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In the autoimmune disorder myasthenia gravis (MG), the nicotinic acetylcholine receptors (nAChRs) are the primary targets of pathogenic antibodies. While MG mechanisms have been extensively studied in animal models, functional insights into how antibody binding disrupts nAChR-dependent calcium signaling and the effects of complement inhibition in human muscle cells remain limited. We used real-time live-cell calcium imaging to assess the effects of cholinergic stimulation or inhibition on human muscle cells with pharmacological agents, sera from patients with acetylcholine receptor antibody seropositive (AChR+) MG, purified recombinant antibodies targeting α- and β-subunits, and a complement C3 inhibitor. Transcriptional changes in nAChR subunits, muscle markers, voltage-gated calcium channels (VGCCs), and complement-related genes were analysed by RT-qPCR. Immunocytochemistry and quantitative image analysis were performed to assess nAChR distribution and membrane attack complex (MAC) deposition. Cholinergic stimulation of human muscle cells activated nAChRs, resulting in membrane depolarisation, which in turn led to VGCC opening and calcium transients. MG-associated pathogenic antibodies, particularly those present in sera from patients with AChR + MG and pure recombinant AChR α-subunit-specific monoclonal antibody (mAb), but not β-subunit-specific, abolished choline-induced calcium responses in myotubes. α-subunit-specific mAb also induced transcriptional upregulation of nAChR subunits, muscle structural proteins, and complement components, and were associated with nAChR loss and MAC formation. Importantly, pharmacological inhibition of C3 activation restored calcium signaling, preserved nAChR distribution, and reduced MAC formation induced by α-subunit-specific mAb, implicating complement activation as a key driver of pathogenic effects. These findings indicate that targeting the α-subunit impairs nAChR-dependent calcium signaling and can induce complement activation. Disrupted signaling and reduced nAChR levels were effectively restored by C3 inhibition, which blocks multiple downstream pathways; thus, terminal complement activation leading to MAC formation is a suggested, but it may not be the only mechanism. Overall, the results highlight C3 as a promising upstream therapeutic target and support combining subunit-specific interventions with proximal complement blockade in MG. This work was supported by Familjen Erling-Perssons Stiftelse (grant # 2022_0030 to ARP), the Myasthenia Gravis Foundation of America, and the Swedish Research Council (grant # 2025-02779 to ARP). MLF part of the work was supported by a grant from the Deutsche Gesellschaft für Muskelkranke e.V. (DGM).

Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) is an immune-mediated neuropathy with heterogeneous presentation and variable treatment response. Blood-based biomarkers remain lacking, and interpretation is confounded by widespread immunoglobulin (IG) therapy. The primary aim was to identify serum inflammatory proteomic signatures associated with CIDP; exploratory aims included associations with disease activity, phenotype, and treatment response. In this case-control study, 92 proteins were quantified using multiplex proximity extension assay and ELISA in 358 sera samples from patients with CIDP, multiple sclerosis (MS), and IG-treated myasthenia gravis (MG) as well as age- and sex- matched healthy controls (HC). Logistic regression with Bonferroni correction, principal component analysis, and correlation analyses were applied to identify differential expression across diagnoses and CIDP subgroups. Seven proteins, TNFSF14, CD40, SIRT2, CCL3, IL8, TGFα, and uPA, consistently distinguished CIDP from HC, MS, and IG-treated MG, representing disease-specific signatures independent of IG exposure. Six additional proteins (STAMBP, CASP-8, EN-RAGE, OSM, HGF, and CXCL6) were IG-responsive. CXCL9, CDCP1, and CCL20 correlated with muscle weakness, while calprotectin and neurofilament light chain reflected broader inflammatory and axonal injury signatures. Patients with unstable active disease exhibited higher CCL4, IL-8, CCL3, FGF-21, and IL-17A. IL-8, EN-RAGE, and CASP-8 predicted clinical improvement, and IL-5 tracked longitudinal disability changes. CIDP is characterised by distinct serum inflammatory proteomic signatures comprising disease-specific and IG-responsive signatures. These candidate biomarkers may support improved patient stratification, disease monitoring, and prediction of treatment response, advancing individualised therapy in CIDP. Erling-Persson Foundation, Sweden (#2022_0030 to ARP) and the German Research Foundation, Germany (KFO5023 TP8 to AM).

