Shakespeare as a vehicle for empathy and diagnostic skills training in undergraduate medical students in their psychiatry posting

Psychiatry undergraduate training has been significantly curtailed by the advent of the COVID-19 pandemic. This article examines the use of Shakespeare's Hamlet, especially via the characters of Hamlet and Ophelia, to impart two core skills in psychiatry, namely diagnostic abilities and empathy. Medical students undergoing the psychiatry posting watched Kenneth Branagh's Hamlet online, focusing on identifying psychopathology, forming diagnoses, identifying countertransferences, and developing empathy through acting out close passages. Students were able to identify the features of bipolar disorder in Hamlet, correlating his behavior with separate depressive and manic episodes. They were also able to appreciate the unique quality of dissociation in Ophelia, especially in Act 4 of Hamlet, and recognize it as a manifestation of post-traumatic stress disorder. Through acting out closed passages, students were also able to feel empathy by putting themselves into the shoes of Hamlet and Ophelia. Such a pedagogical approach has additional unexpected utility in view of the COVID-19 pandemic, which has significantly curtailed face-to-face medical education, leading to alternative online methods such as movies and Shakespearean plays in psychiatry education. In conclusion, though online methods cannot fully supplant face-to-face patient contact, they can be crucial tools in times of necessity and allow students to engage in interdisciplinary education, marrying the arts and the humanities.

A phenoxy-bridged trinuclear Ni(ii) complex: synthesis, structural elucidation and molecular docking with viral proteins

A novel phenoxy-bridged trinuclear nickel(ii) complex [Ni3(mu-L)2(bipy)3](1) (where H3L= (E)-2-hydroxy-N-(2-hydroxy-3,5-diiodophenyl)-3,5-diiodobenzohydrazonic acid, bipy = 2,2'-bipyridyl) has been designed and synthesized as a potential antivirus drug candidate. The trinuclear Ni(ii) complex [Ni3(mu-L)2(bipy)3](1) was fully characterized via single crystal X-ray crystallography. The unique structure of the trinuclear nickel(ii) complex crystallized in a trigonal crystal system with P3221 space group and revealed distorted octahedral coordination geometry around each Ni(ii) ion. The X-ray diffraction analysis established the existence of a new kind of trinuclear metal system containing nickel(ii)-nickel(ii) interactions with an overall octahedral-like geometry about the nickel(ii) atoms. The non-bonded Ni-Ni distance seems to be 3.067 and 4.455 A from the nearest nickel atoms. The detailed structural analysis and non-covalent supramolecular interactions are also investigated by single crystal structure analysis and computational approaches. Hirshfeld surfaces (HSs) and 2D fingerprint plots (FPs) have been explored in the crystal structure to investigate the intermolecular interactions. The preliminary analysis of redox and magnetic characterization was conducted using cyclic voltammetry measurements and a vibrating sample magnetometer (VSM), respectively. This unique structure shows good inhibition performance for SARS-CoV-2, Omicron and HIV viruses. For insight into the potential application of the Ni(ii) coordination complex as an effective antivirus drug, we have examined the molecular docking of the trinuclear Ni(ii) complex [Ni3(mu-L)2(bipy)3](1) with the receptor binding domain (RBD) from SARS-CoV-2 (PDB ID: 7MZF), Omicron BA.3 variant spike (PDB ID: 7XIZ), and HIV protease (PDB ID: 7WCQ) viruses. This structure shows good inhibition performance for SARS-CoV-2, Omicron S protein and HIV protease viruses;the binding energies (DELTAG) and the respective Ki/Kd (inhibition/dissociation constants) correlation values are -8.9 (2.373 muM or 2373 nM), -8.1 (1.218 muM or 1218 nM) and -7.9 (0.874 muM or 874 nM), respectively. The results could be used for rational drug design against SARS-CoV-2 Omicron variant and HIV protease viruses.Copyright © 2023 The Royal Society of Chemistry.

