Comparative Risk of Neuropsychiatric Adverse Events Associated With Leukotriene-Receptor Antagonists Versus Inhaled Corticosteroids.

BACKGROUND: Leukotriene-receptor antagonists (LTRA) and inhaled corticosteroids (ICS) are common controller medications for asthma, but limited studies examine their comparative risks on neuropsychiatric adverse events (NAEs) in asthma patients. OBJECTIVE: To investigate the comparative risks of LTRA versus ICS on seven distinct categories of NAEs in asthma patients at a nationwide level. METHODS: We conducted a nationwide cohort study during 2010-2021. Incident NAEs and its clinical subgroups (e.g., psychotic disorders, anxiety disorders, movement disorders, behavioral and emotional disorders, mood disorders, sleep-related disorders, and personality disorders) were assessed. Cox proportional hazards regressions were employed to quantify the comparative risks. RESULTS: There were 1,249,897 asthma patients aged 6-64 years. Incidence rates for NAEs were 25.10 per 1000 person-years among patients treated with LTRA, and 23.46 per 1000 person-years among those treated with ICS. The incidence rate difference was 1.64 [95%CI: 0.30-2.98] per 1000 person-years. Positive associations of NAEs and three clinical subgroups were found in patients treated with LTRA compared to ICS (hazard ratios (HR): 1.06 [95%CI: 1.00-1.12] for NAEs; HR: 1.88 [95%CI: 1.24-2.84] for psychotic disorders; HR: 1.10 [95%CI: 1.01-1.20] for anxiety disorders; and HR: 1.27 [95%CI: 1.02-1.58] for behavioral and emotional disorders), but not for movement disorders, mood disorders, sleep-related disorders, and personality disorders. CONCLUSIONS: This nationwide cohort study identified heightened risks, ranging from 6% to 88%, of NAEs and three clinical subgroups in asthma patients treated with LTRA compared to ICS. These findings underscore the necessity for clinicians to communicate with patients regarding potential neuropsychiatric harms when prescribing LTRA.

Cumulative risk factors for flap failure, thrombosis, and hematoma in free flap reconstruction for head and neck cancer: a retrospective nested case-control study.

BACKGROUND: Free flap construction enhances quality of life for head and neck cancer (HNC) patients; however, complications, such as thrombosis and hematoma, threaten flap survival. This study aimed to identify factors influencing flap failure, thrombosis, and hematoma. METHODS: A retrospective nested case-control study was conducted on HNC patients who underwent free flap reconstruction at a tertiary medical center between January 2019 and January 2022. All patients received antithrombotic prophylaxis consisting of prostaglandin E1, dextran, aspirin, and dipyridamole. Risk factors were analyzed using multivariate logistic regression. RESULTS: Among 548 flaps analyzed, flap failure, thrombosis, and hematoma rates were 4.74%, 3.83%, and 9.65%, respectively. Risk factors for flap failure included thrombosis (OR 86.42, 95% CI 15.73-474.89), smoking (OR 49.44, 95% CI 1.28->1000), posteromedial thigh (PMT) flap usage (OR 14.05, 95% CI 2.48-79.54), hematoma (OR 9.68, 95% CI 2.35-39.79), and younger age (OR 0.93, 95% CI 0.87-0.99). Thrombosis risk factors included PMT usage (OR 11.45, 95% CI 2.60-50.38) and anastomosis with the superior thyroid vein (SThV) as the recipient vein after multiple reconstructions (OR 7.91, 95% CI 2.06-30.39). Hematoma risk factors included fibula osteocutaneous flap usage (OR 9.22, 95% CI 2.71-31.42), double-flap usage (OR 8.88, 95% CI 1.80-43.81), liver cirrhosis (OR 6.28, 95% CI 1.44-27.47), and postsurgery hypertension (OR 2.77, 95% CI 1.39-5.50), whereas ipsilateral recurrence (OR 0.14, 95% CI 0.03-0.73) and using the external jugular vein (EJV) as the recipient vein (OR 0.22, 95% CI 0.08-0.61) were protective factors. CONCLUSION: Thrombosis poses a greater risk than hematoma for flap failure. Utilization of the PMT flap and the SThV markedly increased the risk of thrombosis and flap failure. These findings highlight the importance of antithrombotic prophylaxis and the selection of flaps and recipient veins in recurrent HNC patients.

