Mechanistic Cascade Tracing: From Hypothesis to Clinical Probe

Chapter Abstract

For every major mechanistic hypothesis in the ME/CFS paper, this chapter traces the full downstream cascade from the proposed trigger to its terminal neurochemical, metabolic, and immunological consequences. At each node: (1) which existing medications could intercept, (2) the expected clinical effect if that node is rate-limiting, and (3) the expected clinical effect if that node is NOT rate-limiting — i.e., what a null response tells you about where the bottleneck really is.

How to use this chapter: Look up a hypothesis, follow the cascade from trigger to symptom, note which medication at which node provides the most specific diagnostic information. Each node’s null response pushes the bottleneck downstream. A pattern of responses across multiple nodes localizes the lesion.

Structure: Each hypothesis is presented in three parts: (a) a cascade diagram in text form (trigger → step1 → step2 → … → symptom), (b) at each step, the drug(s) that could intercept, and (c) the differential diagnostic logic: “if drug X works, the lesion is at or above step N; if it doesn’t, the lesion is below step N.”

Disclaimer: This chapter is a constructed mechanistic framework prompted by the Gerlier skeletal asymmetry hypothesis (2026-07-21, personal communication) and extended to all major hypotheses in the paper. Drug-response logic throughout is mechanistic inference — not clinical evidence. No medication listed here should be prescribed based on this chapter alone. Certainty values are the chapter author’s assessment based on the supporting evidence for each cascade link. Where not explicitly stated, default certainties apply: 0.25–0.40 for mechanistic-inference content, 0.10 for the Gerlier model (per the paper). Each section closes with a Consequence line summarizing practical significance and an Origin line identifying provenance.

Chapter Roadmap: How to Use This Chapter

For patients: little direct use — this is a mechanistic framework for interpreting drug responses, not a treatment guide; if you want to understand your own response pattern, the cross-reference matrix and synthesis algorithm sections are the most readable entry points, but do not prescribe from this chapter.

For caregivers: little direct use; the chapter informs how medications reveal which mechanism is broken, not how to give care.

For clinicians: look up a hypothesis and follow its cascade from trigger to symptom; note which drug at which node gives the most specific diagnostic information, since each node’s null response pushes the bottleneck downstream and a pattern of responses localises the lesion.

For researchers: the primary audience — the cross-hypothesis-convergence-patterns and pathway-coverage sections show which hypotheses lack specific pharmacological probes, mapping open targets for validation.

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