Dissociation Among Women with Chronic Pelvic Pain: Relation to Surgical Treatment, Pelvic Pain Severity, and Health-Related Quality of Life.

Chronic pelvic pain (CPP) is associated with a history of trauma and symptoms of somatoform dissociation. We aimed to describe how somatoform dissociation impacts CPP symptoms, surgical treatment, and health-related quality of life (HRQOL). Patients (N = 133) diagnosed with CPP presenting for an appointment at a women's health clinic between November, 2019 - July, 2021 were recruited to participate in a cross-sectional study and complete a survey assessing symptoms of somatoform dissociation, post-traumatic stress disorder (PTSD), pelvic pain severity, history of CPP-related surgeries, and mental and physical HRQOL. We also conducted a post-hoc analysis assessing correlations of individual symptom items on the Somatoform Dissociation Questionnaire (SDQ-20) with HRQOL outcomes. We did not find a relationship between somatoform dissociation and pelvic pain severity or surgical history. Physical HRQOL outcomes were related to somatoform dissociation, PTSD symptoms, and pelvic pain severity, while mental HRQOL outcomes were connected to somatoform dissociation and PTSD symptoms. Our study reveals preliminary evidence suggesting that among CPP patients, HRQOL outcomes are affected by unique profiles of positive and negative symptoms of somatoform dissociation, including sensory disturbances, localized genital pain, and generalized numbness and bodily analgesia. Addressing specific symptoms of somatoform dissociation may enhance HRQOL among trauma-exposed women with CPP. Replication studies are needed to validate our findings. Integrating trauma-informed approaches, including standardized evaluations of trauma exposure and symptoms of somatoform dissociation into routine care for women with CPP is encouraged.

A novel computational approach for rapid screening of antibody therapeutics for efficacy against SARS-CoV-2 variants of concern including Omicron variant

Multiple severe acute respiratory syndrome coronavirus 2 (SARSCoV- 2) variants continue to evolve carrying flexible amino acid substitutions in the spike protein's receptor binding domain (RBD). These substitutions modify the binding of the SARS-CoV-2 to human angiotensin-converting enzyme 2 (hACE2) receptor and have been implicated in altered host fitness, transmissibility and efficacy against antibody therapeutics and vaccines. Reliably predicting the binding strength of SARS-CoV-2 variants RBD to hACE2 receptor and neutralizing antibodies (NAbs) can help assessing their fitness, and rapid deployment of effective antibody therapeutics, respectively. Here, we introduced a two-step computational framework with threefold validation that first identified dissociation constant as a reliable predictor of binding affinity in hetero-dimeric and -trimeric protein complexes. The second step implements dissociation constant as descriptor of the binding strengths of SARS-CoV-2 variants RBD to hACE2 and NAbs. Then, we examined several variants of concern (VOCs) such as Alpha, Beta, Gamma, Delta, and Omicron and demonstrated that these VOCs RBD bind to the hACE2 with enhanced affinity. Furthermore, the binding affinity of Omicron variant's RBD was reduced with majority of the RBD-directed NAbs, which is highly consistent with the experimental neutralization data. By studying the atomic contacts between RBD and NAbs, we revealed the molecular footprints of four NAbs (GH-12, P2B-1A1, Asarnow-3D11, and C118)-that may likely neutralize the recently emerged omicron variant-facilitating enhanced binding affinity. Finally, our findings suggest a computational pathway that could aid researchers identify a range of current NAbs that may be effective against emerging SARS-CoV-2 variants.

