Search Results (5,849)

Anxiety and depression affect millions worldwide, yet stigma and long wait times often delay access to care. Mobile mental health apps can decrease these barriers by offering on-demand screening and support. Nevertheless, many machine and deep learning methods used in such tools perform poorly under severe class imbalance, yielding biased, poorly calibrated predictions. To address this challenge, this study proposes MCoG-LDPSNet, a brain-inspired model that combines dual, orthogonal encoding pathways with a novel Loss-Driven Parametric Swish (LDPS) activation. LDPS implements a neurobiologically motivated adaptive-gain mechanism via a learnable β parameter driven by calibration and confidence-aware loss signals that amplifies minority-class patterns while preserving overall reliability, enabling robust predictions under severe data imbalance. On a benchmark mental health corpus, MCoG-LDPSNet achieved AUROC = 0.9920 and G-mean = 0.9451, outperforming traditional baselines like GLMs, XGBoost, state-of-the-art deep models (CNN-BiLSTM-ATTN), and transformer-based approaches. After transfer learning to social media text, the MCoG-LDPSNet maintained a near-perfect AUROC of 0.9937. Integrated into the EmotiZen App with enhanced app features, MCoG-LDPSNet was associated with substantial symptom reductions (anxiety 28.2%; depression 42.1%). These findings indicate that MCoG-LDPSNet is an accurate, imbalance-aware solution suitable for scalable mobile screening of individuals for anxiety and depression. Full article

Multiple sclerosis (MS) is an autoimmune and neurodegenerative disease affecting approximately 1 million people in the United States. Despite extensive research into the mechanisms of disease development, many aspects of the biological changes during MS progression and the varying symptoms among patients remain unclear. In the era of high-throughput sequencing, transcriptome databases are flooded with data. However, bulk RNA sequencing (RNA-seq) data are typically used only for differential gene expression analysis. Alternative splicing, a key process that alters the transcriptome, can also be identified from bulk data. Here, we accessed 11 studies with bulk RNA-seq data of postmortem MS patients’ brain samples via NCBI’s Gene Expression Omnibus (GEO). We extracted additional information from these data by identifying exclusively alternatively spliced genes via replicate multivariate analysis of transcript splicing (rMATS) analysis. Our analyses revealed that changes in RNA splicing mediate distinct biological signals compared to those driven by differential gene expression. Gene ontology and protein do-main analyses of genes exclusively regulated by alternative splicing revealed distinct molecular differences between progressive and relapsing–remitting MS as well as among lesions from different brain regions and between white and gray matter. These findings highlight the critical role of alternative splicing and its associated pathways in MS disease development and progression. Full article

Background: Autoimmune diseases and other immune-mediated disorders are associated with an increased risk of malignancy, influenced by chronic inflammation, immune dysregulation, and treatment-related factors. Clarifying cancer risk patterns across specific conditions is essential to improve clinical vigilance and inform screening practices. Objective: The aim of this study was to synthesise current evidence on the association between autoimmune and immune-mediated diseases and cancer, with a focus on practical implications for clinicians. Methods: Recent cohort studies, meta-analyses, and expert consensus documents were analysed to describe cancer epidemiology, pathogenic mechanisms, high-risk phenotypes, and treatment considerations across major autoimmune diseases and other immune-mediated conditions. The review covers idiopathic inflammatory myopathies, Sjögren’s syndrome, systemic sclerosis, systemic lupus erythematosus, rheumatoid arthritis, antiphospholipid syndrome, ANCA-associated vasculitis, giant cell arteritis, polymyalgia rheumatica, sarcoidosis, mixed connective tissue disease, IgG4-related disease, VEXAS syndrome, and eosinophilic fasciitis. Special attention was given to identifying warning features for underlying malignancy and evaluating cancer screening strategies. Results: The magnitude and distribution of cancer risk vary across diseases. In some conditions such as dermatomyositis, systemic sclerosis or Sjögren’s syndrome, increased risk is well established, particularly for haematological and certain solid tumours. However, tumour patterns may differ across populations, and findings are not always consistent. Distinct clinical and serological features help stratify individual cancer risk and may guide the intensity of screening. The first years after disease onset often represent a window of higher vulnerability, during which intensified surveillance may be warranted in selected patients. Conclusions: Cancer risk in autoimmune diseases should be assessed on an individual basis. Awareness of disease-specific risk factors and clinical warning signs supports early recognition of malignancy and informs screening decisions in routine practice. Full article

