Six failures of the Doherty Modelling Report

The Doherty Model is being used in Australia to justify partial reopening with 70% of adults vaccinated. However, we have identified six critical failures of the model: failure to model uncertainties; failure to use appropriate premises; failure to model subgroup vaccine takeup; failure to correctly model child transmission; failure to include relevant outcomes; and failure to consider longer time-frames. These failures result in missing over 200,000 cases of long covid in children, underestimating death counts by a factor of up to ten, underestimating the severity of the delta variant by a factor of two, and greatly underestimating the potential downside risk.

Wright on McKinsey One More Time

In this essay, Crispin Wright’s various attempts at solving the so-called McKinsey paradox are reconstructed and criticized. In the first section, I argue against Anthony Brueckner that Wright’s solution does require that there is a failure of warrant transmission in McKinsey’s argument. To this end, a variant of the McKinsey paradox for earned a priori warrant is reconstructed, and it is claimed that Wright’s putative solution of this paradox is best understood as drawing on the contention that there is a transmission failure in the argument in question. In section II, I focus on Wright’s views in the second part of his pivotal article on the McKinsey paradox (published in 2003). It is argued that the solution to the paradox proposed there by Wright is convincing if his theory of entitlements is accepted. In the third section, however, I raise an objection against Wright’s account of entitlements. Finally, in section IV, Wright’s views in his most recent essay on the McKinsey paradox are examined. It is shown that his new solution to this problem does not work any better than his earlier attempts at solving it.

Diaphragm Neuromuscular Transmission Failure in a Mouse Model of an Early-Onset Neuromotor Disorder

The spa transgenic mouse displays spasticity and hypertonia that develops during the early postnatal period, with motor impairments that are remarkably similar to symptoms of human cerebral palsy. Previously, we observed that spa mice have fewer phrenic motor neurons innervating the diaphragm muscle (DIAm). We hypothesize that spa mice exhibit increased susceptibility to neuromuscular transmission failure (NMTF) due to an expanded innervation ratio. We retrogradely-labeled phrenic motor neurons with rhodamine and imaged them in horizontal sections (70 µm) using confocal microscopy. Phrenic nerve-DIAm strip preparations from wildtype and spa mice were stretched to optimal length, and force was evoked by phrenic nerve stimulation at 10, 40 or 75 Hz in 330 ms duration trains repeated each s (33% duty cycle) across a 120 s period. To assess NMTF, force evoked by phrenic nerve stimulation was compared to force evoked by direct DIAm stimulation superimposed every 15 s. Total DIAm fiber number was estimated in hematoxylin and eosin stained strips. Compared to wildtype, spa mice had over two-fold greater NMTF during the first stimulus train that persisted throughout the 120 s period of repetitive activation. In both wildtype and spa mice, NMTF was stimulation-frequency dependent. There was no difference in neuromuscular junction morphology or the total number of DIAm fibers between wildtype and spa mice, however there was an increase innervation ratio (39%) in spa mice. We conclude that early-onset developmental neuromotor disorders impair the efficacy of DIAm neuromuscular transmission, likely to contribute to respiratory complications.

Diaphragm neuromuscular transmission failure in aged rats

In aging Fischer 344 rats, phrenic motor neuron loss, neuromuscular junction abnormalities, and diaphragm muscle (DIAm) sarcopenia are present by 24 mo of age, with larger fast-twitch fatigue-intermediate (type FInt) and fast-twitch fatigable (type FF) motor units particularly vulnerable. We hypothesize that in old rats, DIAm neuromuscular transmission deficits are specific to type FInt and/or FF units. In phrenic nerve/DIAm preparations from rats at 6 and 24 mo of age, the phrenic nerve was supramaximally stimulated at 10, 40, or 75 Hz. Every 15 s, the DIAm was directly stimulated, and the difference in forces evoked by nerve and muscle stimulation was used to estimate neuromuscular transmission failure. Neuromuscular transmission failure in the DIAm was observed at each stimulation frequency. In the initial stimulus trains, the forces evoked by phrenic nerve stimulation at 40 and 75 Hz were significantly less than those evoked by direct muscle stimulation, and this difference was markedly greater in 24-mo-old rats. During repetitive nerve stimulation, neuromuscular transmission failure at 40 and 75 Hz worsened to a greater extent in 24-mo-old rats compared with younger animals. Because type IIx and/or IIb DIAm fibers (type FInt and/or FF motor units) display greater susceptibility to neuromuscular transmission failure at higher frequencies of stimulation, these data suggest that the age-related loss of larger phrenic motor neurons impacts nerve conduction to muscle at higher frequencies and may contribute to DIAm sarcopenia in old rats. NEW & NOTEWORTHY Diaphragm muscle (DIAm) sarcopenia, phrenic motor neuron loss, and perturbations of neuromuscular junctions (NMJs) are well described in aged rodents and selectively affect FInt and FF motor units. Less attention has been paid to the motor unit-specific aspects of nerve-muscle conduction. In old rats, increased neuromuscular transmission failure occurred at stimulation frequencies where FInt and FF motor units exhibit conduction failures, along with decreased apposition of pre- and postsynaptic domains of DIAm NMJs of these units.