SARS-CoV-2 antibody avidity responses in natural infection and vaccination

Background: In ongoing SARS CoV-2 pandemic, understanding antibody responses have played a key role in measuring extent of exposure, protection from reinfection, vaccine efficacy and serodiagnosis. Antibody avidity is total binding strength of immunoglobulin G (IgG) toward its target epitope. High antibody avidity has been correlated with effective neutralization of the SARSCoV-2 virus. However, the data on avidity responses against COVID-19 infection and vaccination are limited. Objective(s): To understand the avidity responses among sera of naturally infected, recovered COVID-19 patients;naive Covaxin, Covishield vaccinees and breakthrough infections. Material(s) and Method(s): In this study, we utilized an in-house developed SARS-CoV-2 anti-spike receptor binding domain (SRBD) IgG ELISA to optimize the avidity assay. A panel of anti-SARS-CoV- 2 SRBD IgG positive serum samples were treated with known concentration of a chaotropic agent (urea) for disruption of the noncovalent interactions of the antigen-antibody complex. This disruption causes low avidity antibodies to dissociate which gives the percentage of high avidity antibodies present in a serum sample. Additionally, the optimized assay was used to understand the avidity responses among sera belonging to individuals naturally infected and recovered after COVID-19, naive Covaxin and Covishield vaccinees;followed by breakthrough infections. Result(s) and Conclusion(s): The anti-SRBD avidity progressively elevated over a period of twelve months. Moreover, overall antibody avidity responses were similar in the case of natural infection and naive two doses of Covaxin and Covishield vaccinated individuals. However, avidity responses were high among individuals with a breakthrough infection as compared to naive vaccinees.

THE ESTIMATION OF HARD-TO-MEASURE PHYSICAL PARAMETERS OF THERMAL DISSOCIATION OF BIOMOLECULES FROM RESULTS OF INDIRECT MEASUREMENTS br

The present paper is devoted to finding the necessary minimum of experimental information on biomolecules for quantitative evaluation of such physical parameters which cannot be directly measured for some reason, but are connected by known mathematical re-lations to any measureable quantities. For the case when thermal dissociation of a complex molecule is possible through several channels due to breaking of various intramolecular bonds, an original analytic expression relating the association degree of biomolecules to its physical parameters and the environment temperature has been deduced. It was exemplified the possi-bility to evaluate (with satisfactory accuracy) some physical parameters of thermal dissociation protease SARS-CoV-2 dimer and the temperature dependence of the association degree of this dimer as well

Spinopelvic In Situ Fixation and Early Mobilization: A Case Report and Literature Review.

Pelvic fractures with sacroiliac extension are significant and complicated orthopedic injuries that pose a challenge in management and favorable outcomes. A 50-year-old obese female presented after a motor vehicle accident with pelvic fracture lateral compression. The patient underwent anterior external fixation with a left sacroiliac screw (SIS) on the next day of admission and was kept in a non-weight-bearing state. During her hospital stay, she developed deep vein thrombosis (DVT) and was treated. During the follow-up on the sixth week, the patient was not complying with her immobilization instructions and was exposing the left lower limb to weight bearing. The radiologic evaluation demonstrated a pulled-out SIS with a stable fracture. Considering that the patient was obese, had a history of DVT and COVID-19 infection, and the fracture was minimally displaced, it was decided to perform a spinopelvic in-situ fixation from L4 to S2 and augment it with a left SIS. The patient tolerated the surgery well and was referred to physiotherapy for early mobilization with full weight bearing. During her six-month and two-year follow-ups, she was well mobilized with no active complaints, and radiographic studies showed good healing, no displacement, no signs of instability, and a stable construct. Our case report presents a very rare and difficult but successful management of a fracture displacement in a non-compliant patient with one pulled-out screw through fast-tracked in situ spinopelvic fixation with early mobilization and full weight bearing. To our knowledge, this is one of the rare reports detailing a patient undergoing in situ spinopelvic fixation due to minimally displaced fracture with comorbidities such as obesity and DVT. Our report demonstrates the viability of accepting pulled-out screws, with respect to the patient's health, the fracture's geometry, a quick follow-up in situ spinopelvic fixation, early mobilization, full weight-bearing outcomes, and a lower risk for complications.

MOTOR CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY IN A CHILD.

