of unsampled sources. The system utilises Bayesian phylogenetics to capture evolutionary and infection dynamics of SARS-CoV-2. It identified the effectiveness of preventive measures in Canadas Atlantic bubble and mobile populations such as New York State. Its robustness extends to the prediction of cross-species disease transmission as we inferred SARS-CoV-2 transmission from humans to lions and tigers in New York Citys Bronx Zoo. The proposed methods ability to generate such complete transmission networks, provides a more detailed insight into the transmission dynamics within a population. This potential frontline tool will be of direct help in "the battle to bend the curve".

Medical Applications for 3D Printing: Recent Developments.

This is a review of some of the recent developments in the application of 3D printing to medicine. The topic is introduced with a brief explanation as to how and why 3D is changing practice, teaching, and research in medicine. Then, taking recent examples of progress in the field, we illustrate the current state of the art. This article concludes by evaluating the current limitations of 3D printing for medical applications and suggesting where further progress is likely to be made.

Optimization of Axial Pump Characteristic Dimensions and Induced Hemolysis for Mechanical Circulatory Support Devices.

The application of axial pumps as ventricular assist devices (VADs) requires significant modifications to the size and characteristics of industrial pumps due to the difference in flow fields of industrial and medical pumps. Industrial pumps operate in the region of Reynolds number Re = 10, whereas axial blood pumps operate in Re < 10. The common pump design technique is to rely on the performance of previously designed pumps using the concept of fluid dynamic similarity. Such data are available for industrial pumps as specific speed-specific diameter (ns-ds) graphs. The difference between the flow fields of industrial and medical pumps makes the industrial ns-ds graphs unsuitable for medical pumps and consequently several clinically available axial blood pumps operate with low efficiencies. In this article, numerical and experimental techniques were used to design 62 axial pump impellers with different design characteristics suitable for VADs and mechanical circulatory support devices (MCSDs). The impellers were manufactured and experimentally tested in various operating conditions of flow, pressure, and rotational speed. The hemocompatibility of the impellers was numerically investigated by modeling shear stress and hemolysis. The highest efficiency of each pump impeller was plotted on an ns-ds diagram. The nondimensional results presented in this article enable preliminary design of efficient and hemocompatible axial flow pumps for VADs and MCSDs.

Computational Parametric Study of the Axial and Radial Clearances in a Centrifugal Rotary Blood Pump.

In centrifugal rotary blood pumps (RBP), clearances are a critical parameter in determining blood trauma. This study investigates the effect of axial clearance (Cax) and radial clearance (Crad) on the hydrodynamic and hemolytic performance of a centrifugal RBP. A centrifugal pump was parameterized so that it could be defined by geometric variables Cax and Crad. Optimal Latin hypercube sampling was used to determine design points based on Cax, Crad, and rotor speed (ω). For each design point, a computational simulation was conducted to determine efficiency (η) and normalized index of hemolysis (NIH). Next, a response surface (RS) was created to estimate these performance parameters based on the design variables. The results show that for a given Cax, when Crad is decreased, η increases until Crad = 0.15 mm, beyond which η deceases. For a given Crad, Cax has a unimodal relationship with η. The NIH has a unimodal relationship with both Cax and Crad. The mechanisms behind these relationships were investigated by various analytical methods. It was found that vortices in the secondary flow paths were a critical factor in determining efficiency and hemolysis. The optimal clearance values discerned in this study are only valid for the specific impeller geometry and operating conditions analyzed.

Remixing Leadership Practices with Emerging Technologies.

The authors present an overview of the historical trends in and current state of technology in leadership education (P-20), including the influence of related platforms, tools, and theories.

The Effect of Geometry on the Efficiency and Hemolysis of Centrifugal Implantable Blood Pumps.

