Sepsis-induced B-cell dysfunction is a pivotal driver of adaptive immunosuppression, although the underlying molecular mechanisms remain incompletely elucidated. CD74, a multifunctional immunoregulatory protein, is known to mediate tumor immune evasion and immunosuppression during infection via modulation of inflammatory pathways; however, its specific role in B-cell dysfunction during sepsis has not been defined. Through integrated clinical and experimental analyses, we observed significant downregulation of CD74 in the peripheral blood of septic patients (based on GSE datasets), which correlated with adverse clinical outcomes. Validation in a cecal ligation and puncture-induced sepsis model in C57BL/6J mice demonstrated that CD74 deficiency markedly increased mortality, elevated pro‑inflammatory cytokine levels (tumor necrosis factor‑α, interleukin [IL]‑6, IL‑1β, monocyte chemoattractant protein-1; measured by enzyme-linked immunosorbent assay), and impaired bacterial clearance. Mechanistically, CD74 is a member of the regulated intramembrane proteolysis protein family. Following intramembrane cleavage, its intracellular domain (CD74‑ICD) is released and translocates to the nucleus, where it interacts with the key transcription factor Pax5 (as confirmed by co‑immunoprecipitation and immunofluorescence). This interaction leads to activation of the PI3K‑AKT signalling pathway, thereby preserving B-cell functional competence. Single‑cell transcriptomic analysis further supported the functional relevance of the CD74‑Pax5 axis in septic B cells. In summary, this study identifies CD74 as a critical regulator of sepsis-associated B-cell immunosuppression and highlights its therapeutic potential for immune reconstitution in sepsis.

Oral propranolol, with or without corticosteroids, has been shown to benefit diffuse infantile hepatic haemangioma (IHH); randomized trial evidence is lacking. We aimed to evaluate the efficacy and safety of propranolol monotherapy versus propranolol plus prednisone for the treatment of problematic IHHs to determine whether oral prednisone provided an added benefit to propranolol. We conducted an open-label, multicenter, randomized controlled trial across six referral centers in China from July 2019 to November 2023 (clinicaltrials.gov registration: NCT03331744). Infants with problematic diffuse IHH were assigned (1:1) to oral propranolol alone or propranolol plus a short course of prednisone. The primary endpoint was the proportion of patients who achieved a lesion response at week 4 on serial ultrasound. Analyses followed the intention-to-treat principle. Forty-five patients were included in this study (propranolol, n = 22; propranolol plus prednisone, n = 23). Four weeks following treatment, lesion response rates were higher with propranolol plus prednisone than with propranolol alone [21/23 (91.3

Heatstroke has high mortality, requiring early risk stratification. This study aimed to compare the predictive value of the reverse shock index multiplied by Glasgow Coma Scale score (rSIG) with shock index (SI), GCS, and qSOFA score for mortality in ICU heatstroke patients. The reverse shock index multiplied by Glasgow Coma Scale score (rSIG), calculated as GCS × (SBP / HR) using the first recorded values at ICU admission. This multicenter retrospective study included 671 heatstroke patients from 83 ICUs. Predictive performance was compared using receiver operating characteristic (ROC) curves. Independent risk factors were identified via logistic regression, and a nomogram was developed. Subgroup analysis was conducted to assess the consistency of the predictive value of rSIG. The mortality rate was 17.88%. rSIG demonstrated the highest predictive ability (AUC = 0.739), outperforming SI, GCS, and qSOFA. Prothrombin time, creatinine, lactate, and rSIG were independent predictors. The nomogram integrating these factors achieved an AUC of 0.80. Subgroup analysis confirmed the consistent predictive value of rSIG across various patient subgroups. The rSIG is a simple and effective early screening tool for rapid risk stratification in ICU patients with heatstroke. The predictive model combining rSIG with PT, Cr, and Lac further enhances prognostic accuracy, offering significant clinical utility.

