Inflammatory activation is a major cause to nasal diseases, such as chronic rhinosinusitis and allergic rhinitis. However, in vitro research model to mimic the process of olfactory inflammation and to screen new therapeutic target is still lacking. We established three inflammatory models based on olfactory epithelium (OE) organoids, using lipopolysaccharide (LPS), TNFα treatment and doxycycline induction. The efficacy of these models was evaluated by immunostaining, RNA sequencing, qPCR, and functional assays. These inflammatory organoid models mimicked impairment in cell proliferation and neuronal genesis, and showed upregulation of inflammation-related signaling pathway and downregulation of cell cycle-related pathway. We identified that DNA damage inducible transcript 3 (Ddit3) was upregulated in all inflammatory organoid models. Ddit3 downregulation counteracted apoptosis, alleviated cell proliferation and neuronal differentiation, and recovered the functional response to odor stimulation in all three inflammatory organoid models. Ddit3 deficiency counteracted effect of LPS instillation by promoting cell proliferation, recovering neurogenesis, attenuating inflammation, and improving electrophysiological response to odor mixes in the OE. Single-cell RNA sequencing analysis showed that Ddit3 upregulation in mature olfactory sensory neurons of inducible inflammation model and patients with aging-related olfactory dysfunction correlated with endoplasmic reticulum stress and neuron apoptotic process. We established olfactory inflammation organoid models, and made use of these models to identify Ddit3 as a potential therapeutic target against inflammation-related olfactory neuronal loss and functional deficit.
Cancer remains as the most feared human disease and embodies deep psychological and physical suffering (1). It is one of the unsolved medical problems nowadays and constitutes a heavy burden not only for the individual and his family but also for health systems worldwide (2). In this context, cancer prevention and early diagnosis and treatment is of cardinal importance; hence, identification of cancer risk factors in the genesis of human cancer is an urgent necessity. Among these deleterious influences, obesity and aberrantly increased growth hormone receptor (GHR) signaling have been identified as two of the most relevant factors in the etiology of malignancy (3, 4). Considering the above premises, attempts at effectively and safely treating patients with cancer are within the noblest aims in medicine and science. At present, radical surgery, radio and chemotherapy, targeted therapy, and immunotherapy are the basis for dealing with this widespread issue (5). Nevertheless, and especially in several types of cancer, all efforts are ineffective (6). In consequence, strategies to discover new medicines aimed at safely and effectively treating individuals affected by cancer are needed. Similarly, adjuvant methods aimed at making more effective use of standard therapies are required. Contextually, a new experimental approach to dealing with melanoma, liver cancer, pancreatic cancer, and cholangiocarcinoma, some of the most lethal malignancies in humans, has been developed based on the previous discovery of a GHR antagonist used for acromegaly and its mode of action (7, 8). Development of new drugs for cancer treatment is partially based on observations in humans who have a distinct phenotype that combines obesity -the most epidemiologic risk factor in cancer etiology- along with absent growth hormone receptor (GHR) signaling (4, 9).
Natural polymers can be engineered into nanoscale "molecular traps", the bioMIPs, by the technique of molecular imprinting, which is a template-directed synthesis to generate selective binding sites in a crosslinked matrix. To date, bioMIPs are synthesized in solution by nano-aggregation of the polymeric units around a template, yielding to selective meta-biomaterials. Yet, the in-solution process limits the uniformity and scale-up of the bioMIPs. Here we report the first solid-phase synthesis (SPS) of interleukin-6 (IL-6) selective bioMIPs made of Gelatin methacryloyl (GelMA) and establish design rules for producing monomodal bioMIPs from protein building blocks. SPS synthesis is based on the oriented immobilization of the template to a solid support. SPS nucleation was studied on a plasmonic surface permitting real-time monitoring of bioMIP genesis. Subsequently, it was translated into a prototype reactor for scaling up the production. Guided by Flory-Huggins-De Gennes theory, we mapped the synthetic space by varying GelMA concentration, density and architecture of the surface-immobilized templates, and nucleation-time. The formed SPS bioMIPs were structurally and functionally characterized. Compared with analogous bioMIPs prepared by in-solution imprinting, SPS bioMIPs displayed a low picomolar dissociation constant, surpassing the in-solution ones by 3 orders of magnitude; showed ∼1 ng/μg IL-6 uptake in human serum, i.e., ∼45-fold increase with respect to in-solution ones, underscoring robust selective recognition under physiologically relevant conditions. Overall, the SPS strategy enables template-free isolation of high-quality bioMIPs and provides a practical route toward manufacturing cytokine-targeting nanotraps for inflammation-modulating biomedical applications.