An effective vaccine against influenza A virus based on the matrix protein 2 (M2).

The ever-increasing antigenic diversity of the hemagglutinin (HA) of influenza A virus (IAV) poses a significant challenge for effective vaccine development. Notably, the matrix protein 2 (M2) is a highly conserved 97 amino acid long transmembrane tetrameric protein present in the envelope of IAV. More than 99 % of IAV strains circulating in American swine herds share the identical pandemic (pdm) isoform of M2, making it an ideal target antigen for a vaccine that could elicit broadly protective immunity. Here, using soluble nanoscale membrane assemblies termed nanodiscs (NDs), we designed this membrane mimetic nanostructures displaying full-length M2 in its natural transmembrane configuration (M2ND). Intramuscular (IM) immunization of swine with M2ND mixed with conventional emulsion adjuvant elicited M2-specific IgG antibodies in the serum that recognized influenza virions and M2-specific interferon-γ secreting cells present in the blood. Intranasal (IN) immunization with M2ND adjuvanted with a mycobacterial extract elicited M2-specific IgA in mucosal secretions that also recognized IAV. Immunization with an influenza whole inactivated virus (WIV) vaccine supplemented with a concurrent IM injection of M2ND mixed with an emulsion adjuvant increased the level of protective immunity afforded by the former against a challenge with an antigenically distinct H3N2 IAV, as exhibited by an enhanced elimination of virus from the lung. The lone IM administration of the M2ND vaccine mixed with an emulsion adjuvant provided measurable protection as evidenced by a >10-fold reduction or complete elimination of the challenge virus from the lung, but it did not diminish the viral load in nasal secretions nor the extent of pneumonia that ensued after the virus challenge. In contrast, an improved formulation of the M2ND vaccine that incorporated synthetic CpG oligodeoxynucleotides (CpG-ODN) in the nanostructures administered alone, via the IN and IM routes combined, provided a significant level of protective immunity against IAV as evidenced by a decreased viral load in both the upper and lower respiratory tracts and fully eliminated the occurrence of pneumonia in 89 % of the pigs immunized with this biologic. Notably, to be effective, the M2 protein must be displayed in the ND assemblies, as shown by the observation that simply mixing M2 with empty NDs incorporating CpG-ODN (eND-CpG-ODN) did not provide protective immunity. This novel M2-based vaccine offers great promise to help increase the breadth of protection afforded by conventional WIV vaccines against the diversity of IAV in circulation and, plausibly, as a broadly protective stand-alone biologic.

Fabrication of a Microfluidic-Based Device Coated with Polyelectrolyte-Capped Titanium Dioxide to Couple High-Performance Liquid Chromatography with Inductively Coupled Plasma Mass Spectrometry for Mercury Speciation.

Mercury (Hg) is a toxic element which impacts on biological systems and ecosystems. Because the toxicity of Hg species is highly dependent on their concentration levels and chemical forms, the sensitive identification of the chemical forms of Hg-i.e., Hg speciation-is of major significance in providing meaningful information about the sources of Hg exposure. In this study, a microfluidic-based device made of high-clarity poly(methyl methacrylate) (PMMA) was fabricated. Then, titanium dioxide nanoparticles (nano-TiO2s) were attached to the treated channel's interior with the aid of poly(diallyldimethylammonium chloride) (PDADMAC). After coupling the nano-TiO2-coated microfluidic-based photocatalyst-assisted reduction device (the nano-TiO2-coated microfluidic-based PCARD) with high-performance liquid chromatography (HPLC) and inductively coupled plasma mass spectrometry (ICP-MS), a selective and sensitive, hyphenated system for Hg speciation was established. Validation procedures demonstrated that the method could be satisfactorily applied to the determination of mercury ions (Hg2+) and methylmercury ions (CH3Hg+) in both human urine and water samples. Remarkably, the zeta potential measured clearly indicated that the PDADMAC-capped nano-TiO2s with a predominance of positive charges indeed provided a steady force for firm attachment to the negatively charged device channel. The cause of the durability of the nano-TiO2-coated microfluidic-based PCARD was clarified thus.

MCTP1 increases the malignancy of androgen-deprived prostate cancer cells by inducing neuroendocrine differentiation and EMT.