The application of centrifugal pumps as heart assist devices imposes design limitations on the impeller geometry. Geometry and operating parameters will affect the performance and the hemocompatibility of the device. Among all the parameters affecting the hemocompatibility, pressure, rotational speed, blade numbers, angle, and width have significant impact on the blood trauma. These parameters directly (pressure, speed) and indirectly (geometry) affect the efficiency of the pump as well. This study describes the experimental investigation on geometric parameters and their effect on the performance of small centrifugal pumps suitable for Mechanical Circulatory Support (MCS) devices. Experimental and numerical techniques were implemented to analyze the performance of 15 centrifugal impellers with different characteristics. The effect of each parameter on the pump performance and hemolysis was studied by calculating the normalized index of hemolysis (NIH) and the shear stress induced in each pump. The results show five and six blades, 15-35° outlet angle, and the lowest outlet width that meets the required pressure rise are optimum values for an efficient hemocompatible pump.

The Effects of Ambulatory Accelerations on the Stability of a Magnetically Suspended Impeller for an Implantable Blood Pump.

This article describes the effects of ambulatory accelerations on the stability of a magnetically suspended impeller for use in implantable blood pumps. A magnetic suspension system is developed to control the radial position of a magnetic impeller using coils in the pump casing. The magnitude and periodicity of ambulatory accelerations at the torso are measured. A test rig is then designed to apply appropriate accelerations to the suspension system. Accelerations from 0 to 1 g are applied to the suspended impeller with ambulatory periodicity while the radial position of the impeller and power consumption of the suspension system are monitored. The test is carried out with the impeller suspended in air, water, and a glycerol solution to simulate the viscosity of blood. A model is developed to investigate the effects of the radial magnetic suspension system and fluid damping during ambulatory accelerations. The suspension system reduces the average displacement of the impeller suspended in aqueous solutions within its casing to 100 µm with a power consumption of below 2 W during higher magnitude ambulatory accelerations (RMS magnitude 0.3 g). The damping effect of the fluid is also examined and it is shown that buoyancy, rather than drag, is the primary cause of the damping at the low displacement oscillations that occur during the application of ambulatory accelerations to such a suspension system.

Optimization of Centrifugal Pump Characteristic Dimensions for Mechanical Circulatory Support Devices.

The application of artificial mechanical pumps as heart assist devices impose power and size limitations on the pumping mechanism, and therefore requires careful optimization of pump characteristics. Typically new pumps are designed by relying on the performance of other previously designed pumps of known performance using concepts of fluid dynamic similarity. Such data are readily available for industrial pumps, which operate in Reynolds numbers region of 10. Heart assist pumps operate in Reynolds numbers of 10. There are few data available for the design of centrifugal pumps in this characteristic range. This article develops specific speed versus specific diameter graphs suitable for the design and optimization of these smaller centrifugal pumps concentrating in dimensions suitable for ventricular assist devices (VADs) and mechanical circulatory support (MCS) devices. A combination of experimental and numerical techniques was used to measure and analyze the performance of 100 optimized pumps designed for this application. The data are presented in the traditional Cordier diagram of nondimensional specific speed versus specific diameter. Using these data, nine efficient designs were selected to be manufactured and tested in different operating conditions of flow, pressure, and rotational speed. The nondimensional results presented in this article enable preliminary design of centrifugal pumps for VADs and MCS devices.

In-vitro investigation of cerebral-perfusion effects of a rotary blood pump installed in the descending aorta.

This study describes use of a cardiovascular simulator to replicate the hemodynamic responses of the cerebrovascular system with a mechanical circulatory support device operating in the descending aorta. To do so, a cerebral autoregulation unit was developed which replicates the dilation and constriction of the native cerebrovascular resistance system and thereby regulates the cerebral flow rate within defined limits. The efficacy of the replicated autoregulation mechanism was investigated by introducing a number of step alterations in mean aortic pressure and monitoring the cerebral flow. The steady responses of the cerebral flow to changes in mean aortic pressure were in good agreement with clinical data. Next, a rotary pump, modeling a mechanical circulatory support device, was installed in the descending aorta and the hemodynamic responses of the cerebral system were investigated over a wide range of pump operating conditions. Insertion of a mechanical circulatory support device in the descending aorta presented an improved cardiac output as a result of afterload reduction. It was observed that the primary drop in cerebral flow, caused by the pump in the descending aorta, was compensated over the course of five seconds due to a gradual decrease in cerebrovascular resistance. The experimental results suggest that the implantation of a mechanical circulatory support device in the descending aorta, a less invasive procedure than typical mechanical circulatory support implantation, will not have an adverse effect on the cognitive function, provided that the cerebral autoregulation is largely unimpaired.

