Tag: 2026

Knowing or not knowing: the practical and moral complexity of diagnostic-seeking pathways in situations of medical uncertainty

Abstract:

In this paper, we discuss the practical and moral complexities of diagnostic-seeking pathways for three uncertain medical conditions: fibromyalgia, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and long COVID. We analyse qualitative data collected in the UK between 2023 and 2025, comprising in-depth interviews with medical professionals, researchers, and patients, as well as documentary sources.

Drawing on the anthropology and sociology of diagnosis, this paper discusses how chronic illness can be marked by challenging and unstable pathways, influenced by the organisation of the medical system and the resources patients have to navigate it. Diagnoses further do not guarantee a solution to the condition, and can, on the other hand, produce stigma. Medical professionals recognise the uncertain nature of these conditions and emphasise how diagnosis can play an instrumental role in providing patients with access to therapies, benefits, or acceptance. Patients discuss the complexity of the strategies they deploy not only to obtain a diagnosis but also to navigate the practical and moral complexities associated with their condition.

Analysing the practical and moral complexity of diagnostic-seeking pathways represents a way to enrich anthropological reflections on diagnosis by demonstrating how this key concept of biomedicine is strongly influenced by social, economic, and moral, as well as biological, factors.

Source: Greco C, Cross S. Knowing or not knowing: the practical and moral complexity of diagnostic-seeking pathways in situations of medical uncertainty. Anthropol Med. 2026 Sep 25:1-16. doi: 10.1080/13648470.2026.2709278. Epub ahead of print. PMID: 42788232. https://www.tandfonline.com/doi/full/10.1080/13648470.2026.2709278 (Full text)

DNA methylation: unifying framework for complex chronic conditions

Abstract:

Complex chronic conditions represent a growing health burden that is poorly understood and inadequately managed within current health systems. This review focuses on the potential of epigenetic DNA methylation to provide a pathway for better understanding of four closely related conditions: myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), long COVID (LC), fibromyalgia (FM), and hypermobile Ehlers-Danlos syndrome (hEDS).

These conditions have extensive overlapping symptoms, suggesting shared underlying pathophysiological mechanisms. Epigenetic regulation, particularly DNA methylation, provides a powerful framework for comparative and longitudinal studies across these clinically overlapping conditions.

Here, we synthesise evidence from current DNA methylation studies in ME/CFS, LC, and FM, and consider how an integrated cross-condition approach could advance mechanistic insight, enable diagnostic stratification, and improve patient outcomes.

Source: Sharma S, Rodger EJ, Chatterjee A, Tate WP. DNA methylation: unifying framework for complex chronic conditions. Trends Genet. 2026 Sep 24:S0168-9525(26)00221-0. doi: 10.1016/j.tig.2026.09.001. Epub ahead of print. PMID: 42786072. https://www.cell.com/trends/genetics/fulltext/S0168-9525(26)00221-0 (Full text)

Hemodynamic Phenotyping in ME/CFS and ANOCA: Complementary Insights from Coronary Function Testing and Invasive Cardiopulmonary Exercise Testing

Abstract:

This single-center cohort study sought to evaluate the association between Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Angina with Non-Obstructive Coronary Arteries (ANOCA), by determining the observed frequency of ME/CFS among patients with ANOCA diagnosed by coronary function testing (CFT). Additionally, we performed an exploratory analysis of the diagnostic utility of invasive cardiopulmonary exercise testing (iCPET) in ME/CFS patients with CFT-confirmed ANOCA, with the aim of identifying the predominant physiological mechanism responsible for exertional limitation in this population.

Systematic medical record review of 261 patients with CFT-confirmed ANOCA was performed using standardized diagnostic criteria to identify concurrent ME/CFS diagnosis. ME/CFS was identified in 47 patients, representing an observed frequency of 18%. The only statistically significant difference between ANOCA patients with and without ME/CFS was a higher frequency of connective tissue disease in the ME/CFS group (p = 0.0221). In a separate cohort of 27 patients with ME/CFS who underwent iCPET, 24 patients (89%) had CFT-confirmed ANOCA.

