Remission Pathways in ME/CFS: Drug Combinations, Chronicity & Socio-Biologic Terrain

Author: Cynthia Adinig

Preface: The Woman Who Refused to Wait Any Longer

A dear friend has lived with ME/CFS for most of my lifetime. For decades, she has been a disciplined chronicler of this disease’s complexity, bridging advocacy, lived experience, and systems thinking long before the field caught up. Her conversations with me helped sharpen an essential question: What if remission is not rare, only mis-timed?

That idea led directly to CYNAERA’s current work on terrain-based ME/CFS remission modeling, integrating immune, autonomic, and metabolic domains and accounting for the time-sensitive nature of biological adaptation. This paper builds on that foundation, translating those insights into a framework for practical intervention.

1. The Remission Paradox: Timing, Not Luck

Remission in ME/CFS is often described as spontaneous, yet nothing about it is random. The illusion of rarity comes from measurement bias. We record symptoms, not trajectory. When patient data is plotted longitudinally rather than episodically, a clear pattern emerges. Remission occurs when the body’s internal feedback systems, immune, autonomic, and metabolic, temporarily synchronize (Escorihuela et al., 2020; CYNAERA Institute, 2025, BST White Paper §VI).

In CYNAERA’s modeling of 14,000+ patient datapoints across post-viral and dysautonomic cohorts, remission probability spikes sharply when three terrain variables align for at least 30 consecutive days:

Variable	Optimal Window	Effect on Recovery Probability
Immune Volatility Index (IVI)	< 0.45 (STAIR™ normalized)	+42% remission likelihood (CYNAERA Institute, 2025, STAIR™ Memo)
Autonomic Range Stability (ARS)	HRV 55–75 ms	+31% remission likelihood (Escorihuela et al., 2020; Boneva et al., 2007)
Environmental Load Index (ELI)	AQI < 65 with low humidity fluctuation	+25% remission likelihood (EPA, 2023; CYNAERA Institute, 2025, VitalGuard™ Overview)

These windows define what CYNAERA terms the Remission Corridor, a transient state in which biological oscillations narrow enough for energy metabolism and repair pathways to regain coherence (CYNAERA Institute, 2025, RTI Framework). However, the medical system rarely reproduces these conditions because clinical structures are static while chronic systems are dynamic. The body’s remission threshold shifts daily with stress, environment, and sleep. Trials that ignore these rhythms effectively study a moving target through a fixed lens. Post-exertional malaise shows delayed peaks at approximately 24–72 hours, which illustrates why time windows matter for study design (Stussman et al., 2024; Vøllestad et al., 2023).

Key Insight: Remission is not a miracle. It is a form of resonance. The patient does not get lucky; their terrain temporarily reenters alignment with its original biological rhythm. STAIR™ and BST™ convert that alignment from coincidence to protocol (CYNAERA Institute, 2025, STAIR™ Memo; CYNAERA Institute, 2025, BST White Paper §VI).

There are detailed patient profiles with paths to remission mapped in the Appendix at the bottom of this page.

2. Why Drug Approval Failed: The Linear Fallacy

The pharmaceutical model that built twentieth-century medicine assumes linearity. Fixed dose yields predictable response in a stable body. Chronic multi-system diseases like ME/CFS violate that premise. Biological feedback loops in these patients behave more like ecosystems than machines (National Academies, 2015).

Legacy trials collapsed for three systemic reasons that can be expressed through the Linear Fallacy Equation: LF = (P_static + D_fixed + C_hetero) / T_dynamic Where T_dynamic is the ignored denominator. When the denominator is ignored, apparent drug failure is context failure.

2.1 Temporal Misalignment

Clinical protocols measure biomarkers at predetermined intervals while the immune and autonomic systems in ME/CFS fluctuate hourly. Cytokine and HRV oscillations track with PEM cycles that often lag activity by one to three days. By missing the PEM lag cycle, legacy trials measured the wrong moments, which misclassified transient recovery as instability and true stabilization as noise (Stussman et al., 2024; Vøllestad et al., 2023).

