To Ground Research in the Lived Experience of Patients and Caregivers, Give Us a Voice!

Abstract:

My daughter has been diagnosed with a range of chronic conditions, including Hyper-mobile Ehlers-Danlos Syndrome and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). I have approached my role as caregiver in the same way I approach my day job leading social science research: reading the literature, carefully observing her condition, and developing hypotheses about her conditions and how they might be treated. I now have more than 7 years of longitudinal observation-a wealth of data-but no easy way to share with the medical research community the hypotheses these observations have engendered and my ideas about how to productively structure future research to accelerate progress toward treatments for her and others like her. In this essay, I share my thoughts on why patient and caregiver observations and hypotheses are important and how the medical research field might tap into them to make faster progress toward effective treatments for complex medical conditions.

Source: Lubell J. To Ground Research in the Lived Experience of Patients and Caregivers, Give Us a Voice! Ann Fam Med. 2025 Nov 24;23(6):570-572. doi: 10.1370/afm.240494. PMID: 41285594. https://www.annfammed.org/content/23/6/570 (Full text)

Functional olfactory impairment and fatigue in post-COVID-19 syndrome including ME/CFS – a longitudinal prospective observational study

Abstract:

Post-COVID-19 syndrome (PCS) affects a significant proportion of individuals, with olfactory impairment and fatigue as prominent long-term symptoms. A subset of PCS patients with pronounced fatigue meets the diagnostic criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), here referred to as PCS-ME/CFS. This study explores the relationship between PCS, fatigue, and olfactory function, and investigates the potential of olfactory impairment as a diagnostic and prognostic marker.

We assessed olfactory function up to 28 months post-COVID-19 in 45 PCS patients (22 PCS, 23 PCS-ME/CFS) using the extended Sniffin’ Sticks test, which evaluates odor threshold, discrimination, and identification, providing a composite score. Fatigue severity and health-related quality of life were assessed using validated questionnaires, a standardized test measured cognitive function, and handgrip strength indicated physical fatiguability. Both PCS and PCS-ME/CFS patients showed significant improvement in olfactory function, with all patients returning to normosmia after 20 months, regardless of diagnosis.

While odor threshold was the most affected olfactory measure in Sniffin’ Sticks testing, odor identification was the only measure that remained impaired over time. Olfactory impairment correlated with cognitive, physical, and mental performance, with stronger correlations in the PCS group, particularly linking better odor discrimination at baseline to improved daily functioning and health-related quality of life after 20 months.

Our findings suggest that odor identification assessed in standardized testing may remain impaired the longest in patients with persisting symptoms after COVID-19, reflecting persisting central processing difficulties. Correlations between olfactory performance, cognitive function, and physical ability point to shared underlying mechanisms. Early olfactory improvements may be linked to better long-term cognitive outcomes, highlighting a possible prognostic role of olfactory function in these patients.

Source: Meyer-Arndt L, Pierchalla G, Mödl L, Wohlrab F, Legler F, Hoppmann U, Kedor C, Wittke K, Freitag H, Konietschke F, Olze H, Paul F, Scheibenbogen C, Bellmann-Strobl J, Förster-Ruhrmann U. Functional olfactory impairment and fatigue in post-COVID-19 syndrome including ME/CFS – a longitudinal prospective observational study. Brain Behav Immun Health. 2025 Oct 14;50:101124. doi: 10.1016/j.bbih.2025.101124. PMID: 41281896; PMCID: PMC12634829. https://pmc.ncbi.nlm.nih.gov/articles/PMC12634829/ (Full text)

Virus Genome Sequences in the Blood of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a baffling disease. The disease has a wide spectrum of severity, to date has no established molecular marker, no known causation, and no cure. Many patients report in retrospect that they suffered a virus infection prior to suffering their first symptoms of ME/CFS. Therefore, we report a search for virus genome sequences in the cell-free blood of ME/CFS patients and healthy controls. We used a panel of molecular probes to assess the presence or absence of 185 diverse human viruses in each sample. We identified a total of seventeen viruses, with more in the healthy controls than in the ME/CFS patients.

Source: Hyman RW, Xu W, Roy KR, Suresh S, St Onge RP, Davis RW. Virus Genome Sequences in the Blood of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients. medRxiv [Preprint]. 2025 Nov 7:2025.11.06.25339689. doi: 10.1101/2025.11.06.25339689. PMID: 41282945; PMCID: PMC12637746. https://pmc.ncbi.nlm.nih.gov/articles/PMC12637746/ (Full text available as PDF file)

ME/CFS as a sickness behaviour-like response to HSV-1 infection within the brain: A hypothesis

Highlights:

  • Subset of ME/CFS cases proposed to be caused by a ‘noisy’ latent HSV-1 infection within the brain.
  • HSV-1 proposed to cause local sickness behaviour-like response in the brain.
  • IL-1β, IL-6, TNF-α in the brain proposed to increase sensations of fatigue and pain.

