{
  "id": "21",
  "title": "Inflammasomes and pyroptosis",
  "summary": "Inflammasome activation may produce gasdermin-D pores that cause local injury and terminal loss.",
  "source_title": "NLRP3-associated gasdermin-D membrane injury",
  "page": "21_inflammasome_pyroptosis.html",
  "source_markdown": "sources/21_inflammasome_pyroptosis.md",
  "structured_data": "data/21_inflammasome_pyroptosis.json",
  "snapshot_date": "2026-09-14",
  "source_review_date": "2026-09-14",
  "scope_label": "Early type 2 diabetes",
  "scope_exception": false,
  "source_headline_markdown": "**Best judgment: about 6%; skeptical–favorable sensitivity: 0.08%–56%.** These are subjective probabilities of the complete human proposition, not treatment effects or statistical confidence limits. The main uncertainty is whether local gasdermin-D pores, rather than other inflammasome effects, cause early human terminal loss. Reviewed 14 September 2026. [Probability method](probability_method.md) · [Collection index](README.md).",
  "probability_percent": {
    "skeptical": 0.08203125,
    "base": 6.318,
    "favorable": 55.7685
  },
  "probability_meaning": "Subjective belief in the complete causal proposition. Scenario endpoints are sensitivity products, not confidence limits.",
  "causal_proposition_markdown": "In adults with type 2 diabetes diagnosed within five years and no clinical DPN at entry, NLRP3 inflammasome activation generates gasdermin-D pores in the plasma membranes of connected peripheral sensory cells before terminal injury. Selectively preventing those pores from entry would avert at least **20% of five-year net peptidergic C-fiber terminal loss**, in a baseline-defined group accounting for at least **10% of reference-care incident DPN**.\n\nThe claim includes **sublytic pore injury and completed lytic death** as alternatives. It does not assert that every activated inflammasome kills its cell, or that completed pyroptotic death mediates the benefit. That narrower death-mediated proposition is not identified by the available structural interventions. Conversely, inflammasome-dependent receptor cleavage or cytokine maturation without gasdermin pores is outside this price. Other gasdermins, mitochondrial membrane pores, pancreatic injury and spinal pain processing are also outside it.\n\n**Population, reference and endpoint.** Reference care is contemporary diabetes care without the selective intervention below, with comparable initiating glycemic, lipid, nutritional and mechanical exposures. Identify adult peptidergic, unmyelinated sensory neurons at entry using combined molecular and anatomical classification, and physically follow their distal skin arbors. Loss of staining or peptide expression alone does not count as disappearance.\n\nFor each person, five-year net terminal loss is physical destruction minus replacement, divided by baseline terminal amount. A terminal formed and then destroyed contributes to both totals. Average people equally. Define:\n\n`B = (mean reference net loss − mean loss with Q) / mean reference net loss.`\n\nThe reference mean must be positive. B is a relative reduction in structural loss, not a pain score, nerve-conduction change or myelin measurement.\n\n**Finite groups.** Candidates are the whole eligible population, males, females, baseline BMI ≥30 kg/m², baseline HbA1c ≥7.5%, and a baseline local-inflammasome-positive group. No additional intersections are searched. The last group has the R1 molecular event in at least 10% of mapped target units during a 30-day entry observation. Incident DPN means new bilateral length-dependent peripheral nerve signs accompanied by objective small-fiber loss or abnormal conduction, with another cause excluded. Coverage is `C = P(group membership | incident DPN under reference care)`. Future treatment response never defines a group.\n\n**Cells and molecular events.** A connected unit comprises the target neuron, its Remak Schwann cells and satellite glia, tissue macrophages within 100 µm of its soma or peripheral arbor, and endothelial or mural cells of vessels demonstrably supplying these structures. CNS microglia and the neuron's central terminal are excluded.\n\nR1 requires direct observation of an assembled **NLRP3–ASC complex with catalytically active caspase-1** in a specified cell during the first follow-up year, before the first tracked terminal destruction in its connected arbor. At least **10% of mapped baseline units**, averaged with equal person weight within a candidate group, must contain such an event. This is activation, without assuming damage. Increased NLRP3 expression or colocalized staining alone is insufficient.