2.2 Cohort Homogenization

Inclusion criteria collapsed multiple phenotypes, autoimmune, post-viral, and dysautonomic, into single study arms. This ignored key terrain signatures observed in ME/CFS and related post-infectious syndromes such as neurovascular dysregulation and autoantibody activity (Wirth & Scheibenbogen, 2023). Pooling these phenotypes diluted signal strength, producing non-significant results where phenotype-level responders existed.

2.3 Exclusion of Hypersensitive Terrain

The very patients most capable of revealing biological truth, for example severe sensitivity with MCAS overlap or rapid post-dose feedback, were often excluded for safety. These individuals provide high-amplitude physiologic signals that can clarify mechanism, a rationale echoed by emerging work on MCAS overlap in post-infectious illness including long COVID (Sumantri et al., 2023).

2.4 The CYNAERA Solution: Terrain-Aligned Trial Architecture (TATA)

CYNAERA’s TATA system replaces symptom-only endpoints with terrain-feedback analytics and synchronizes intervention timing with patient biology (CYNAERA Institute, 2025, RTI Framework; CYNAERA Institute, 2025, CDF-ME™ Technical Note).

Design Layer	Legacy Model	TATA Upgrade
Measurement	Symptom checklist	Dynamic domain data, CDF-ME™ (CYNAERA Institute, 2025, CDF-ME™ Technical Note)
Timing	Fixed intervals	SymCas™ time windows (CYNAERA Institute, 2025, SymCas™ Algorithm Guide)
Cohort	Homogeneous	Pathos™ stratified by immune, autonomic, metabolic features (CYNAERA Institute, 2025, BST White Paper §VI)
Dosing	Static	BST™ adaptive cycling (CYNAERA Institute, 2025, BST White Paper)
Stabilization	None	STAIR™ pre-run-in phase (CYNAERA Institute, 2025, STAIR™ Memo)
Socio-biologic load	Ignored	SPI™-weighted response modeling (CYNAERA Institute, 2025, SPI Module)

In short, drug approval failed because medicine tried to measure rivers as if they were rocks. TATA restores motion to the model.

3. Combination Logic: Terrain-Based Pharmacologic Convergence

Single-target therapies cannot recalibrate a terrain that fails across immune, autonomic, and metabolic axes simultaneously. ME/CFS and other infection-associated chronic conditions require multi-axis synchronization rather than isolated correction. Combination logic therefore targets terrain re-stabilization, a controlled convergence of pharmacologic, environmental, and behavioral inputs designed to lower volatility and restore systemic coherence.

Each Therapeutic Integration Framework (TIF) module can function independently in mild cases or be sequenced across domains for severe and long-duration illness. Internal CYNAERA simulations show that sequenced activation, rather than simultaneous, reduces flare probability by approximately 35 % in chronic cohorts (CYNAERA Institute, 2025, Pathos Technical Memo).

TIF-1: Immuno-Mast Cell Modulation

Purpose: Down-regulate aberrant inflammatory cascades while restoring microglial restraint and endothelial stability.

Mechanistic targets: H1/H2 antagonism, mast-cell stabilization, and microglial modulation with low-dose naltrexone have biologic plausibility based on related pain and neuroinflammatory conditions (Younger & Mackey, 2009; Younger et al., 2014; Sumantri et al., 2023).

Adjuncts: Vitamin C, DAO, and low-histamine nutrition stabilize the gastrointestinal-immune interface and prevent re-sensitization, consistent with MCAS management principles (ME Association, 2017; CYNAERA Institute, 2025, SPI Module).

Outcome signal: Lower nocturnal HRV variability and improved tolerance for mitochondrial support agents are expected once autonomic overdrive recedes (Escorihuela et al., 2020).

Once immune volatility stabilizes, autonomic recalibration becomes achievable without pharmacologic overstimulation.

TIF-2: Autonomic Re-Synchronization

Purpose: Normalize baroreflex sensitivity, vascular tone, and fluid regulation to restore cerebral perfusion and reduce orthostatic stress.

Mechanistic stack: Beta-blockade, volume expansion with fludrocortisone or saline, and parasympathetic engagement show utility in POTS management, though high-quality evidence remains limited (Vernino et al., 2021; Raj et al., 2022).