The concept of inter-organ cross-talk, central to understanding physiological adaptations to exercise and disease progression, has been significantly advanced by identifying skeletal muscle as an endocrine organ. This article traces the historical quest for an 'exercise factor', beginning with early speculations in the 19th century and culminating in the discovery of interleukin (IL)-6 as the first myokine and exercise factor in 2003. Initially explored through the works of Julius Geppert and Nathan Zuntz, and later Erling Asmussen and Marius Nielsen, as well as Maurice Goldstein and Bengt Saltin, the search focused on substances released during muscle work, which could influence systemic physiological responses. Despite controversies and the challenge of isolating such factors, the concept gained clarity with the identification of IL-6 that is released from contracting skeletal muscles and plays a crucial role in glucose homeostasis and other processes across various organs, comprising a breakthrough that established skeletal muscle as an endocrine organ.

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Uveal melanoma is a rare melanoma subtype characterized by a liver-dominant pattern of metastasis which is associated with a lack of durable responses to immunotherapies. Adoptive cell transfer of autologous tumor-infiltrating lymphocytes (TILs) has been shown to induce responses in a subset of patients with metastatic uveal melanoma. The safety and feasibility of locoregional administration of TIL therapy via hepatic arterial infusion (HAI) have not previously been evaluated. This prospective, open-label, phase I trial investigated the safety and feasibility of one-time TIL therapy administered via HAI in patients with liver metastases of uveal melanoma. Preconditioning chemotherapy with melphalan (1 mg/kg, intravenous) was administered on day -5. TILs were delivered via percutaneous catheterization of the hepatic artery according to a dose escalation scheme (0.1, 0.3, or 1×109 cells) on day 0. Patients received daily subcutaneous interleukin-2 (IL-2, 2 MIU) up to 14 days after TIL administration. The primary endpoint was the incidence and severity of adverse events (AEs). Secondary endpoints included clinical efficacy and the feasibility of TIL production using a semiautomated manufacturing system. Six patients received TIL therapy manufactured using the CliniMACS Prodigy platform; five were treated according to protocol, while one received a lower TIL dose than planned. All had received prior systemic treatment. No AEs related to the HAI procedure were observed. All patients experienced grade ≥3 hematologic AEs related to preconditioning chemotherapy, and two patients experienced grade ≥3 AEs attributed to TIL/IL-2. Best overall response was stable disease in all patients (100%). Median progression-free survival was 4 months, and median overall survival was 14 months. TILs can be manufactured using the CliniMACS Prodigy. Administration of TIL via HAI was safe and feasible in patients with liver-dominant metastatic uveal melanoma. The used regimen appears insufficient to achieve durable clinical efficacy and implies a need for further testing to obtain conclusive results. NCT04812470, EUCT number: 2024-512877-28-00, EudraCT number: 2020-006126-31.

In this study, we analyzed biomarkers of neuronal, glial, and vascular injury in longitudinal paired samples of blood and cerebrospinal fluid after prophylactic cranial irradiation in patients with small cell lung cancer. Neurofilament light chain protein (NfL) and glial fibrillary acidic protein (GFAP) increased in serum and cerebrospinal fluid after irradiation; serum NfL correlated with cerebrospinal fluid values, apparently independent of blood-brain barrier function, whereas GFAP correlations were weaker. Although several patients developed brain metastases, linear mixed model results were consistent with an independent effect of radiotherapy on serum NfL and GFAP. Serum placental growth factor also rose and correlated with the albumin ratio. Our results support a radiotherapy-associated increase of NfL and GFAP in blood.

There is an unmet need for predictive biomarkers in Guillain-Barré syndrome (GBS). We aimed to determine whether cerebrospinal fluid (CSF) alpha-internexin (AINX) concentrations are associated with disease severity and outcome in GBS. This retrospective cohort included 100 GBS patients. AINX concentrations were measured at diagnosis using a sensitive Simoa assay. Disease severity at nadir was assessed with the GBS Disability Scale (GBSDS) and the need for mechanical ventilation. Poor outcome was defined as GBSDS > 2 at 12 months. Logistic regression with log-transformed AINX assessed associations with severe disease at nadir (GBSDS > 2), need for mechanical ventilation, and poor outcome at 12 months (GBSDS > 2). ROC curve analysis assessed the ability of AINX to predict poor outcome and compared its performance with previously reported biomarkers re-analyzed in this cohort. AINX concentrations at diagnosis were higher in patients with poor outcome and remained associated with poor outcome after adjustment for age (OR 12.48, 95% CI 1.20-129.1, p = 0.034). This association remained significant after additional adjustment for axonal subtypes (OR 26.38, 95% CI 1.12-619.77, p = 0.042). ROC analysis demonstrated good discriminative performance (AUC of 0.79, 95% CI 0.61-0.97, p = 0.002). The optimal cutoff of 2.9 ng/L yielded 50% sensitivity and 95.7% specificity. AINX concentrations were not associated with disease severity at nadir or with need for mechanical ventilation. Elevated CSF AINX at diagnosis was associated with poor long-term outcome in GBS, consistent with a possible contribution of CNS-related injury to recovery.