Microglia and macrophages are critical immune cells within the central nervous system (CNS), with distinct roles in development, homeostasis, and disease. Once viewed as passive bystanders, these cells are now recognized for their dynamic phenotypic plasticity, which enables them to respond to a wide range of physiological and pathological stimuli. During homeostasis, microglia and CNS-resident macrophages actively participate in synaptic pruning, neuronal support, myelin regulation, and immune surveillance, contributing to CNS integrity. However, under pathological conditions, these cells can adopt neurotoxic phenotypes, exacerbating neuroinflammation, oxidative stress, and neuronal damage in diseases such as Alzheimer’s, Parkinson’s, multiple sclerosis, and glioblastoma. This review synthesizes emerging insights into the molecular, epigenetic, and metabolic mechanisms that govern the behavior of microglia and macrophages, highlighting their developmental origins, niche-specific programming, and interactions with other CNS cells. We also explore novel therapeutic strategies aimed at modulating these immune cells to restore CNS homeostasis, including nanotechnology-based approaches for selective targeting, reprogramming, and imaging. Understanding the complex roles of microglia and macrophages in both health and disease is crucial for the development of precise therapies targeting neuroimmune interfaces. Continued advances in single-cell technologies and nanomedicine are paving the way for future therapeutic interventions in neurological disorders. Full article

Background/Objectives: Patients with erythropoietic protoporphyria (EPP) have a decreased activity of the ferrochelatase enzyme which converts protoporphyrin IX (PpIX) into heme, causing PpIX to accumulate in erythrocytes. The ensuing release of PpIX to the skin when exposed to visible light causes a phototoxic reaction with severe pain, erythema, and edema. Erythrocyte PpIX levels in adult EPP patients are rather stable and largely unaffected by pharmaceutical treatments. It is important to be aware of drugs causing an increase in PpIX as this may increase the risk of liver toxicity. Method: The patient had blood samples taken regularly for analyses of PpIX, znPpIX, ALT, ALP, iron, leucocytes, C-reactive protein, and hemoglobin before, during, and after treatment with teriflunomide. Additionally, we tested if teriflunomide increased PpIX in vitro. Results: A female EPP patient was treated for 7 years with teriflunomide for multiple sclerosis attacks. During treatment, her natural PpIX level increased from about 30 µmol/L to about 200 µmol/L, without significant simultaneous changes in hemoglobin, iron levels, alanine transaminase (ALT), or alkaline phosphatase (ALP). The patient experienced no increase in photosensitivity. In vitro addition of teriflunomide did not affect PpIX levels. Discussion: In patients with lead intoxication, the release of PpIX from erythrocytes is very slow. The increase in PpIX during treatment with teriflunomide compared to periods with no medication could be caused by a similar slow PpIX release from the erythrocytes. This theory is supported by the patient’s unchanged light sensitivity and stable levels of hemoglobin, iron, and liver enzymes. Full article