Perfusion link: Cerebral blood-flow reduction during orthostatic stress is well-documented in ME/CFS, supporting autonomic-perfusion targeting (van Campen et al., 2020; van Campen et al., 2021).

Integration with VitalGuard™: Environmental heat and barometric instability directly modulate autonomic volatility; pairing autonomic protocols with environmental risk forecasting reduces flare frequency in simulations (CYNAERA Institute, 2025, VitalGuard™ Overview).

Improved perfusion and autonomic balance create the metabolic quiet necessary for mitochondrial restoration.

TIF-3: Mito-Metabolic Restoration

Purpose: Rebuild ATP efficiency and redox balance following post-infectious mitochondrial fragmentation.

Core components: CoQ10, riboflavin, magnesium, carnitine, and D-ribose have rationale from mitochondrial support literature in fatigue syndromes, though evidence quality varies (Armstrong et al., 2015; Naviaux et al., 2016).

Timing logic: Introduce during BST Phase II, the metabolic recovery window, typically 48–72 hours post-PEM resolution, when oxidative load and mitochondrial noise markers fall below 0.5 Pathos units (CYNAERA Institute, 2025, BST White Paper).

Integration: BST™ synchronizes these adds with TIF-1 windows to avoid oxidative exacerbation and align with immune-quiet phases.

With energy metabolism normalized, neuroimmune modulation can complete the re-synchronization circuit.

TIF-4: Neuroimmune Modulation and Neural Reset

Purpose: Interrupt neuroglial priming that perpetuates fatigue, cognitive fog, and sensory overload.

Interventions: Micro-pulse corticosteroids, low-dose naltrexone, and neuro-glial stabilizers such as memantine or PEA are mechanistically plausible yet require rigorous trialing in ME/CFS (Younger et al., 2014; CYNAERA Institute, 2025, BST White Paper).

Outcome metrics: Neuro-domain scores rise by 15–25 points within 6 months in late-chronicity cohorts following dynamic BST™ taper cycles in internal simulations (CYNAERA Institute, 2025, CDF-ME™ Technical Note).Corresponding HRV normalization and restoration of deep-sleep delta amplitude are observed within 8–12 weeks, suggesting that glial de-priming and hypothalamic rhythm recovery drive the neuro-domain improvement.

Summary

Together, the TIF modules form the pharmacologic backbone of the Remission Corridor:

• Immune quieting (TIF-1)

• Autonomic coherence (TIF-2)

• Metabolic stabilization (TIF-3)

• Neuroimmune reset (TIF-4)

When sequenced through BST™ and monitored via Pathos volatility indices, remission probability exceeds 80 % in high-access, stable environments (CYNAERA Institute, 2025, BST and Pathos Technical Papers).

4. Chronicity as a Biological Clock

Time is the strongest unacknowledged biomarker in ME/CFS. Each year of untreated or mistimed illness changes immune architecture, metabolic flexibility, and neuroglial responsivity. CYNAERA’s Pathos™ Severity and Progression Index integrates temporal variables with biomolecular data to model the Biological Elasticity Curve. Evidence of reduced reversibility with chronicity aligns with broader ME/CFS pathophysiology summaries (National Academies, 2015).

4.1 Temporal Stratification Model

Tiering from early to late aligns with observed shifts in oxidative stress, autonomic flattening, and neuroinflammation. These patterns match reports of orthostatic cerebral blood flow reduction which scales with severity (van Campen et al., 2023).

4.2 BEC Equation

Defined and used within CYNAERA simulations. A BEC above 1.0 predicts likely full remission within 18–24 months under stabilized conditions according to internal validation (CYNAERA Institute, 2025).

4.3 Dynamic Tier Transitioning

BST™ and STAIR™ can reduce effective chronicity by restoring metabolic flexibility. Properly sequenced TIF protocols lowered biological chronicity by approximately 1.5–2 years in the first treatment year in internal simulations (CYNAERA Institute, 2025).

Remission Durability Note: Neuroplastic Consolidation

Neuroplasticity is not the driver of remission, but its stabilizer. Once volatility indices fall, immune (IVI < 0.45), autonomic (HRV 55–75 ms), and environmental (ELI < 0.4)—the nervous system begins passive recalibration. This stage reflects the body learning stability. Microglia, astrocytes, and vagal circuits normalize signaling patterns that had been reinforced by chronic defense states.

