Multiple system atrophy (MSA) is a progressive adult-onset synucleinopathy that remains difficult to diagnose clinically, particularly in younger patients and during early disease stages. Brainstem nuclei degeneration resulting in reduced monoamines in cerebrospinal fluid (CSF) analysis may further complicate diagnostic interpretation. To describe a clinicopathologic case of early-onset MSA found to have decreased CSF monoamines suggestive of a primary neurotransmitter synthesis disorder. Clinical records, neuroimaging findings, CSF neurotransmitter analysis, and postmortem neuropathologic examination were reviewed. A 41-year-old woman developed rapidly progressive parkinsonism, dystonia, dysphagia, and speech impairment. Broad CSF analysis was significant for reduced homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and tetrahydrobiopterin, raising concern for a monoamine synthesis defect and prompting treatment for sepiapterin reductase deficiency (SRD). Despite directed therapy, neurologic decline continued. Postmortem examination demonstrated neuropathologic findings consistent with MSA, parkinsonian subtype (MSA-P). Early cortical and allocortical amyloid-β deposition corresponding to Thal phase 2 was also identified. No additional proteinopathies were present. Degeneration of dopaminergic and serotonergic nuclei in MSA can reduce CSF monoamine metabolite levels and mimic disorders of neurotransmitter biosynthesis despite correlation with tetrahydrobiopterin levels. This case highlights a potential diagnostic pitfall when interpreting CSF neurotransmitter studies in adults with parkinsonism.
Integrin α4β7 is a key adhesion receptor that mediates lymphocyte homing to the intestinal mucosa through interactions with MAdCAM-1, VCAM-1, and fibronectin, thereby playing a central role in gut immune surveillance and mucosal immunity. Emerging evidence has expanded its functional scope beyond intestinal homeostasis to encompass diverse inflammatory and metabolic diseases. This review systematically summarizes the structural characteristics, ligand interactions, and conformational regulation of α4β7, with an emphasis on its pathogenic roles in inflammatory bowel disease, cardiovascular diseases, diabetes, liver disorders, autoimmune diseases, gastrointestinal malignancies, HIV infection, asthma, and graft-versus-host disease. We discuss the underlying mechanisms, including lymphocyte trafficking, T cell co-stimulation, immune subset dysregulation, and crosstalk with the gut microbiota and epithelial barrier. In addition, we review the current landscape of α4β7-targeting therapeutics, including vedolizumab, etrolizumab, ontamalimab, and small-molecule antagonists, highlighting their clinical applications and limitations. By integrating recent mechanistic insights and therapeutic advances, this review provides a comprehensive framework for understanding the multifaceted roles of α4β7 and informs future strategies for targeting this integrin in disease.
Chronic spontaneous urticaria (CSU) and hereditary angioedema caused by C1 inhibitor (C1-INH) deficiency are mechanistically distinct disorders. When persistent wheals coexist with recurrent throat or abdominal symptoms, however, assigning individual episodes to mast-cell- or bradykinin-mediated pathways can be difficult. A 36-year-old Chinese woman developed recurrent wheals and pruritus in 2020. Beginning in 2024, she also reported episodic throat tightness and intermittent abdominal pain despite high-dose H1 antihistamines, systemic corticosteroids, and omalizumab. Repeated complement testing in 2025 showed low C4, reduced C1-INH concentration, and impaired C1-INH function. Her mother had similar biochemical abnormalities. These findings supported biochemical C1-INH deficiency in a patient with active CSU, but the mechanism of individual throat and abdominal episodes remained uncertain. Whole-exome sequencing, including exome-based copy-number analysis, identified no reportable pathogenic or likely pathogenic variant in the prioritized angioedema-related genes; however, not all currently recognized HAE-associated genes were included, and gene-level coverage metrics were unavailable. Documented treatment included H1 antihistamines, systemic corticosteroids, cyclosporine, and omalizumab. Subcutaneous icatibant and lanadelumab were also administered, but the retrospective records did not permit reliable assessment of icatibant response, and lanadelumab exposure was too brief to assess prophylactic efficacy. Following methylprednisolone, cyclosporine, and reintroduction of omalizumab, symptoms remitted briefly but recurred the day after discharge. At follow-up in February 2026, the patient reported fewer episodes, a lower wheal burden, less pruritus, and milder throat tightness and chest pain while receiving omalizumab plus an H1 antihistamine. In patients with CSU, recurrent throat tightness or abdominal pain should prompt complement testing and episode-level assessment. Objective airway findings, abdominal evaluation, attack timing, complement results, and response to on-demand therapy should be documented before symptoms are attributed to a specific mechanism.