[This retracts the article DOI: 10.1016/j.heliyon.2022.e12517.].

BackgroundPrimary lymphedema (PLE) and kaposiform hemangioendothelioma-related lymphedema (KLE) are rare vascular anomalies (VAs). This study aimed to examine the clinical features, management, and prognosis of PLE and KLE.MethodThe clinical features, imaging, treatments, and outcomes of 12 patients with PLE and 12 patients with KLE were retrospectively reviewed.ResultsThe mean age at which signs/symptoms were diagnosed was 68.2 months for PLE patients and 25 months for KLE patients. In PLE, the involvement of multiple sites is common, whereas in KLE, it typically affects a single site. Morbid obesity, which is common in adult patients, is rare in pediatric PLE and KLE patients. Imaging agent accumulation was observed in KLE but not in PLE via lymphoscintigraphy. In contrast, complications of PLE primarily involve skin and soft tissue, whereas musculoskeletal system complications are more common in KLE. Regarding prognosis, most patients stabilize or even experience lesion regression after standard treatment.ConclusionPLE and KLE share clinical symptoms. PLE often involves multiple sites, whereas KLE typically presents unilaterally with local lymphatic stasis. Standardized treatment enables the majority of children with lymphedema to control the disease without progression, with KLE showing potential reversibility. Given their rarity, a multidisciplinary approach is crucial for diagnosis and management.

BACKGROUND:Infantile hemangioma (IH) is the most common benign tumor in infancy and severely affects aesthetics and function. Hemangioma-derived endothelial cells (HemECs) are the main cellular component of IH and contribute to angiogenesis in IH. TGF-β1 (transforming growth factor β1) can induce endothelial-to-mesenchymal transition (EndoMT). Few studies have investigated the role and mechanism of TGF-β1-mediated EndoMT in IH angiogenesis. METHODS:The expression of EndoMT markers in IH samples was evaluated via multiplexed immunofluorescence assay. Lentiviruses and small interfering RNA were used to regulate gene expression. Targeted lipidomic analysis was subsequently conducted. Protein interactions between TGF-β1 and potential effectors were examined. Biological changes in function were measured by migration, invasion, and tube formation in vitro and vessel formation in vivo. Autophagy-related structures were detected via transmission electron microscopy. BALB/C-nude mice were used for the hemangioma model. RESULTS:In this study, the active participation of EndoMT in proliferating IH was verified. TGF-β1OE (TGF-β1 overexpression) induced EndoMT and promoted the migration, invasion, and angiogenic abilities of HemECs. In addition, TGF-β1OE decreased the protein expression of CPT1A (carnitine palmitoyltransferase 1A). TGF-β1 treatment decreased the levels of L-palmitoylcarnitine (a downstream metabolite of CPT1A) in HemECs. Supplementation with L-palmitoylcarnitine partly reversed the functional changes caused by CPT1AKD (CPT1A knockdown). Furthermore, the effect of TGF-β1OE+overexpression model of CPT1A was similar to that of CPT1AKD+L-palmitoylcarnitine in regulating the functional behaviors of HemECs. R(+) propranolol inhibited HemECs EndoMT and vessel formation in vivo. CONCLUSIONS:TGF-β1-mediated EndoMT promotes angiogenesis in IH. Targeting TGF-β1 could be a promising therapeutic strategy for inhibiting IH progression.