Objective: We aimed to quantify multiple sclerosis (MS)-related work productivity and to illustrate the longitudinal trends for relapses, disease progression, and utilization of health care resources in a nationally representative cohort of working North Americans living with MS. Background: The North American Registry for Care and Research in Multiple Sclerosis (NARCRMS) is a multicentered physician-reported registry which prospectively collects clinical information including imaging data over a long period of time from people with MS from sites across the U.S. and Canada. The Health Economics Outcomes Research (HEOR) Advisory Group has also incorporated Health-Related Productivity and Health Resource Utilization questionnaires, which collect information about health care economics of people with MS and its effects on daily life. Design/Methods: This is a prospective observational study utilizing data from NARCRMS. Socio-demographic, clinical, and health economic outcome data were collected through previously validated and structured questionnaires. Logistic regression was used to calculate the relative odds of symptom impact, with a generalized logit link for number of relapses. Cox proportional hazards regression was used to calculate hazard ratios for time to first relapse. Results: Six hundred and eighty-two (682) people with MS were enrolled in NARCRMS and had completed the HEOR questionnaires at the time of the analysis. Among the participants, 61% were employed full-time and 11% were employed part time. Fatigue was the leading symptom reported to impact both work and household chores. Among the employed participants, 13% reported having missed work with a median of 6.8 (IQR: 3.0–9.0) missed hours due to MS symptoms (absenteeism), while 35% reported MS having impacted their work output (presenteeism). The odds of higher disease severity (EDSS 2.0–6.5 vs. 0.0–1.5) were 2.29 (95% CI = 1.08, 4.88; p = 0.011) times higher for participants who identified reduction of work output. Fatigue was the most identified symptom attributed to work output reduction. Among all participants, 33% reported having missed planned household work with a median of 3.0 (IQR: 2.0–5.0) hours. The odds of higher disease severity were 2.49 (95% CI = 1.37, 4.53; p = 0.006) times higher for participants who identified reduction in household work output, and 1.70 (CI = 1.27, 2.49; p = 0.006) times higher for those whose fatigue affected housework output as compared to other symptoms. Conclusions: A preliminary review of the first 682 patients showed that people with MS had reduced work and housework productivity even at an early disease state. Multiple sclerosis (MS) can significantly impair individuals’ ability to function fully at work and at home, with fatigue overwhelmingly identified as the primary contributing factor. The economic value of finding an effective treatment for MS-related fatigue is substantial, underscoring the importance of these findings for policy development, priority setting, and the strategic allocation of healthcare resources for this chronic and disabling condition. Full article

Background: Considering the lack of studies regarding the localized evaluation of the macular inner retina in multiple sclerosis patients without optic neuritis (MSnoON eyes), we investigated the structure and function of retinal ganglion cells (RGCs) located in different macular areas. Methods: In 24 MSnoON patients (mean age: 45.22 ± 5.57 years; 14 females and 10 males; mean MS disease duration: 11.07 ± 5.88 years) and in 30 age-similar (mean age: 45.09 ± 5.08 years) control subjects, complete ophthalmological examination, optical coherence tomography (OCT) and multifocal photopic negative response (mfPhNR) were performed. The ganglion cell layer thickness (GCL+-T) via OCT and the response amplitude density (RAD) through mfPhNR were measured from localized macular regions, including rings and Early Treatment of Diabetic Retinopathy Study (ETDRS) sectors. Results: When comparing MSnoON data from all tested areas with respect to the controls, macular GCL+-T and mfPhNR RAD mean values were found to be significantly (ANOVA, p < 0.01) reduced. In the MSonON group, considering both rings and sectors, the GCL+-T values were significantly and linearly correlated (Pearson’s test, p < 0.01) to the mfPhNR RAD values. Conclusions: In MS, even in the absence of optic neuritis, potential primary morpho-functional involvement of the inner macular elements can occur. This impairment widely involves all macular areas and sectors. Full article

Multiple sclerosis (MS) is a chronic, immune-mediated neurological disorder with increasing global prevalence. Emerging evidence underscores the role of lifestyle interventions (particularly diet and physical activity) in modulating disease progression and improving quality of life. This narrative review synthesizes current scientific literature on the effects of dietary interventions, including the Mediterranean, ketogenic, Swank, Wahls, gluten-free, and fasting-based diets, alongside various physical activity regimens. The Mediterranean and ketogenic diets show promise in reducing inflammation, enhancing neuroprotection, and improving metabolic health. Similarly, structured physical activity (including aerobic, resistance, sensorimotor, and mind–body exercises) demonstrates benefits in mobility, fatigue, and mental well-being. The review highlights the need for personalized, sustainable approaches that integrate nutritional and exercise-based strategies for optimal MS management in the long term. Full article