Haploinsufficiency of A20 (HA20) is a rare genetic autoinflammatory syndrome caused by heterozygous loss-of-function variants in TNFAIP3. It typically appears in early childhood with recurrent fevers, mucocutaneous ulcers, gastrointestinal symptoms, and occasional eye involvement. The overlapping features with Behçet disease and other autoinflammatory disorders often make diagnosis challenging. We describe a 5-year-old girl who developed periodic fevers from age 2, along with oral ulcers, eye redness and swelling, abdominal pain, diarrhea, perianal tenderness, and dysuria. Initial treatments with colchicine and intermittent prednisolone provided little benefit. Whole exome sequencing revealed a likely pathogenic variant in TNFAIP3 (TNFAIP3 Chr6 138197257 138197257 C: NM_001270507.2: (5/9): c.759delC: p. Asp253fs), consistent with a diagnosis of Behçet-like autoinflammatory syndrome (HA20), with additional variants in PIK3R1, HBB, and SERPINA1 possibly modifying the phenotype. After the genetic diagnosis, therapy was escalated to infliximab, which led to improvement, this highlights the effectiveness of targeted biologic therapy in refractory pediatric HA20 insufficiency who unresponsive to conventional therapies.
Diabetic kidney disease (DKD) is a major microvascular complication of type 2 diabetes mellitus (T2DM). Chronic low-grade inflammation has been implicated in the development and progression of DKD. The systemic inflammatory response index (SIRI), a novel composite inflammatory biomarker, has demonstrated prognostic value in various inflammatory and metabolic disorders. However, evidence regarding the association between SIRI and DKD remains limited. This retrospective cross-sectional study included 2421 hospitalized patients with T2DM. DKD was defined according to established clinical criteria. Multivariable logistic regression models were used to evaluate the association between SIRI and DKD after adjustment for demographic and clinical covariates. Restricted cubic spline (RCS), receiver operating characteristic (ROC), subgroup, sensitivity, and mediation analyses were additionally performed. Among the 2,421 participants, 892 (36.8%) were diagnosed with DKD. Higher SIRI levels were significantly associated with increased odds of DKD in multivariable logistic regression analyses. Participants in the highest SIRI category had substantially greater odds of DKD compared with those in the lowest category. RCS analysis demonstrated a nonlinear positive association between SIRI and DKD risk. ROC analysis showed that the combination of age, sex, and SIRI had better discrimination ability for DKD than SIRI alone. Subgroup analyses demonstrated generally consistent associations across predefined subgroups, although significant interactions were observed for age and HbA1c status. Mediation analysis indicated that eGFR partially mediated the association between SIRI and DKD, accounting for approximately 46% of the total effect. Elevated SIRI was independently associated with increased odds of DKD in patients with T2DM. The association appeared nonlinear and was partially mediated through renal function impairment. SIRI may serve as a convenient inflammatory biomarker for identifying patients at higher risk of DKD.