The diagnosis of ANOCA by CFT prompted a change in medical management in 81% of patients in this cohort. iCPET revealed a primary peripheral limitation to exercise, characterized by impaired peak systemic oxygen extraction despite normal peak oxygen delivery. This study demonstrates a clinically significant association between ME/CFS and ANOCA.

These findings underscore the clinical value of CFT in patients with ME/CFS and exertional chest pain and highlight iCPET as a complementary tool for hemodynamic phenotyping in this population. Prospective studies incorporating simultaneous CFT and iCPET with molecular phenotyping are warranted.

Source: Mackay Z, Shah S, Villalobos JG, Latif N, Arun A, Joseph P, Heerdt P, Singh I. Hemodynamic Phenotyping in ME/CFS and ANOCA: Complementary Insights from Coronary Function Testing and Invasive Cardiopulmonary Exercise Testing. Am J Physiol Heart Circ Physiol. 2026 Sep 21. doi: 10.1152/ajpheart.90080.2026. Epub ahead of print. PMID: 42767811. https://journals.physiology.org/doi/abs/10.1152/ajpheart.90080.2026 (Full text available as PDF file)

Clinical Symptomatology, Cognition and Psychosocial Wellbeing in Adolescents With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Cross-Sectional Observational Study

Abstract:

Aim: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disabling illness that frequently begins in adolescence, yet adolescents with ME/CFS remain an under-researched population. We aimed to characterise the cognitive and psychosocial wellbeing of adolescents with ME/CFS relative to normative benchmarks and unaffected age-peers.

Methods: Adolescents with mild-to-moderate ME/CFS (n = 25) and healthy controls (n = 25) aged 10-19 years were recruited in Melbourne, Australia. Each completed a set of clinical questionnaires and cognitive assessments to assess ME/CFS symptomatology, school functioning, psychosocial wellbeing and cognition. Their caregivers also completed questionnaires regarding their psychosocial wellbeing and everyday executive functioning.

Results: Adolescents with ME/CFS showed significantly reduced information processing speed, though other measures of intellectual functioning did not differ consistently between groups. The ME/CFS group also reported significantly poorer sleep, quality of life and higher levels of anxiety and depression. Caregivers further identified significant attention and working memory concerns in the ME/CFS group, but reported no differences in internalising behaviours between groups.

Conclusion: Adolescents with ME/CFS experience substantial psychosocial and physical burden because of their illness. Cognitive difficulties in ME/CFS may reflect inefficiencies in information processing speed and fluctuating symptom burden. Discrepancies between adolescent self-report and caregiver ratings underscore the importance of inclusive perspectives in ME/CFS management. These findings support the need for flexible, paced educational and clinical accommodations and for further research into the dynamic cognitive profile of adolescents with ME/CFS across a more representative population.

Source: Chau T, Josev EK, Scheinberg A, Thomas N, McDonald F, Reveley C, Gooley PR, Armstrong C, Knight S. Clinical Symptomatology, Cognition and Psychosocial Wellbeing in Adolescents With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Cross-Sectional Observational Study. J Paediatr Child Health. 2026 Sep 20. doi: 10.1111/jpc.70587. Epub ahead of print. PMID: 42764669. https://onlinelibrary.wiley.com/doi/10.1111/jpc.70587 (Full text)

Postural orthostatic tachycardia syndrome in adolescents with ME/CFS – a case control study

Abstract:

Introduction: Postural orthostatic tachycardia syndrome (PoTS) can be associated with myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS). Pediatric PoTS requires a “sustained” rise in orthostatic heart rate ≥40 bpm above supine heart rate (relative limit), often >120 bpm (absolute limit). However, the diagnostic criteria for PoTS in adolescents remain underexplored, particularly regarding the definition of “sustained” tachycardia, which poses challenges in clinical and research settings. This study examined orthostatic intolerance criteria, including PoTS, in adolescents with ME/CFS and healthy controls.

