Engineered ACE2-Fc counters murine lethal SARS-CoV-2 infection through direct neutralization and Fc-effector activities

Soluble Angiotensin-Converting Enzyme 2 (ACE2) constitutes an attractive antiviral receptor decoy that targets the vulnerable site on SARS-CoV-2 spike (S). Here, using structure-guided approaches, we developed divalent ACE2 molecules by grafting the extracellular ACE2-domain onto a human IgG1 or IgG3 (ACE2-Fc). These ACE2-Fcs harbored structurally validated mutations that enhance S binding and remove enzymatic activity. The lead variant bound tightly to S, mediated in vitro neutralization of SARS-CoV-2 variants of concern (VOCs) with sub-nanomolar IC50 and was capable of robust Fc-effector functions, including antibody-dependent cellular cytotoxicity, phagocytosis and complement deposition. When tested in a stringent K18-hACE2 mouse model, the lead variant prevented or delayed lethal SARS-CoV-2 infection in a prophylactic or therapeutic setting utilizing the combined effect of neutralization and Fc-effector functions. These data confirm the utility of ACE2-Fcs as valuable agents in preventing and eliminating SARS-CoV-2 infection and demonstrate that ACE2-Fc therapeutic activity require Fc-effector functions.

Nanobody-Based Theranostic Agents for HER2-Positive Breast Cancer: Radiolabeling Strategies

The overexpression of human epidermal growth factor 2 (HER2) in breast cancer (BC) has been associated with a more aggressive tumor subtype, poorer prognosis and shorter overall survival. In this context, the development of HER2-targeted radiotracers is crucial to provide a non-invasive assessment of HER2 expression to select patients for HER2-targeted therapies, monitor response and identify those who become resistant. Antibodies represent ideal candidates for this purpose, as they provide high contrast images for diagnosis and low toxicity in the therapeutic setting. Of those, nanobodies (Nb) are of particular interest considering their favorable kinetics, crossing of relevant biological membranes and intratumoral distribution. The purpose of this review is to highlight the unique characteristics and advantages of Nb-based radiotracers in BC imaging and therapy. Additionally, radiolabeling methods for Nb including direct labeling, indirect labeling via prosthetic group and indirect labeling via complexation will be discussed, reporting advantages and drawbacks. Furthermore, the preclinical to clinical translation of radiolabeled Nbs as promising theranostic agents will be reported.

OT Interventions for Anxiety and Depressive Symptoms in Physical Inpatient Rehabilitation: A Systematic Review

Date Presented Accepted for AOTA INSPIRE 2021 but unable to be presented due to online event limitations. This systematic review examined interventions for anxiety and depressive symptoms among inpatient physical rehabilitation patients. Results were framed by intervention type, context, and concentration of current literature among patient groups. Setting specific analyses does not seem to be common, because patient groups are often considered regardless of therapeutic setting and therefore regardless of recovery stage. Setting-specific information can aid resource development and literature navigation. Primary Author and Speaker: Janell Pisegna Additional Authors and Speakers: Sarah E. Anderson Contributing Authors: Jessica L. Krok-Schoen

Mentalizing Glasses: Multifocal Attention in Mentalization-Based Treatment and the Role of the Supervision

Bifocal attention has been conceptualized differently by various scholars; however, all converge in the idea that the therapeutic process includes the need for the therapist to focus his attention on more than one aspect of the therapeutic setting. We propose a novel view in the application of bifocal attention within the mentalizing framework (MBT) of working with children, adolescents, and their families. We start by providing a short history of the evolution of the construct of bifocal attention, followed by a brief description of the structure of MBT for children and adolescents, emphasizing the crucial role of bifocal and multiple attentions in the mentalizing therapist. We close by discussing the importance of continued supervision in facilitating the maintaining of mentalizing glasses in therapy.

An Orally Available Cathepsin L Inhibitor Protects Lungs Against SARS-CoV-2-Induced Diffuse Alveolar Damage in African Green Monkeys

The COVID-19 pandemic resulted from global infection by the SARS-CoV-2 coronavirus and rapidly emerged as an urgent health issue requiring effective treatments. To initiate infection, the Spike protein of SARS-CoV-2 requires proteolytic processing mediated by host proteases. Among the host proteases proposed to carry out this activation is the cysteine protease cathepsin L. Inhibiting cathepsin L has been proposed as a therapeutic strategy for treating COVID-19. SLV213 (K777) is an orally administered small molecule protease inhibitor that exhibits in vitro activity against a range of viruses, including SARS-CoV-2. To confirm efficacy in vivo, K777 was evaluated in an African green monkey (AGM) model of COVID-19. A pilot experiment was designed to test K777 in a prophylactic setting, animals were pre-treated with 100mg/kg K777 (N=4) or vehicle (N=2) before inoculation with SARS-CoV-2. Initial data demonstrated that K777 treatment reduced pulmonary pathology compared to vehicle-treated animals. A second study was designed to test activity in a therapeutic setting, with K777 treatment (33 mg/kg or 100 mg/kg) initiated 8 hours after exposure to the virus. In both experiments, animals received K777 daily via oral gavage for 7 days. Vehicle-treated animals exhibited higher lung weights, pleuritis, and diffuse alveolar damage. In contrast, lung pathology was reduced in K777-treated monkeys, and histopathological analyses confirmed the lack of diffuse alveolar damage. Antiviral effects were further demonstrated by quantitative reductions in viral load of samples collected from upper and lower airways. These preclinical data support the potential for early SLV213 treatment in COVID-19 patients to prevent severe lung pathology and disease progression.