Neuroendocrine prostate cancer (PCa) (NEPC), an aggressive subtype that is associated with poor prognosis, may arise after androgen deprivation therapy (ADT). We investigated the molecular mechanisms by which ADT induces neuroendocrine differentiation in advanced PCa. We found that transmembrane protein 1 (MCTP1), which has putative Ca2+ sensing function and multiple Ca2+-binding C2 domains, was abundant in samples from patients with advanced PCa. MCTP1 was associated with the expression of the EMT-associated transcription factors ZBTB46, FOXA2, and HIF1A. The increased abundance of MCTP1 promoted PC3 prostate cancer cell migration and neuroendocrine differentiation and was associated with SNAI1-dependent EMT in C4-2 PCa cells after ADT. ZBTB46 interacted with FOXA2 and HIF1A and increased the abundance of MCTP1 in a hypoxia-dependent manner. MCTP1 stimulated Ca2+ signaling and AKT activation to promote EMT and neuroendocrine differentiation by increasing the SNAI1-dependent expression of EMT and neuroendocrine markers, effects that were blocked by knockdown of MCTP1. These data suggest an oncogenic role for MCTP1 in the maintenance of a rare and aggressive prostate cancer subtype through its response to Ca2+ and suggest its potential as a therapeutic target.

The impact of premature rupture of membrane on neonatal outcomes in infants born at 34 weeks gestation or later.

BACKGROUND: Premature rupture of membranes (PROMs) is a known risk for adverse neonatal outcomes, often leading to neonatal hospitalization due to suspected perinatal infection or other issues. This study assesses PROM's clinical impact on neonatal outcomes in infants born at 34 weeks of gestation or later. METHODS: We studied hospitalized neonates born between December 2018 and November 2019, with gestational ages of 34 weeks or more and PROM diagnosis. We extracted patient data from clinical records, including demographics, maternal history, medical profiles, and neonatal outcomes. Neonates were categorized based on symptoms, PROM duration, neonatal intensive care unit (NICU) stay, and respiratory support. Data underwent thematic analysis. RESULTS: Of 275 neonates, the average PROM duration was 7.9 ± 8.1 hours, with 247 cases (89.8%) showing symptoms. Among them, 34 (12.4%) had PROM lasting over 18 hours, 48 (17.5%) were born prematurely, and 79 (28.7%) required intensive care. Symptomatic neonates had significantly higher rates of needing intensive care, respiratory support, prolonged antibiotics, and extended hospitalization ( p < 0.05). NICU stays (≥3 days) were significantly associated with prematurity (odds ratio [OR] = 5.49; 95% CI, 2.39-12.60) and an initial pH level <7.25 (OR = 3.35; 95% CI, 1.46-7.68). Extended respiratory support (≥3 days) was significantly correlated with tocolysis ≥7 days (OR = 13.20; 95% CI, 3.94-44.20), Apgar score <7 at 1 minute after birth (OR = 4.28; 95% CI, 1.67-10.97), and inadequate intrapartum antibiotic prophylaxis (IAP) (OR = 2.34; 95% CI, 1.04-5.23). CONCLUSION: Neonates born at or after 34 weeks of gestation with PROM should undergo vigilant monitoring if early symptoms (<24 hours) manifest. Risk factors for requiring NICU care or extended respiratory support (≥3 days) include prematurity, low initial pH (<7.25), prolonged tocolysis requirement (≥7 days), an Apgar score below 7 at 1 minute, and inadequate IAP.

Binding of interleukin-1 receptor antagonist to cholinergic receptor muscarinic 4 promotes immunosuppression and neuroendocrine differentiation in prostate cancer.