Methods: Medical history of orthostatic intolerance was assessed by a semi-structured interview with 18 ME/CFS patients and 18 matched healthy controls (14-17 years). A passive 10-min standing test with minute-by-minute heart rate and blood pressure registration was performed. PoTS was diagnosed by a clinical expert based on current consensus criteria. Data were analyzed using Fisher’s exact test and receiver operating characteristic analysis.

Results: Although history of orthostatic intolerance was positive in 15/18 ME/CFS [83%, 0.95 CI (61; 94)] and 3/18 healthy controls [17%, 0.95 CI (5.9; 39)], PoTS was diagnosed in only 7/18 ME/CFS [39%, 0.95 CI (20; 61)] vs. no healthy controls [0%, 0.95 CI (0; 18)]. Subgroups were identified, e.g., positive history of orthostatic intolerance yet physiological passive 10-min standing test, or negative history of orthostatic intolerance yet tachycardia in passive 10-minute standing test. PoTS diagnosis by the clinical expert matched best with the passive 10-min standing test alone when at least 60% of upright heart rate values were above one or both limits. The absolute limit was superior to the relative limit in distinguishing adolescents with and without PoTS.

Discussion: PoTS was observed only in ME/CFS. In adolescents with ME/CFS, positive history of orthostatic intolerance, along with at least 60% of heart rate values above published upright-position limits, may allow non-experts to make a valid diagnosis, facilitating clinical care and future studies. Further research will show if these results can be generalized.

Source: Leone A, Gerrer K, Viereck A, Grabbe A, Kircher A, Behrends U, Maier A. Postural orthostatic tachycardia syndrome in adolescents with ME/CFS – a case control study. Front Pediatr. 2026 Sep 1;14:1836407. doi: 10.3389/fped.2026.1836407. PMID: 42746015; PMCID: PMC13574936. https://pmc.ncbi.nlm.nih.gov/articles/PMC13574936/ (Full text)

Total blood volume and red blood cell volume are not associated with orthostatic intolerance in adults with myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Orthostatic intolerance is common in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and may worsen daily functioning. Although hypovolemia has been proposed as a contributor, its relationship to objective orthostatic abnormalities remains uncertain. We examined whether measured blood-volume abnormalities were associated with standardized lean-test outcomes.

Adults meeting the 1994 ME/CFS criteria and reporting substantial post-exertional malaise underwent a 10-min lean test with capnography, followed 8 days later by total blood volume (TBV) measurement using the Daxor BVA-100. Supine hypocapnia was defined as baseline end-tidal CO2 (eTCO2) <34 mmHg; postural orthostatic syndrome of hypocapnia (POSH) as normal supine eTCO2 with any leaning value <34 mmHg; and postural orthostatic tachycardia syndrome (POTS) as a heart-rate increase ≥30 beats/min or absolute heart rate ≥120 beats/min.

Among 49 participants, TBV was hypovolemic in 35%, normovolemic in 43%, and hypervolemic in 22%; red blood cell volume was deficient in 49%. Overall, 55.1% had at least one lean-test abnormality, most commonly POSH (40.8%). Abnormalities did not differ by TBV or red blood cell volume category. Static blood-volume categories were not associated with lean-test-defined orthostatic abnormalities in ME/CFS, suggesting contributions from autonomic, vascular, respiratory, or cerebrovascular mechanisms.

Source: Yamazaki T, Mancini DM, Blate M, Quan P, Norweg A, Cook DB, Natelson BH. Total blood volume and red blood cell volume are not associated with orthostatic intolerance in adults with myalgic encephalomyelitis/chronic fatigue syndrome. Physiol Rep. 2026 Sep;14(17):e71087. doi: 10.14814/phy2.71087. PMID: 42717554. https://physoc.onlinelibrary.wiley.com/doi/10.14814/phy2.71087 (Full text)

When do infections lead to long COVID? Scientists close in on triggers and treatments for post-viral syndromes

Hundreds of millions of people have long-term conditions as a result of an infection. Researchers are working out how to help them.
By Simon Makin

In 2004, Amy Proal got an infection that changed her life. “I was in my pre-med, last year of college, and totally tanked,” she says. “No one could tell me what it was, everybody said my blood work was fine — sent to a psychiatrist, the usual story.” She started reading papers from her sickbed and soon realized that she wasn’t the only one with unexplained symptoms that lingered after an infection.