Motor chronic inflammatory demyelinating polyneuropathy (M-CIDP) is a form of atypical CIDP. This article presents a clinical observation of M-CIDP in a 15-year-old boy, as well as a description of laboratory and instrumental diagnostic data. The boy had a chronic development (> 2 months) of flaccid tetraparesis, predominantly of the proximal muscles of the limbs, without sensory disorders. According to electroneuromyography, there were signs of demyelinating lesions of the proximal parts of the peripheral nerves. There was an increase in the thickness of the nerves of the upper limbs according to ultrasound. In the liquor protein-cell dissociation, as well as in the blood, IgG antibodies to the surface glycoprotein S of the SARS-CoV-2 coronavirus were found. The clinical and neurophysiological picture corresponded to the reliable criteria for CIDP. The therapy with intravenous immunoglobulins had a significant positive effect in the form of an increase in the strength of the limb muscles.Copyright © Russian Neurological Journal. All rights reserved.

MOTOR CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY IN A CHILD.

Motor chronic inflammatory demyelinating polyneuropathy (M-CIDP) is a form of atypical CIDP. This article presents a clinical observation of M-CIDP in a 15-year-old boy, as well as a description of laboratory and instrumental diagnostic data. The boy had a chronic development (> 2 months) of flaccid tetraparesis, predominantly of the proximal muscles of the limbs, without sensory disorders. According to electroneuromyography, there were signs of demyelinating lesions of the proximal parts of the peripheral nerves. There was an increase in the thickness of the nerves of the upper limbs according to ultrasound. In the liquor protein-cell dissociation, as well as in the blood, IgG antibodies to the surface glycoprotein S of the SARS-CoV-2 coronavirus were found. The clinical and neurophysiological picture corresponded to the reliable criteria for CIDP. The therapy with intravenous immunoglobulins had a significant positive effect in the form of an increase in the strength of the limb muscles.Copyright © Russian Neurological Journal. All rights reserved.

It Takes Two to Make a Thing Go Wrong

Seventy-three-year-old diabetic male was a high-risk transfer from Alaska for respiratory decompensation in the setting of progressive bulbar and proximal weakness. He was diagnosed with COVID-19 two months prior and viral mononucleosis 1 month prior to presentation. While the patient had a fall 3 months prior to presentation, and decreased mobility at home, there was abrupt onset of progressive upper/lower extremity weakness, dysphagia, and difficulties managing secretions 2 weeks prior to presentation. Initial exam was notable for MRC 3-4/5 proximal upper/lower extremity weakness, areflexia, and negative inspiratory force of 224 to 230 cm H20. A subtle periorbital heliotrope rash was documented. Lumbar puncture demonstrated albumino-cytologic dissociation (protein 142 mg/dL, 6 WBCs) and CK remained elevated (1930 U/L) despite intravenous hydration. Outside electrodiagnostic testing demonstrated a sensorimotor axonal neuropathy with questionable myopathic features on needle electromyography. Given concern for an inflammatory neuropathy and concomitant inflammatory myopathy, intravenous immunoglobulin 2G/kg and IV methylprednisolone 1G/day over 5 days was started. He was transferred for further diagnostic workup and supportive care 6 days after presentation and required intubation within 24 hours of admission. Exam showed progressive proximal and distal weakness of the extremities and general areflexia/hyporeflexia. Repeat electromyography confirmed a severe sensorimotor axonal polyneuropathy without acquired demyelinating features and normal repetitive nerve stimulation. While the patient could no longer activate muscles voluntarily, proximal muscles had increased spontaneous activity with predominant myotonia. Neuroaxis imaging was notable only for enhancement of the lumbar nerve roots. Combined vastus lateralis muscle biopsy and serologic testing confirmed a second pathologic process contributing to the patient's weakness. This case highlights the cooccurrence of 2 distinct neuropathological entities, with potential relation to a prior viral infection, and the importance of ancillary testing to guide treatment for acute causes of neuromuscular respiratory failure.