Abstract:

This work presents the hypothesis that a Herpes Simplex Virus 1 (HSV-1) infection in the brain is a significant contributor to the symptoms experienced by a subset of ME/CFS patients. In these patients, an HSV-1 infection has spread from the trigeminal ganglia to the brain, leading to a sickness behaviour-like response that amplifies sensations such as fatigue, pain, and nausea. The hypothesis proposes that ME/CFS is a heterogeneous condition, with a ‘noisy’ latent HSV-1 infection of the brain, and an enduring sickness behaviour-style immune response, an underlying factor for a subset of patients.
Source: John Campbell. ME/CFS as a sickness behaviour-like response to HSV-1 infection within the brain: A hypothesis. Medical Hypotheses, Volume 204, 2025, 111788. ISSN 0306-9877 https://doi.org/10.1016/j.mehy.2025.111788. https://www.sciencedirect.com/science/article/abs/pii/S0306987725002270 (Full text)

Urinary Peptidomic Profiling In Post-Acute Sequelae of SARS-CoV-2 Infection: A Case-Control Study

Abstract:

Post-acute sequelae of severe acute respiratory syndrome coronavirus 2-infection (PASC) is challenging to diagnose and treat, and its molecular pathophysiology remains unclear. Urinary peptidomics can provide valuable information on urine peptides that may enable improved and specified PASC diagnosis.
Using standardized capillary electrophoresis-MS, we examined the urinary peptidomes of 50 patients with PASC 10 months after COVID-19 and 50 controls, including healthy individuals (n = 42) and patients with non-COVID-19-associated myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) (n = 8).Based on peptide abundance differences between cases and controls, we developed a diagnostic model using a support vector machine. The abundance of 195 urine peptides among PASC patients significantly differed from that in controls, with a predominant abundance of collagen alpha chains. This molecular signature (PASC195) effectively distinguished PASC cases from controls in the training set (AUC of 0.949 [95% CI 0.900–0.998; p < 0.0001]) and independent validation set (AUC of 0.962 [95% CI 0.897–1.00]; p < 0.0001]). In silico assessment suggested exercise, GLP-1RAs and mineralocorticoid receptor antagonists (MRAs) as potentially efficacious interventions. We present a novel and non-invasive diagnostic model for PASC. Reflecting its molecular pathophysiology, PASC195 has the potential to advance diagnostics and inform therapeutic interventions.

Statement of Significance of the Study

Despite the recent emergence of omics-derived candidates for post-acute sequelae of SARS-CoV-2 infection (PASC), the pending validation of proposed markers and lack of consensus result in the continuous reliance on symptom-based criteria, being subject to diagnostic uncertainties and potential recall bias. Building upon prior findings of renal involvement in acute COVID-19 pathophysiology and PASC-associated alterations, we hypothesized that the use of urinary peptides for PASC-specific biomarker discovery, unlike conventional specimens that have been utilized thus far, may offer complementary information on putative disease mechanisms.

In the present study, 195 significantly expressed peptides were used to form a classifier termed PASC195, which effectively discriminated PASC from non-PASC (p < 0.0001), including healthy individuals and non-COVID-19-associated myalgic encephalomyelitis/chronic fatigue syndrome, in both the derivation (n = 60) and an independent validation set (n = 40). The peptidome profile associated with PASC was consistent with a shift in collagen turnover, with most PASC195 peptides derived from alpha chains. Ongoing inflammatory responses, hemostatic imbalances, and endothelial damage were indicated by cross-sectional variations in endogenous peptide excretion.

Source: Gülmez D, Siwy J, Kurz K, Wendt R, Banasik M, Peters B, Dudoignon E, Depret F, Salgueira M, Nowacki E, Kurnikowski A, Mussnig S, Krenn S, Gonos S, Löffler-Ragg J, Weiss G, Mischak H, Hecking M, Schernhammer E, Beige J; UriCoV Working Group. Urinary Peptidomic Profiling In Post-Acute Sequelae of SARS-CoV-2 Infection: A Case-Control Study. Proteomics. 2025 Nov 21:e70074. doi: 10.1002/pmic.70074. Epub ahead of print. PMID: 41273049. https://analyticalsciencejournals.onlinelibrary.wiley.com/doi/10.1002/pmic.70074 (Full text)

Temporal dynamics of the plasma proteomic landscape reveals maladaptation in ME/CFS following exertion

Abstract:

The overarching symptom of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is post-exertional malaise (PEM), an exacerbation of symptoms following physical or mental exertion. To investigate the molecular underpinnings of PEM, we performed longitudinal plasma proteomics using the Somascan® 7K aptamer-based assay to monitor 6,361 unique plasma proteins in 132 individuals (96 females and 36 males) subjected to two maximal cardiopulmonary exercise tests separated by a 24-hour recovery period.