Cross-linking of extruded collagen fibers--a biomimetic three-dimensional scaffold for tissue engineering applications.

The repair of tissue defects remains a challenging clinical problem. Extruded collagen fibers comprise a promising scaffold for anterior cruciate ligament and tendon reconstruction; however the engineering of these fibers has still to be improved to bring this material to clinical practice. In this study, for the first time we investigated the influence of a wide range of cross-linking approaches (chemical, physical, and biological) on the properties of these fibers. Ultrastructural evaluation revealed a closely packed interfiber structure independent of the cross-linking method employed. The thermal properties were dependent on the cross-linking method employed and closely matched native tissues. The stress-strain curves were found to depend on the water content of the fibers, which was influenced by the cross-linking method. An inversely proportional relationship between both dry and wet fiber diameter and stress at break was found, which indicates that tailored-made biomaterials can be produced. Overall, the chemical stabilizations were more potent than both physical and biological approaches. Bifunctional agents such as hexamethylene diisocyanate and ethylene glycol diglycidyl ether or agents that promote matrix formation such as glutaraldehyde produced fibers with properties similar to those of native or synthetic fibers to suit a wide range of tissue engineering applications.

Consensus judgments of discharge readiness based on paranoid behavior: to what are clinical staff responding?

BACKGROUND: Salinas et al. (J Consult Clin Psychol 4:1029-1039, 2002) found that, contrary to widely held beliefs, paranoid behavior was a positive prognostic indicator for psychiatric inpatients only due to artifactual restrictions on overall level of functioning that result from traditional classification procedures. Paranoid functioning, in fact, negatively impacted consensus staff discharge-readiness judgments. This discrepancy between clinical lore and empirical findings raises a question about the aspects of paranoid functioning to which staff responds. METHOD: Those aspects of paranoid functioning are examined in this study, using the same sample of 469 inpatients from 19 treatment units reported in the Salinas et al. investigation. RESULTS: Both dimensionally measured paranoid functioning and overall level of disability were independently associated with negative discharge-readiness decisions. However, rather than delusions or hallucinations, hostility entirely accounted for the contribution of paranoid functioning to these prognostic judgments. CONCLUSION: We discuss implications of an alternative approach to classifying patients' problem behavior for clinical research and practice.

Predicting time-to-independent-release from current level of functioning for psychiatric inpatients: a "survivor" analysis.

Non-optimal psychiatric discharges occur frequently and result in high costs. The Time-Sample Behavioral Checklist (TSBC) has been demonstrated to be the best method for determining successful independent discharge within 2 weeks of assessment for adult inpatients. This study examined the extent to which TSBC indexes and perceived dangerousness predict staff independent discharge-readiness judgments up to 6 months after initial assessment. Data from 22 acute and chronic/mixed units (N = 362) were analyzed using Cox proportional hazard regression. TSBC appropriate interpersonal interaction and appropriate behavior variability predicted shorter time-to-independent-release (TTIR). TSBC bizarre facial expressions and verbalizations predicted longer TTIR. Post hoc analyses suggest that acutely admitted inpatients perceived to be dangerous were discharged sooner than others-a finding that is likely attributable to differential psychotropic medication responsiveness. Implications are discussed for TSBC implementation for earlier identification of discharge-ready inpatients and for tailoring interventions to target behavior that predicts independent discharge success.

Is paranoid status prognostic of good outcomes? It depends.

Better outcomes for psychiatric inpatients classified as paranoid rather than nonparanoid could be due to group differences in disability levels created by traditional classification approaches. Paranoid functioning, per se, may not predict good institutional outcomes. The authors retrieved community outcome data for 469 inpatients from 19 wards, a subsample of participants that had been previously examined during their inpatient stay. Paranoid groups showed better community outcomes as an artifact of differences in disability levels when classifications were based on the traditional approach that requires a predominance of paranoid over nonparanoid behavior. No differential outcomes appeared when classifications were based on dimensionally measured paranoid functioning alone. In fact, dispositions of patients suggest that staff view paranoid behavior as a negative rather than positive prognostic indicator.