\n\nR2 requires that the same activated cell produce a caspase-1-cleaved gasdermin-D N-terminal fragment that inserts into its **plasma membrane and forms a conducting pore within 24 hours** of the R1 event. Pore identity must be established molecularly and functionally, rather than inferred from a nonspecific permeability dye. At least 10% of mapped units must complete that connected sequence, still before the first tracked terminal destruction. A small pore can qualify while the cell survives. Completed cell death is recorded separately and is not a mandatory additional discount.\n\n**Selective intervention Q.** From entry for five years, Q prevents plasma-membrane insertion and oligomerization of the gasdermin-D N-terminal fragments generated by NLRP3-associated caspase-1 in the named peripheral cells. It directly changes that molecular step only, without inhibiting NLRP3 assembly, caspase-1's other substrates, other gasdermins, mitochondrial pores, or neuronal trophic pathways. It does not supply energy or independently change systemic metabolism.\n\nCytokine maturation can continue, but cytokine release through the blocked pores can change. Ion balance, cell viability, immune recruitment, alternative death pathways, support-cell function and terminal replacement remain free to respond. Their favorable and unfavorable consequences count in B. Q therefore has a defined molecular target; it is not a switch that removes only whichever inflammasome effects prove harmful.\n\nThe unit, 24-hour interval and prevalence thresholds define a bounded proposition, not known biological constants. Unlimited molecular tracing and selective intervention are assumed for the ideal tests.",
  "claims": [
    {
      "id": "R1",
      "source_id": "R1",
      "claim": "A candidate group meets the defined pre-loss peripheral NLRP3–ASC–caspase-1 activation criterion in at least 10% of target units.",
      "claim_markdown": "A candidate group meets the defined pre-loss peripheral NLRP3–ASC–caspase-1 activation criterion in at least 10% of target units.",
      "conditional_percent": {
        "skeptical": 35.0,
        "base": 65.0,
        "favorable": 90.0
      },
      "cumulative_base_percent": 65.0,
      "source_cumulative_display": "65.0%",
      "reason_markdown": "Mouse DRG and Schwann-cell results support activation; exact early human cell identity and timing are unmeasured.",
      "question": "Does the NLRP3–ASC–caspase-1 inflammasome pathway activate before terminal loss in at least 10% of target nerve units?"
    },
    {
      "id": "R2",
      "source_id": "R2",
      "claim": "In at least one R1 group, the same sequence proceeds to conducting plasma-membrane GSDMD pores within 24 hours in at least 10% of units.",
      "claim_markdown": "In at least one R1 group, the same sequence proceeds to conducting plasma-membrane GSDMD pores within 24 hours in at least 10% of units.",
      "conditional_percent": {
        "skeptical": 15.0,
        "base": 45.0,
        "favorable": 85.0
      },
      "cumulative_base_percent": 29.25,
      "source_cumulative_display": "29.3%",
      "reason_markdown": "Cleavage and membrane staining support plausibility, but signaling without pores and uncertain human exposure remain major alternatives.",
      "question": "Does NLRP3-associated caspase-1 activation lead to conducting gasdermin-D membrane pores within 24 hours in at least 10% of nerve units?"
    },
    {
      "id": "R3",
      "source_id": "R3",
      "claim": "In one same R1–R2 group, Q reduces five-year net terminal loss by at least 5%: B≥0.05.",
      "claim_markdown": "In one same R1–R2 group, Q reduces five-year net terminal loss by at least 5%: B≥0.05.",
      "conditional_percent": {
        "skeptical": 25.0,
        "base": 60.0,
        "favorable": 90.0
      },
      "cumulative_base_percent": 17.55,
      "source_cumulative_display": "17.6%",
      "reason_markdown": "Genetic traumatic-repair evidence and a diabetic structural drug result support causation, without isolating this pore route in humans.",
      "question": "Would preventing gasdermin-D pores produced by NLRP3-associated caspase-1 avert at least 5% of five-year net terminal loss?"