Common bile duct stones (CBDS) are a common finding during laparoscopic cholecystectomy, yet the optimal treatment strategy remains under debate. In Sweden, CBDS are usually managed by intraoperative endoscopic retrograde cholangiopancreatography using the rendezvous technique (RV-ERCP). An alternative treatment approach is laparoscopic transcystic placement of an endobiliary stent with postoperative ERCP (TCStent-ERCP). The aim of this study was to compare these two treatment strategies in terms of complication rates. Data were extracted from the Swedish Registry for Gallstone surgery and ERCP (GallRiks) from three different hospitals between 2010 and 2023. All cholecystectomies in which CBDS were detected intraoperatively and ERCP was carried out, either during the same session or later, were collected. Procedures involving TCStent-ERCP or RV-ERCP were identified. Complications within 30 days related to the cholecystectomy as well as to the ERCP were compared between the two groups. In total, 929 patients were included. The overall complication rates were 21/183 (11%) in the TCStent-ERCP group and 140/746 (19%) in the RV-ERCP group. In adjusted multivariable regression analysis, fewer overall complications were found using the TCStent-ERCP strategy compared with RV-ERCP (OR 0.60, 95% CI 0.35-0.97). However, no statistically significant differences were observed between the groups for surgical complications or post-procedural pancreatitis. Transcystic stenting with postoperative ERCP appears to be a safe alternative to intraoperative rendezvous ERCP for the management of CBDS encountered during intraoperative cholangiography. This might be beneficial in surgical units where resources required for unplanned ERCP are limited or lacking.

Physical activity and sleep influence fatigue in myasthenia gravis (MG), and digital health technologies (DHT) enable objective monitoring of these behaviors in daily life. Using this approach, we evaluated whether a lifestyle intervention targeting physical activity or sleep hygiene could reduce fatigue in MG. In this three-arm, randomized controlled trial (DIG-MG; NCT05992025), 72 MG patients completed 6 weeks of baseline monitoring with a DHT ring (OURA), followed by 12 weeks of (i) physical activity guidance, (ii) sleep hygiene education, or (iii) observation, and a 6-week follow-up. The primary outcome was the MG Activities of Daily Living (MG-ADL) score 1 week postintervention. Secondary outcomes included Fatigue Severity Scale (FSS) scores; exploratory outcomes were DHT-derived physical activity and sleep parameters. Baseline MG-ADL scores were similar (median: 5.0). Postintervention medians were 4.0 (physical activity), 3.5 (sleep hygiene), and 3.0 (control), with no significant differences (p = 0.073). Clinically meaningful MG-ADL improvement occurred in six, seven, and six participants, respectively. FSS scores showed no group differences (p = 0.992), with clinically relevant improvement in eight participants in each intervention group and five controls. Participants were more physically active than expected: 64.7% exceeded 600 MET-min/week at baseline. DHT adherence was excellent. REM sleep was lower than expected, while deep sleep was preserved. Self-reported data aligned with DHT measurements. Digital lifestyle interventions were feasible and well-accepted but did not improve MG-ADL or FSS in this unusually active population. However, DHT-based monitoring may support individualized follow-up, and reduced REM sleep warrants further investigation as a fatigue-related factor.

