Polyarteritis nodosa with isolated organ involvement requiring resection in the genitourinary system.

Adult disease burden in patients with mucopolysaccharidosis type I H (Hurler syndrome): A comprehensive literature review with patient case analysis.

About 3-6% of individuals infected with SARS-CoV-2 develop post-COVID-19 condition (post-COVID), also known as multisystem disease, which comprises somatic and psychological symptoms. Nevertheless, there is an absence of research findings that differentiate patients with post-COVID from those with psychosomatic problems, for instance with regard to the presence of mental disorders. In addition, a comprehensive understanding of the factors that influence the manifestation of psychological symptoms in these patients is crucial for the development of multimodal interventions and lead to a destigmatization of post-COVID. A cross-sectional study was conducted at a Clinic for Psychotherapy and Psychosomatics (Dresden University Hospital) to compare the self-reported sociodemographic, clinical, and psychopathological characteristics of post-COVID patients (n = 357), attending a psychosomatic post-COVID outpatient clinic, with those of a group of patients with different psychosomatic disorders, attending a general psychosomatic outpatient clinic (n = 991). Clinical diagnoses were assessed by clinical experts according to the International Classification of Diseases (ICD-10), somatic symptom severity, depressive symptoms and anxiety, using the Patient Health Questionnaire (PHQ-D) (primary outcomes). In addition, in the post-COVID group, the influence of sociodemographic, clinical, and psychopathological variables on primary outcomes and incapacity to work were analyzed. The statistical methods encompassed linear and logistic regression analyses, generalized linear models, Mann-Whitney U-tests and chi-squared tests. Post-COVID patients demonstrated a greater degree of PHQ-15 somatic symptom severity (B = 1.37, p < .001) and higher levels of somatic and psychological multimorbidity (OR = 1.14, p = .005). At the level of specific disorders, post-COVID patients demonstrated an elevated risk of somatoform disorders (OR = 3.25, p < .001), while the risk of anxiety disorders (OR = .40, p < .001), affective disorders (OR = .52, p < .001) and personality disorders (OR = .11, p < .001) was reduced. In post-COVID, female gender (p = .003), somatic and psychological multimorbidity (p ≤ .025), experience of psychotherapy (p ≤ .031), and stress (p < .001) were associated with increased psychological symptom burden. Post-COVID patients can be regarded as a specific group, distinguishable from psychosomatic patients and presumably with prevailing somatoform processing mechanisms. In accordance with the recommendations of the German post-COVID guideline, mental disorders should be accorded serious consideration in the treatment of post-COVID, with the objective of averting the risk of chronicity through early intervention. The present study does not report results of a health care intervention on human participants. Therefore no registration was necessary.

Coronavirus disease 2019 (COVID-19) is frequently associated with neurological manifestations, most notably anosmia, raising questions regarding central nervous system involvement. Neuropathological studies have reported heterogeneous findings, and the relative contribution of direct viral neurotropism versus indirect systemic mechanisms remains controversial. An autopsy-based case-control study was conducted including 16 COVID-19-positive decedents and 15 age- and sex-matched COVID-19-negative controls. Histopathological examination focused on the olfactory bulb, olfactory tract, and frontal cortex. Reactive gliosis, microglial activation, perivascular inflammation, microvascular injury, neuronal eosinophilia, and corpora amylacea were assessed using standardized semiquantitative criteria and compared between groups. COVID-19-positive cases demonstrated significantly increased reactive gliosis and microglial activation in the olfactory bulb, along with a higher frequency of mild perivascular lymphocytic infiltration in the frontal cortex. In contrast, corpora amylacea and petechial hemorrhages were observed in both COVID-19-positive and control groups, without statistically significant differences. No evidence of viral cytopathic changes or diffuse encephalitis was identified. Systemic pathological findings in COVID-19-positive cases were consistent with severe multisystem disease. COVID-19 is associated with region-specific but non-uniform neuropathological alterations dominated by reactive and vascular changes rather than encephalitic processes. The inclusion of a contemporaneous control group demonstrates that several commonly reported histological findings represent nonspecific background changes. These findings support predominantly reactive and vascular mechanisms of CNS involvement in COVID-19 rather than direct encephalitic processes.