The human vascular network is a highly dynamic, complex and organ-specific microenvironment essential for organ homeostasis. Traditional 2D cell cultures fail to capture its complex intercellular interactions, tissue-specific architectures, and mechanobiological cues. Blood vessel organoids (BVOs) generated from human induced pluripotent stem cells (hiPSCs) replicate the structure and function of blood vessels. Because hiPSCs preserve the donor's telomere length and epigenetic memory, BVOs may preserve the genesis memory, opening up a completely new avenue for the study of vascular disorders. In this review, we systematically outline the methods for in vitro blood vessel generation and explore how vascularizing parenchymal organoids actively drives tissue maturation while overcoming hypoxic limitations. We assess the vital transition from biochemical induction to biomechanical integration, highlighting how microfluidic organ-on-a-chip (OoC) platforms resolve the lineage-specific media dilemma and impose the physiological shear stress necessary for definitive vascular maturation. Furthermore, we comprehensively summarize the applications of BVOs as personalized preclinical avatars across diverse pathologies, including diabetic vasculopathy, cerebrovascular and cardiovascular diseases, tumor immune evasion, hereditary anomalies, and infectious vasculotropism. Finally, we address critical current bioengineering constraints-notably incomplete vessel maturation, the absence of functional lymphatic systems, and the lack of immunocompetent microenvironments-providing strategic future perspectives to accelerate the translation of BVOs in precision and regenerative medicine.
Congenital heart disease is among the most common fetal abnormalities and birth defects. Despite identifying numerous risk factors influencing its onset, a comprehensive understanding of its genesis and management across diverse populations remains limited. Recent advancements in machine learning have demonstrated the potential for leveraging patient data to enable early congenital heart disease detection. Over the past seven years, researchers have proposed various data-driven and algorithmic solutions to address this challenge. This paper presents a systematic review of congenital heart disease recognition using machine learning, conducting a meta-analysis of 432 references from leading journals published between 2018 and 2025. A detailed investigation of 74 scholarly works highlights key factors, including databases, algorithms, applications, and solutions. Additionally, the survey outlines reported datasets used by machine learning experts for congenital heart disease recognition. Using a systematic literature review methodology, this study identifies critical challenges and opportunities in applying machine learning to congenital heart disease.
Fatigue is one of the most prevalent and debilitating symptoms in individuals with multiple sclerosis (MS). We recorded somatosensory high-frequency oscillatory (HFO) thalamocortical activity in a group of MS patients without history of optic neuritis (ON). Furthermore, we examined if, like what was previously observed in response to visual stimuli, patients exhibit diminished amplitude habituation, and whether this may further exacerbate fatigue in individuals with MS. Twenty patients diagnosed with relapsing-remitting MS were prospectively enrolled. The MS cohorts were compared with a cohort of 20 healthy volunteers (HV). Fatigue Severity Scale (FSS) was employed to evaluate the trait levels of reported fatigue. We assessed the N20 somatosensory evoked potentials (SSEPs) parameters and N20-P25 amplitude habituation, and, following the application of a band-pass filter (450-750 Hz), we evaluated electrophysiological parameters of pre- and post-synaptic HFOs. The latency and amplitude of the N20 SSEP and its habituation do not exhibit significant differences between MS patients and HVs. MS patients exhibited delayed latency of negative oscillatory maximum and reduced maximum peak-to-peak amplitude of the pre-synaptic HFOs (all p < 0.01). In patients, post-synaptic HFOs showed a significant delayed latency and a trend towards a reduction in the maximal peak-to-peak amplitude. The pre-synaptic HFO latency of the negative oscillatory maximum, reflecting thalamocortical activity, shows a correlation with the FSS in MS patients (r = 0.522, p = 0.018). No significant ophthalmological anomalies were identified. Our data revealed a significant reduction and slowing of somatosensory thalamocortical network activity in MS patients without history of ON. Furthermore, our findings showed that fatigue levels may be affected by slowed thalamocortical activity, but not by habituation of cortical responses. Our findings suggest a potential role of the thalamo-cortical network on the genesis of MS-related fatigue.