Hydromethylthionine mesylate (HMTM) targets tau pathology and also has tau-independent symptomatic activity. A traditional randomised placebo-controlled trial (RCT) was precluded by loss of blinding due to urinary colouration and therapeutic activity at the minimum dose required to maintain blinding. To evaluate the efficacy of HMTM in participants with mild cognitive impairment (MCI) and mild to moderate dementia due to Alzheimer's disease (AD). Because a traditional RCT was not feasible without loss of blinding, we compared HMTM 16 mg/day in TRx-237-039 with propensity score matched true placebo controls from the FDA-sponsored Critical Path for AD (CPAD) database with the same inclusion/exclusion criteria (protocol TRx-237-080). We also compared HMTM 16 mg/day with matched natural history controls from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and with a meta-analysis of placebo arms from trials in comparable populations in analyses specified prior to the 104-week database lock of TRx-237-039. Propensity score matching yielded 127 pairs (HMTM n = 127; CPAD placebo n = 127) in the CPAD comparison, and 189 pairs in the ADNI comparison. A total of 218 receiving HMTM 16 mg/day were compared with meta-analytic controls (n = 1805-8567). HMTM 16mg/day MEASUREMENTS: Primary outcomes in TRx-237-080 were change from baseline to 78 weeks in ADAS-Cog13 and whole brain volume (WBV). CDR-Sum of Boxes (CDR-SB) and CDR-Global were analysed at 104 weeks. ADAS-cog11 and WBV were analysed in ADNI comparisons, and ADAS-cog11, ADCS-ADL23, CDR-SB and WBV were analysed in meta-analytic comparisons. Compared with matched CPAD placebo, HMTM 16 mg/day produced statistically significant differences in change on ADAS-Cog13 (p < 0.0001) and WBV at 78 (primary; p < 0.0001) and 104 weeks (p < 0.0001), and CDR-SB differed significantly overall (104-weeks; p < 0.001) and in MCI (p = 0.007). The odds of progressing to a more advanced CDR-Global stage were lower with HMTM (overall OR 0.31) and particularly in MCI (OR 0.15) versus CPAD placebo. Clinical and brain atrophy outcomes were similarly statistically significant in comparisons with ADNI case-matched natural history data and in meta-analytic comparisons. Comparisons of HMTM treatment with CPAD, ADNI, and meta-analytic controls provide evidence consistent with clinical benefit HMTM. It has the potential to offer an accessible oral treatment option which could be delivered with minimal patient/physician burden.

An accurate understanding of prognosis in Parkinson's disease (PD) is important for patient information provision, personalized treatment, and clinical trial design, but most previous research has been biased towards younger, healthier patients. To describe key clinical outcomes longitudinally and identify baseline prognostic factors (predictors) for these outcomes using population-representative PD cohorts. We meta-analyzed individual patient data from six incidence cohorts in Western Europe (Norway, Sweden, and UK). Each cohort aimed to recruit and follow up all newly diagnosed cases in defined population/incidence periods (between 2000 and 2011). We described postural instability (Hoehn & Yahr Stage 3), functional dependency (needing help with daily activities), dementia, and death with up to 12&#x2009;years' follow-up and investigated clinical and genetic predictors using frailty Cox models. In 883 population-based incident patients, median age at motor symptom onset was 69.2&#x2009;years. Median time to postural instability and functional dependency was 7.4&#x2009;years. Dementia affected 49.6% by 10&#x2009;years and 54.7% had died by 12&#x2009;years (median survival 9.4&#x2009;years). Older age, higher Movement Disorder Society-Unified Parkinson's Disease Rating Scale-Part III (MDS-UPDRS-III) score, and lower Mini-Mental State Examination (MMSE) were significantly associated with all outcomes; cognitive symptoms and GBA polymorphisms with each outcome except mortality; and APOE &#x3b5;4 with increased mortality and dementia. This first individual patient data meta-analysis of population-based incidence cohorts provides robust prognostic data, with fewer selection biases than previous PD studies, for informing people with PD about prognosis. In incidence cohorts, overall PD prognosis is worse than previously suggested, with key outcomes often occurring early. Further work should develop validated prognostic models for objective stratification of prognostic risk and for personalized medicine. &#xa9; 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Epithelial-to-mesenchymal transition (EMT), driven by cues from the tumor microenvironment, is a critical initiator of metastatic progression. In breast cancer patients, elevated expression of cartilage oligomeric matrix protein (COMP) is associated with shorter survival and increased metastatic risk. Here, we investigated the role of COMP in regulating EMT in breast cancer. Breast cancer cells treated with recombinant COMP or engineered to overexpress COMP exhibited a marked decrease in the epithelial marker CDH1 and an increase in mesenchymal markers such as VIM and VCAN. Consistent with these in vitro findings, COMP-expressing xenograft tumor tissues showed enhanced EMT characteristics. Functionally, COMP promoted increased migration and invasion of breast cancer cells in both autocrine and paracrine manners, dependent on its thrombospondin (TSP) and C-terminal domains. We further identified protein TMEPAI (encoded by gene PMEPA1) as a functional COMP-binding partner that mediates COMP-induced EMT, primarily through interaction with the TSP domain of COMP. Mechanistically, COMP shifted transforming growth factor beta (TGF&#x3b2;) signaling from canonical phosphorylated mothers against decapentaplegic homolog 2/3 (pSMAD2/3) activation toward pSMAD1/5, likely through its interaction with PMEPA1. This study suggests the COMP-PMEPA1 axis as a new driver of EMT in breast cancer models.