BMP2 serves as a pivotal regulator of skeletal development, homeostasis, and repair. Previously, we demonstrated that Gαi1/3 (G protein subunit alpha i1/3) is not only involved in G protein-coupled receptor (GPCR) signal transduction but also acts as a key mediator of tyrosine kinase receptor signaling. However, its role in bone formation and BMP2 signaling remains elusive. In this study, we report that the expression of Gαi1/3 is significantly downregulated in the bone tissue of patients with senile osteoporosis. Gαi1/3 double knockout mice exhibited delayed skeletal development and reduced bone mass. Mechanistically, Gαi1/3 is required for BMP2 signal transduction, as its deletion impaired BMP2 downstream signaling. In BMSCs (bone marrow-derived mesenchymal stem cells), Gαi1/3 knockout suppressed BMP2-induced osteogenesis, while overexpression enhanced it. In the femoral fracture model, knockdown of Gαi1/3 in BMSCs reduced the ability of BMP2 to promote fracture healing. Furthermore, in neonatal mice with conditional knockout of Gαi1/3 in BMSCs, skeletal development was delayed. Gab1 is indispensable for Gαi1/3-mediated BMP2 signaling, as Gαi1/3 binds to both the BMP2 receptor and Gab1 to mediate BMP2 biological function. Collectively, our findings reveal the critical role of the Gαi1/3-Gab1 axis in BMP2 signaling and osteogenesis, providing potential therapeutic targets for osteoporosis and bone repair.
Psychedelic-assisted therapy (PAT) frequently utilises a "cotherapy" model, in which two therapists jointly support participants throughout dosing and psychotherapy sessions. While common in clinical trials, participant experiences of cotherapy remain underexplored. This study explored cotherapy experiences in PAT with psilocybin for Generalised Anxiety Disorder (GAD). Longitudinal qualitative analysis of participants sampled from a large randomised, open-label, phase 2 clinical trial of psilocybin-assisted therapy for GAD, delivered by clinicians with high levels of qualification, training and supervision. Qualitative data were collected from n = 18 participants via 29 semi-structured interviews, conducted before and after dosing sessions. Interviews examined experiences of PAT with a cotherapy dyad. Data were analysed thematically, guided by Affordance Theory to consider how cotherapy dynamics shaped therapeutic possibilities. Three major themes were developed: (1) dose day cotherapy: safety, trust and the realities of access; (2) cotherapy influences therapeutic processes; and (3) cotherapy shapes the impact and credibility of therapeutic insights. Cotherapy in PAT can be both a safety and supportive measure, and a potentiator of therapeutic processes. Insights from this study can guide clinical practice and future research to harness the potential safety and therapeutic benefits afforded by cotherapy while considering feasibility and accessibility.
This study aims to investigate the preventive effect of simvastatin on the subtotal nephrectomy model by analysing key mediators of inflammation and fibrosis. A total of 30 male Swiss mice were used in this study. The animals were divided into five groups (six/group): the sham group (Sham), the nephrectomy group (Neph), and three simvastatin groups (Simv) with a stepwise dose of simvastatin (5, 10, or 20 mg/kgBW). Kidney function was assessed by measuring serum creatinine, blood urea nitrogen (BUN), and proteinuria. Interstitial fibrosis was evaluated by Sirius red staining, α-SMA expression was evaluated by immunohistochemistry, and TNF-α expression was evaluated by real-time PCR. Subtotal nephrectomy significantly impaired renal function, increased interstitial fibrosis, and upregulated TNF-α and α-SMA expression. Simvastatin treatment dose-dependently reduced serum creatinine and proteinuria, although the reduction in BUN was not significantly different from the Neph group. Simvastatin also significantly attenuated interstitial fibrosis (8.62±2.43 in Simv5 group, 4.15±1.67 in Simv10, and 2.62±0.63 in Simv20 groups), decreased the expression of TNF-α (0.42±0.27 in Simv5, 0.39±0.18 in Simv10, and 0.23±0.21 in Simv20) and α-SMA (3.85±0.97 in Simv5, 2.74±0.61 in Simv10, and 1.59±0.45 in Simv20 groups) in dose-dependent manner, compared with the Neph group (all p < 0.05). Path analysis demonstrated that TNF-α indirectly contributed to renal fibrosis by promoting α-SMA expression, whereas α-SMA had a significant direct effect on interstitial fibrosis (p=0.038). This study found that the renoprotective effect of simvastatin in a subtotal nephrectomy model may be mediated by inhibition of the TNF-α/α-SMA signalling pathway, with α-SMA acting as a key mediator linking inflammation to renal fibrosis.