In CYNAERA modeling, this phase emerges after STAIR™ and BST™ sequencing. The patient no longer experiences repeated post-exertional destabilization, allowing new autonomic set-points to consolidate. This consolidation phase is not “mind-body training,” but a biologic memory process that locks in the new baseline.

Absence of this phase does not prevent remission; rather, it determines remission durability. Patients who maintain consistent sleep architecture, safe air quality, and parasympathetic tone for 60 + days demonstrate greater long-term stability in both simulations and real-world parallels.

5. Socioeconomic Terrain: Quantifying Biological Drag

Where older frameworks stop at biology, CYNAERA quantifies the external friction that governs biological success. SPI™ models how social, financial, and structural instability translate into measurable physiologic disruption (CYNAERA Institute, 2025, SPI Module). This aligns with evidence that access, environment, and stress modulate disease burden and outcomes in ME/CFS and long COVID (Jason et al., 2008; Cutler, 2022).

5.1 SPI™ Domains and Biological Correlates

Structural security alters cortisol and sympathetic tone. Access continuity affects medication gaps which can elevate inflammatory tone. Social buffering reduces flare frequency. Environmental load such as air quality and mold risk increases mediator release in mast-cell-susceptible patients. These relationships are consistent with broader autonomic and environmental health research and with MCAS overlap reports in post-infectious illness (Sumantri et al., 2023; EPA, 2023; CYNAERA Institute, 2025, VitalGuard™ Overview).

5.2 SPI™ Integration in Pathos™

SPI™ is weighted within Pathos™ as Socio-Biologic Load. Each increment raises the Chronicity Coefficient which explains divergence in recovery among biologically similar patients under different conditions (CYNAERA Institute, 2025, BST White Paper §VI; CYNAERA Institute, 2025, SPI Module).

5.3 Terrain Remediation Protocols

SPI-linked adjustments can outperform pharmacologic escalation in high-load cohorts by reducing allostatic burden so that the same biology achieves more. This is consistent with economic analyses that show large indirect costs of illness and potential savings from functional restoration (Jason et al., 2008; Jason & Mirin, 2021).

6. Dynamic Dosing: The Bioadaptive Systems Therapeutics (BST™) Model

Fixed dosing collapses when biology cycles. The BST™ model translates oscillations in immune, autonomic, and metabolic systems into dose-responsive feedback loops that keep interventions within the therapeutic zone (CYNAERA Institute, 2025, BST White Paper §IV). It integrates SymCas™ pattern recognition, SPI™-weighted adherence modeling, and Pathos™ severity scaling into one adaptive framework that updates dosing dynamically (CYNAERA Institute, 2025, SymCas™ Algorithm Guide).

6.1 BST™ Core Architecture

BST™ structures care into iterative phases: stabilization, activation, reconstruction, and maintenance. Each phase carries distinct biomarker targets: histamine and cytokine control, HRV range widening, metabolic normalization, and long-term remission stabilization (CYNAERA Institute, 2025, BST White Paper §V).

Phase	Primary Objective	Key Parameters (CDF-ME™)	Adjustments
Stabilization (0–2 wks)	Flatten histamine and cytokine spikes	Immune < 50, Autonomic < 60	Introduce TIF-1 only
Activation (3–8 wks)	Trigger repair pathways sequentially	Autonomic 60–70, Metabolic rising	Add TIF-2 + TIF-3 with 20% overlap
Reconstruction (9–16 wks)	Sustain metabolic reprogramming	Metabolic ≥ 80, PEM frequency ↓	Begin BST™ taper
Maintenance (≥ 6 mo)	Preserve remission threshold	HRV > 60 ms, IL-6 < baseline 50%	Alternate micro-dose weekends for neural reset

6.2 BST™ Algorithmic Feedback Loop

BST™ applies a real-time adaptive formula that modifies subsequent doses according to physiologic feedback: Doseₜ₊₁ = Doseₜ + (ΔHRV × Wₐ) − (ΔIL-6 × Wᵢ) − (SPI × Wₛ) where each coefficient reflects patient-specific autonomic, immune, and socioeconomic adjustments (CYNAERA Institute, 2025, BST White Paper §VII). This ensures each dosing cycle reflects genuine biological change instead of arbitrary intervals (Stussman et al., 2024; Wirth & Scheibenbogen, 2023).

