Part I. SARS-CoV-2 triggered \u27PANIC\u27 attack in severe COVID-19

The coronavirus disease 2019 (COVID-19) pandemic has produced a world-wide collapse of social and economic infrastructure, as well as constrained our freedom of movement. This respiratory tract infection is nefarious in how it targets the most distal and highly vulnerable aspect of the human bronchopulmonary tree, specifically, the delicate yet irreplaceable alveoli that are responsible for the loading of oxygen upon red cell hemoglobin for use by all of the body\u27s tissues. In most symptomatic individuals, the disease is a mild immune-mediated syndrome, with limited damage to the lung tissues. About 20% of those affected experience a disease course characterized by a cataclysmic set of immune activation responses that can culminate in the diffuse and irreversible obliteration of the distal alveoli, leading to a virtual collapse of the gas-exchange apparatus. Here, in Part I of a duology on the characterization and potential treatment for COVID-19, we define severe COVID-19 as a consequence of the ability of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to trigger what we now designate for the first time as a ‘Prolific Activation of a Network-Immune-Inflammatory Crisis’, or ‘PANIC’ Attack, in the alveolar tree. In Part II we describe an immunotherapeutic hypothesis worthy of the organization of a randomized clinical trial in order to ascertain whether a repurposed, generic, inexpensive, and widely available agent is capable of abolishing ‘PANIC’; thereby preventing or mitigating severe COVID-19, with monumental ramifications for world health, and the global pandemic that continues to threaten it

Mitigating alemtuzumab-associated autoimmunity in MS: A whack-a-mole B-cell depletion strategy

Objective: To determine whether the punctuated administration of low-dose rituximab, temporally linked to B-cell hyperrepopulation (defined when the return of CD19+ B cells approximates 40%-50% of baseline levels as measured before alemtuzumab treatment inception), can mitigate alemtuzumab-associated secondary autoimmunity. Methods: In this hypothesis-driven pilot study, 10 patients received low-dose rituximab (50-150 mg/m2), a chimeric anti-CD20 monoclonal antibody, after either their first or second cycles of alemtuzumab. These patients were then routinely assessed for the development of autoimmune disorders and safety signals related to the use of dual monoclonal antibody therapy. Results: Five patients received at least 1 IV infusion of low-dose rituximab, following alemtuzumab therapy, with a mean follow-up of 41 months. None of the 5 patients developed secondary autoimmune disorders. An additional 5 patients with follow-up over less than 24 months received at least 1 infusion of low-dose rituximab treatment following alemtuzumab treatment. No secondary autoimmune diseases were observed. Conclusions: An anti-CD20 whack-a-mole B-cell depletion strategy may serve to mitigate alemtuzumab-associated secondary autoimmunity in MS by reducing the imbalance in B- and T-cell regulatory networks during immune reconstitution. We believe that these observations warrant further investigation. Classification of evidence: This study provides Class IV evidence that for people with MS, low-dose rituximab following alemtuzumab treatment decreases the risk of alemtuzumab-associated secondary autoimmune diseases

Part II. high-dose methotrexate with leucovorin rescue for severe COVID-19: An immune stabilization strategy for SARS-CoV-2 induced \u27PANIC\u27 attack

Here, in Part II of a duology on the characterization and potential treatment for COVID-19, we characterize the application of an innovative treatment regimen for the prevention of the transition from mild to severe COVID-19, as well as detail an intensive immunotherapy intervention hypothesis. We propose as a putative randomized controlled trial that high-dose methotrexate with leucovorin (HDMTX-LR) rescue can abolish \u27PANIC\u27, thereby \u27left-shifting\u27 severe COVID-19 patients to the group majority of those infected with SARS-CoV-2, who are designated as having mild, even asymptomatic, disease. HDMTX-LR is endowed with broadly pleiotropic properties and is a repurposed, generic, inexpensive, and widely available agent which can be administered early in the course of severe COVID-19 thus rescuing the critical and irreplaceable gas-exchange alveoli. Further, we describe a preventative treatment intervention regimen for those designated as having mild to moderate COVID-19 disease, but who exhibit features which herald the transition to the severe variant of this disease. Both of our proposed hypothesis-driven questions should be urgently subjected to rigorous assessment in the context of randomized controlled trials, in order to confirm or refute the contention that the approaches characterized herein, are in fact capable of exerting mitigating, if not abolishing, effects upon SARS-CoV-2 triggered \u27PANIC Attack\u27. Confirmation of our immunotherapy hypothesis would have far-reaching ramifications for the current pandemic, along with yielding invaluable lessons which could be leveraged to more effectively prepare for the next challenge to global health

A Contribution of the Trivial Connection to Jones Polynomial and Witten's Invariant of 3d Manifolds I

We use the Chern-Simons quantum field theory in order to prove a recently conjectured limitation on the 1/K expansion of the Jones polynomial of a knot and its relation to the Alexander polynomial. This limitation allows us to derive a surgery formula for the loop corrections to the contribution of the trivial connection to Witten's invariant. The 2-loop part of this formula coincides with Walker's surgery formula for Casson-Walker invariant. This proves a conjecture that Casson-Walker invariant is a 2-loop correction to the trivial connection contribution to Witten's invariant of a rational homology sphere. A contribution of the trivial connection to Witten's invariant of a manifold with nontrivial rational homology is calculated for the case of Seifert manifolds.Comment: 28 page

Application of an evidence-based, out-patient treatment strategy for COVID-19: Multidisciplinary medical practice principles to prevent severe disease☆

The COVID-19 pandemic has devastated individuals, families, and institutions throughout the world. Despite the breakneck speed of vaccine development, the human population remains at risk of further devastation. The decision to not become vaccinated, the protracted rollout of available vaccine, vaccine failure, mutational forms of the SARS virus, which may exhibit mounting resistance to our molecular strike at only one form of the viral family, and the rapid ability of the virus(es) to hitch a ride on our global transportation systems, means that we are will likely continue to confront an invisible, yet devastating foe. The enemy targets one of our human physiology’s most important and vulnerable life-preserving body tissues, our broncho-alveolar gas exchange apparatus. Notwithstanding the fear and the fury of this microbe\u27s potential to raise existential questions across the entire spectrum of human endeavor, the application of an early treatment intervention initiative may represent a crucial tool in our defensive strategy. This strategy is driven by evidence-based medical practice principles, those not likely to become antiquated, given the molecular diversity and mutational evolution of this very clever “world traveler