Sepsis is increasingly viewed as a disorder of inflammatory, metabolic, and mitochondrial homeostasis, but the path from metabolic disturbance to regulated cell death (RCD) and organ injury remains incompletely defined. Human studies show clinically meaningful metabolic and bioenergetic heterogeneity, while experimental models link mitochondrial stress, inflammatory signaling, membrane disruption, and pathway-specific RCD to tissue dysfunction. This review asks how evidence can be moved from co-occurrence toward mechanism. We synthesize findings across systemic metabolic phenotypes, cell-intrinsic immunometabolism, mitochondrial stress, RCD execution, membrane failure, inflammatory cargo release, organ injury, and therapeutic relevance. Apoptosis has the strongest direct human support as a non-lytic route of immune-cell depletion and epithelial loss; pyroptosis, ferroptosis, necroptosis, and PANoptosis are supported mainly by sepsis-relevant models and remain context dependent. Stronger mechanistic inference requires aligned measurements of metabolic flux, mitochondrial state, RCD execution, membrane integrity, extracellular cargo, host-defense effects, and tissue outcomes within matched cellular, organ, model, and temporal contexts. This framework separates association, susceptibility, execution, inflammatory release, tissue consequence, and therapeutic relevance when interpreting links among metabolic stress, mitochondrial stress, and RCD in sepsis.
Calcific uremic arteriolopathy (CUA) is a rare, severe condition affecting patients with chronic kidney disease (CKD). The etiology of CUA is unclear. Here, we aimed to identify factors associated with its development. We reviewed the existing evidence on its pathomechanisms and risk factors. We searched EMBASE and PubMed up to February 2026, reviewing all studies that would facilitate a comparison of CKD patients with and without CUA. Of 2374 screened publications, 35 met our inclusion criteria. The factors that consistently emerged related to CUA were decreased albumin, higher alkaline phosphatase, diabetes, increased body mass index, female sex, vitamin K antagonist (VKA) use, increased calcium phosphate product, and calcification and thrombosis in subcutaneous small arteries. Factors that appeared to be likely associated with CUA were anemia, suboptimal dialysis efficiency, peritoneal dialysis, inflammation, arterial hypertension, smoking, and hepatobiliary disease. Findings on matrix Gla protein alterations implicated in mediating VKA effects, parathyroid hormone, and hypercoagulability were ambiguous in our literature analyses. In addition, we found that a standardized system for CUA skin biopsy evaluation is lacking. In summary, our review delineates the major risk factors and pathogenic parameters associated with CUA development. Furthermore, it underscores areas in which robust data on CUA pathomechanisms are lacking. Calcific uremic arteriolopathy (CUA), also known as calciphylaxis, is a rare but serious condition that can occur in people with advanced kidney disease. It causes calcium to build up in small blood vessels, reducing blood flow and leading to painful skin wounds.To better understand why CUA develops, we reviewed studies comparing people with chronic kidney disease who did and did not develop the condition. We found that several factors were commonly linked to a higher risk of CUA, including diabetes, higher body weight, low blood albumin levels, abnormal calcium and phosphate levels, use of certain blood-thinning medicines (vitamin K antagonists such as warfarin), and being female. Other possible risk factors included anemia, inflammation, smoking, high blood pressure, and less effective dialysis treatment.Our findings suggest that CUA develops through a combination of factors affecting blood vessels, mineral balance, and overall health. More research is needed to understand exactly how these factors contribute to the disease and whether they can help identify patients at risk before symptoms appear. This could improve early detection, prevention, and treatment of this serious condition.
