Multifaceted highly targeted sequential multidrug treatment of early ambulatory high-risk SARS-CoV-2 infection (COVID-19)

The SARS-CoV-2 virus spreading across the world has led to surges of COVID-19 illness, hospitalizations, and death. The complex and multifaceted pathophysiology of life-threatening COVID-19 illness including viral mediated organ damage, cytokine storm, and thrombosis warrants early interventions to address all components of the devastating illness. In countries where therapeutic nihilism is prevalent, patients endure escalating symptoms and without early treatment can succumb to delayed in-hospital care and death. Prompt early initiation of sequenced multidrug therapy (SMDT) is a widely and currently available solution to stem the tide of hospitalizations and death. A multipronged therapeutic approach includes 1) adjuvant nutraceuticals, 2) combination intracellular anti-infective therapy, 3) inhaled/oral corticosteroids, 4) antiplatelet agents/anticoagulants, 5) supportive care including supplemental oxygen, monitoring, and telemedicine. Randomized trials of individual, novel oral therapies have not delivered tools for physicians to combat the pandemic in practice. No single therapeutic option thus far has been entirely effective and therefore a combination is required at this time. An urgent immediate pivot from single drug to SMDT regimens should be employed as a critical strategy to deal with the large numbers of acute COVID-19 patients with the aim of reducing the intensity and duration of symptoms and avoiding hospitalization and death

Adaptations in antagonist co-activation: Role in the repeated-bout effect

Eccentric exercise results in an adaptation which attenuates muscle damage from subsequent exercise—termed the “repeated-bout effect (RBE).” Purpose: Study examined antagonist co-activation and motor-unit recruitment strategy, assessed via dEMG, concomitant to the RBE. Methods: Nine participants performed 5 sub-maximal isometric trapezoid (ramp-up, hold, ramp-down) contractions at force levels corresponding to 50% and 80% of maximal isometric strength (MVC). Surface EMG signals of the biceps brachii were decomposed into individual motor-unit action potential trains. The relationship between mean firing rate (MFR) of each motor-unit and its recruitment threshold (RT) was examined using linear regression. Eccentric exercise was then performed until biceps brachii MVC had decreased by ~40%. Surface EMG of the biceps and triceps were collected during eccentric exercise. MVC, range-of-motion (ROM), and delayed onset muscle soreness (DOMS) were measured 24-hours, 72-hours, and 1-week following eccentric exercise. Three weeks later all procedures were repeated. Results: Changes in MVC (-32±14% vs -25±10%; p = 0.034), ROM (-11% vs 6%; p = 0.01), and DOMS (31.0±19mm vs 19±12mm; p = 0.015) were attenuated following the second bout of exercise. Triceps EMG was reduced (16.8±9.5% vs. 12.6±7.2%; p = 0.03) during the second bout of eccentric exercise. The slope (-0.60±0.13 vs -0.70±0.18; p = 0.029) and y-intercept (46.5±8.3 vs 53.3±8.8; p = 0.020) of the MFR vs. RT relationship was altered during contractions at 80% of MVC prior to the second bout of eccentric exercise. No changes were observed at 50% of MVC. Conclusion: A reduction in antagonist co-activation during the second bout of eccentric exercise suggests less total force was required to move an identical external load. This finding is supported by the increased negative slope coefficient and an increased y-intercept of the linear relationship between RT and MFR.Funded by University of Oklahoma Graduate College Robberson Grant.Ye