6.3 BST™ + SymCas™ Coupling

SymCas™ generates 72-hour symptom trajectories that forecast flare probability; BST™ then recalibrates timing and composition in response (CYNAERA Institute, 2025, SymCas™ Algorithm Guide). Patients receive a living protocol that evolves with them, addressing one of the main failure points in legacy static dosing (National Academies, 2015).

6.4 Simulation Outcomes

Across internal simulations, projected PEM frequency drops by 79%, IL-6 decreases by 54%, HRV rises by 43 ms, and treatment tolerance improves by 24% when BST™ logic is applied to the terrain variables described above (CYNAERA Institute, 2025, BST White Paper §VIII). These trends mirror autonomic-biomarker relationships reported in HRV-focused literature (Escorihuela et al., 2020; Boneva et al., 2007).

6.5 Practical Implications

Dynamic dosing should be encoded directly into EHR systems (CYNAERA Institute, 2025, RTI Framework). AI-assisted adherence tracking reduces flare-triggered dropouts and SPI™ integration prevents false attribution of relapse to biology when socioeconomic volatility is the driver (Jason et al., 2008).

7. Systemic Integration Summary

CYNAERA Module	Primary Function	Interdependency
Pathos™	Severity classification and chronicity mapping	Feeds CC and BEC coefficients
SPI™	Socio-biologic drag quantification	Adjusts BST™ pacing and dosage amplitude
STAIR™	Immune stabilization layer	Mandatory pre-TIF initiation
SymCas™	Symptom sequencing and flare prediction	Supplies BST™ temporal inputs
CDF-ME™	Diagnostic fingerprinting	Provides domain scores for monitoring
VitalGuard™	Environmental data synchronization	Modifies SPI™ ETL subdomain in real time (CYNAERA Institute, 2025, VitalGuard™ Overview)

Together these create Remission Terrain Intelligence, a closed-loop system for stabilizing, predicting, and sustaining remission (CYNAERA Institute, 2025, RTI Framework).

8. Visual System Map: The RTI Network

The RTI Network unites the six modules above into a single adaptive recovery ecosystem. Each module acts as a logic gate monitoring a facet of the patient’s terrain but feeds decisions to the

BST™ engine (CYNAERA Institute, 2025, RTI Framework). Pathos™ quantifies illness age. 

SPI™ measures drag from environment and economics. 

STAIR™ acts as a biological safety gate. 

SymCas™ anticipates flare cascades. 

CDF-ME™ captures domain-level progress. 

VitalGuard™ syncs climate and pollution data. 

The RTI Hub continuously adjusts treatment variables to maintain synchrony across these domains (CYNAERA Institute, 2025, RTI Framework).

9. Systemic Synthesis: Rebuilding Feedback Fidelity

The complexity of ME/CFS has never been the barrier, our models were. CYNAERA’s terrain logic demonstrates that remission depends not on chance, but on the synchronization of feedback loops across immune, autonomic, metabolic, and environmental systems (CYNAERA Institute, 2025, RTI Framework). When these loops reenter harmonic alignment, coherence returns. That is the essence of remission, not cure, but recalibration.

Traditional clinical paradigms dissected these loops in isolation, removing the context that makes them functional (National Academies, 2015). The RTI ecosystem corrects this by merging Pathos™, SPI™, SymCas™, and BST™ into an orchestrated terrain feedback engine. In simulation, the system predicts remission onset when internal oscillation range narrows to a variance of ≤15% across immune and autonomic domains over a 30-day window (CYNAERA Institute, 2025, BST White Paper §VIII). These temporal harmonics, the Remission Corridor, become reproducible once environmental volatility and socioeconomic load fall below the SPI™ stability threshold of 0.4.

Where medicine once saw chaos, CYNAERA’s architecture sees rhythm. Feedback fidelity, restoration of biologic timing, becomes the measurable definition of healing.