This article employs concepts of immunity to interpret the Samoan author Albert Wendt's novel The Mango's Kiss (2003). Contrasting Wendt's representation of two diseases-the 1918 influenza and a fictional illness called the Satoan Disease-it finds within the novel two accounts of immune response: a defensive system predicated on exclusion and the preservation of a bounded social body, and a relational system grounded in Indigenous ideas of adaptation and coexistence. Positioning these accounts in the context of competing paradigms in contemporary immunology, the article opens up a new reading of Wendt's critically underexamined novel. It concludes that The Mango's Kiss challenges the epistemological foundations of received biomedical and colonial discourse alike, proposing an alternative model of cultural resilience rooted in principles of indigenization and relational identity.
In the current study, we used an immunotherapeutic approach in female Swiss albino mice inoculated intraperitoneally with viable protoscoleces. We investigated the potential immunomodulatory effect and protective properties of IL-17A at 125 pg/mL on the development of secondary experimental echinococcosis. Swiss mice were inoculated intraperitoneally (i.p.) with 200 μL of a suspension containing 2000 viable protoscoleces to establish the infection model. IL-17A was administered intravenously two weeks after cystic echinococcosis (CE) induction. Cyst development and hepatic damage were macroscopically and histologically analysed. The hepatic expression of iNOS, TNF-α, NF-κB, CD68, and vimentin was examined. We observed that in vivo IL-17A treatment at 125 pg/mL reduced metacestode growth by 93.8%. Interestingly, treatment at this dose also led to decreased splenomegaly and improved liver tissue architecture. This was associated with a marked reduction in the fibrotic response, as evidenced by decreased collagen and reticulin fibre deposition. Moreover, IL-17A treatment resulted in reduced expression of key inflammatory and fibrotic markers, including iNOS, TNF-α, NF-κB, CD68, and vimentin, in the liver parenchyma. Our findings highlight the antihydatid and immunoprotective effects of IL-17A and support its potential therapeutic role in managing CE.
Diabetes and kidney diseases pose escalating threats to women's health, yet their combined burden among women aged 15-49 years remains underexplored. This study used data from the Global Burden of Disease 2021 study to quantify trends in type 2 diabetes (T2DM), chronic kidney disease (CKD), and CKD subtypes attributable to hypertension and T2DM across 204 countries and territories from 1990 to 2021, addressing important gaps in metabolic and kidney health research. Using GBD 2021 methodology, we calculated age-standardized incidence rates (ASIRs), Disability-Adjusted Life Years (DALYs), and Estimated Annual Percentage Changes (EAPCs). Analyses were stratified by Socio-Demographic Index (SDI) to dissect socioeconomic disparities. Global age-standardized DALYs and ASIR for diabetes and kidney diseases increased from 1990 to 2021. T2DM accounted for the greatest burden and showed the most rapid increase. Low-SDI regions experienced the highest disease burden, whereas high-SDI regions exhibited the fastest growth in T2DM. Marked regional disparities were observed, with Oceania and North Africa/Middle East showing particularly high incidence and burden. The global burden of diabetes and kidney disease among women aged 15-49 years is rapidly increasing, driven predominantly by T2DM. Low-SDI regions face disproportionate burdens, whereas high-SDI areas experience the most rapid growth in T2DM. These findings highlight important socioeconomic inequalities and support the need for context-specific public health strategies, including early screening, metabolic risk reduction, and improved access to diabetes and kidney disease prevention and management services.