    },
    {
      "id": "R4",
      "source_id": "R4",
      "claim": "At least one same group satisfying R3 reaches B≥0.20.",
      "claim_markdown": "At least one same group satisfying R3 reaches B≥0.20.",
      "conditional_percent": {
        "skeptical": 25.0,
        "base": 60.0,
        "favorable": 90.0
      },
      "cumulative_base_percent": 10.53,
      "source_cumulative_display": "10.5%",
      "reason_markdown": "The animal structural contrast permits materiality, but does not identify prospective terminal-loss prevention or long-term compensation.",
      "question": "Would preventing gasdermin-D pores produced by NLRP3-associated caspase-1 avert at least 20% of five-year net terminal loss?"
    },
    {
      "id": "R5",
      "source_id": "R5",
      "claim": "At least one same group satisfying R4 accounts for C≥0.10 of reference-care incident DPN.",
      "claim_markdown": "At least one same group satisfying R4 accounts for C≥0.10 of reference-care incident DPN.",
      "conditional_percent": {
        "skeptical": 25.0,
        "base": 60.0,
        "favorable": 90.0
      },
      "cumulative_base_percent": 6.318,
      "source_cumulative_display": "6.3%",
      "reason_markdown": "A common metabolic trigger is plausible; qualifying local pore exposure and causal coverage have not been measured.",
      "question": "Does the benefiting subgroup account for at least 10% of incident DPN cases under reference care?"
    }
  ],
  "sections": [
    {
      "heading": "The causal claim and its scope",
      "markdown": "In adults with type 2 diabetes diagnosed within five years and no clinical DPN at entry, NLRP3 inflammasome activation generates gasdermin-D pores in the plasma membranes of connected peripheral sensory cells before terminal injury. Selectively preventing those pores from entry would avert at least **20% of five-year net peptidergic C-fiber terminal loss**, in a baseline-defined group accounting for at least **10% of reference-care incident DPN**.\n\nThe claim includes **sublytic pore injury and completed lytic death** as alternatives. It does not assert that every activated inflammasome kills its cell, or that completed pyroptotic death mediates the benefit. That narrower death-mediated proposition is not identified by the available structural interventions. Conversely, inflammasome-dependent receptor cleavage or cytokine maturation without gasdermin pores is outside this price. Other gasdermins, mitochondrial membrane pores, pancreatic injury and spinal pain processing are also outside it.\n\n**Population, reference and endpoint.** Reference care is contemporary diabetes care without the selective intervention below, with comparable initiating glycemic, lipid, nutritional and mechanical exposures. Identify adult peptidergic, unmyelinated sensory neurons at entry using combined molecular and anatomical classification, and physically follow their distal skin arbors. Loss of staining or peptide expression alone does not count as disappearance.\n\nFor each person, five-year net terminal loss is physical destruction minus replacement, divided by baseline terminal amount. A terminal formed and then destroyed contributes to both totals. Average people equally. Define:\n\n`B = (mean reference net loss − mean loss with Q) / mean reference net loss.`\n\nThe reference mean must be positive. B is a relative reduction in structural loss, not a pain score, nerve-conduction change or myelin measurement.\n\n**Finite groups.** Candidates are the whole eligible population, males, females, baseline BMI ≥30 kg/m², baseline HbA1c ≥7.5%, and a baseline local-inflammasome-positive group. No additional intersections are searched. The last group has the R1 molecular event in at least 10% of mapped target units during a 30-day entry observation. Incident DPN means new bilateral length-dependent peripheral nerve signs accompanied by objective small-fiber loss or abnormal conduction, with another cause excluded. Coverage is `C = P(group membership | incident DPN under reference care)`. Future treatment response never defines a group.\n\n**Cells and molecular events.