The cohort included 79 ME/CFS cases compared to 53 age- and BMI-matched sedentary controls, allowing us to distinguish disease-specific molecular alterations from those due to physical deconditioning. Longitudinal profiling revealed widespread proteomic changes following exertion, with the most pronounced alterations observed in ME/CFS participants during the recovery phase, coinciding with the onset of PEM.

Compared to controls, ME/CFS subjects showed persistent dysregulation of immune, metabolic, and neuromuscular pathways. Key findings included suppression of T and B cell signaling, downregulation of IL-17 and cell-cell communication pathways, and upregulation of glycolysis/gluconeogenesis, suggestive of mitochondrial stress and impaired immune recovery from exercise. Proteomic associations with physiological performance (VO2max, anaerobic threshold) revealed disruptions between protein abundance and exercise capacity in ME/CFS versus controls.

Correlations with symptom severity linked changes in immune-related proteins and ME/CFS symptoms including muscle pain, recurrent sore throat, and lymph node tenderness. Sex-stratified analyses revealed distinct molecular responses between females and males, emphasizing the importance of considering sex as a biological variable in ME/CFS research.

Finally, our analysis of sedentary controls contributes new data of molecular responses to acute exertion in a predominantly female sedentary cohort, a population historically underrepresented in exercise physiology studies. Together, these findings underscore the value of dynamic, proteomic profiling over time for characterizing maladaptive responses to exertion in ME/CFS and provide a foundation for deeper mechanistic investigation into PEM.

Source: Germain A, Glass KA, Eckert MA, Giloteaux L, Hanson MR. Temporal dynamics of the plasma proteomic landscape reveals maladaptation in ME/CFS following exertion. Mol Cell Proteomics. 2025 Nov 12:101467. doi: 10.1016/j.mcpro.2025.101467. Epub ahead of print. PMID: 41237904. https://www.mcponline.org/article/S1535-9476(25)00566-3/fulltext (Full text)

The Role of Nuclear and Mitochondrial DNA in Myalgic Encephalomyelitis: Molecular Insights into Susceptibility and Dysfunction

Abstract:

Myalgic Encephalomyelitis (ME), also known as chronic fatigue syndrome (CFS), is a debilitating and heterogeneous disorder marked by persistent fatigue, post-exertional malaise, cognitive impairment, and multisystem dysfunction. Despite its prevalence and impact, the molecular mechanisms underlying ME remain poorly understood.
This review synthesizes current evidence on the role of DNA, both nuclear and mitochondrial, in the susceptibility and pathophysiology of ME. We examined genetic predispositions, including familial clustering and candidate gene associations, and highlighted emerging insights from genome-wide and multi-omics studies.
Mitochondrial DNA variants and oxidative stress-related damage are discussed in relation to impaired bioenergetics and symptom severity. Epigenetic modifications, particularly DNA methylation dynamics and transposable element activation, are explored as mediators of gene–environment interactions and immune dysregulation.
Finally, we explored the translational potential of DNA-based biomarkers and therapeutic targets, emphasizing the need for integrative molecular approaches to advance diagnosis and treatment. Understanding the DNA-associated mechanisms in ME offers a promising path toward precision medicine in post-viral chronic diseases.
Source: Elremaly W, Elbakry M, Vahdani Y, Franco A, Moreau A. The Role of Nuclear and Mitochondrial DNA in Myalgic Encephalomyelitis: Molecular Insights into Susceptibility and Dysfunction. DNA. 2025; 5(4):53. https://doi.org/10.3390/dna5040053 https://www.mdpi.com/2673-8856/5/4/53 (Full text)

Leveraging Explainable Automated Machine Learning (AutoML) and Metabolomics for Robust Diagnosis and Pathophysiological Insights in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Abstract:

Background/Objectives: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating complex disease with an elusive etiology, lacking objective diagnostic biomarkers. This study leverages advanced Automated Machine Learning (AutoML) to analyze plasma metabolomic and lipidomic profiles for the purpose of ME/CFS detection.

Methods: We utilized a publicly available dataset comprising 888 metabolic features from 106 ME/CFS patients and 91 matched controls. Three AutoML frameworks-TPOT, Auto-Sklearn, and H2O AutoML-were benchmarked under identical time constraints. Univariate ROC and PLS-DA analyses with cross-validation, permutation testing, and VIP-based feature selection were applied to standardized, log-transformed omics data to identify significant discriminatory metabolites/lipids and assess their intercorrelations.