The tumor microenvironment (TME) of prostate cancer (PCa) is characterized by high levels of immunosuppressive molecules, including cytokines and chemokines. This creates a hostile immune landscape that impedes effective immune responses. The interleukin-1 (IL-1) receptor antagonist (IL1RN), a key anti-inflammatory molecule, plays a significant role in suppressing IL-1-related immune and inflammatory responses. Our research investigates the oncogenic role of IL1RN in PCa, particularly its interactions with muscarinic acetylcholine receptor 4 (CHRM4), and its involvement in driving immunosuppressive pathways and M2-like macrophage polarization within the PCa TME. We demonstrate that following androgen deprivation therapy (ADT), the IL1RN-CHRM4 interaction in PCa activates the MAPK/AKT signaling pathway. This activation upregulates the transcription factors E2F1 and MYCN, stimulating IL1RN production and creating a positive feedback loop that increases CHRM4 abundance in both PCa cells and M2-like macrophages. This ADT-driven IL1RN/CHRM4 axis significantly enhances immune checkpoint markers associated with neuroendocrine differentiation and treatment-resistant outcomes. Higher serum IL1RN levels are associated with increased disease aggressiveness and M2-like macrophage markers in advanced PCa patients. Additionally, elevated IL1RN levels correlate with better clinical outcomes following immunotherapy. Clinical correlations between IL1RN and CHRM4 expression in advanced PCa patients and neuroendocrine PCa organoid models highlight their potential as therapeutic targets. Our data suggest that targeting the IL1RN/CHRM4 signaling could be a promising strategy for managing PCa progression and enhancing treatment responses.

Cell therapies and its derivatives as immunomodulators in vascularized composite allotransplantation.

The adverse effects of traditional pharmaceutical immunosuppressive regimens have been a major obstacle to successful allograft survival in vascularized composite tissue allotransplantation (VCA) cases. Consequently, there is a pressing need to explore alternative approaches to reduce reliance on conventional immunotherapy. Cell therapy, encompassing immune-cell-based and stem-cell-based regimens, has emerged as a promising avenue of research. Immune cells can be categorized into two main systems: innate immunity and adaptive immunity. Innate immunity comprises tolerogenic dendritic cells, regulatory macrophages, and invariant natural killer T cells, while adaptive immunity includes T regulatory cells and B regulatory cells. Investigations are currently underway to assess the potential of these immune cell populations in inducing immune tolerance. Furthermore, mixed chimerism therapy, involving the transplantation of hematopoietic stem and progenitor cells and mesenchymal stem cells (MSC), shows promise in promoting allograft tolerance. Additionally, extracellular vesicles (EVs) derived from MSCs offer a novel avenue for extending allograft survival. This review provides a comprehensive summary of cutting-edge research on immune cell therapies, mixed chimerism therapies, and MSCs-derived EVs in the context of VCAs. Findings from preclinical and clinical studies demonstrate the tremendous potential of these alternative therapies in optimizing allograft survival in VCAs.

Adipose-derived stem cell modulate tolerogenic dendritic cell-induced T cell regulation is correlated with activation of Notch-NFκB signaling.

BACKGROUND: Adipose-derived stem cells (ASCs) are recognized for their potential immunomodulatory properties. In the immune system, tolerogenic dendritic cells (DCs), characterized by an immature phenotype, play a crucial role in inducing regulatory T cells (Tregs) and promoting immune tolerance. Notch1 signaling has been identified as a key regulator in the development and function of DCs. However, the precise involvement of Notch1 pathway in ASC-mediated modulation of tolerogenic DCs and its impact on immune modulation remain to be fully elucidated. This study aims to investigate the interplay between ASCs and DCs, focusing the role of Notch1 signaling and downstream pathways in ASC-modulated tolerogenic DCs. METHODS: Rat bone marrow-derived myeloid DCs were directly co-cultured with ASCs to generate ASC-treated DCs (ASC-DCs). Notch signaling was inhibited using DAPT, while NFκB pathways were inhibited by NEMO binding domain peptide and si-NIK. Flow cytometry assessed DC phenotypes. Real-time quantitative PCR, Western blotting and immunofluorescence determined the expression of Notch1, Jagged1 and the p52/RelB complex in ASC- DCs. RESULTS: Notch1 and Jagged1 were highly expressed on both DCs and ASCs. ASC-DCs displayed significantly reduced levels of CD80, CD86 and MHC II compared to mature DCs. Inhibiting the Notch pathway with DAPT reversed the dedifferentiation effects. The percentage of induced CD25+/FOXP3+/CD4+ Tregs decreased when ASC-DCs were treated with DAPT (inhibition of the Notch pathway) and si-NIK (inhibition of the non-canonical NFκB pathway). CONCLUSIONS: ASCs induce DC tolerogenicity by inhibiting maturation and promoting downstream Treg generation, involving the Notch and NFκB pathways. ASC-induced tolerogenic DCs can be a potential immunomodulatory tool for clinical application.