Background/Objectives: Quantitative intravoxel incoherent motion (IVIM) imaging, incorporating both diffusion- and perfusion-derived metrics, offers a promising non-invasive approach for assessing tissue microstructure and clinical disability in multiple sclerosis (MS). This study aimed to investigate the correlation and predictive values of the IVIM apparent diffusion coefficient (ADC), true diffusion coefficient (D), and perfusion-derived pseudo-diffusion coefficient (D*) and perfusion fraction (f) parameters with disability status, measured using the Expanded Disability Status Scale (EDSS), in relapsing–remitting MS patients. Methods: This cross-sectional study retrospectively analyzed MRI data from 197 MS patients. Quantitative IVIM parameters were extracted from scans obtained using a 1.5 T MRI scanner. Clinical data were also obtained, including age, disease duration, number of relapses, disease-modifying therapy (DMT) status, and need for mobility assistance. Bivariate analyses were conducted to compare mean values across subgroups. Pearson correlation was used to examine associations between EDSS score and imaging/clinical variables. Multiple linear regression was applied to identify independent predictors of EDSS score. Results: The bivariate analyses revealed that ADC, D, D*, and EDSS values were higher in patients over 50 years old, those with a longer disease duration, and those who required mobility assistance. f was higher in females and DMT-treated patients, but it had no effect on EDSS score. Patients with longer disease duration and limited mobility had a higher number of MS lesions and relapses. EDSS score exhibited positive Pearson correlations with ADC, D, D*, the number of MS lesions, and the number of relapses (p-value < 0.001). In the multivariate regression analysis, only the number of MS lesions and relapses emerged as independent predictors of EDSS score (p-value < 0.001). Other variables, including ADC, D, D*, f, age, and disease duration, were not independently associated with EDSS score (p-value > 0.05). Conclusions: This study demonstrates the utility of IVIM parameters in detecting microstructural alterations associated with MS impairment. Despite relapse frequency and lesion count being the strongest predictors of EDSS score, IVIM metrics showed meaningful clinical correlations. The findings support combining IVIM biomarkers with clinical data for better disability assessment. Full article

Amyotrophic lateral sclerosis (ALS) is still a heterogeneous neurodegenerative disorder that can be identified clinically and biologically, without a strong set of biomarkers that can adequately measure its fast rate of progression and molecular heterogeneity. In this review, we intend to consolidate the most relevant and timely advances in ALS biomarker discovery, in order to begin to bring molecular, imaging, genetic, and digital areas together for potential integration into a precision medicine approach to ALS. Our goal is to begin to display how several biomarkers in development (e.g., neurofilament light chain (NfL), phosphorylated neurofilament heavy chain (pNfH), TDP-43 aggregates, mitochondrial stress markers, inflammatory markers, etc.) are changing our understanding of ALS and ALS dynamics. We will attempt to provide a framework for thinking about biomarkers in a systematic way where our candidates are not signals alone but part of a tethered pathophysiological cascade. We are particularly interested in the fast progressor phenotype, a devastating and under-characterized subset of ALS due to a rapid axonal degeneration, early respiratory failure, and very short life span. We will try to highlight the salient molecular features of this ALS subtype, including SOD1 A5V toxicity, C9orf72 repeats, FUS variants, mitochondrial collapse, and impaired autophagy mechanisms, and relate these features to measurable blood and CSF (biomarkers) and imaging platforms. We will elaborate on several interesting tools, for example, single-cell transcriptomics, CSF exosomal cargo analysis, MRI techniques, and wearable sensor outputs that are developing into high-resolution windows of disease progression and onset. Instead of providing a static catalog, we plan on providing a conceptual roadmap to integrate biomarker panels that will allow for earlier diagnosis, real-time disease monitoring, and adaptive therapeutic trial design. We hope this synthesis will make a meaningful contribution to the shift from observational neurology to proactive biologically informed clinical care in ALS. Although there are still considerable obstacles to overcome, the intersection of a precise molecular or genetic association approach, digital phenotyping, and systems-level understandings may ultimately redefine how we monitor, care for, and treat this challenging neurodegenerative disease. Full article