Heart failure with preserved ejection fraction (HFpEF) is a poorly understood, multisystem disease with high morbidity and mortality. To improve understanding of its pathobiology, we analyzed single-nucleus RNA sequencing in human HFpEF myocardium versus controls. Septal myocardial biopsies from 19 HFpEF and 24 nonfailing controls were analyzed using the 10× Genomics Chromium platform, with nuclei isolated from combined samples (6 patients/pool). Genotype-based demultiplexing was performed with souporcell, and gene expression was quantified with CellRanger and CellBender. After quality control, nuclei were annotated by cell types, and differential expression was performed between HFpEF versus controls using limma-voom. Functional analysis was performed using Gene Set Enrichment Analysis. Data were compared with prior single-nucleus RNA sequencing in dilated cardiomyopathy versus controls. We successfully demultiplexed pooled myocardial biopsies, assigning >70% of nuclei to individuals. After quality control, we recovered 48 886 nuclei and identified 14 cell types. Many differentially expressed genes across cell types were detected in HFpEF versus controls (fibroblasts, 5905; cardiomyocytes, 5159; endothelial cells, 2143; pericytes, 1812; and macrophages, 1405). Enriched pathways common to multiple cell types included immune activation, transcription/translation, metabolism, and protein quality control. They were particularly shared between cardiomyocytes and fibroblasts. Vascular smooth muscle cells had a more synthetic, proliferative phenotype. Immune cell analyses suggested enhanced T-cell activation and reduced macrophage clearance programs. Comparative analysis between HFpEF and dilated cardiomyopathy identified transcriptional differences primarily in cardiomyocytes. Two of 3 cardiomyocyte differential expression genes unique to HFpEF were validated to have concordant protein expression changes in HFpEF (MAP2K6 and PLPP3). Our findings reveal a distinct, cell-type-specific transcriptomic landscape in the human HFpEF myocardium. While HFpEF and dilated cardiomyopathy share significant molecular pathways across most cell types, the profound divergence within cardiomyocytes suggests a unique pathological driver for HFpEF. These signatures may provide a high-resolution roadmap for identifying precision therapeutic targets in HFpEF.

Inflammatory bowel disease and psoriasis as causal drivers of psychiatric disorders: A two-stage Mendelian randomization study grounded in the gut-brain-skin axis.

Myhre syndrome is a rare autosomal-dominant disorder caused by gain-of-function pathogenic variants in SMAD4 and is now recognized as a progressive multisystem fibrotic disease. Although transforming growth factor-β (TGF-β) signaling plays a central role in hepatic fibrogenesis, hepatobiliary involvement in Myhre syndrome has not been systematically evaluated. We report the first case of Myhre syndrome complicated by rapidly progressive biliary cirrhosis requiring liver transplantation in a 15-year-old male with a confirmed SMAD4 p.Ile500Val variant. Following an infectious episode, the patient developed severe cholestasis with imaging and histopathologic findings consistent with fibro-obliterative cholangiopathy, ultimately necessitating living donor liver transplantation. A systematic review of 55 published reports comprising 217 patients with Myhre syndrome revealed that hepatic evaluation was rarely performed and that previously reported liver abnormalities were mild and secondary, most commonly related to right heart dysfunction or metabolic disease, with no prior cases of progressive biliary fibrosis. This case suggests that dysregulated SMAD4-TGF-β signaling may predispose selected organs to fibro-obliterative injury and that infection-driven inflammation may act as a critical trigger for hepatic fibrosis in Myhre syndrome, expanding the recognized spectrum of organ involvement in this disorder.