From verbal to bodily thinking. Commentary on 'from functional dissociation to creativity in groups: The effects of a pandemic on a dance company' by Clarisse Vollon and Guy Gimenez

Comments on an article by Clarisse Vollon and Guy Gimenez (see record 2023-30637-009). This article by Vollon and Gimenez is excellent, well written and highly interesting. Its theoretical perspective is clearly more psychoanalytical than group analytical, in accordance with Didier Anzieu's and Rene Kaes's conception of the 'psychoanalytic work with groups'. However the subject of the authors' analysis and research cannot fail to attract the attention of the readers, since it not only deals with a traumatic experience that all of us have suffered-the unavoidable isolation generated by the COVID-19 pandemic-but also with the major accommodations and technical changes that all analysts-psychoanalysts and group analysts alike-have had to implement in order to face this new and unprecedented situation, and still continue their work. Its main argument is that an abrupt rupture of an interpersonal and transpersonal container-thought in terms of Anzieu's and Kaes's concept of 'psychic envelopes'-unleashes traumatic experiences that have to be worked-through by means of creativity. In this, they rely on Winnicott's concepts on creativity and the 'intermediate area'. This phenomenon and process is not only personal, but also interpersonal and transpersonal-i.e., collective (group). (PsycInfo Database Record (c) 2023 APA, all rights reserved)

Screening for Potential Traditional Herbal Inhibitors Against 3-Chymo-trypsin-like Main Protease (3CLpro) from Four Different Coronaviruses: An in silico Approach

Background: The recent outbreak of the COVID-19 pandemic has raised a global health concern due to the unavailability of any vaccines or drugs. The repurposing of traditional herbs with broad-spectrum anti-viral activity can be explored to control or prevent a pandemic. Objective(s): The 3-chymotrypsin-like main protease (3CLpro), also referred to as the "Achilles' heel" of the coronaviruses (CoVs), is highly conserved among CoVs and is a potential drug target. 3CLpro is essential for the virus' life cycle. The objective of the study was to screen and identify broad--spectrum natural phytoconstituents against the conserved active site and substrate-binding site of 3CLpro of HCoVs. Method(s): Herein, we applied the computational strategy based on molecular docking to identify potential phytoconstituents for the non-covalent inhibition of the main protease 3CLpro from four different CoVs, namely, SARS-CoV-2, SARS-CoV, HCoV-HKU1, and HCoV-229E. Result(s): Our study shows that natural phytoconstituents in Triphala (a blend of Emblica officinalis fruit, Terminalia bellerica fruit, and Terminalia chebula fruit), namely chebulagic acid, chebulinic acid, and elagic acid, exhibited the highest binding affinity and lowest dissociation constants (Ki), against the conserved 3CLpro main protease of SARSCoV-2, SARS-CoV, HCoV-HKU1, and HCoV-229E. Besides, phytoconstituents of other herbs like Withania somnifera, Glycyrrhiza glabra, Hyssopus officinalis, Camellia sinensis, Prunella vulgaris, and Ocimum sanctum also showed good binding affinity and lower Ki against the active site of 3CLpro. The top-ranking phyto-constituents' binding interactions clearly showed strong and stable interactions with amino acid residues in the catalytic dyad (CYS-HIS) and substrate-binding pocket of the 3CLpro main proteases. Conclusion(s): This study provides a valuable scaffold for repurposing traditional herbs with anti--CoV activity to combat SARS-CoV-2 and other HCoVs until the discovery of new therapies.Copyright © 2021 Bentham Science Publishers.

Associations between trauma and substance use among healthcare workers and public safety personnel during the SARS-CoV-2 (COVID-19) pandemic: the mediating roles of dissociation and emotion dysregulation.