Adipocytokines are involved in the pathogenesis of multiple sclerosis by modulating inflammation, blood–brain barrier function and immune responses, which may affect disease course and treatment outcomes. Our study assessed serum levels of visfatin, adiponectin and resistin in patients with relapsing–remitting multiple sclerosis treated with fingolimod or natalizumab. We examined 49 patients with relapsing–remitting multiple sclerosis and 38 healthy controls. Participants were divided into three groups: patients treated with fingolimod, those treated with natalizumab and the controls. Serum levels of visfatin, adiponectin and resistin were measured. We analyzed correlations with disease duration, treatment duration and body mass index. Adiponectin levels were significantly higher in patients treated with natalizumab compared to those receiving fingolimod and healthy controls (p < 0.05). In the fingolimod group, visfatin levels increased with treatment duration. The mean level was 51.27 pg/mL for treatment shorter than eighteen months and 59.12 pg/mL for longer treatment (p < 0.05). In the same group, resistin levels correlated positively with body mass index (p < 0.05), while visfatin levels showed a negative correlation (p < 0.05). Fingolimod may affect adipocytokine levels, which could support patient monitoring. Increased adiponectin in natalizumab-treated patients suggests its possible role in the therapeutic mechanism of the treatment. Full article

Background/Objectives: Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation and holds promise as a therapeutic strategy against cancers with elevated iron metabolism. However, many tumors evade ferroptosis through the upregulation of specialized antioxidant defense mechanisms. Here, we investigated ferroptosis susceptibility and resistance mechanisms in TSC models and in ovarian and breast cancer cell lines, aiming to identify potential therapeutic targets. Methods: Ferroptosis sensitivity was assessed using RSL3 and erastin. We explored the contribution of ferroptosis defense pathways using inhibitors of NRF2 (ML385) and FSP1 (iFSP1). RNA sequencing was performed to evaluate the expression of ferroptosis resistance genes and to explore NRF2-regulated transcriptional programs. Results: TSC2-deficient cells were resistant to RSL3- and erastin-induced ferroptosis. This resistance correlated with upregulation of ferroptosis defense genes, including NRF2 and its downstream targets. Pharmacological inhibition of NRF2 resensitized TSC2-deficient cells to ferroptosis, confirming a protective role for NRF2. However, FSP1 inhibition did not restore ferroptosis sensitivity in TSC2-deficient angiomyolipoma cells. In contrast, FSP1 knockdown significantly enhanced ferroptosis sensitivity in ovarian (PEO1, PEO4, OVCAR3) and breast (MDA-MB-436) cancer cells. Notably, in MDA-MB-436 cells, FSP1 knockdown was more effective than NRF2 inhibition to enhance ferroptosis sensitivity. FSP1 expression was not regulated by NRF2, suggesting that NRF2-targeted therapies alone may be insufficient to overcome ferroptosis resistance in certain cancer contexts. Conclusions: TSC2-deficient cells resist ferroptosis via an adaptive antioxidant response that protects against elevated iron-mediated lipid peroxidation. Our findings identify NRF2 and FSP1 as key, but mechanistically distinct, regulators of ferroptosis resistance. The differential efficacy of targeting these pathways across cancer types highlights the potential need for patient stratification. Dual targeting of NRF2 and FSP1 may offer an effective therapeutic strategy for iron-dependent, ferroptosis-resistant cancers. Full article