** A connected unit comprises the target neuron, its Remak Schwann cells and satellite glia, tissue macrophages within 100 µm of its soma or peripheral arbor, and endothelial or mural cells of vessels demonstrably supplying these structures. CNS microglia and the neuron's central terminal are excluded.\n\nR1 requires direct observation of an assembled **NLRP3–ASC complex with catalytically active caspase-1** in a specified cell during the first follow-up year, before the first tracked terminal destruction in its connected arbor. At least **10% of mapped baseline units**, averaged with equal person weight within a candidate group, must contain such an event. This is activation, without assuming damage. Increased NLRP3 expression or colocalized staining alone is insufficient.\n\nR2 requires that the same activated cell produce a caspase-1-cleaved gasdermin-D N-terminal fragment that inserts into its **plasma membrane and forms a conducting pore within 24 hours** of the R1 event. Pore identity must be established molecularly and functionally, rather than inferred from a nonspecific permeability dye. At least 10% of mapped units must complete that connected sequence, still before the first tracked terminal destruction. A small pore can qualify while the cell survives. Completed cell death is recorded separately and is not a mandatory additional discount.\n\n**Selective intervention Q.** From entry for five years, Q prevents plasma-membrane insertion and oligomerization of the gasdermin-D N-terminal fragments generated by NLRP3-associated caspase-1 in the named peripheral cells. It directly changes that molecular step only, without inhibiting NLRP3 assembly, caspase-1's other substrates, other gasdermins, mitochondrial pores, or neuronal trophic pathways. It does not supply energy or independently change systemic metabolism.\n\nCytokine maturation can continue, but cytokine release through the blocked pores can change. Ion balance, cell viability, immune recruitment, alternative death pathways, support-cell function and terminal replacement remain free to respond. Their favorable and unfavorable consequences count in B. Q therefore has a defined molecular target; it is not a switch that removes only whichever inflammasome effects prove harmful.\n\nThe unit, 24-hour interval and prevalence thresholds define a bounded proposition, not known biological constants. Unlimited molecular tracing and selective intervention are assumed for the ideal tests."
    },
    {
      "heading": "Reasoning from the biology",
      "markdown": "An inflammasome is a protein complex that activates an inflammatory protease. NLRP3 abundance, complex assembly, caspase-1 activity, cytokine processing, gasdermin cleavage, membrane insertion and cell rupture are different events. Evidence for one does not automatically establish the next.\n\nGasdermin pores can disturb ions or allow secretion while a cell remains alive. Membrane repair can remove pores; a cell can also progress to death. Even terminal plasma-membrane rupture has additional machinery: NINJ1-dependent rupture is distinguishable from the earlier loss of viability. Preventing visible rupture does not necessarily save the cell. [Kayagaki et al., 2021](https://doi.org/10.1038/s41586-021-03218-7).\n\nThe priced sequence is:\n\n`NLRP3–caspase-1 activation → GSDMD plasma-membrane pores → altered neuronal/support-cell function or survival → altered terminal destruction and replacement.`\n\nLysis and sublytic pore effects are an OR branch after pore formation. Caspase-1-mediated cleavage of a trophic receptor is a parallel branch that Q does not block. This distinction matters because a caspase-1 inhibitor can preserve nerves through that parallel branch even when GSDMD pore prevention would fail.\n\nA neuron could lose its own membrane integrity, or another cell could lose support capacity or release injurious contents. Those are alternatives within the connected unit. The net structural comparison includes compensation and replacement rather than assuming that one marker-positive support cell determines axon survival."