A year later, she was diagnosed with ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome). She managed to improve her symptoms with antivirals and other drugs, and went on to do a PhD in microbiology, studying the lasting consequences of pathogens. In 2018, she co-founded PolyBio, a foundation in Medford, Massachusetts, that advances research on infection-associated chronic illnesses. “Then,” Proal says, “COVID hit.”

Read the rest of this Nature article HERE.

Beyond genes: EpiSwitch® and Orion platform-powered 3D genome architecture biomarkers reveal shared biology across ME/CFS, long COVID, PTSD, rheumatoid arthritis, and multiple sclerosis

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), Long COVID (LC19), post-traumatic stress disorder (PTSD), rheumatoid arthritis (RA), and multiple sclerosis (MS) are clinically distinct disorders that share substantial symptom overlap, including persistent fatigue, cognitive impairment, autonomic dysfunction, and immune dysregulation. Although these conditions differ in diagnosis and clinical presentation, their underlying biological mechanisms remain poorly understood and may involve convergent regulatory pathways.

Methods: The EpiSwitch® 3D genomics platform and Orion knowledgebase were used to integrate chromosome conformation signatures with genome-wide association study (GWAS)-derived datasets across ME/CFS, LC19, PTSD, RA, and MS. Three-dimensional genomic anchors were mapped to coding genes and analysed using STRING protein-protein interaction networks and Cytoscape-based systems biology approaches. Disease-specific anchor datasets were generated and compared at both gene and network levels to identify shared biological processes and regulatory mechanisms.

Results: Analysis of the ME/CFS dataset identified 552 unique 3D genomic anchors mapped to 567 genes, with analogous disease-specific anchor sets generated for LC19, PTSD, RA, and MS. Direct overlap between disease-associated genes was limited; however, higher-order network analyses revealed substantial interconnectivity and convergence across conditions. Shared biological pathways included immune and cytokine signalling, interferon responses, mitochondrial function, metabolic regulation, and neuroendocrine processes. Highly connected hub genes included immune regulatory nodes such as LAG3 and components of the mTOR signalling pathway, implicating T-cell exhaustion, chronic immune activation, and immunometabolic dysregulation as common mechanisms underlying these disorders.

Conclusions: These findings support a systems-level model in which clinically overlapping fatigue-associated syndromes arise from perturbations of interconnected regulatory networks rather than discrete disease-specific pathways. Despite limited genetic overlap, substantial convergence at the network level suggests shared biological architecture across ME/CFS, LC19, PTSD, RA, and MS. The identification of common regulatory pathways provides a mechanistic framework for the development of cross-disease diagnostic and therapeutic strategies. By capturing dynamic regulatory states, 3D genomic biomarkers offer significant potential for objective blood-based diagnostics, patient stratification, and the identification of shared therapeutic targets across complex chronic disorders. These findings support the application of precision medicine approaches and may accelerate the development of novel interventions for fatigue-associated multisystem diseases.

Source: Hunter E, Alshaker H, Vugrinec D, Bautista S, Gebregzabhar A, Virdi A, Croxford J, Dring A, Powell R, Salter M, Kingdon C, Green J, Akoulitchev A, Pchejetski D. Beyond genes: EpiSwitch® and Orion platform-powered 3D genome architecture biomarkers reveal shared biology across ME/CFS, long COVID, PTSD, rheumatoid arthritis, and multiple sclerosis. J Transl Med. 2026 Aug 22;24(1):1134. doi: 10.1186/s12967-026-08874-9. PMID: 42693463. https://link.springer.com/article/10.1186/s12967-026-08874-9 (Full text)

Impact of post-exertional malaise frequency and fatigue in Long COVID patients on health-related quality of lif

Abstract:

Purpose: The aim of this study was to investigate the impact of post-exertional malaise (PEM) frequency and PEM severity on health-related quality of life (HRQoL) among individuals with Long COVID.