This article reviews the evolving landscape and high prevalence of hyperaldosteronism and hypercortisolism, two previously under-recognized disorders for which cardiologists should have a high index of suspicion when managing patients with resistant hypertension. Resistant hypertension is estimated to occur in approximately 10-20% of people with hypertension, or 10 million people in the United States, and is associated with substantially increased cardiovascular morbidity and mortality. Hyperaldosteronism, previously considered a rare disease, has been shown to be a relatively common cause of hypertension and is a multisystem disease associated with a significantly higher risk of multiple comorbid conditions, including resistant hypertension. Likewise, endogenous hypercortisolism, once considered a rare disease, is now known to have a higher prevalence than previously estimated and is associated with a wide spectrum of clinical and biochemical presentations, including resistant hypertension, that result from prolonged exposure to excess cortisol activity. However, despite the prevalence and negative clinical consequences of hyperaldosteronism and hypercortisolism, screening rates remain low. Cardiologists are well positioned to provide timely screening for both hyperaldosteronism and hypercortisolism. To optimize clinical outcomes, patients with these endocrine causes of resistant hypertension require aldosterone-directed and/or cortisol-directed therapy in addition to therapy for hypertension.

Design and Rationale of the FICAPP Study: Frailty in Cardiac Amyloidosis: Profiling the Phenotype.

Axial spondyloarthritis: Moving beyond cytokine based therapies to cellular targets and advanced therapeutics.

Vacuoles, E1 enzyme, X-linked, autoinflammatory somatic (VEXAS) syndrome is a recently described multisystem disease. Opportunistic infections in VEXAS syndrome are increasingly being recognized and attributed to multiple factors, including immune dysregulation due to an aberrant ubiquitination pathway, secondary effects from chronic immunosuppressive treatments and underlying patient comorbidities. Given the limited consensus on antimicrobial prophylaxis, clinical practice is heterogeneous, with varying treatment outcomes. Herein, we report a rare case of cryptococcal meningitis in a patient with treatment-refractory VEXAS syndrome, on chronic moderate-dose corticosteroids (an average of 20mg prednisolone equivalent per day) and ruxolitinib. The patient initially presented with acute confusion and fevers, with elevated inflammatory markers and worsening cytopenia. The differential diagnoses included an acute flare of VEXAS syndrome and intercurrent infection. Further testing revealed the presence of Cryptococcus neoformans in the cerebrospinal fluid. Treatment with prolonged antifungal therapy was successful. The case raises important considerations, firstly regarding antimicrobial - particularly antifungal - prophylaxis given limited evidence in the literature, secondly a prompt diagnosis and treatment of cryptococcal infections, and finally regular interval screening for opportunistic infections in this vulnerable patient cohort. A multidisciplinary approach to care is required to improve morbidity and mortality from atypical infections in VEXAS syndrome.

Multicentric reticulohistiocytosis (MRH) is a rare non-Langerhans cell histiocytosis characterised by erosive arthritis and papulonodular skin lesions, frequently associated with autoimmune features. Therapeutic strategies remain empirical despite the potentially severe and disabling course. We report three cases of MRH with heterogeneous systemic involvement, all showing sustained, multidomain responses to Janus kinase (JAK) inhibitors.All patients developed inflammatory arthritis, ranging from arthralgia to destructive arthropathy, and early cutaneous papules predominantly affecting the face and trunk. Systemic manifestations included digital microangiopathy with a scleroderma-like capillaroscopic pattern in one patient and interstitial lung disease with lymphocytic alveolitis in another. Two patients fulfilled criteria for Sjögren's syndrome, and all were positive for anti-Sjögren's-syndrome-related antigen A/Ro52kD antibodies, highlighting the autoimmune overlap of MRH.Diagnosis was confirmed histologically by CD68-positive histiocytic and multinucleated giant cell infiltration. Conventional synthetic disease-modifying antirheumatic drugs and tumour necrosis factor inhibitors were ineffective or poorly tolerated, whereas tofacitinib and upadacitinib induced rapid and durable improvement across articular, cutaneous, vascular and pulmonary domains. These observations support a role for JAK-STAT signalling in MRH and suggest JAK inhibition as a rational therapeutic option in refractory multisystem disease.

Oral sarcoidosis: A systematic review of dental implications.

Respiratory infections due to human common cold coronaviruses, SARS-CoV, MERS-CoV, and SARS-CoV-2: epidemiology, pathogenesis, clinical features, diagnostics, therapeutics, and vaccine landscapes.