    },
    {
      "heading": "Evidence that moves the judgment",
      "markdown": "**The cellular glucose experiment has a real osmotic control, but limited target specificity.** Cheng and colleagues exposed the rat RSC96 Schwann-cell line to 25 mM glucose for 48 hours, compared with 5.6 mM glucose and a 19.4 mM mannitol osmotic control. Twenty-five millimolar corresponds to approximately 450 mg/dL: severe hyperglycemia, not an impossible concentration, but not a typical sustained early-T2 exposure. Loganin at 1 µM reduced propidium-iodide uptake, NLRP3/ASC signals and GSDMD N-terminal protein and membrane staining. The experiments used about three independent culture repetitions; fields and cells do not create human donors. Loganin and the antioxidant comparator NAC affect several processes, and there was no GSDMD-specific genetic loss-and-rescue comparison. The findings support a pore-associated cellular possibility, not a quantified human causal fraction. [Cheng et al., 2020](https://pmc.ncbi.nlm.nih.gov/articles/PMC7564733/).\n\n**The TET2/NLRP3 study is principally pain evidence.** In STZ-diabetic mice, MCC950 and the chemically different NLRP3 inhibitor CY-09 reduced mechanical hypersensitivity; the principal behavioral contrasts used approximately 10–11 mice per arm. The effect peaked over hours. The study documented diabetic epidermal fiber loss, but did not show that these interventions preserved those fibers. TET2 knockdown also changed the TXNIP/NLRP3 pathway and pain. None of those observations establishes gasdermin-mediated membrane injury as the structural mediator. [Chen et al., 2022](https://pmc.ncbi.nlm.nih.gov/articles/PMC9756585/).\n\nIts culture comparison is not an isolated glucose perturbation: raising glucose from 5 to 25 mM also removed 0.6 nM insulin. The additional 25-to-45 mM experiment likewise changed to insulin-free B27 supplement. Mannitol controls retained insulin. Cultures pooled roughly 150 DRGs from five mice per preparation, with three reported culture repetitions. Thus glucose and withdrawal of trophic insulin signaling remain competing explanations for the cultured-neuron response. [Chen et al., 2022](https://pmc.ncbi.nlm.nih.gov/articles/PMC9756585/).\n\n**A diabetic structural benefit exists, with uncertain pore attribution.** Liao and colleagues treated male db/db mice with established painful neuropathy using oral amlexanox for four weeks. At 25 mg/kg/day, IENFD improved. Digitization of the **six visible points per arm** in Fig. 7I estimates that treatment closed about **45% of the concurrent control–diabetic density difference**, with an exploratory animal-bootstrap interval of approximately **27%–67%**. This is a cross-sectional density contrast in treated established disease, not a fraction of five-year net loss prevented. The source figure labels density as fibers/µm while the methods say fibers/cm; the dimensionless contrast avoids assigning an unsupported physical unit. The approximate three-arm Tukey p=0.024 agrees with the plotted significance. [Liao et al., 2024](https://pmc.ncbi.nlm.nih.gov/articles/PMC11264750/).\n\nThe same paper's intrathecal TBK1-siRNA structural contrast is imprecise, rather than zero. The six plotted points per arm in Fig. 5J give about **26% of the control–diabetic difference closed**; an exploratory bootstrap interval is roughly **10%–41%**, but the source's three-arm Tukey comparison is nonsignificant, reproduced approximately at p=0.15. The two interventions were separate experiments, not a randomized comparison of delivery routes. The different tests and their assumptions must not be selected according to the desired story. Neither a significant systemic result nor a nonsignificant central result proves the anatomical mediator. [Liao et al., 2024](https://pmc.ncbi.nlm.nih.gov/articles/PMC11264750/).