Results: TPOT significantly outperformed its counterparts, achieving an area under the curve (AUC) of 92.1%, accuracy of 87.3%, sensitivity of 85.8%, and specificity of 89.0%. The PLS-DA model revealed a moderate but statistically significant discrimination between ME/CFS and controls. Explainable artificial intelligence (XAI) via SHAP analysis of the optimal TPOT model identified key metabolites implicating dysregulated pathways in mitochondrial energy metabolism (succinic acid, pyruvic acid, leucine), chronic inflammation (prostaglandin D2, 11,12-EET), gut-brain axis communication (glycocholic acid), and cell membrane integrity (pc(35:2)a).

Conclusions: Our results demonstrate that TPOT-derived models not only provide a highly accurate and robust diagnostic tool but also yield biologically interpretable insights into the pathophysiology of ME/CFS, highlighting its potential for clinical decision support and elucidating novel therapeutic targets.

Source: Yagin FH, Colak C, Al-Hashem F, Alzakari SA, Alhussan AA, Aghaei M. Leveraging Explainable Automated Machine Learning (AutoML) and Metabolomics for Robust Diagnosis and Pathophysiological Insights in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Diagnostics (Basel). 2025 Oct 30;15(21):2755. doi: 10.3390/diagnostics15212755. PMID: 41226047. https://www.mdpi.com/2075-4418/15/21/2755 (Full text)

Systematic literature review: treatment of postural orthostatic tachycardia syndrome (POTS)

Abstract:

Postural orthostatic tachycardia syndrome (POTS) is a condition defined by symptoms of orthostatic intolerance and a sustained heart rate (HR) increment of ≥ 30 beats per minute (bpm) upon postural change to the upright position in the absence of orthostatic hypotension, defined as a sustained decrease in systolic blood pressure (SBP) of ≥ 20 mmHg or a decrease in diastolic blood pressure (DBP) of ≥ 10 mmHg within 3 min of standing. In children, a sustained HR increment of at least 40 bpm is required for diagnosis of POTS. POTS is a common condition in adults and children suffering from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). In daily clinical practice, therapeutic recommendations are rare and evidence is missing.

The objective of this review is to present the current knowledge on non-pharmacological and pharmacological approaches in POTS with a special focus on POTS therapy in children and people with ME/CFS. Of 3853 studies, 45 studies were included in the systematic review.

on therapy in POTS is rare and large randomized controlled trials (RCT) on single interventions are needed. Non-pharmacological approaches such as the use of compression garments, physical training, salt supplementation and transdermal vagal nerve stimulation could be possible treatment options in POTS because they are easy to implement as first-line therapeutic measures in clinical practice. For pharmaceuticals, several studies showed significant effects following therapy with ivabradine and β-adrenergic blocking agents. There are single studies which imply that midodrine (hydrochloride) and pyridostigmine seem to have a beneficial effect on hemodynamics in POTS.

Source: Schiweck N, Langer K, Maier A, Vilser D, Spiegler J. Systematic literature review: treatment of postural orthostatic tachycardia syndrome (POTS). Clin Auton Res. 2025 Nov 12. doi: 10.1007/s10286-025-01172-2. Epub ahead of print. PMID: 41225175. https://link.springer.com/article/10.1007/s10286-025-01172-2 (Full text)

Contested and neglected: Social and medical marginalization in severe Chronic Fatigue Syndrome

Highlights:

  • Severe ME/CFS patients face deep social, medical, and structural exclusion.
  • Delegitimation of illness leads to isolation, distress, and denied support.
  • Gendered stigma shapes how women’s pain is dismissed in health care.
  • Twitter (now X) offers access to the voices of an otherwise unreachable patient group.
  • This study urges reforms in care, disability access, and illness recognition.

Abstract:

This study addresses the persistent invisibility of people with severe Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) in research by centering their voices and examining how social and institutional forces shape their lives. As a medically contested illness, ME/CFS—especially in its severe form—renders patients both physically incapacitated and socially invisible.
Drawing on qualitative content analysis of 342 tweets under the hashtag #severeME, we identify how contested legitimacy, gendered stigma, and systemic marginalization structure the daily realities of 161 individuals with severe ME/CFS or their caregivers. Our findings highlight profound functional debilitation, emotional isolation, and exclusion from care and disability systems. We argue for the urgent need to legitimize contested illnesses, reform models of care, and extend disability protections to restore dignity and support to this neglected population.
Source: Bita Nezamdoust, Erin Ruel. Contested and neglected: Social and medical marginalization in severe Chronic Fatigue Syndrome. Social Science & Medicine, Volume 388, 2026, 118766. ISSN 0277-9536. https://www.sciencedirect.com/science/article/pii/S0277953625010974 (Full text)