Cancer risks of individuals heterozygous for an ATM pathogenic or predicted pathogenic variant (PV/PPV) remain imprecise to guide optimal clinical management. Therefore, we aimed to estimate these risks in different family settings. Data were collected on 141 ataxia-telangiectasia families, 398 Hereditary Breast and Ovarian Cancer families and 96 families with a history of pancreatic cancer enrolled in French nation-wide epidemiological studies CoF-AT2, TUMOSPEC or GENESIS. Hazard ratios (HR) and cumulative risks were estimated using a modified segregation analysis method. An increased risk of breast and pancreatic cancers was observed for PV/PPV heterozygotes, and HRs were similar in the three family sets. When combined, HR were 4.0 (95%CI:2.9-5.6) for female breast cancer, 6.6 (95%CI:3.6-12.1) for female pancreatic cancer, and 2.8 (95%CI:1.4-5.5) for male pancreatic cancer. In birth cohort 1960-1969, female heterozygotes had a cumulative risk of breast cancer of 9.9% (95%CI:7.1%-13%) by age 50, and of 40% (95%CI:31%-51%) by age 80. Their risk of pancreatic cancer by age 80 was 8.1% (95%CI:4.3%-14%). The risk of male pancreatic cancer by age 80 was 5.1% (95%CI:2.4%-9.3%). No increased risk of ovarian and prostate cancers was observed. Our findings will help in the clinical management of families where an ATM PV/PPV segregates.
GABAA and protein hypotheses aside, the lipid theory remains the most influential account of anaesthetic effects in modern pharmacology. An apparent aspect of the lipoidal model's continued dominance is its long historical pedigree, frequently aligned with a process of steady refinement from Bibra and Harless to Hermann, Pohl, and finally Meyer/Overton. This paper problematizes this continuum by placing the genesis of a short-lived experimental entity-protagon-at the centre of the transition from the fat-solvation theory to the modern lipoidal theory of anaesthesia, which broadly identifies fat as a central mediating substance. A 'historical ontology' of protagon and an outline of the 19th century history of brain composition in relation to the early history of anaesthetic pharmacology, it treats the initial appearance of fat-oriented theories of anaesthesia as emergent of the focus on cerebral fat endemic to early 19th century organic principle analysis.
The pathogenesis of Parkinson's disease (PD) has been linked to environmental factors, toxins, genetics, and peripheral inflammation. Importantly, intestinal inflammation like that seen in Crohn's disease (CD) or food allergies has been implicated in risk for neurodegeneration and late-onset PD. Further, CD and PD share genetic risk factors including gain-of-function leucine-rich repeat kinase 2 (LRRK2) mutations. Here, we aim to better understand how intestinal inflammation synergizes with Lrrk2 levels or kinase activation to promote neurodegeneration in young and old mice. We utilized bacterial artificial chromosome (BAC) mice overexpressing wildtype mouse Lrrk2 or mutant G2019S mouse Lrrk2 and compared them with C57B6J mice at baseline and under conditions of intestinal inflammation using dextran sodium sulfate (DSS) colitis models. While our data revealed regulation of the brain inflammatory state by Lrrk2, we did not observe age-dependent selective vulnerability or protection in Lrrk2 mouse lines in colitis protocols. Instead, DSS phenotypes were associated with increased nigrostriatal dysregulation in all genotypes independent of age. While Lrrk2 mutations appear to influence the genesis of peripheral inflammation, our data suggest that Lrrk2 activation due to a gain-of-function mutation does not exacerbate the effects of inflammation on nigrostriatal degeneration in this model.