\n\nAmlexanox is not a selective gasdermin pore intervention. It changed insulin levels and inflammatory and vascular measures despite no reported blood-glucose or body-weight improvement. The paper's “improved insulin resistance” interpretation is based on more limited metabolic measurements, not a direct clamp experiment. Intrathecal siRNA can also reach DRG-related compartments and is not a microglia-specific manipulation. Ac-YVAD-cmk, a caspase-1 inhibitor, provided analgesic evidence without the corresponding terminal structural comparison. These observations leave the pore-specific interpretation substantially weaker than the existence of a drug-associated structural benefit. [Liao et al., 2024](https://pmc.ncbi.nlm.nih.gov/articles/PMC11264750/).\n\n**A more specific genetic study concerns traumatic repair.** Following sciatic transection and surgical rejoining, global Gsdmd deletion improved regeneration, sciatic functional index and motor conduction in female mice. The principal functional comparison was **six mice per group**; electron microscopy and comparisons with other inflammasome knockouts generally used three. The authors explicitly report no blinding. Nlrp3, ASC and caspase-1 deletion also improved recovery, while IL-1β deletion did not give the same result. This supplies genetic evidence beyond a nonspecific antioxidant, but the small multiple comparisons do not quantify an independent human effect. Global deletion also changes the inflammatory environment. The injury, regeneration endpoint and largely myelinated nerve differ from early diabetic peptidergic terminal preservation. [Tao et al., 2021](https://pmc.ncbi.nlm.nih.gov/articles/PMC8203780/).\n\n**New evidence directly separates inflammasome signaling from lysis.** A 2026 study activated NLRP3 in primary neonatal mouse Schwann cells and RSC96 cells with LPS and millimolar ATP. Only about **8% of primary cells and 2%–3% of RSC96 cells** became propidium-iodide positive; most maintained membrane integrity. GSDMD N-terminal levels were approximately 2%–4% of the macrophage comparator. Caspase-1 instead cleaved the trophic receptor Tyro3. A cleavage-resistant Tyro3 mutant and caspase-1 inhibition supported receptor preservation and myelination. This is a concrete alternative explanation for benefit from an upstream inflammasome inhibitor. It is not evidence that all Schwann cells resist pore injury, and its acute injury/stimulation conditions are not diabetic human exposure. [Sublytic Schwann-cell study, 2026](https://pmc.ncbi.nlm.nih.gov/articles/PMC13001282/).\n\nGasdermin-E offers another distinction. Experiments in cortical neurons, human induced neurons and ALS-related systems found mitochondrial damage and neurite loss before overt cell death. This demonstrates that “gasdermin-associated degeneration” need not mean plasma-membrane lysis. Different protein, membrane and disease context prevent using it as direct evidence for the NLRP3–GSDMD route priced here. [Neel et al., 2023](https://pmc.ncbi.nlm.nih.gov/articles/PMC10121894/).\n\nOther diabetic studies using Jinmaitong or Tangzu granule report pain, DRG or sciatic pathology and inflammasome/GSDMD markers. They are multicomponent interventions, with no demonstrated selective pore-mediated terminal effect. Jinmaitong used eight rats per arm over 12 weeks; detailed animal-level Tangzu data were not accessible. A TUDCA report combines fecal associations in 50 people with a Schwann-cell experiment, not a human nerve intervention. [Sun et al., 2021](https://pmc.ncbi.nlm.nih.gov/articles/PMC8596020/), [Feng et al., 2025](https://doi.org/10.1016/j.jep.2024.118792), [Wang et al., 2024](https://doi.org/10.1002/bab.2518).\n\nThe registered Dapan-Dia trial of dapansutrile has estimated enrollment of 300 and posted HbA1c/fasting-glucose outcomes, with no posted results in the accessed record. It does not provide a structural DPN test or a negative result for this hypothesis. [NCT06047262](https://clinicaltrials.gov/study/NCT06047262)."