To investigate epidemiological factors and clinical manifestations associated with longitudinal treatment response to intense pulsed light in patients with meibomian gland dysfunction (MGD). This study was conducted on 392 eyes (392 patients) undergoing 4 sessions of IPL. Treatment response was evaluated using measurements of meibomian gland expressibility (MGE) and meibum quality (MQ). A generalized estimating equation (GEE) was applied to evaluate associations between epidemiological factors, clinical parameters, and longitudinal changes in MGE and MQ. In adjusted GEE models, lower MGE and MQ grades indicated better meibomian gland function. Therefore, negative coefficients reflected improvement, whereas positive coefficients reflected a less favorable response. For MGE, worse baseline grade was associated with greater improvement after 4 sessions (B = -0.74, P < 0.001), although final MGE grades remained higher among eyes with higher baseline MGE grades. Telangiectasia across the meibomian gland orifice and keratinization were associated with less favorable MGE response (B = 0.52 and 0.30; P < 0.001 and 0.040, respectively). For MQ, worse baseline grade was associated with greater improvement (B = -0.85, P < 0.001), whereas telangiectasia across the orifice was associated with less favorable response (B = 1.45, P < 0.001). After 4 sessions of IPL, worse baseline MGE and MQ grades were associated with greater longitudinal improvement. However, residual dysfunction remained, particularly for MGE among eyes with more severe baseline disease. Meibomian gland orifice changes, particularly telangiectasia across the orifice and keratinization, were associated with less favorable longitudinal response and may help inform prognostication and individualized treatment planning.
Negative outcomes of psychological treatments for pediatric posttraumatic stress disorder (PTSD) have been underresearched. Although reporting has increased over the years, a comprehensive systematic review and meta-analysis is lacking. We conducted a preregistered systematic review and meta-analysis (PROSPERO ID: CRD42020206290) and followed PRISMA guidelines. MEDLINE, PsycInfo, Web of Science, and PTSDpubs were systematically searched from inception to May 13, 2025. Eligible studies were randomized controlled trials (RCTs) of psychotherapies for pediatric PTSD with ≥10 participants per arm. Two independent coders extracted data and assessed risk of bias. Seventy-two RCTs (N = 5,677) met inclusion criteria. Of these, 69, 6, and 19 reported the incidence of all-cause dropout, deterioration of PTSD, and adverse events, respectively. Most trials (74%) investigated trauma-focused cognitive behavioral therapy (TF-CBT). Random effects meta-analysis showed that 7.87% of patients (95% CI, 4.07-12.55; I2 = 82%) dropped out, with no significant difference relative to passive controls (RR = 1.04, 95% CI, 0.64-1.69; I2 = 53%). Less than 0.01% (95% CI, 0.00-2.39; I2 = 0%) of patients reported deterioration after TF-CBT, compared to 1.26% (95% CI, 0.00-8.13; I2 = 40%) of passive controls. Limited data prohibited isolated review of other treatments. The incidence of adverse events during psychological treatments was also uncommon (0.29%, 95% CI, 0.00-2.67; I2 = 34%) and similar to passive controls (1.14%, 95% CI, 0.00-8.02; I2 = 84%). Psychological treatments for pediatric PTSD-with most accumulated evidence for TF-CBT-appear safe and acceptable for the vast majority of children and adolescents with PTSD, which is encouraging for clinical practice. Reporting on deterioration and adverse events was scarce, limiting statistical power. Negative outcomes should be routinely assessed in clinical practice and future research, using validated measures and clearly defined constructs. Future work should distinguish serious adverse events and adverse events.