Sorbin and SH3 Domain Containing 2 (SORBS2), a multifunctional scaffold protein harbouring Sorbin homology (SoHo) and Src homology 3 (SH3) domains, serves as a molecular hub in human diseases by integrating cytoskeletal remodelling, signal transduction and RNA metabolic regulation. This study systematically analyses SORBS2's molecular features, expression regulatory mechanism and disease associations. In oncology, it suppresses metastasis via enhancing the stability of certain mRNAs and immunomodulation yet exhibits oncogenic properties in triple-negative breast cancer. Cardiovascular manifestations demonstrate dose-sensitive pathology: deficiency causes arrhythmogenic cytoskeletal disorganization, while overexpression induces β-tubulin hyper polymerization and ventricular maldevelopment. Epigenetic silencing by miR-484 exacerbates metabolic liver disease, whereas defective interaction with the large-conductance Ca2+-activated K+ (BK) channel drives diabetic vasculopathy. Neurologically, it modulates synaptic remodelling and neuroinflammatory pathways. Functioning as a signalling nexus, SORBS2 interconnects chronic inflammation, oxidative stress and metabolic dysfunction, supporting 'one target for multiple diseases' strategy. Future research requires integration of single-cell omics, Artificial intelligence (AI)-based drug design and epigenetic editing for clinical translation.

Telomere length in patients with Marfan Syndrome.

This study aimed to evaluate the global trends in systemic sclerosis (SSc)-related mortality by age, sex, and geographic region. SSc is a multisystem autoimmune disease characterized by tissue fibrosis, vascular dysfunction, and multi-organ involvement, which is associated with a high mortality risk. Using the World Health Organization Mortality Database, we examined trends in SSc-related crude mortality rates (SSc-CRs) and age-standardized mortality rates (SSc-ASMR) per 1,000,000 population from 2001 to 2023. Locally weighted regression was applied to visualize long-term patterns, and Joinpoint regression was used to assess the national trends from 2010 to 2023. Across 74 countries, 85,291 SSc-related deaths were reported, with 79.41% occurring in females. The SSc-CR steadily increased from 1.97 (95% confidence interval [CI]: 1.71-2.23) in 2001 to 2.34 (95% CI: 2.01-2.68) in 2023, while the SSc-ASMR decreased from 1.58 (95% CI: 1.42-1.74) to 1.29 (95% CI: 1.08-1.50), respectively. Regionally, mortality was the highest in the Western Pacific region and declined in the Americas and Europe, with temporal fluctuations. The SSc-ASMR was highest in countries with a middle sociodemographic index (SDI). While overall age-standardized mortality from SSc has declined in many regions, disparities persist. These results underscore the importance of sustaining research and enhancing disease awareness, as well as developing strategies to reduce mortality in high-risk populations and regions. Key Points • First global analysis ofmortality trends across 74 countries (2001-2023) • Age-standardized mortality declined globally, but crude mortality increased, with persistent female predominance • Findings highlight need for targeted strategies, early diagnosis, and improved care to reduce mortality.

Abstract Granulomatosis with polyangiitis (GPA) is a rare multi-system disease characterized by non-caseating granulomatous vasculitis. It can involve any organ system; however, it commonly affects the lungs and kidneys. Over the course of the disease, pulmonary involvement occurs in approximately 90% of patients while only 9% have sole pulmonary involvement. Fever and weight loss are the most common presenting symptoms, and pulmonary manifestations include cough, dyspnea, chest pain, and, rarely, subglottic stenosis (SGS). We report a case of female patient who initially experienced sinonasal symptoms followed by cough, wheezing, and stridor. She was diagnosed with granulomatosis with polyangiitis after a laryngoscopy revealed subglottic stenosis and autoimmune serology was positive for MPO-ANCA. A 26-year-old Hispanic female with a history of severe hypertension since adolescence, an atrophic left kidney, and chronic nasal congestion presented with progressive upper and lower airway disease. She first experienced sinonasal symptoms, including obstruction, crusting, and septal deviation, that ultimately required septoplasty and turbinectomy in 2020. By age 25, she developed persistent cough, wheezing, and stridor unresponsive to bronchodilators or corticosteroids. Pulmonary function testing suggested obstructive physiology, and laryngoscopy revealed subglottic stenosis. Cross-sectional imaging demonstrated airway narrowing with bronchial wall thickening and a thin web within the left mainstem bronchus, while bronchoscopy confirmed scarring at the carina, circumferential narrowing of the left mainstem bronchus, and multifocal airway stenoses. Biopsies showed chronic inflammation without granulomas or necrosis. Autoimmune serologies revealed a strongly positive MPO-ANCA with negative PR3-ANCA. Taken together, her chronic sinonasal disease, subglottic stenosis, multifocal bronchial involvement, and positive MPO-ANCA were diagnostic of granulomatosis with polyangiitis with pulmonary involvement, limited form, despite nondiagnostic histopathology. She was started on azathioprine, and balloon dilation of her subglottic stenosis was deferred pending immunosuppressive control. This case highlights a limited form of GPA with SGS and possible treatment modalities. While over 90% of patients with GPA present with upper and/or lower respiratory tract symptoms, 20% develop SGS, which reflects the chronic phase of airway obstruction from GPA. The acute phase occurs from fixation of the vocal folds from inflammation of the laryngeal joints. Patients with symptoms such as stridor, hoarseness, and dyspnea necessitate urgent evaluation for impending airway obstruction. Treatment for GPA typically consists of induction therapy, including glucocorticoids, followed by a maintenance regimen with the use of immunosuppressive medications. Patients with symptomatic SGS are usually treated with bronchoscopic techniques, including dilation, laser debridement, and corticosteroid injection. Refractory disease may require tracheostomy. This abstract is funded by: None