Sirolimus and everolimus, two representative inhibitors of the mammalian target of rapamycin (mTOR), have distinct therapeutic effects on numerous paediatric diseases that do not have specific treatments, particularly vascular abnormalities, but their safety regarding the growth and development of children is still worth considering. The most frequent adverse reaction in clinical practice, elevated liver enzymes, has not yet been thoroughly investigated to determine whether it is hepatotoxic to growth and development. In this study, experiments with zebrafish models revealed that sirolimus and everolimus caused hepatotoxicity, on the basis of the delayed rate of yolk sac absorption, even at a standard dose (≤ 0.1 μM). At high concentrations (≥ 0.5 μM), more pronounced hepatotoxic effects were observed, including significant reductions in liver size, elevated ALT levels, widened gaps between hepatocytes and increased vacuolization within hepatocytes, as assessed by liver morphology, functional biomarkers and histopathology. Integrated transcriptomic and metabolomic analyses revealed that the hepatotoxicity was associated with aberrant activation of the PI3K/AKT pathway and disrupted lipid metabolism, primarily driven by downregulation of phosphoenolpyruvate carboxykinase 1 (PCK1). These findings underscore the importance of regular monitoring of drug blood concentrations in paediatric patients and provide new insights into dose optimization and toxicity surveillance in children.

BACKGROUND:It remains unknown whether low-dose sirolimus can replace high-dose sirolimus for the treatment of kaposiform hemangioendothelioma (KHE) without the Kasabach-Merritt phenomenon. OBJECTIVE:To evaluate the noninferiority and safety of low-dose versus high-dose sirolimus in KHE patients. METHODS:This randomized, multicenter, open-label, noninferiority trial was conducted from February 2021 to August 2022. Participants received either a low-dose sirolimus regimen (blood trough concentration 5-8 ng/mL) or a high-dose sirolimus regimen (blood trough concentration 10-15 ng/mL). The primary endpoint was the difference in the proportion of patients between groups who achieved an objective response, defined as a ≥20% reduction in KHE volume at month 12. RESULTS:In this study, 39 were in the low-dose group, and 40 were in the high-dose group. At 1 year of treatment, 90.0% in the high-dose group and 89.7% in the low-dose group achieved an objective response (difference, 0.3%; 95% confidence interval -13.1 to 13.6). The incidences of total adverse events and serious adverse events were similar between the 2 groups, but respiratory, skin, and mucosal adverse events were less common in the low-dose group. LIMITATIONS:The patients enrolled were not associated with Kasabach-Merritt phenomenon. CONCLUSION:Low-dose sirolimus is noninferior to high-dose sirolimus in treating KHE.

BACKGROUND:Oral propranolol is the first-line treatment for problematic infantile hemangiomas (IHs) requiring systematic therapy. Several retrospective studies have reported the successful treatment of facial IHs with propranolol. In this study, the authors conducted a prospective trial to evaluate the long-term outcomes of oral propranolol use in patients with facial IHs. METHODS:The primary outcome was the clinical response 4 years after treatment. RESULTS:A total of 272 patients were analyzed, including 38 patients (14.0%) with ulcerated IHs. Four years after treatment, propranolol treatment had resulted in no/minimal sequelae in 232 patients (85.3%). A total of 265 patients (97.4%) reported a durable response to propranolol therapy. Major rebound occurred in 16.9% of patients after propranolol discontinuation. Additional surgery and laser treatment were required in 8.1% and 8.8% of patients, respectively. Logistic regression analyses revealed that age 3 months or older (95% CI, 1.488 to 31.023; P = 0.013), nasal IH (95% CI, 2.143 to 97.571; P = 0.006), and hemangioma ulceration (95% CI, 2.673 to 49.034; P = 0.001) were independent factors predictive of long-term severe/significant sequelae. Segmental subtype (95% CI, 2.081 to 45.597; P = 0.004), mixed IH (95% CI, 3.249 to 26.841; P < 0.001), and lip IH (95% CI, 2.224 to 92.278; P = 0.005) were independent risk factors for major rebound. CONCLUSIONS:In this large cohort of patients with facial IHs, propranolol treatment was effective and induced no/minimal sequelae at 4 years after treatment. However, long-term severe/significant sequelae and major rebound after propranolol treatment remain challenges.