    },
    {
      "heading": "Probabilities of the logical claims",
      "markdown": "Each conditional assumes the preceding claims hold for the **same candidate group and connected molecular sequence**. If several groups qualify, later requirements ask whether one of those same groups continues to satisfy the chain.\n\n| # | Claim | Skeptical / best / favorable | Best cumulative | Basis |\n|---|---|---:|---:|---|\n| R1 | A candidate group meets the defined pre-loss peripheral NLRP3–ASC–caspase-1 activation criterion in at least 10% of target units. | 35 / **65** / 90% | 65.0% | Mouse DRG and Schwann-cell results support activation; exact early human cell identity and timing are unmeasured. |\n| R2 | In at least one R1 group, the same sequence proceeds to conducting plasma-membrane GSDMD pores within 24 hours in at least 10% of units. | 15 / **45** / 85% | 29.3% | Cleavage and membrane staining support plausibility, but signaling without pores and uncertain human exposure remain major alternatives. |\n| R3 | In one same R1–R2 group, Q reduces five-year net terminal loss by at least 5%: B≥0.05. | 25 / **60** / 90% | 17.6% | Genetic traumatic-repair evidence and a diabetic structural drug result support causation, without isolating this pore route in humans. |\n| R4 | At least one same group satisfying R3 reaches B≥0.20. | 25 / **60** / 90% | 10.5% | The animal structural contrast permits materiality, but does not identify prospective terminal-loss prevention or long-term compensation. |\n| R5 | At least one same group satisfying R4 accounts for C≥0.10 of reference-care incident DPN. | 25 / **60** / 90% | **6.3%** | A common metabolic trigger is plausible; qualifying local pore exposure and causal coverage have not been measured. |\n\nR2 is about a physical membrane event, not presumed toxicity. R3 tests the additional structural effect. R4 asks about magnitude conditional on an effect; R5 asks whether the qualifying group is sufficiently common. Completed lysis is neither silently assumed nor charged as an extra requirement."
    },
    {
      "heading": "Ideal experiments that would resolve each claim",
      "markdown": "Use a representative early-T2 cohort with matched nondiabetic reference measurements, entry-defined groups, identified peptidergic neurons, their connected cells and physical terminal tracking. Follow for five years. The idealizations are direct molecular event tracing, selective Q and nonperturbing longitudinal structural measurement.\n\n**R1 — activation, with no predecessor assumed.** Observe assembled NLRP3–ASC complexes and their catalytically active caspase-1 in the named peripheral cells. Determine cell identity and time relative to the first tracked terminal destruction. **YES:** one candidate group meets the first-year, pre-loss and 10%-of-units criterion. **NO:** complete observation shows all candidate groups fail it. Blood cytokines, late tissue expression or an unresolved cell source leave R1 **unresolved**.\n\n**R2 — pores conditional on R1.** Track the activated complex's caspase-1 cleavage of GSDMD, plasma-membrane insertion and actual conductance in the same cells, with molecularly specific pore blockade as a functional identity control. **YES:** one R1 group meets the stated 24-hour, pre-loss and 10%-of-units sequence. **NO:** all compatible groups fail it, including a response confined to cytokine processing, Tyro3 cleavage or mitochondrial pores. A cleaved GSDMD band without demonstrated membrane pores leaves R2 **unresolved**. Surviving cells with confirmed pores can satisfy it.\n\n**R3 — causal structure conditional on R1–R2.** Randomly allocate people in each compatible group to reference care or Q from entry. Verify sustained prevention of the named pore formation while preserving the intervention's molecular specificity. Measure physical destruction and replacement, allowing downstream secretion, compensatory death and repair to change. **YES:** one compatible group has a positive reference-loss denominator and B≥0.05. **NO:** all faithfully implemented comparisons have B<0.05, including net worsening. Pain relief, missing structural follow-up or an intervention that also independently changes metabolism leaves this causal comparison **unresolved**. This experiment resolves the pore route, not the proportion mediated specifically by lysis.\n\n**R4 — magnitude conditional on R1–R3.** Use the same people, intervention and five-year endpoint. **YES:** one R3 group has B≥0.20. **NO:** every R3 group has 0.05≤B<0.20. A transient early difference does not qualify if the five-year effect falls below the boundary. An interval crossing 0.20 leaves the finite result **unresolved**.\n\n**R5 — coverage conditional on R1–R4.** Determine baseline membership and incident DPN under reference care in the representative population. **YES:** one R4 group has C≥0.10. **NO:** all such groups have C<0.10. Missing incident ascertainment is unresolved. Do not form a new union of groups or select responders after seeing the results.\n\nExact population values determine the claims' truth; finite results can remain unresolved around a boundary."