We examined neurofibrillary tangle (NFT) pathology using 18F-RO-948 tau positron emission tomography (PET) in cognitively unimpaired individuals and its associations with amyloid plaques, fluid biomarkers, and cognition in early preclinical Alzheimer's disease (AD). We analyzed 97 participants from the ALFA+ cohort with tau and amyloid PET, magnetic resonance imaging, fluid biomarkers (cerebrospinal fluid [CSF]/plasma), and cognitive data. Braak staging was applied, and correlations with biomarkers and cognitive measures were assessed. Receiver operating characteristic analyses evaluated biomarker performance in predicting tau PET positivity RESULTS: CSF and plasma tau phosphorylated at threonine 217 (p-tau217) showed the strongest correlation with early Braak I/II tau PET signal (r&#xa0;=&#xa0;0.58, and r&#xa0;=&#xa0;0.37, respectively), while plasma p-tau181 and p-tau181/A&#x3b2;42 showed moderate associations (r &#x223c; 0.25). However, positive predictive values were low (PPV&#xa0;=&#xa0;0.09-0.33). 18F-RO-948 PET detected early tau pathology in individuals with low to moderate amyloid load. Fluid biomarkers, especially in plasma, had limited predictive power but high negative predictive value, supporting their use in ruling out early tau pathology in preclinical AD.

High-grade serous ovarian carcinoma (HGSOC) presents a significant therapeutic challenge. Late-stage disease is frequently associated with peritoneal carcinomatosis. The peritoneal metastases exhibit a unique tumour microenvironment (TME) distinct from the primary tumours and other metastatic sites. Understanding the critical influence of the extracellular matrix (ECM) in shaping the tumour phenotype is essential for the development of effective new therapies. This study introduces a three-dimensional (3D) model of HGSOC peritoneal metastases using a porcine decellularised peritoneal-derived ECM scaffold, referred to as peritoneal matrix (PerMa). We show that the decellularisation maintains the structural integrity and composition of ECM molecules. Comparative analysis reveals structural, compositional, and mechanical similarities between porcine and human peritoneal matrices, underscoring the porcine model's translational relevance for modelling human peritoneum physiology. The PerMa supports the 3D growth of HGSOC cell lines. The model enables the assessment of sensitivity to traditional chemotherapy and novel cell-based immunotherapy through confocal imaging and quantification of cell volume. Our model offers a valuable platform for investigating peritoneal carcinomatosis in HGSOC, with the potential to contribute significantly to developing novel therapeutic approaches. Financial support was provided by the University of Bergen, Helse Vest RHF (F-12183-D10616, 779, 911182, 912035, and 912146), Helse Bergen HF (240222), the Norwegian Cancer Society (6833652 and 182735), the Research Council of Norway grants (250317, 326300, 223250, 262652, and 295910), the Novo Nordisk Foundation (NNF21OC0070381), the Kolbj&#xf8;rn Brambani Legat for Kreftforskning, the National Institute of Health (R01CA199646) and the Swedish Cancer Society (21 1888 Pj).

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High-risk plasma p-tau217 levels predict amyloid-&#x3b2; pathology in Alzheimer's disease, but little is known about the prevalence and temporal dynamics in the general population. Participants from the Gothenburg H70 Birth Cohort Study in Sweden were examined (n&#xa0;=&#xa0;1157) and re-examined after 5-7 years (n&#xa0;=&#xa0;771). Prevalence and 5-7 year transition of high-risk plasma p-tau217 status was determined among community-dwelling 70-year-olds. High-risk plasma p-tau217 prevalence was 3.6% at age 70 and 7.0% at age 75-77 years. Eighty-nine percent remained low-risk and 4% converted to high-risk at follow-up. Prevalence of dementia at follow-up was 1.7% if remaining in the low-risk group and 21.4% if transitioning to the high-risk group. Prevalence of dementia among participants staying in the high-risk group was 16.7% at follow-up. Individuals with low-risk plasma p-tau217 were unlikely to transition over 5-7 years. However, transitioning to a higher risk-category was associated with a higher prevalence of cognitive disability.