Objective: The diagnosis of abdominal lymphatic malformations (ALMs) is often overlooked in clinical practice. However, reports in the literature about ALMs are limited to case reports and series with small sample sizes. This study aimed to review our currently available data to describe the clinical characteristics of ALMs and evaluate the risk factors for acute abdomen caused by ALMs. Methods: We reviewed the records of patients with ALMs who were diagnosed between December 2008 and January 2023 in our institution. The associations between acute abdomen and ALMs were analyzed based on single-factor and multivariate logistic regression analyses. Results: This study included 345 patients with pathologically confirmed ALMs, with a slight female predominance of 1:1.4. Approximately 39.1% (135/345) of patients were asymptomatic, and 24.6% (85/345) presented with acute abdomen. Among the ALMs in the cohort, 42.6% (147/345) were retroperitoneal lymphatic malformations (LMs). The maximal lesion dimensions in patients with acute abdomen and nonacute abdomen were 10.0 cm and 7.8 cm, respectively, with no significant difference based on multivariate analyses. Children were more likely to develop acute abdomen than adults were (P = . 002: odds ratio, 5.128: 95% confidence interval, 1.835-14.326). ALMs accompanying acute abdomen were more common for lesions involving the small intestinal mesentery (P = . 023: odds ratio, 2.926: 95% confidence interval, 1.157-7.400). Conclusions: ALMs are rare with an insidious onset, and retroperitoneal LMs are the most common ALMs, followed by jejunal mesenteric LMs. Our retrospective analysis suggested that young age and small intestinal mesenteric lymphatic malformation are independent risk factors for acute abdomen with ALMs. (J Vasc Surg Venous Lymphat Disord 2025:13:101969.)

BackgroundOur previous research confirmed that vitamin A (VA) deficiency commonly occurs in children with sepsis, and serum VA levels negatively correlate with disease severity. This study aimed to evaluate the efficacy and safety of VA supplementation (VAS) in children with sepsis.MethodsA randomized, single-blind, single-center trial was conducted from June 2020 to March 2024 involving children diagnosed with sepsis. Participants were randomly allocated to either the VAS group or the placebo group. The primary outcome was length of stay in the ICU, and secondary outcomes included hospital length of stay, 28-day mortality, duration of mechanical ventilation, and antibiotic usage. Vital signs, clinical symptoms, and laboratory data were recorded, and statistical analyses assessed the efficacy and safety of VAS.ResultsA total of 156 children with sepsis were enrolled: 72 in the VAS group and 84 in the placebo group. The median baseline VA level among participants was 147.22 (97.20–258.04) ng/ml. There was no significant difference in ICU length of stay between the VAS and placebo groups [14 (7–27) vs. 16.5 (9.3–26) days, P = 0.451]. Similarly, no significant differences were observed between groups regarding hospital length of stay, 28-day mortality, duration of mechanical ventilation, or antibiotic usage. In addition, we performed a post hoc analysis of biomarkers. VAS showed a significant downward trend in lactate levels (P < 0.001), higher 24-h lactate clearance rate (25%), and significantly lower lactate levels on the third day post-intervention (1.28 ± 0.50 vs. 2.20 ± 2.21, P = 0.001). Additionally, VA levels positively correlated with serum albumin (ALB) (r = 0.479, P < 0.001). Procalcitonin (PCT) levels were significantly lower in the VAS group on the 3rd (P = 0.032) and 7th day (P = 0.001) post-intervention, and white blood cell (WBC) count was lower on the 3rd day (P = 0.022). Furthermore, compared with the placebo group, the VAS group had a greater reduction in PCT levels within 24 h following intervention (73% vs. 48%, P = 0.001). No adverse reactions associated with VAS were observed.ConclusionsVAS did not significantly reduce ICU length of stay or 28-day mortality in children with septic shock, however, it may have beneficial effects on systemic inflammation and lactate metabolism. Further studies are warranted to explore the relationship between VA and ALB.Clinical Trial RegistrationClinicaltrials.gov, identifier NCT04127968.