Methods: We conducted a cross-sectional online survey including adults in Germany with self-reported Long COVID and PEM. Fatigue severity was assessed with the Fatigue Assessment Scale (FAS), and HRQoL was measured using the EQ-5D-3L (descriptive index and visual analogue scale [EQ-VAS]). Associations between PEM frequency, fatigue, and HRQoL were examined using correlations and non-parametric group comparisons. Multiple linear regression models were fitted to predict HRQoL while controlling for age, sex, employment status, and subjective social status.

Results: Higher PEM frequency was associated with significantly lower EQ-5D index scores (ρ = – 0.32, p<.001). PEM severity was also strongly correlated with reduced HRQoL (EQ-5D index: ρ = – 0.43, p<.001). In multivariable regression models, greater fatigue and higher PEM frequency independently predicted poorer HRQoL, even after adjustment for sociodemographic factors.

Conclusion: Both PEM frequency and PEM severity substantially impair HRQoL in individuals with Long COVID. These findings underscore the clinical relevance of PEM as a key symptom and highlight the need for targeted management strategies to mitigate its impact on daily life.

Clinical trial number: German Clinical Trials Register DRKS00026007; registration date: 9 September 2021.

Source: Thölking T, Müller F, Riester T, Lampe V, Theil LM, Hummers E, Sarpari K, Dopfer-Jablonka A, Happle C, Steffens S, Meier-Maiwald M, Mikuteit M, Schröder D. Impact of post-exertional malaise frequency and fatigue in Long COVID patients on health-related quality of life. Health Qual Life Outcomes. 2026 May 11;24(1):64. doi: 10.1186/s12955-026-02523-x. PMID: 42116095; PMCID: PMC13162394. https://pmc.ncbi.nlm.nih.gov/articles/PMC13162394/ (Full text)

Micronutrition as a Therapeutic Strategy for Mitochondrial Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Fibromyalgia: A Narrative Review

Abstract:

Fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are chronic multisystem disorders characterized by persistent fatigue, pain, cognitive dysfunction, sleep disturbances, and reduced quality of life. Increasing evidence implicates mitochondrial dysfunction, oxidative and nitrosative stress, immune dysregulation, and altered redox and nicotinamide adenine dinucleotide (NAD+) metabolism as interconnected mechanisms contributing to fatigue, although the strength of evidence varies across these pathways. Micronutrients are essential components of mitochondrial bioenergetics, antioxidant defense, and immune-metabolic regulation.

This narrative review critically examines the mechanistic and clinical evidence supporting mitochondrial-oriented micronutritional interventions in fibromyalgia and ME/CFS, including NAD+ precursors, B-complex vitamins, magnesium, coenzyme Q10, alpha-lipoic acid, GlyNAC, L-carnitine, pyrroloquinoline quinone, taurine, and creatine. Mechanistic plausibility is distinguished from clinical efficacy, as disease-specific randomized controlled evidence remains limited for several interventions. We further discuss biomarkers, metabolic phenotyping, and precision nutrition within a systems-based micronutrition framework.

Finally, we present the rationale for a future randomized, double-blind, placebo-controlled trial in fibromyalgia patients with clinically significant fatigue, which is planned for 2027, subject to ethics approval and prospective registration, as a strategy for future clinical validation.

Source: Abanades S, Fernández I, Capdevila N, Cardona F. Micronutrition as a Therapeutic Strategy for Mitochondrial Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Fibromyalgia: A Narrative Review. Nutrients. 2026 Aug 19;18(16):2702. doi: 10.3390/nu18162702. PMID: 42654282. https://www.mdpi.com/2072-6643/18/16/2702 (Full text)