BACKGROUND: Given the highly stressful environment surrounding the SARS-CoV-2 pandemic, healthcare workers (HCW) and public safety personnel (PSP) are at an elevated risk for adverse psychological outcomes, including posttraumatic stress disorder (PTSD) and alcohol/substance use problems. As such, the study aimed to identify associations between PTSD severity, related dissociation and emotion dysregulation symptoms, and alcohol/substance use problems among HCWs and PSP. METHODS: A subset of data (N = 498; HCWs = 299; PSP = 199) was extracted from a larger study examining psychological variables among Canadian HCWs and PSP during the pandemic. Structural equation modelling assessed associations between PTSD symptoms and alcohol/substance use-related problems with dissociation and emotion dysregulation as mediators. RESULTS: Among HCWs, dissociation fully mediated the relation between PTSD and alcohol-related problems (indirect effect ß = .133, p = .03) and emotion dysregulation partially mediated the relation between PTSD and substance-related problems (indirect effect ß = .151, p = .046). In PSP, emotion dysregulation fully mediated the relation between PTSD and alcohol-related problems (indirect effects ß = .184, p = .005). For substance-related problems among PSP, neither emotion dysregulation nor dissociation (ps >.05) had any effects. CONCLUSION: To our knowledge, this is the first study examining associations between PTSD severity and alcohol/substance use-related problems via mediating impacts of emotion dysregulation and dissociation among HCWs and PSP during the SARS-CoV-2 pandemic. These findings highlight dissociation and emotion dysregulation as important therapeutic targets for structured interventions aimed at reducing the burden of PTSD and/or SUD among Canadian HCWs or PSP suffering from the adverse mental health impacts of the SARS-CoV-2 pandemic.

Among healthcare workers, dissociation mediated relation between posttraumatic stress disorder (PTSD) severity and alcohol-related problems and emotion dysregulation mediated relation between PTSD severity and substance-related problems.Among public safety personnel, emotion dysregulation mediated relation between PTSD severity and alcohol-related problems. Neither dissociation nor emotion dysregulation mediated relation between PTSD severity and substance-related problems.Results underscore dissociation and emotion dysregulation as potential key therapeutic targets for intervention for healthcare workers and public safety personnel struggling with PTSD and comorbid alcohol/substance use-related problems.

The oxygen dissociation curve of blood in COVID-19-An update.

An impressive effect of the infection with SARS-Co-19 is the impairment of oxygen uptake due to lung injury. The reduced oxygen diffusion may potentially be counteracted by an increase in oxygen affinity of hemoglobin. However, hypoxia and anemia associated with COVID-19 usually decrease oxygen affinity due to a rise in [2,3-bisphosphoglycerate]. As such, COVID-19 related changes in the oxygen dissociation curve may be critical for oxygen uptake and supply, but are hard to predict. A Pubmed search lists 14 publications on oxygen affinity in COVID-19. While some investigations show no changes, three large studies found an increased affinity that was related to a good prognosis. Exact causes remain unknown. The cause of the associated anemia in COVID-19 is under discussion. Erythrocytes with structural alterations of membrane and cytoskeleton have been observed, and virus binding to Band 3 and also to ACE2 receptors in erythroblasts has been proposed. COVID-19 presentation is moderate in many subjects suffering from sickle cell disease. A possible explanation is that COVID-19 counteracts the unfavorable large right shift of the oxygen dissociation curve in these patients. Under discussion for therapy are mainly affinity-increasing drugs.

A Practical Ambulatory Approach to Atrioventricular Block Secondary to Lyme Carditis.

Lyme carditis (LC) is a potentially reversible cause of complete atrioventricular (AV) dissociation that rarely requires a permanent pacemaker. The time to resolution is variable, sometimes requiring weeks, making a temporary permanent pacemaker (TPPM) a suitable bridge to recovery. We report on a 31-year-old man with serology-confirmed Lyme disease with complete heart block during the peak of the coronavirus disease 2019 pandemic. A TPPM was implanted and the patient was discharged the following day with regular follow-up in the ambulatory setting. Once 1:1 AV conduction was reestablished, the TPPM was removed. Our case demonstrates that the use of a TPPM for AV-dissociation secondary to LC is a safe and feasible strategy in select individuals which can minimize patient morbidity as well as hospital length of stay and overall health care costs.