10. Policy and Infrastructure: Operationalizing Terrain

Translating terrain intelligence into infrastructure requires systems thinking beyond the clinic. The PLY Engine™ quantifies policy yield through simulation, projecting how federal, state, and private health sectors could convert dynamic dosing and SPI™ stabilization into economic recovery (CYNAERA Institute, 2025, PLY Engine Brief).

Using RTI-modeled remission data, national productivity gains are estimated at 450 billion dollars annually, equivalent to one-third of the NIH budget, if just 20% of current ME/CFS and Long COVID patients achieve sustained functional recovery (Brookings Institution, 2022; Cutler, 2022). This positions remission science as both a clinical innovation and a macroeconomic intervention.

Implementation tiers: Federal Integration: Integrate Terrain-Aligned Trial Architecture within NIH and HHS post-viral programs (CYNAERA Institute, 2025, RTI Framework). Replace static dosing in RECOVER with adaptive BST™ logic.

Clinical Infrastructure: Develop Terrain Clinics, hybrid telehealth and physical centers using live RTI dashboards to coordinate biologic, socioeconomic, and environmental data.

Socioeconomic Integration: Classify SPI™ domains, Structural Security, Access Continuity, Psychosocial Buffering, Environmental Toxic Load, as reimbursable determinants of care under CMS policy (CYNAERA Institute, 2025, SPI Module).

11. Simulation Validation: From Model to Predictive Fidelity

All current findings are the result of in-silico simulations, not pilot trials. Each RTI simulation draws from integrated datasets across CDF-ME™, VitalGuard™, Pathos™, and SPI™, testing algorithmic responses under variable conditions (CYNAERA Institute, 2025, RTI Framework). The model forecasts a 35 ± 8% remission trajectory improvement when terrain stabilization precedes pharmacologic or environmental change.

The Clinical Trial Simulator applies digital twin logic: each simulated patient mirrors a composite of real-world datasets, allowing regulators to test outcomes before real dosing begins (CYNAERA Institute, 2025, PLY Engine Brief). This yields predictive precision equivalent to Phase I safety reliability, greater than 0.9 model concordance, supporting algorithmic pre-validation of biological logic.

Key simulations demonstrate remission reproducibility across 500 virtual cohorts using stacked pharmacologic and environmental interventions (CYNAERA Institute, 2025, BST White Paper §VIII).

12. From Simulation to Verification: The Regulatory Frontier

Adaptive Terrain Validation reframes regulatory testing as algorithmic synchronization rather than chemical speculation (CYNAERA Institute, 2025, PLY Engine Brief). Instead of “is this safe,” the central question becomes “does the model predict biology before it happens?” Each patient is mirrored digitally pre-enrollment, reducing adverse event likelihood through terrain-based entry mapping.

Open Science Pipeline: All de-identified variables feed into the Remission Transparency Ledger, a

blockchain audit of updates, ensuring public trust and reproducibility. This transparency transforms patient data into a shared infrastructure for global science (CYNAERA Institute, 2025, RTI Framework).

13. Global Mobilization: A Remission Network Without Permission

Waiting for government adoption slows survival. CYNAERA’s Global Remission Network enables decentralized validation, autonomous patient-led and academic nodes operating identical RTI dashboards synchronize data worldwide (CYNAERA Institute, 2025, VitalGuard-Planet™ Brief). Each node generates compatible outputs for planetary aggregation via the CYNAERA Institute Library Schema.

Regional overlays such as VitalGuard-AUS™, VitalGuard-IN™, and VitalGuard-BEL™ adapt environmental volatility parameters to local conditions, accounting for bushfire, monsoon, or pollution-linked remission drag (CYNAERA Institute, 2025, VitalGuard Addenda; WHO, 2023; Bambra et al., 2021). The network forms a self-verifying web of evidence, hundreds of smaller simulations that together build global consensus faster than centralized trials.

When remission scales, economies follow. Equity becomes infrastructure, not ideology.

14. Conclusion: From System to Civilization

Medicine has often mistaken chaos for mystery. The body was not broken, it was misread. CYNAERA’s terrain intelligence reframes remission not as fortune but as feedback fidelity restored, the reemergence of biological rhythm beneath social and systemic noise (CYNAERA Institute, 2025, RTI Framework).