Emerging evidence suggests a correlation between CD8+ T cell-tumour cell proximity and anti-tumour immune response1,2. However, it remains unclear whether these cells exist as functional clusters that can be isolated from clinical samples. Here, using conventional and imaging flow cytometry, we show that from 21 out of 21 human melanoma metastases, we could isolate heterotypic clusters, comprising CD8+ T cells interacting with one or more tumour cells and/or antigen-presenting cells (APCs). Single-cell RNA-sequencing analysis revealed that T cells from clusters were enriched for gene signatures associated with tumour reactivity and exhaustion. Clustered T cells exhibited increased TCR clonality indicative of expansion, whereas TCR-matched T cells showed more exhaustion and co-modulation when conjugated to APCs than when conjugated to tumour cells. T cells that were expanded from clusters ex vivo exerted on average ninefold increased killing activity towards autologous melanomas, which was accompanied by enhanced cytokine production. After adoptive cell transfer into mice, T cells from clusters showed improved patient-derived melanoma control, which was associated with increased T cell infiltration and activation. Together, these results demonstrate that tumour-reactive CD8+ T cells are enriched in functional clusters with tumour cells and/or APCs and that they can be isolated and expanded from clinical samples. Typically excluded by single-cell gating in flow cytometry, these distinct heterotypic T cell clusters are a valuable source to decipher functional tumour-immune cell interactions and may also be&#xa0;therapeutically explored.

Antibody therapies can remove amyloid plaques from the brain and slow cognitive decline in people with Alzheimer's disease who are mildly impaired. These drugs are now being evaluated in participants who are cognitively unimpaired but positive for a biomarker of Alzheimer's disease for their safety, tolerability, disease-modifying and cognitive preserving effects, and ability to avert the onset of cognitive impairment. If these studies are successful, and the drugs get regulatory approval, they could accelerate the evaluation and approval of related Alzheimer's disease-modifying treatments in people who are unimpaired with or without a biomarker of the disease. Preclinical Alzheimer's disease therapies that modify the underlying disease in people who are unimpaired with a biomarker of Alzheimer's disease and primary prevention therapies that avert the onset of amyloid plaques in those with a negative test have the potential to substantially prevent ensuing biological and clinical manifestations of Alzheimer's disease. In this Policy View, we assess the challenges and opportunities that trials of these drug treatments will bring, and consider the blood tests, cognitive assessments, and post-marketing strategies needed to enable the approval, affordability, health-care insurance coverage, and equitable use. Our recommendations are intended for consideration in the USA, and relevant refinement in other countries.

Bloating refers to the sensation of tension in the abdomen, reported in the presence or absence of visible abdominal distension. These and other gas-related symptoms are often reported by patients with irritable bowel syndrome (IBS) and functional dyspepsia (FD). However, the prevalence of bloating and visible abdominal distension as separate symptoms in these disorders is not well known. The aim of this study was to investigate the link between bloating, distension, and intestinal gas-related symptoms with IBS and FD, and their overall impact. Data from a population-based internet survey of adults from the US, UK, and Mexico were used. This survey included Rome IV diagnostic questions for IBS and FD, questions to distinguish between&#xa0;&#x2265;&#xa0;weekly bloating and/or distension, and the Intestinal Gas Questionnaire (IGQ) to assess the impact of six gas-related symptoms. The analyses included 131 individuals with only IBS, 360 with only FD, 217 with IBS&#xa0;+&#xa0;FD and 4740 without IBS and FD (reference group). Individuals with IBS (64.9%), FD (50.6%), and especially IBS&#xa0;+&#xa0;FD (88.5%) reported bloating and/or distension more frequently than the reference group (13.7%). Bloating and distension as distinct and combined symptoms were strongly linked to IBS and FD even after correcting for confounding factors. Also, other gas-related symptoms had a higher impact on individuals with IBS and/or FD compared with the reference group. Bloating and visible abdominal distension can occur as concomitant or distinct impactful symptoms and are, together with other gas-related symptoms, strongly linked to IBS and FD. These findings may provide arguments to include bloating and distension as supportive criteria for IBS and FD diagnoses.