    },
    {
      "heading": "Uncertainty and numerical sensitivity",
      "markdown": "The best conditionals **[65,45,60,60,60]%** give **6.318%**, reported as about 6%. Skeptical **[35,15,25,25,25]%** and favorable **[90,85,90,90,90]%** scenarios give **0.0820%** and **55.7685%**. These coordinated interpretations have no assigned weights or justified variance. Their width reflects molecular specificity and human transport uncertainty, not merely the standard errors of the mouse plots.\n\nIf most intervention effects operate outside GSDMD plasma-membrane pores, **[45,25,35,40,40]%** gives **0.63%**. If the exact early human pore sequence is common and the structural effects transfer well, **[85,75,80,80,85]%** gives **34.68%**.\n\nConvincing direct human pore evidence could raise R2 from 45% to 75%, giving **10.53%** with the other judgments unchanged. Adequate evidence of activation without pores could reduce R2 to 15%, giving **2.106%**. The new sublytic Schwann-cell observation is relevant to that distinction but does not alone establish either human update.\n\nMerging R1 and R2 must give **29.25%**, preserving the headline. Their probabilities are conditional beliefs, not independent estimates fitted to separate experiments. Requiring completed lytic death as an additional necessary mediator would strengthen the proposition and cannot raise its probability; the present evidence does not support a precise conversion to that narrower claim.\n\nLowering the 20% preservation or 10% coverage boundary weakens the claim. Relaxing the unit fraction or extending the permitted activation-to-pore interval also weakens it, with other definitions fixed. Exact numerical prices for these alternative definitions are unsupported.\n\nThe [quantitative finding](../../../findings/damage_calibration_pyroptosis_quantitative.md) contains the digitized structural contrasts, coordinate sensitivity and source-unit limitations. Neither those contrasts nor the headline is an empirically calibrated prediction of a future human trial."
    },
    {
      "heading": "Overlap and boundary",
      "markdown": "This route can connect [TNF/TLR4 signaling](19_tnf_tlr4_inflammation.md), [macrophage support](20_loss_of_protective_macrophages.md), [glial support](17_schwann_metabolic_support.md), and [oxidative stress](39_oxidative_nitrosative_injury.md). A single pore-dependent effect can appear under several descriptions; prevented fractions and probabilities cannot be added.\n\n[Apoptosis](30_neuronal_soma_apoptosis.md) and [ferroptosis](29_ferroptosis.md) can compensate when another death route is blocked. Shared markers do not establish several independent execution mechanisms. The present assessment concerns a named plasma-membrane pore sequence and its net structural consequence."
    }
  ],
  "source_claim_table_markdown": "| # | Claim | Skeptical / best / favorable | Best cumulative | Basis |\n|---|---|---:|---:|---|\n| R1 | A candidate group meets the defined pre-loss peripheral NLRP3–ASC–caspase-1 activation criterion in at least 10% of target units. | 35 / **65** / 90% | 65.0% | Mouse DRG and Schwann-cell results support activation; exact early human cell identity and timing are unmeasured. |\n| R2 | In at least one R1 group, the same sequence proceeds to conducting plasma-membrane GSDMD pores within 24 hours in at least 10% of units. | 15 / **45** / 85% | 29.3% | Cleavage and membrane staining support plausibility, but signaling without pores and uncertain human exposure remain major alternatives. |\n| R3 | In one same R1–R2 group, Q reduces five-year net terminal loss by at least 5%: B≥0.05. | 25 / **60** / 90% | 17.6% | Genetic traumatic-repair evidence and a diabetic structural drug result support causation, without isolating this pore route in humans. |\n| R4 | At least one same group satisfying R3 reaches B≥0.20. | 25 / **60** / 90% | 10.5% | The animal structural contrast permits materiality, but does not identify prospective terminal-loss prevention or long-term compensation. |\n| R5 | At least one same group satisfying R4 accounts for C≥0.10 of reference-care incident DPN. | 25 / **60** / 90% | **6.3%** | A common metabolic trigger is plausible; qualifying local pore exposure and causal coverage have not been measured. |"
}