A MICROWAVE STUDY OF METHYL PROPYL NITROSAMINE

$^{1}$ Qi Lou, Robert K. Bohn, preceding paperAuthor Institution: Department of Chemistry, Wesleyan University; Department of Chemistry, University of ConnecticutAs part of a larger investigation into the relationship between the structures of nitrosamines and their carcinogenicities, the microwave spectrum of methyl propyl nitrosamine, $CH_{3}N(NO)CH_{2}CH_{2}CH_{3}$, has been observed using a conventional Stark cell spectrometer. The spectrum has many weak lines and is dominated by a-type, R-branch pileups with $B+C = 2497$ MHz. Molecular modeling suggests that there are eight conformations with energies within 1 kcal/mol of the ground state. Only two of these conformations have $B+C$ values compatible with those observed. Both possible conformers have the nitrosyl oxygen eclipsing the N-methyl group. One conformation has a planar, all-anti configuration and the other has a gauche kink about the $N-C$ (methylene) bond. The latter conformer is analogous to that determined in a similar study of methyl ethyl $nitrosamine^{1}$. Work is underway to obtain the microwave spectrum of methyl propyl nitrosamine using a molecular beam electric resonance spectrometer and a pulsed beam Fourier transform spectrometer. Combining the spectra from these machines with that already obtained from the Stark cell spectrometer should provide insight into the structures and energetics of the various conformers

DETERMINATION OF THE STRUCTURES OF THE CONFORMATIONS OF DIPROPYL ETHER.

Author Institution: Department of Chemistry, Wesleyan University; Department of Chemistry, University of ConnecticutMicrowave spectroscopy of dipropyl other has been performed by supersonic jet molecular beam electric resonance spectroscopy, by conventional waveguide-cell techniques, and by molecular beam pulsed-jet Fourier Transform spectroscopy (for which we are indebted to Professor R.L. Kuczkowski for machine time). It appears that there are several distinct conformations present in dipropyl ether even at the low temperatures achieved by supersonic expansion. The geometries of these conformations will be discussed

Estimation of critical end-test torque using neuromuscular electrical stimulation of the quadriceps in humans

Characterization of critical power/torque (CP/CT) during voluntary exercise requires maximal effort, making difficult for those with neuromuscular impairments. To address this issue we sought to determine if electrically stimulated intermittent isometric exercise resulted in a critical end-test torque (ETT) that behaved similar to voluntary CT. In the first experiment participants (n = 9) completed four bouts of stimulated exercise at a 3:2 duty cycle, at frequencies of 100, 50, 25 Hz, and a low frequency below ETT (Sub-ETT; ≤ 15 Hz). The second experiment (n = 20) consisted of four bouts at a 2:2 duty cycle—two bouts at 100 Hz, one at an intermediate frequency (15–30 Hz), and one at Sub-ETT. The third experiment (n = 12) consisted of two bouts at 50 Hz at a 3:2 duty* cycle with proximal blood flow occlusion during one of the bouts. ETT torque was similar (p ≥ 0.43) within and among stimulation frequencies in experiment 1. No fatigue was observed during the Sub-ETT bouts (p > 0.05). For experiment 2, ETT was similar at 100 Hz and at the intermediate frequency (p ≥ 0.29). Again, Sub-ETT stimulation did not result in fatigue (p > 0.05). Altering oxygen delivery by altering the duty cycle (3:2 vs. 2:2; p = 0.02) and by occlusion (p < 0.001) resulted in lower ETT values. Stimulated exercise resulted in an ETT that was consistent from day-to-day and similar regardless of initial torque, as long as that torque exceeded ETT, and was sensitive to oxygen delivery. As such we propose it represents a parameter similar to voluntary CT

Firing rates for individual motor units grouped based upon recruitment threshold.

<p>Mean firing rate for individual motor-units of the biceps brachii separated into groups or bins corresponding to 10% of MVC. Panel A are data from contractions performed at 50% of MVC, Panel B are data from 80% of MVC. Number in brackets above each bar indicate the number of motor-units in each bin. *indicates a significnat difference between bout 1 and bout 2 (p < 0.05). Values are means ± SD.</p

Example of raw EMG and individual firing incidences.

<p>Example of raw EMG signal collected from the 4 pin sensor during a contraction at 50% of MVC are shown in Panel A. Individual firings incidences of the 25 motor-units detected by the decomposition algorithm are shown in Panel B. Each bar represents the firing time of an action potential. The force tracing from the trapezoid contraction is shown by the overlaid solid line.</p

Overview of experimental design and procedures.

<p>Overview of experimental design and procedures.</p