Malnutrition is one of the common complications of patients with systemic sclerosis (SSc). However, several nutritional assessment tools are implemented in Thailand. The study aimed to compare the performance of nutritional assessment tools including Nutritional Assessment Form (NAF) and Nutritional Triage 2013 (NT-2013) to Subjective Global Assessment (SGA) in SSc patients. A cross-sectional diagnostic study was conducted in adult SSc patients at Srinagarind Hospital, Thailand. To elucidate the efficacy and correlations of these tools, descriptive statistics, Pearson correlation analyses, and kappa coefficient of agreement were employed. A total of 208 SSc patients were included, of which 70.7% were females. The respective mean age and body mass index was 59.3 years and 21.1 kg/m². Nearly half (45.7%) were malnourished based on SGA. Malnutrition diagnosis using the NAF and NT-2013 criteria were found in 80.3% and 34.6%, respectively. The respective sensitivity and specificity of NAF for diagnosis of malnutrition was 93.7% and 31.9%, while NT-2013 was 60.0% and 90.3%. Both NAF and NT-2013 had slight agreement with SGA with a kappa of 0.149 for NAF and 0.131 for NT-2013. Adjusting the cut-off points of NAF and NT-2013 could enhance sensitivity, specificity, and improve agreement for diagnosis with SGA. Full article

Background and Objectives: Decreased balance function in multiple sclerosis (MS) patients is influenced by impaired gravity perception, which can be measured by the subjective visual vertical (SVV) test. The value of this test can be increased by executing it in a moving visual background (i.e., dynamic SVV). However, clinicians and researchers use varying dynamic stimulus properties due to the lack of consensus on optimal parameters for reliably distinguishing between health and disease. Materials and Methods: To evaluate how dynamic visual stimulus intensity affects the perception of verticality in patients with MS and healthy individuals. Materials and Methods: We assessed static and dynamic SVV in 31 MS patients with dizziness and 32 age- and sex-matched controls using the virtual reality application VIRVEST. We evaluated the effects of modifying two parameters in dynamic SVV testing: rotation velocity (10°/s, 30°/s, and 60°/s) and visual field coverage (small vs. large). Results: The median of static SVV deviations was significantly greater in the MS group (1.8° vs. 0.9°). The mildest dynamic stimulus intensity of 10°/s, with a small visual field coverage, yielded the greatest discriminatory capacity to differentiate between the groups (AUC = 0.897; p < 0.001). This stimulus elicited a median SVV deviation of 4.3° in the MS group and 2.1° in the control group (p < 0.001) while also inducing significantly lower test-induced dizziness compared with stronger stimuli. Median visual dependence values measured at 10°/s with a small visual field coverage were 4.2 in the MS group and 2.02 in the control group (p < 0.001), also yielding the greatest AUC values compared to stronger stimuli (AUC = 0.828; p < 0.001). Conclusions: Our results support the use of relatively mild dynamic stimulus intensity. Future studies are encouraged to evaluate different dynamic stimulus parameters and patient populations. Full article

Many patients with spasticity report pain which can be debilitating. Numerous studies have shown onabotulinumtoxinA (onabotA) is efficacious in the management of spasticity but comprehensive data on its impact on spasticity-associated pain is limited. This systematic review aimed to assess the published evidence on the efficacy of onabotA in the management of pain in adults with spasticity. Search strategies were conducted from 1990 to 2023 for journal publications and from 2020 to 2023 for congress proceedings to identify relevant studies on onabotA in adults with spasticity where pain was a reported outcome. Of 665 records identified, 31 unique studies from 33 publications were included (2740 patients). Twenty-seven studies demonstrated a reduction in pain compared to baseline following treatment with onabotA in adults with spasticity (n = 2740). Of these, 12 studies reported a statistically significant reduction in pain with onabotA versus baseline. Sixteen studies reported a clinically meaningful reduction in pain (≥30% reduction). The reduction in pain with onabotA was consistent across etiologies and a range of pain measures. There was a high level of heterogeneity in the design and quality of the studies identified, which limited statistical analysis; however, the published evidence overall shows a consistent positive trend for the use of onabotA in reducing spasticity-related pain in adults. Full article