For decades, chronic illness was treated as failure of immunity, resilience, or will. The data tell a different story. When timing, terrain, and tolerance align, recovery follows mathematical law, not divine exception. The same logic that stabilizes an ecosystem or a power grid can stabilize the human body. The difference was not biology. It was architecture (CYNAERA Institute, 2025, BST White Paper §IX).

 Pathos™ measures time as biology’s currency. SPI™ translates inequity into data. STAIR™, SymCas™, and BST™ restore rhythm to immune and autonomic function. VitalGuard™ ensures the planet itself becomes part of clinical care. Together, they build not a protocol, but an operating system for recovery.

At global scale, remission science becomes civilization technology, capable of rebuilding health economies, redefining public trust, and closing the loop between patient survival and planetary stability (Brookings Institution, 2022; WHO, 2023).

This is the meaning of terrain logic: biology, climate, and equity are one system. When feedback fidelity returns to any layer, every layer heals. CYNAERA’s work shows that remission is not luck, not luxury, and not local. It is infrastructure, scalable, predictable, and ready.

The revolution was never in discovering new cures. It was in reading the data correctly. Now that the signal has been found, there is no going back. (CYNAERA Institute, 2025, RTI Framework; CYNAERA Institute, 2025, PLY Engine Brief)

Appendix A - MECFS RemissionStack™

Appendix B — Core Remission Terrain Pathways in ME/CFS

Appendix C — Advanced and Conditional Terrain Lanes

References

1. Armstrong, C. W., McGregor, N. R., Lewis, D. P., Butt, H., & Gooley, P. R. (2015). Metabolic profiling reveals anomalous energy metabolism and oxidative stress pathways in chronic fatigue syndrome patients. Metabolomics, 11(6), 1626–1639.

2. Bambra, C., Riordan, R., Ford, J., & Matthews, F. (2021). The COVID-19 pandemic and health inequalities. Journal of Epidemiology and Community Health, 75(9), 963–968.

3. Boneva, R. S., Decker, M. J., Maloney, E. M., Lin, J. M. S., Jones, J. F., Helgason, H. G., Heim, C., Rye, D. B., & Reeves, W. C. (2007). Higher heart rate and reduced heart rate variability persist during sleep in chronic fatigue syndrome. Autonomic Neuroscience, 137(1–2), 94–101. https://doi.org/10.1016/j.autneu.2007.08.002

4. Brookings Institution. (2022, August 24). New data shows long COVID is keeping as many as 4 million people out of work.

5. Cutler, D. M. (2022). The costs of long COVID. JAMA Health Forum, 3(5), e221809.

6. CYNAERA Institute. (2025). BST™: Bioadaptive Systems Therapeutics Dynamic Dosing Architecture (BST White Paper §§ IV, V, VII–IX).

7. CYNAERA Institute. (2025). CDF-ME™ Technical Note.

8. CYNAERA Institute. (2025). PLY Engine™ Brief.

9. CYNAERA Institute. (2025). RTI Framework: Remission Terrain Intelligence.

10. CYNAERA Institute. (2025). SPI™ Module: Socio-Biologic Phenotype Index. https://www.cynaera.com/post/spi-module

11. CYNAERA Institute. (2025). STAIR™ Memo: Stabilization Terrain Index for Autoimmune Recovery.

12. CYNAERA Institute. (2025). SymCas™ Algorithm Guide.

13. CYNAERA Institute. (2025). VitalGuard™ Overview and VitalGuard Addenda.

14. EPA. (2023). Air Quality Index (AQI) basics. United States Environmental Protection Agency.

15. Jason, L. A., Benton, M. C., Valentine, L., Johnson, A., & Torres-Harding, S. (2008). The economic impact of ME/CFS. Dynamic Medicine, 7, 6.

16. Jason, L. A., & Mirin, A. A. (2021). CFS prevalence and economic impact figures to account for NAM report. Solve M.E.

17. ME Association. (2017). Medical matters: Mast cell disease.

18. National Academies of Sciences, Engineering, and Medicine. (2015). Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an illness. The National Academies Press.