Air pollution is responsible for millions of global deaths annually. The most dangerous pollutants for health are particulate matter (PM), nitrogen oxides (NOx), sulfur dioxide (SO2), and carbon monoxide (CO). Recent studies have demonstrated an increased probability of cardiac arrhythmias, such as atrial fibrillation (AF). AF is the most common type of sustained cardiac arrhythmia, characterized by a process of atrial remodeling, where fibrosis is a hallmark of arrhythmogenic structural remodeling, which alters tissue composition and function. In addition to AF, both the genesis and aggravation of fibrosis have been reported as an effect of exposure to air pollutants. However, since most studies are epidemiological, the pathophysiological mechanisms by which pollutants aggravate AF in humans remain unclear. In this study, the effects of major atmospheric pollutants on the aggravation of AF were evaluated. Mathematical formulations describing pollutant-induced alterations in ionic currents were incorporated into a Courtemanche human atrial myocyte model previously remodeled for AF, which was then coupled to a three-dimensional atrial model. Structural remodeling was represented using the MacCannell fibroblast model. Electrogram recordings from virtual basket catheters were analyzed, and approximate entropy was computed. Results showed that pollutant exposure produced a marked loss of the action potential plateau and, at high concentrations, reduced action potential duration by approximately 35% in both atria. Likewise, pollutants favor the aggravation of AF, characterized by a greater number of reentries, in a concentration-dependent manner. The left atrial electrograms exhibited significantly increased approximate entropy; the effect was larger as the concentrations of the pollutants increased. These findings provide mechanistic insights into the effect of pollutants on the aggravation of atrial arrhythmias and may support public policies aimed at mitigating air pollution.
Oncogenic tyrosine kinase activity of BCR::ABL1 is causally associated with chronic phase (CP) of chronic myeloid leukemia (CML) and its inhibition by tyrosine kinase inhibitors (TKIs) induces remission in majority of patients. However, in the terminal blast crisis (BC) phase, 80% patients are resistant to TKIs. Forty percent among them are resistant despite inhibition of BCR::ABL1 activity by TKIs and in earlier study, we observed similar antithesis in K562 cells resistant to TKI-imatinib. We demonstrated active BCR::ABL1 signaling downstream of inactivated BCR::ABL1 and its causal association with resistance. This study explores the involvement of ITGB1, integrin with significant role in genesis of CML and differentially expressed in resistant K562 cells, in mediation of atypical activation of BCR::ABL1 pathway and thus resistance. Imatinib-sensitive and resistant K562 cells as well as sensitive cells with ITGB1 knockdown (KD) to mimic resistant cells, were analyzed for proteome and phosphoproteome by mass spectrometry and kinome was profiled by quantification of kinase activities in an array-based assay. The commonality between differentially expressed proteins (DEPs) identified in resistant cells and ITGB1-KD cells together with ITGB1 interactors, identified from ITGB1-immunoprecipitate by mass spectrometry, provided a comprehensive sketch of ITGB1-mediated signaling in resistant cells. The proteins identified as key players in ITGB1-mediated activation of BCR::ABL1 signaling were validated in K562 and KU812 cells, CD34+ cells from patient samples and their functional significance was assessed by inhibition studies in K562 cells. It was observed that the reduced levels of ITGB1 in resistant cells activated BCR::ABL1 downstream signaling kinases- p38MAPK and ERK. Though not influenced by ITGB1, LYN was active in resistant cells. Inhibition studies revealed that p38MAPK, ERK and LYN regulate the activity of each other, thereby explaining ITGB1-independent activation of LYN. The three kinases in turn activate members of CDK, MAPK, AKT and PKC families while ERK alone modulates EPH activity. Thus, reduction in level of ITGB1 in resistant cells leads to activation of ERK and p38MAPK belonging to BCR::ABL1 pathway, despite inactivation of BCR::ABL1, which in turn leads to activation of LYN. Together, these kinases activate members of vital pro-survival pathways, thereby imparting imatinib resistance in CML-BC cells.