BACKGROUND:Primary lesions of the spleen are very rare, and splenic lymphatic malformations (SLMs) account for 0.007% of all splenic lesions; thus, SLMs are often ignored in clinical practice. The aim of this study was to review the clinical and imaging features of 35 patients with SLMs, classify them on imaging and provide a reference for treatment. METHODS:We reviewed the records of patients with SLMs who entered the medical system at our institution from December 2008 to March 2023. The clinical characteristics and imaging features of these patients were collected to classify SLMs. RESULTS:In our case series, 82.9% (29/35) of the patients with SLMs were adults, whereas only 6 patients were children, and 97.1% of (34/35) patients were women. A total of 68.6% (24/35) of the patients were asymptomatic. Seven patients experienced complications, such as cyst rupture, cyst bleeding, and mass effects. On imaging, the average cyst diameter of the SLMs was 5.2 cm, and macrocystic SLMs (23/35) were the most common. SLMs can be divided into isolated SLMs, multiple SLMs, and diffuse SLMs, of which 17 cases were isolated lesions, 14 cases were multiple lesions, and 4 cases were diffuse lesions. Some lesions were accompanied by cyst wall calcification. All patients underwent surgical removal, and no signs of recurrence were found during the 5-year postoperative follow-up. CONCLUSION:SLMs are uncommon with insidious onset, and most patients are asymptomatic; however, complications still exist. Partial splenectomy is an option for isolated SLMs, whereas total splenectomy is necessary for diffuse SLMs.

Gorham-Stout disease (GSD) is a rare complex lymphatic malformation. Since its initial description in 1838, only approximately 400 patients have been documented. There is currently no consensus on the diagnostic criteria or treatment options for GSD. The objective of this study was to review the clinical characteristics of patients with GSD and determine the current diagnostic and treatment models. A comprehensive search of the PubMed, Web of Science, Embase, and Cochrane Library databases was conducted to identify all relevant literature on GSD published over the decade from 2013 to 2023. The clinical information extracted from these publications was analyzed. A total of 206 patients with GSD were included in the study, comprising 119 males, 81 females and 6 patients with unknown sex. The age of onset of patients was widely distributed, ranging from 0 to 77 years old. However, the majority of cases occurred in childhood (50.7

BACKGROUND:Sepsis-induced liver injury affects about 34.7% of patients and correlates with prognosis. Although vitamin A (VA) and retinol-binding protein 4 [RBP4] are reduced in sepsis, the protective role of VA remains unknown. This study aimed to explore the effects of VA and mechanisms in septic liver injury. METHODS:Cecal ligation puncture was performed in male C57BL/6 mice. After 24 hours, retinol (ROL, 0.01, 0.1, 1 mg/kg), RBP4 (0.5 mg/kg), or their combinations were administered. Liver/serum samples collected 24 hours later assessed injury (histopathology, function) and retinoic acid (RA)-inducible gene-I (RIG-I)/ receptor-interacting protein kinase (RIPK)1/RIPK3/mixed lineage kinase domain-like protein (MLKL) expression via immunohistochemistry, western blotting, and real-time quantitative polymerase chain reaction. In lipopolysaccharide (LPS)-stimulated alpha mouse liver-12 cells, ROL, RBP4, ROL+RBP4, or RA effects were evaluated. RESULTS:Cecal ligation puncture mice showed decreased serum ROL at 12 hours (lowest at 24 hours), while RBP4 transiently rose at 3 hours before declining (lowest at 24 hours). ROL (1 mg/kg) + RBP4 significantly improved survival, reduced liver injury (low Knodell scores), and suppressed RIG-I/TNF-α/RIPK1-RIPK3-MLKL necroptosis. LPS reduced RBP4 in alpha mouse liver-12 cells ( P < 0.001); ROL + RBP4 and RA alleviated damage via inhibiting necroptosis. CONCLUSIONS:VA may exert hepatoprotection by suppressing RIG-I, reducing tumor necrosis factor-α, and inhibiting RIPK1/RIPK3/MLKL-mediated necroptosis.