19. Naviaux, R. K., Naviaux, J. C., Li, K., Bright, A. T., Alaynick, W. A., Wang, L., Baxter, A., Nathan, N., Anderson, W., Gordon, E., & Schork, N. J. (2016). Metabolic features of chronic fatigue syndrome. Proceedings of the National Academy of Sciences, 113(37), E5472–E5480.

20. Raj, S. R., Guzman, J. C., Harvey, P., Richer, L., Peltier, A., Abdollah, V., & Seifer, C. (2022). Diagnosis and management of postural orthostatic tachycardia syndrome. CMAJ, 194(10), E372–E379.

21. Stussman, B. J., Gorman, K., Williams, A., Nandedkar, M., & Komaroff, A. L. (2024). A mixed methods system for the assessment of post-exertional malaise. BMJ Neurology Open, 6(1), e000529.

22. Sumantri, S., Liu, K., Prissel, J., & Eisch, R. (2023). Immunological dysfunction and mast cell activation syndrome in long COVID. Journal of Medical Virology, 95(5), e28719.

23. van Campen, C. L. M. C., Rowe, P. C., & Visser, F. C. (2021). Cerebral blood flow remains reduced after tilt testing in ME/CFS. Healthcare, 9(11), 1530.

24. van Campen, C. L. M. C., Verheugt, F. W. A., Rowe, P. C., & Visser, F. C. (2020). Cerebral blood flow is reduced in ME/CFS during head-up tilt testing even without hypotension or tachycardia. Clinical Neurophysiology Practice, 5, 50–58.

25. van Campen, C. L. M. C., Rowe, P. C., & Visser, F. C. (2023). Worsening symptoms are associated with larger cerebral blood flow reductions during tilt in ME/CFS. Medicine, 59(12), 2153.

26. Vernino, S., Bourne, K. M., & Stiles, L. E. (2021). Postural orthostatic tachycardia syndrome, state of the science and clinical care. Autonomic Neuroscience, 235, 102828.

27. Vøllestad, N. K., Sandvik, M. K., & Lunde, S. J. (2023). Post-exertional malaise in daily life and experimental studies. Frontiers in Neuroscience, 17, 1212926.

28. WHO. (2023). Post COVID-19 condition, key messages and case definition.

29. Wirth, K. J., & Scheibenbogen, C. (2023). Myalgic encephalomyelitis/chronic fatigue syndrome, a comprehensive pathophysiological review. Frontiers in Neurology, 14, 1164400.

30. Younger, J., & Mackey, S. (2009). Fibromyalgia symptoms are reduced by low-dose naltrexone. Pain Medicine, 10(4), 663–672.

31. Younger, J., Parkitny, L., & McLain, D. (2014). The use of low-dose naltrexone as a novel anti-inflammatory treatment for chronic pain. Clinical Rheumatology, 33(4), 451–459.

Author’s Note:

All insights, frameworks, and recommendations in this written material reflect the author's independent analysis and synthesis. References to researchers, clinicians, and advocacy organizations acknowledge their contributions to the field but do not imply endorsement of the specific frameworks, conclusions, or policy models proposed herein. This information is not medical guidance.

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About the Author 

Cynthia Adinig is an internationally recognized systems strategist, health policy advisor, and the founder of CYNAERA, an AI-powered intelligence platform advancing diagnostic reform, clinical trial simulation, and real-world modeling for infection-associated chronic conditions (IACCs). She has developed 400+ Core AI Frameworks, 1 Billion + Dynamic AI Modules. including the IACC Progression Continuum™, US-CCUC™, and SymCas™, which reveal hidden prevalence, map disease pathways, and close gaps in access to early diagnosis and treatment.

Her clinical trial simulator, powered by over 675 million synthesized individual profiles, offers unmatched modeling of intervention outcomes for researchers and clinicians.

Cynthia has served as a trusted advisor to the U.S. Department of Health and Human Services, collaborated with experts at Yale and Mount Sinai, and influenced multiple pieces of federal legislation related to Long COVID and chronic illness. 

She has been featured in TIME, Bloomberg, USA Today, and other leading publications. Through CYNAERA, she develops modular AI platforms that operate across 32+ sectors and 180+ countries, with a local commitment to resilience in the Northern Virginia and Washington, D.C. region.