Heterozygous missense mutations of TAU cause frontotemporal dementia with parkinsonism linked to chromosome 17 with tau pathology (FTDP-17T). FTDP-17T neurodegeneration of hippocampal and substantia nigra dopaminergic cells causes dementia and parkinsonism motor deficits. FTDP-17T cellular model of mutant TAU-expressing differentiated dopaminergic or hippocampal neurons was utilized to test hypothesis that FTDP-17T (R5H), (N279K), (K298E), (P301S), (K317M) and (G389R) TAUs located in different domains of TAU cause neurodegeneration with the same pathomechanism. (R5H), (N279K), (K298E), (P301S), (K317M) and (G389R) TAUs caused degeneration of dopaminergic or hippocampal neurons via mutation-induced gain-of-neurotoxicity. (R5H), (N279K), (K298E), (P301S), (K317M) and (G389R) mutations promoted Ser202/Ser396/Ser404 phosphorylations of TAU and formation of phospho-FTDP-17T TAUSer202/Ser396/Ser404 oligomers in dopaminergic or hippocampal neurons. GSK-3β inhibitor AR-A014418 completely blocked (R5H), (N279K), (K298E), (P301S), (K317M) and (G389R) TAUs-induced neurotoxicity by preventing (R5H), (N279K), (K298E), (P301S), (K317M) and (G389R) mutations-augmented Ser202/Ser396/Ser404 phosphorylations and genesis of phospho-FTDP-17T TAUSer202/Ser396/Ser404 oligomers. Phospho-(R5H), phospho-(N279K), phospho-(K298E), phospho-(P301S), phospho-(K317M) or phospho-(G389R) TAUSer202/Ser396/Ser404 oligomers were found in ER of dopaminergic or hippocampal neurons and activated ER stress, UPR and ER stress apoptotic signaling. Overexpression of mitochondrial phospho-FTDP-17T TAUSer202/Ser396/Ser404 oligomers caused mitochondrial malfunction via depolarizing mitochondrial membrane potential and oxidative damage by increasing ROS. Phospho-FTDP-17T TAUSer202/Ser396/Ser404 oligomers-evoked upregulation of Noxa, Bim or Puma and mitochondrial defect and oxidative stress excited mitochondrial pro-apoptotic pathway. Our results suggest that shared pathomechanism underlying FTDP-17T (R5H), (N279K), (K298E), (P301S), (K317M) and (G389R) TAUs-induced neurotoxicity is mutation-augmented GSK-3β-mediated Ser202/Ser396/Ser404 phosphorylations and generation of phospho-FTDP-17T TAUSer202/Ser396/Ser404 oligomers, which cause neurodegeneration by stimulating ER stress and mitochondrial pro-apoptotic cascades.
After February 1948, the new communist regime began to subordinate areas of life in Czechoslovakia to advocated political and ideological demands. Consequently, the unification of physical education and sports into Sokol was declared. In addition to institutional and legislative changes, the system of training for specialists was reorganized. The genesis of the Institute of Physical Education and Sport is reconstructed to illustrate organization and management of Czechoslovak physical education. The process of adopting the Soviet model of direct state control is described in the context of the geographic, historical, economic, and social specifics of a given territory. This research was based on the study of archival documents from the provenance of the State Committee and the State Office for Physical Education and Sport. This paper examines the intentions of the competent authorities, the circumstances of the foundation, mission, application of graduates and the content of studies at the Institute.