Hepatic hemangiomas can be classified into three morphologic patterns: focal (congenital hepatic hemangiomas [CHHs]), multifocal, and diffuse. We aimed to identify the clinical characteristics of CHH and evaluate the changes in CHH management at our institution over the last 2 decades. This was a retrospective cohort study of children diagnosed with CHH who were managed at 8 investigation sites. The primary outcome was changes in CHH size in patients at the last follow-up. The primary exposure of interest was management modality in 2 study periods (2003–2012 versus 2013–2022). Two hundred and eleven patients were analyzed. Four different subtypes of CHH were identified. Rapidly involuting CHH patients had complete involution/nearly complete involution, with a median age of 12.0 months. Noninvoluting CHH presented no change in CHH size. Partially involuting CHH patients presented with partial involution and had a stable tumor size at a median age of 16.0 months. Postnatally proliferating CHHs had an initial postnatal increase in CHH lesion size and underwent involution at a median age of 27.0 months. Further analysis revealed that management strategies for CHHs have shifted over time, with the proportion of patients receiving expectant management increasing from 35.4

To the Editor: Congenital hemangiomas are benign vascular tumors that differ from common infantile hemangiomas biologically and behaviorally.1 Several retrospective studies and case reports have reported the involuting pattern of rapidly involuting congenital hemangiomas (RICHs).2-5 However, no prospective studies reporting on the clinical features of RICH have been published. Although most RICHs are uncomplicated and can resolve spontaneously without causing morbidities, a significant minority of RICHs are associated with complications requiring timely referral to a specialist.

ETHNOPHARMACOLOGICAL RELEVANCE:Goiters are enlargements of the thyroid gland and are a global public issue. Quemeiteng granule (QMTG) is a traditional Chinese medicine (TCM) formula used to treat goiter in Yunnan Province. However, the effectiveness and underlying mechanism of these treatments have not been fully elucidated.AIM OF THE STUDY:This study aimed to investigate the therapeutic effects of QMTG on goiter and the downstream regulatory mechanisms.MATERIALS AND METHODS:In this study, we first evaluated the antigoiter efficacy of QMTG through biochemical indices [body weight, thyroid coefficient, triiodothyronine (T3), thyroxine (T4), free triiodothyronine (FT3), free thyroxine (FT4), and thyroid stimulating hormone (TSH)] and hematoxylin-eosin (HE) staining in a Propylthiouracil (PTU)-induced model. Based on microRNA sequencing (miRNA-seq) and bioinformatics analysis, key miRNA was screened out. A dual-luciferase reporter assay was performed to confirm the transcriptional regulation of the target gene by the miRNA. The viability of rat thyroid microvascular endothelial cells (RTMECs) and human thyroid microvascular endothelial cells (HTMECs) was assessed using the CCK-8 assays. The migration and angiogenesis of RTMECs and HTMECs were visualized through tube formation and wound scratch assays. Proteins involved in angiogenesis and the ERK pathway were assessed via Western blotting.RESULTS:QMTG significantly increased body weight, decreased the thyroid coefficient, increased the levels of T3, T4, FT3 and FT4 and reduced TSH levels in rats with goiter. QMTG also promoted the morphological recovery of thyroid follicles. MiR-217-5p was identified as a key miRNA. Our studies revealed that miR-217-5p directly targets FGF2 and that QMTG promotes the recovery of thyroid hormone (TH) levels and morphological changes in the thyroid, suppresses thyroid microvascular endothelial cell vitality, tube formation and migration, and reduces the expression of VEGF, Ang-1 and VCAM-1 triggered by miR-217-5p, thereby inhibiting the Ras/MEK/ERK cascade through FGF2.CONCLUSIONS:Our experiments demonstrated that the QMTG had therapeutic effects on goiter. These effects were attributed to the inhibition of ERK pathway-induced proliferation and angiogenesis through the targeting of FGF2 by miR-217-5p.