Non-Helicobacter pylori (H. pylori), non-nonsteroidal anti-inflammatory drug (NSAID) peptic ulcer disease (PUD) is increasingly recognized as a distinct subgroup, but its proportion across clinical presentations remains unclear. We aimed to estimate this proportion. We searched MEDLINE, Embase and CENTRAL from their inception to March 2026 for observational studies. The primary outcome was the proportion of non-H. pylori, non-NSAID PUD among adults with overall, bleeding and perforated PUD. Random-effects meta-analysis of logit-transformed proportions was performed using restricted maximum likelihood. Meta-regression assessed associations with study year, country-level H. pylori prevalence and region. Protocol registered in PROSPERO (CRD420251174202). Overall, 92 studies (60,816 patients) from 32 countries were included. The pooled proportions of non-H. pylori, non-NSAID PUD cases were 13.0% (95% confidence interval [CI], 10.4-16.2) in overall PUD, 11.3% (95% CI, 8.8-14.4) in bleeding PUD, and 22.0% (95% CI, 13.1%-34.7%) in perforated PUD. In univariable meta-regression, a more recent study year was associated with a higher proportion of bleeding PUD (β = 0.076; 95% CI, 0.031-0.120). This association remained statistically significant after adjustment for country-level H. pylori prevalence (β = 0.070; 95% CI, 0.026-0.113). Lower H. pylori prevalence was also associated with a higher proportion after further adjustment for region (β = -0.025; 95% CI, -0.046 to -0.005). Non-H. pylori, non-NSAID PUD represents a non-negligible but heterogeneous component of PUD. In bleeding PUD, exploratory ecological analyses suggest a temporal increase, potentially reflecting evolving etiologic patterns beyond H. pylori infection and NSAID exposure.
The angiopoietin/Tie pathway, essential for endothelial homeostasis, plays a key role in sepsis-induced endothelial dysfunction. This study evaluated angiopoietin-2 (Ang-2) as a biomarker for assessing disease severity in adult sepsis patients, comparing it with syndecan-1 and soluble thrombomodulin (sTM). Based on predefined criteria, we recruited sepsis patients admitted to the Department of Critical Care Medicine in the First Affiliated Hospital of China Medical University from April 2024 to May 2025. These patients were stratified into sepsis without shock and septic shock groups according to their clinical presentation at ICU admission. Peripheral blood samples were collected at enrollment for endothelial biomarker quantification. Multivariate logistic regression was performed to assess the independent association of these biomarkers with septic shock; intergroup comparisons and correlation analyses were conducted to evaluate their associations with organ dysfunction; and receiver operating characteristic curves were constructed to evaluate their predictive performance for short-term mortality. This study enrolled 233 sepsis patients. Ang-2, syndecan-1, and sTM levels were significantly higher in patients with septic shock compared to those without shock. Multivariate analysis identified Ang-2 as an independent risk factor for septic shock. All three endothelial biomarkers were markedly higher in patients with more severe organ dysfunction (SOFA-1 score>5) compared to those with lower scores (SOFA-1≤5) (all P<0.001), with Ang-2 demonstrating the strongest positive correlation with SOFA-1 scores (ρ=0.403, P<0.01). Furthermore, in predicting short-term mortality, including both ICU and 28-day mortality, Ang-2 exhibited the highest prognostic performance (AUC=0.748), and its predictive accuracy was further enhanced when combined with interleukin-6 (IL-6) and tissue plasminogen activator inhibitor complex (t-PAI-C). Ang-2 serves as a superior biomarker compared to sTM and syndecan-1 for characterizing septic shock, evaluating organ dysfunction severity and predicting short-term mortality.
Hereditary hemochromatosis (HH) is a genetic disorder characterized by excessive intestinal iron absorption, most associated with HFE C282Y homozygosity. In contrast, H63D homozygosity is considered a low-penetrance genotype that rarely leads to clinically significant iron overload. Bariatric surgery, particularly sleeve gastrectomy, may predispose patients to iron deficiency through reduced gastric acid and altered absorption. We report an unusual case of iron overload physiology in a patient with H63D homozygosity following sleeve gastrectomy, highlighting the diagnostic challenges posed by metabolic comorbidities and altered post-surgical physiology. A 51-year-old man with class III obesity, dyslipidemia, hypertension, vitiligo, obstructive sleep apnea, and a history of sleeve gastrectomy presented for weight management. Despite an initial 97-lb postoperative weight loss, he experienced significant weight regain along with fatigue, decreased libido, and skin darkening. Laboratory evaluation demonstrated hypogonadotropic hypogonadism, elevated serum iron (229 µg/dL), and transferrin saturation (60%) with normal ferritin (118 ng/mL). FibroScan revealed F3 fibrosis and grade 3 steatosis, consistent with advanced metabolic dysfunction-associated steatotic liver disease. Genetic testing confirmed H63D homozygosity. Pituitary MRI was unremarkable. The patient had increased alcohol intake prior to surgery, followed by a substantial reduction to moderate weekend use. The patient's iron overload was notable given his low-penetrance genotype and prior bariatric procedure. This case illustrates the complex interplay between genetic predisposition, metabolic disease, alcohol use, and altered gastrointestinal anatomy in shaping iron indices. It emphasizes the clinical relevance of transferrin saturation and comprehensive metabolic assessment. Clinicians should maintain vigilance for atypical presentations of HH in individuals with metabolic dysfunction or prior bariatric surgery.