Targeting the Regulatory Subunit R2Alpha of Protein Kinase A in Human Glioblastoma through shRNA-Expressing Lentiviral Vectors

Glioblastoma is the most malignant and most common form of brain tumor, still today associated with a poor 14-months median survival from diagnosis. Protein kinase A, particularly its regulatory subunit R2Alpha, presents a typical intracellular distribution in glioblastoma cells compared to the healthy brain parenchyma and this peculiarity might be exploited in a therapeutic setting. In the present study, a third-generation lentiviral system for delivery of shRNA targeting the regulatory subunit R2Alpha of protein kinase A was developed. Generated lentiviral vectors are able to induce an efficient and stable downregulation of R2Alpha in different cellular models, including non-stem and stem-like glioblastoma cells. In addition, our data suggest a potential correlation between silencing of the regulatory subunit of protein kinase A and reduced viability of tumor cells, apparently due to a reduction in replication rate. Thus, our findings support the role of protein kinase A as a promising target for novel anti-glioma therapies.

Understanding Contextual Factors Effects and Their Implications for Italian Physiotherapists: Findings from a National Cross-Sectional Study

An online cross-sectional survey was conducted using Google Docs software. The aim was to understand the management of contextual factors and to identify which are most relevant and which clinicians underestimate. A total of 1250 physiotherapists were chosen from the database of the Manual Therapists group mailing list (GTM-IFOMPT MO) from July to August 2020. A total of 699 responses were received that were considered valid (56%). Participants (40.83%) identified contextual factors (CFs) as “any element, even involuntary, with which the patient interacts during treatment”. Physiotherapists individually chose the representation of CF with the “therapeutic relationship” (82.9%), followed by “therapeutic setting” (75.8%). This choice differed between participants belonging to different age groups. Participants favor communication strategies (76.93%). More than half (57.88%) pay attention to patient involvement during the course of care; and in response to the patients’ doubts about the use of treatments with limited scientific efficacy, they suggest different medical treatments. The patient’s previous clinical experience is not considered significant and does not influence the choice of treatment. Subsequently, however, the participants reported that they stimulate the patients’ positive expectations of the success of the clinical outcome (45.27%). Knowledge of contextual factors in physiotherapy appears limited and very heterogeneous. Future research could increase the focus on professional development.

Smiles as a Signal of Prosocial Behaviors Toward the Robot in the Therapeutic Setting for Children With Autism Spectrum Disorder

We explored how robot-assisted therapy based on smile analysis may facilitate the prosocial behaviors of children with autism spectrum disorder. Prosocial behaviors, which are actions for the benefit of others, are required to belong to society and increase the quality of life. As smiling is a candidate for predicting prosocial behaviors in robot-assisted therapy, we measured smiles by annotating behaviors that were recorded with video cameras and by classifying facial muscle activities recorded with a wearable device. While interacting with a robot, the participants experienced two situations where participants' prosocial behaviors are expected, which were supporting the robot to walk and helping the robot from falling. We first explored the overall smiles at specific timings and prosocial behaviors. Then, we explored the smiles triggered by a robot and behavior changes before engaging in prosocial behaviors. The results show that the specific timing of smiles and prosocial behaviors increased in the second session of children with autism spectrum disorder. Additionally, a smile was followed by a series of behaviors before prosocial behavior. With a proposed Bayesian model, smiling, or heading predicted prosocial behaviors with higher accuracy compared to other variables. Particularly, voluntary prosocial behaviors were observed after smiling. The findings of this exploratory study imply that smiles might be a signal of prosocial behaviors. We also suggest a probabilistic model for predicting prosocial behaviors based on smile analysis, which could be applied to personalized robot-assisted therapy by controlling a robot's movements to arouse smiles and increase the probability that a child with autism spectrum disorder will engage in prosocial behaviors.

A Never-ending Plight for Authentic Love

«Schiz” is a Latinized word-forming element that means split, division or cleavage. In German, the word schizoid, turned up in the 1920’s meaning «resembling schizophrenia”, from the combination of (gr.) schiz + (gr.) oeides, «like”, form eidos, form or shape. In The Betrayal of the Body, The Language of the Body, and Bioenergetics, Dr. Lowen’s works that most thoroughly teach us his views about the schizoid character structure, it becomes evident that the story of the schizoid split is a one of very early rejection and hostile hatred, culminating in profound, many times painfully misunderstood, inner torment. The following article offers some considerations about the schizoid structure illustrated by an analysis of clinical work with a client. Reflecting upon the theoretical proposal of how interaction, in this case, may be felt particularly as an oppressive inner ambivalence, this paper will present considerations about handling with a schizoid client in the therapeutic setting.