General intelligence enables flexible problem solving across diverse contexts by minimizing uncertainty. Symbolic systems such as language extend this capacity, allowing humans to build social groups and construct world models beyond typical biological constraints. Previous research on linguistic communication within active inference has emphasized deep hierarchical models that ensure shared semantics between communicators. We argue that these models, while powerful, require extension to account for symbolic genesis, specifically using morality not only as uncertainty minimization across cultural niches, but also as the mechanism that created the virtual space enabling symbolic cognition. Our ancestors transcended dyadic modeling by implementing cultural layers through novel model selection, enabling in-group signaling and hierarchical social organization through psychological typing. This rendered the generative process endogenous (self-referential). Our emotional and impulsive tendency toward morality, we argue, enabled the deeper level of abstraction and the stable third-party triangulated perspective necessary for symbolic thought. This framework can be evaluated through simulations similar to recent active inference literature and provides a foundation for building generally intelligent systems aligned with human cultural values.
Keloids undergo repeated cycles of regression and recurrence; however, vascular dynamics associated with recurrence remain poorly understood. In this prospective time-series study, we investigated microvascular changes in keloids using longitudinal three-dimensional photoacoustic imaging combined with ultrasonography. Adult patients with trunk or extremity keloids receiving intralesional triamcinolone treatment underwent imaging at four time points over a 6-month period. Vascular morphology and oxygenation were evaluated in superficial and subdermal layers using dual-wavelength near-infrared illumination and relative S-factor values referenced to peri-keloid regions. Six keloids in five patients were analyzed. Regressive lesions demonstrated hypoxic superficial microvessels disconnected from hyperoxic subdermal vessels, whereas recurrent lesions showed emergence of hyperoxic superficial microvessels continuous with hyperoxic subdermal venous networks. Persistent subdermal venous hyperoxia was observed irrespective of clinical status. Combined three-dimensional and longitudinal photoacoustic imaging enabled spatiotemporal identification of activity-dependent microvascular alterations associated with keloid recurrence, supporting a potential arteriovenous shunting mechanism.
To report a case of AA developing during golimumab and leflunomide treatment for seropositive rheumatoid arthritis, with subsequent improvement following initiation of selective Janus kinase 1 (JAK1) inhibition. A 55-year-old woman developed progressive, non-scarring alopecia while rheumatoid arthritis disease activity remained well controlled. Clinical and trichoscopic findings were consistent with AA, and laboratory investigations were unremarkable. The patient received serial intralesional triamcinolone at approximately 4-8 week intervals over a 14-month period, with progression in Severity of Alopecia Tool (SALT) score from approximately 20 to 50. Alopecia developed and progressed despite ongoing TNF-α inhibitor therapy and serial intralesional corticosteroids. Upadacitinib was initiated for rheumatoid arthritis management and escalated from 15 mg to 30 mg. Hair regrowth was observed within six weeks, with SALT improving to approximately 15 by three months. Although spontaneous remission and delayed corticosteroid effects cannot be excluded, the timing and magnitude of improvement support a temporal association with JAK1 inhibition. This case highlights a pragmatic therapeutic consideration when alopecia arises during TNF-α inhibitor therapy.
Current classifications used for total knee arthroplasty (TKA) are static and fail to capture the dynamic behavior of the limb during gait. This study introduces a novel intraoperative method to measure dynamic hip-knee angle (dHKA) using an intra-articular device coupled with a computer-assisted orthopaedic surgery (CAOS) system. This device applies a quasi-constant distraction force throughout the knee joint range of motion. A machine learning (ML) model was utilized to identify natural data groupings and develop a classification based on patient-specific dHKA profiles. We analyzed dHKA before and after the femoral cut (tibia-first TKA workflow) and assessed how often post-cut clusters matched pre-cut clusters across surgeons. A total of 1,890 tibia-first TKA cases performed by 11 surgeons were reviewed. For each case, HKA angles were recorded at 12 flexion angles (0 to 120°) before and after the femoral cut. Using pre-cut data, a 12-dimensional map was created with each dimension representing the degree of HKA at a specific flexion angle. A K-means clustering model was trained on data collected before the tibial cut to identify alignment profiles. The trained model was then applied to data collected after the tibial cut for comparison. A subset of 141 TKA cases from a single surgeon who had one-year Knee Injury and Osteoarthritis Outcome Score for Joint Replacement (KOOS Jr.) scores was analyzed to explore the association between cluster preservation and early functional outcomes. Clustering evaluation identified four clusters and an 8-dimensional feature space as optimal. Pre-cut/post-cut cluster distributions were cluster one (15.3%/14.2%), cluster two (35.9%/30.1%), cluster three (34.2%/35.6%), and cluster four (14.5%/20.2%). Cluster one was characterized as valgus and neutral, cluster two as neutral, cluster three as low to moderate varus, and cluster four as moderate to high varus. Overall, 69.4% of the cases retained the same cluster post-cut, with surgeon-specific match rates ranging from 61 to 88%. In the outcomes subset, 72.3% preserved their pre-cut cluster. Preservation was associated with greater KOOS Jr. improvement, with cluster-specific significance observed in low-to-moderate varus knees. This study demonstrates the first use of unsupervised ML to classify intraoperative dHKA profiles captured with a force-controlled intra-articular device and CAOS system. This enables real-time feedback and offers a foundation for an automated alignment classification guidance in personalized TKA.