The UNC13D gene encodes Munc13-4, a key regulator of cytotoxic granule exocytosis in effector immune cells, enabling the release of perforin and granzymes that are essential for cytotoxic function and immune surveillance. Loss-of-function mutations in UNC13D result in immune dysregulation syndromes, most notably familial hemophagocytic lymphohistiocytosis (fHLH, also referred to as FHL). This review provides a comprehensive overview of UNC13D, including its structural characteristics, biological functions, and spectrum of pathogenic variants. We summarize the mechanistic roles of Munc13-4 in granule-mediated cytotoxicity and examine the clinical correlations between UNC13D mutations and fHLH type 3 (FHL3). Furthermore, we discuss emerging evidence linking UNC13D dysfunction to a broader range of diseases, highlighting its clinical relevance and potential as both a diagnostic biomarker and therapeutic target. Overall, this review aims to bridge the gap between molecular mechanisms and clinical translation in UNC13D-related disorders.

Acid sphingomyelinase deficiency (ASMD) is a rare debilitating lysosomal storage disease resulting in multisystemic disease manifestations, significant disease burden, and early mortality for some individuals. Enzyme replacement therapy (ERT) with olipudase alfa (Xenpozyme) is the first disease-specific treatment indicated for noncentral nervous system manifestations of ASMD in children and adults. During the 1-year primary analysis of the ASCEND placebo-controlled trial in 36 adults with ASMD, olipudase alfa treatment reduced sphingomyelin storage and was associated with clinically significant improvements relative to placebo in multiple endpoints. An open-label extension of the ASCEND trial followed 35 of 36 adults during olipudase alfa treatment for up to 5 years. Mean time on olipudase alfa was 4.2 ± 1.0 years; mean compliance was 90% ± 13%. During long-term olipudase alfa treatment, percent predicted diffusing capacity for carbon monoxide (DLCO) increased (mean 50.1% ± 10.8% at baseline vs. 66.5% ± 13.3% at final assessment; mean change from baseline of 35.9% ± 27.5% (p < 0.0001). Mean baseline spleen volume of 11.5 ± 4.6 multiples of normal (MN) decreased to 4.8 ± 2.1 MN at final assessment, mean change from baseline -57.5% ± 10.1% (p < 0.0001) and mean baseline liver volume (1.5 ± 0.4 MN) decreased to 0.95 ± 0.23 MN at final assessment, (mean change from baseline -36.8% ± 11.5%, p < 0.0001). Plasma lyso-sphingomyelin levels decreased by 72% from baseline to final assessment. Overall, improvements in clinical parameters occurred regardless of baseline severity. No new safety issues emerged during the trial extension and 98% of treatment emergent adverse events were mild/moderate. Improvements in visceral ASMD disease with olipudase alfa treatment will significantly impact the disease burden for those with this progressive multiorgan disorder.