Acute motor and sensory axonal neuropathy in a patient with undiagnosed mixed connective tissue disease

Case Report: Acute motor and sensory axonal neuropathy (AMSAN) syndrome is a rare subtype of Guillain-Barre syndrome (GBS) with poor recovery [1]. While respiratory and gastrointestinal infections may precipitate AMSAN, an underlying autoimmune disorder is seldom reported in literature. We herein report the complex case of a patient with undiagnosed, asymptomatic mixed connective tissue disease (MCTD) who developed AMSAN syndrome. Case: A 44-year-old Asian male without medical history presented with progressively worsening weakness of both upper and lower extremities and inability to perform daily activities. His symptoms started 12 weeks prior with difficulty standing from a seated position. He felt subjectively better for some time until a week prior, when he became bedbound. He had diarrhea 6 months ago, with 5-6 loose bowel movements a day for a few weeks. Vital signs on admission was normal. On neurological examination, he was alert and oriented, with bilateral upper and lower extremity flaccid paralysis, diffuse muscle atrophy, bilateral hand and foot drop, negative Hoover sign, diffuse areflexia, and intact sensation. Cerebrospinal fluid (CSF) analysis showed WBC 0 and protein level 136. MRI cervical, thoracic, and lumbar spine were normal. EMG revealed sensory involvement with positive sharp waves in proximal muscles along with fibrillations. Intravenous immunoglobulin (IVIG) was initiated at 0.4 mg/kg for 5 days. Infectious workup for COVID-19, stool culture, HIV, TB, RPR and campylobacter jejuni antibody (Ab), was negative. ANA was positive in a speckled pattern with titres 1:1280, with a positive RNP Ab, SS-A, and RF IgM, IgG and IgA. Rest of the autoimmune workup (anti-dsDNA, anti-CCP, SS-B, aldolase, anti-Jo-1, anti-Scl-70, p-ANCA, c-ANCA, anti-GM1, anti-GQ1b, and anti-GD1a ganglioside Ab) was negative. The myositis specific 11 Ab panel was negative. Despite IVIG therapy, he developed dysphagia, respiratory distress, with a negative inspiratory force of -0, requiring intubation. He had a tracheostomy and PEG tube placed and remains quadraplegic nearly 120 days later. Discussion(s): The authors report a unique case of a patient who became progressively weak over 3 months, leading to complete quadriplegia. Interestingly, this is more consistent with chronic inflammatory demyelinating poly-neuropathy (CIDP), as AMSAN typically develops over a short period of 2 to 4 weeks [2]. Despite having negative anti-GM1 and anti-GD1a Ab (in which positive Ab are pathognomonic but not always present in AMSAN syndrome), the patient had weakness that began in the lower extremities, progressing to paralysis, along with albuminocytological dissociation on CSF analysis, pointing to a GBS diagnosis [3]. He had sensory involvement in the EMG, thus making the diagnosis as AMSAN. He had an undiagnosed, asymptomatic autoimmune process most consistent with MCTD. Whether the two disease processes are related to each other is a concept that has not yet been investigated. Pediatric Clinical Case Reports Concurrent Session Saturday February 4, 2023 1:00 PM Copyright © 2023 Southern Society for Clinical Investigation.

Evaluation of In Vitro Distribution and Plasma Protein Binding of Selected Antiviral Drugs (Favipiravir, Molnupiravir and Imatinib) against SARS-CoV-2.

There are a number of uncertainties regarding plasma protein binding and blood distribution of the active drugs favipiravir (FAVI), molnupiravir (MOLNU) and imatinib (IMA), which were recently proposed as therapeutics for the treatment of COVID-19 disease. Therefore, proton dissociation processes, solubility, lipophilicity, and serum protein binding of these three substances were investigated in detail. The drugs display various degrees of lipophilicity at gastric (pH 2.0) and blood pH (pH 7.4). The determined pKa values explain well the changes in lipophilic character of the respective compounds. The serum protein binding was studied by membrane ultrafiltration, frontal analysis capillary electrophoresis, steady-state fluorometry, and fluorescence anisotropy techniques. The studies revealed that the ester bond in MOLNU is hydrolyzed by protein constituents of blood serum. Molnupiravir and its hydrolyzed form do not bind considerably to blood proteins. Likewise, FAVI does not bind to human serum albumin (HSA) and α1-acid glycoprotein (AGP) and shows relatively weak binding to the protein fraction of whole blood serum. Imatinib binds to AGP with high affinity (logK' = 5.8-6.0), while its binding to HSA is much weaker (logK' ≤ 4.0). The computed constants were used to model the distribution of IMA in blood plasma under physiological and 'acute-phase' conditions as well.

