Rebuttal by Richard J. A. Wilson and Trevor A. Day
Bibliographic record
Abstract
Our colleagues skillfully addressed how peripheral chemoreceptors interact with systemic effects of CO2. Unfortunately, systemic CO2 affects oxyhaemoglobin dissociation, sympathetic, endocrine and cardiovascular systems, and afferents from lungs and CO2-sensitive upper airway receptors – all capable of having effects on ventilation independent of central chemoreceptors. Duffin's ingenious rebreathing studies add further concerns, namely psychological and physiological aspects of voluntary hyperventilation (e.g. Steinback et al. 2011). Similarly, carotid body denervation (CBD) studies acclaimed by Teppema & Smith (2013) introduce complications including disruption of baroreflex, abolition of central carotid body regulation of sympathetic and parasympathetic outputs, and unknown contribution of changes associated with long-term plasticity. To mitigate these issues, we developed an artificially perfused rat preparation devoid of intact autonomic and respiratory feedback loops, descending and vagal influences (Day & Wilson, 2009). Demonstrations of hypoadditivity in our preparation are reconcilable with work in humans summarized by Duffin & Mateika (2013). While Duffin & Mateika favour the conclusion of additive interactions, simple addition in ventilation mathematically necessitates hypoadditivity in frequency and/or tidal volume (Mitchell, 1990). Moreover, stimulus and state specific parcelling of responses into frequency and tidal volume suggests hypoadditivity translates to ventilation in certain circumstances. However, our findings are not easily reconciled with a hyperadditive system, as argued by Teppema & Smith (2013). So how do we move forward? Pigeonholed discussions addressing the nature of interaction have illustrated the importance of type, magnitude, order and pattern of stimulus, and species and preparation used, but have yet to reconcile hypoadditive and hyperadditive camps. Therefore, we suggest the need for a new paradigm: a hybrid model incorporating multiple forms of interaction depending on systemic CO2 and/or physiological state. In support of this new paradigm, we note (a) even the hyperadditive O2–CO2 carotid body interaction transitions to hypoadditive at severe levels (Fitzgerald & Parks, 1971), (b) the additive-to-hyperadditive transition with long term facilitation cited by Duffin & Mateika (2013), and (c) Hodges et al. (2005), cited by Teppema & Smith (2013), is only partly consistent with hyperadditivity. Hodges et al. show that, while both mild and severe hypercapnic brainstem aCSF cause increased ventilation, only responses to severe hypercapnic aCSF were reduced by CBD. Thus, while Teppema & Smith considered only the blunted responses to severe hypercapnic aCSF, lack of CBD effect on responses to mild hypercapnic aCSF argues for hypoadditivity. These data are therefore consistent with a hybrid system that endows respiratory chemosensitivity with redundancy and a large dynamic range. Readers are invited to give their views on this and the accompanying CrossTalk articles in this issue by submitting a brief comment. Comments may be posted up to 6 weeks after publication of the article, at which point the discussion will close and authors will be invited to submit a ‘final word'. To submit a comment, go to http://jp.physoc.org/letters/submit/jphysiol;591/18/4365 This work was supported by Alberta Innovates-Health Solutions and Canadian Institutes of Health Research (R.J.A.W.) and a Mount Royal University sabbatical (T.A.D.). Neither author has conflicts to disclose. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.003 | 0.014 |
| Meta-epidemiology (narrow) | 0.002 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.002 | 0.004 |
| Scholarly communication | 0.004 | 0.004 |
| Open science | 0.003 | 0.002 |
| Research integrity | 0.011 | 0.020 |
| Insufficient payload (model declined to judge) | 0.065 | 0.099 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".