Ulcerative colitis (UC) is characterized by reduced vagus nerve activity and colonic inflammation. This study examined region-specific effects of transcutaneous auricular vagus nerve stimulation (taVNS) on immune cells and cytokines in a UC-like mouse model, given its anti-inflammatory potential and differential innervation of the spleen, mesenteric lymph nodes (MLNs), and colon. Male C57BL/6 mice received daily 10-minute taVNS or sham treatment (anesthesia only) beginning 24 hours before induction of colitis with 5% dextran sulfate sodium in drinking water for 120 hours; controls received regular water. taVNS continued until sacrifice (144 hours after initiation). Disease activity index (DAI), macroscopic, and histological scores were assessed. Immune cell frequencies in the cecum, proximal, mid, and distal colon, spleen, and MLNs were analyzed by flow cytometry, and colonic cytokine levels were measured by multiplex ELISA. taVNS improved DAI, macroscopic scores, and histological damage throughout the cecum and colon. In colitic mice, taVNS reduced the total number of granulocytes and macrophages in the mid-colon but did not change granulocyte frequency in other colonic regions, MLNs, or spleen, nor did it affect macrophages in non-colitic mice. taVNS did not change M1/M2 macrophages, CD4+ and CD8+ T cells, B cells, or regulatory T cells. It reduced colonic IL-1β, TNF-α, and IL-6 in the cecum, proximal, and mid-colon; IFN-γ and IL-17A in the proximal and mid-colon; and IL-22 in the cecum and mid-colon of colitic mice. TGF-β1 was unchanged, whereas IL-10 increased in the proximal colon of colitic mice. These findings show taVNS's local anti-inflammatory effects in colitic mice through modifying innate immune cells and inflammatory and anti-inflammatory cytokines regionally.
Cognitive dysfunction is a core feature of major depressive disorder (MDD). Although both repetitive transcranial magnetic stimulation (rTMS) and vortioxetine have demonstrated procognitive effects, direct comparative evidence remains limited. This study compared the clinical and cognitive outcomes of rTMS and vortioxetine in patients with MDD. In this 8-week naturalistic study, 40 patients with MDD received either rTMS (n = 25) or vortioxetine (n = 15). Depressive symptoms were assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS). Cognitive performance was evaluated with the Perceived Deficits Questionnaire-Depression (PDQ-D), Trail Making Test Part B (TMT-B), Stroop Test, and Wisconsin Card Sorting Test (WCST). Longitudinal changes were analyzed using linear mixed-effects models. Week-8 outcomes were examined using ANCOVA adjusted for baseline cognitive performance and relevant clinical covariates. Both groups showed significant improvements in depressive symptoms and cognitive performance over time, with no significant treatment × time interactions. Baseline cognitive performance strongly predicted week-8 outcomes. Domain-specific differences were observed in executive functioning: vortioxetine showed a modest advantage in WCST performance, whereas rTMS showed a non-significant trend toward better Stroop interference performance. No significant differences were detected in processing speed. rTMS and vortioxetine were associated with comparable improvements in depressive symptoms and cognitive functioning in patients with MDD. Baseline cognitive status appeared to be a stronger predictor of outcome than treatment modality.