A 65-year-old female patient presented with a slowly progressive right-sided ptosis. A myasthenia was excluded and the medical history included Hashimoto's thyroiditis and a previous pneumonia. After a successful transcutaneous levator resection a recurrence of ptosis developed 2 years later accompanied by a firm, yellowish swelling of the upper eyelid and involvement of the contralateral upper eyelid. The biopsy revealed lymphocytic infiltrates with lymph follicle formation, invasion into striated muscle, foam cells and Touton giant cells as well as mildly fibrotic and necrotic areas, consistent with an adult orbital xanthogranulomatous disease (AOXGD), subtype adult-onset asthma and periocular xanthogranuloma (AAPOX). A differentiation from necrobiotic xanthogranulomatosis and Erdheim-Chester disease was based on the absence of skin necrosis, minimal fibrosis and a lack of systemic involvement. Evidence of an immunoglobulin G4 (IgG4) association was noted clinically (Hashimoto's thyroiditis, chronic sinusitis) and histologically (increased IgG4-positive plasma cells). Following renewed upper eyelid blepharoplasty and multiple triamcinolone injections, a short-term systemic corticosteroid therapy was administered due to insufficient improvement. In the absence of a BRAF mutation, steroid-sparing immunosuppressive treatment with methotrexate was initiated, leading to marked regression of the swelling. This case highlights the diagnostic complexity and the importance of a combined histopathological, immunohistochemical and clinical evaluation in rare xanthogranulomatous eyelid lesions. KLINISCHER VERLAUF: Eine 65-jährige Patientin stellte sich mit einer langsam progredienten rechtsseitigen Ptosis vor. Eine Myasthenie wurde ausgeschlossen, anamnestisch waren eine Hashimoto-Thyreoiditis und eine zurückliegende Pneumonie bekannt. Nach erfolgreicher transkutaner Levatorresektion trat 2 Jahre später ein Rezidiv der Ptosis mit einer harten, gelblichen Oberlidschwellung sowie eine Beteiligung des kontralateralen Oberlids auf. Die Biopsie zeigte lymphozytäre Infiltrate mit Lymphfollikelbildung, Invasion in quergestreifte Muskulatur, Schaum- und Touton-Riesenzellen sowie gering fibrotische und nekrotische Areale, vereinbar mit einer adulten orbitalen xanthogranulomatösen Erkrankung (AOXGD), Subtyp „adult-onset asthma and periocular xanthogranuloma“ (AAPOX). Eine Abgrenzung zur nekrobiotischen Xanthogranulomatose und zur Erdheim-Chester-Erkrankung erfolgte aufgrund fehlender Hautnekrosen, geringer Fibrose und fehlender systemischer Beteiligung. Hinweise auf eine Immunglobulin-G4(IgG4)-Assoziation bestanden klinisch (Hashimoto-Thyreoiditis, chronische Sinusitis) und histologisch(erhöhte IgG4-positive Plasmazellen). Nach erneuter Oberlidblepharoplastik und mehrfachen Triamcinoloninjektionen wurde aufgrund mangelnder Besserung eine kurzfristige systemische Steroidtherapie durchgeführt. Bei negativer BRAF-Mutation erfolgte eine steroidsparende Immunsuppression mit Methotrexat, unter der eine deutliche Rückbildung der Schwellung beobachtet wurde. Der Fall verdeutlicht die diagnostische Herausforderung und die Bedeutung einer kombinierten histopathologischen, immunhistochemischen und klinischen Abklärung bei seltenen xanthogranulomatösen Lidveränderungen.