Properties and Activity of Peptide Derivatives of ACE2 Cellular Receptor and Their Interaction with SARS-CoV-2 S Protein Receptor-Binding Domain.

The aim of this work was to design and characterize peptides based on the α-helices h1 and h2 of the ACE2 receptor, forming the interaction interface between the receptor-binding domain (RBD) of the SARS-CoV-2 S protein and the cellular ACE2 receptor. Monomeric and heterodimeric peptides connected by disulfide bonds at different positions were synthesized. Solubility, RBD-binding affinity, and peptide helicity were experimentally measured, and molecular dynamics simulation was performed in various solvents. It was established that the preservation of the helical conformation is a necessary condition for the binding of peptides to RBD. The peptides have a low degree of helicity and low affinity for RBD in water. Dimeric peptides have a higher degree of helicity than monomeric ones, probably due to the mutual influence of helices. The degree of helicity of the peptides in trifluoroethanol is the highest; however, for in vitro studies, the most suitable solvent is a water-ethanol mixture.

Integrated Quantitative Systems Pharmacology (QSP) Characterizing Viral Dynamics After Intramuscular (IM) Adintrevimab (ADI) Administration in Participants with Mild to Moderate Coronavirus Disease (COVID-19)

Background. ADI is a fully human IgG1 monoclonal antibody engineered to have an extended half-life with high potency and broad neutralization against SARS-CoV-2 and other SARS-like coronaviruses. The goal of our analysis was to develop a QSP model in which ADI concentrations in upper airway (UA) epithelial lining fluid (ELF) were linked to a viral dynamic model to describe the impact of ADI on SARS-CoV-2 viral load relative to placebo. Methods. The QSP model was fit inNONMEMVersion 7.4 using PK data from a Phase 1 study (N=24, IV and IM) and from Phase 2/3 COVID-19 prevention (EVADE;N=659, IM) and treatment (STAMP;N=189, IM) studies. Saliva and NP samples were collected from STAMP study participants (pts) infected with the delta or omicron variants. The viral dynamic model was based on a published model and was modified to include both active (V) and deactivated (DV) virus (Fig). The viral dynamic model was fit to the NP swab viral load data (2 samples/pt) standardized to time since infection based upon recorded symptom onset. Saliva data (7-8 samples/ pt) was fit sequentially using a biophase compartment given the peak viral load was modestly lower and peaked later than Day 1. Viral dynamic model (A) and simulated median (90% PI) NP viral load reduction in ADI-treated or placebo participants for delta (B) and omicron (C) variants Results. The QSP model provided an excellent fit to serum ADI concentrationtime data after estimation of a transit rate to account for IM absorption, plasma volume, and the ADI-neonatal Fc receptor dissociation rate constant. The linked viral dynamic model captured the NP swab viral load data after estimating differences in within-host replication factor (R0) and viral production rate (p) by variant. Maximal ADI-induced effect (Smax) on stimulating viral clearance (c) was fixed to 0.43 based upon prior modeling. ADI concentration in UA ELF resulting in 50% of Smax (SC50) was estimated to be 0.086 for delta and 1.05 mg/L for omicron. Figure B and C show model-based simulated median (90% PI) viral load reduction in ADI-treated or placebo pts for delta and omicron variants. Conclusion. This QSP model, in conjunction with information on new variants available early in outbreaks (IC50, infectivity (R0), viral production rate [each a model parameter]), allows for rapid dose identification in response to emerging variants.