Multiple Sclerosis (MS) is a chronic neurological disorder, prevalent in young adults. MS leads in disability accrual, thus affecting overall patients' quality of life. Moreover, the management of MS poses significant burden on health systems worldwide. The present study delves into the impact of different health providing settings (e.g. private office/Clinic vs. specialized MS Center) on the effectiveness of MS management, as well as on patient-reported outcomes related to the quality of life (Axis A). Moreover, the study addresses their relative effectiveness in a health crisis, such as the COVID-19 pandemic (Axis B). Data were collected based on questionnaires administered to people with MS (pwMS). Upon the pandemic and prior to the COVID-19 vaccines being available, all data were collected via online questionnaires. Since March 2021, data were collected both online and in person. Overall, 776 pwMS participated in the study and answered Axis B questionnaire. Of those, 215 additionally answered Axis A questionnaire. Regarding Axis A, disease management by a specialized MS Center was associated with increased access to healthcare professionals (p < 0.001) and/or MRI examinations (p < 0.001) and was also linked to improved time-to-diagnosis following symptom onset, compared to the disease management in a private office/Clinic (p < 0.001). Regarding Axis B, specialized MS centers demonstrated remarkable adaptability during the pandemic, swiftly implementing remote care solutions to ensure continuity of care. These findings suggest that care delivered in specialized MS centers is associated with improved access to healthcare services and better patient-reported outcomes, both under routine care conditions and during healthcare crises.
Keloids are pathological scars characterized by excessive fibroproliferation and high recurrence rates after surgical excision. Dermal substitutes have been proposed as an adjunct to keloid surgery because they restore a stable dermal matrix, reduce mechanical tension, and may modulate fibroblast activity. However, their clinical effectiveness in preventing recurrence remains insufficiently defined. This study aimed to systematically review the available literature on the use of dermal substitutes following keloid excision. A systematic review was conducted according to PRISMA guidelines. Medline, Embase, Web of Science were searched from inception to January, 2026. Eligible studies included clinical reports using a dermal substitute after complete keloid excision with at least 6 months of follow-up and explicit recurrence data. Case reports, case series, and conference abstracts with sufficient clinical detail were included. Extracted variables comprised patient characteristics, lesion features, substitute type, operative protocol, adjuvant therapy, follow-up, recurrence. Due to heterogeneity, a descriptive synthesis was performed. Twenty studies were included, representing 109 patients and 116 keloid lesions. Most publications ware case series or case reports (Level IV-V evidence). Integra® was the most frequently used substitute, followed by Pelnac®, AlloDerm®, and Apligraf®. Reconstruction was most commonly performed using a two-stage approach with delayed split-thickness skin grafting. At 6 months, only one recurrence was reported among the studies providing early follow-up data. However, a recent larger retrospective cohort reported a recurrence rate of 28.8% after long-term follow-up. Adjuvant therapies such as radiotherapy, triamcinolone, and 5-fluorouracil were frequently combined with dermal substitute reconstruction. Dermal substitutes appear to be a promising adjunct in the surgical management of keloids, providing favorable aesthetic outcomes and low early recurrence rates. However, recurrence remains possible over long-term follow-up, and the independent effect of dermal matrices remains difficult to isolate due to frequent use of multimodal treatment protocols. Prospective studies with standardized surgical techniques and long-term follow-up are needed to better define the role of dermal substitutes in keloid surgery.