Association between Sjögren syndrome, sociodemographic factors, comorbid conditions, and optic neuritis: a Taiwanese population-based study.

Purpose: Our study aimed to explore the correlation between Sjögren syndrome, sociodemographic factors, comorbid conditions, and optic neuritis. Methods: This retrospective, nationwide, population-based, matched case-control investigation involved 33,190 individuals diagnosed with optic neuritis, identified using the International Classification of Diseases, Ninth Revision, Clinical Modification codes 377.30 for optic neuritis or 377.32 for retrobulbar neuritis. Patient data were extracted from the Taiwan National Health Insurance Research Database. Demographic characteristics, the presence of Sjögren syndrome, and pre-existing comorbid conditions were analyzed using univariate logistic regression. Continuous variables were assessed with a paired t-test. Adjusted logistic regression was employed to compare the prognosis odds ratio (OR) of patients with optic neuritis to controls. Results: After adjusting for confounding variables, individuals with Sjögren syndrome exhibited a significantly higher likelihood of developing optic neuritis compared to controls (adjusted OR, 9.79; 95% confidence interval [CI], 7.28-12.98; p < 0.0001). Other conditions associated with increased odds of optic neuritis included rheumatoid arthritis, ankylosing spondylitis, multiple sclerosis, systemic lupus erythematosus, and granulomatous vasculitis (adjusted OR: 1.57, 95% CI: 1.33-1.86; adjusted OR: 2.02, 95% CI: 1.65-2.48; adjusted OR: 140.77, 95% CI: 35.02-565.85; adjusted OR: 2.38, 95% CI: 1.71-3.30; adjusted OR: 18.28, 95% CI: 2.21-151.45, respectively), as well as systemic infections such as human herpes viral infection and tuberculosis infection (adjusted OR: 1.50, 95% CI: 1.35-1.66; adjusted OR: 4.60, 95% CI: 3.81-5.56, respectively). Discussion: Our findings strongly support the existence of an association between Sjögren syndrome, rheumatoid arthritis, ankylosing spondylitis, multiple sclerosis, systemic lupus erythematosus, granulomatous vasculitis, human herpes viral infection, tuberculosis, and optic neuritis.

PET/CT in a 65-Year-Old Woman With Epstein-Barr Virus-Associated Smooth Muscle Tumor After Chemotherapy for Follicular Lymphoma.

ABSTRACT: The Epstein-Barr virus-associated smooth muscle tumor (SMT) is an uncommon neoplasm. It arises mainly in 3 immunosuppression settings: HIV-associated SMT; drug-related immunosuppression in transplant recipients; and congenital immunodeficiency disorder-associated SMT. We present 18 F-FDG PET/CT findings of an adrenal Epstein-Barr virus-associated SMT in a 65-year-old woman with a history of follicular lymphoma after chemotherapy.

Staphylococcus aureus exacerbates dermal IL-33/ILC2 axis activation through evoking RIPK3/MLKL-mediated necroptosis of dry skin.

Atopic dermatitis (AD) is a persistent skin disease typified by symptoms of dry skin and recurrent eczema. Patients with AD are at heightened risk for Staphylococcus aureus infection. Group 2 innate lymphoid cells (ILC2s) are mainly activated by epithelial cell-derived cytokines IL-33 and involved in the pathogenesis of AD. However, little is known about the effect of skin delipidization on the epithelial cell-derived cytokines and dermal ILC2s in AD. In our study, we investigated the mechanism by which S. aureus infection modulates and exacerbates the pathogenesis of dry skin, leading to type 2 inflammation in the context of innate immunity. In vivo, we found that S. aureus infection aggravated delipidization-induced dermal IL-33 release and dermal ILC2 accumulation, which exacerbated skin inflammation. We also noticed that Il33fl/fl K14cre mice and Tlr2-/- mice exhibited attenuated skin inflammation. In vitro, treatment with necroptosis inhibitors reduced IL-33 release from S. aureus-infected keratinocytes. Mechanistically, we observed an increase in the necroptosis-associated kinases, MLKL and RIPK3, in S. aureus-infected mice, indicating that IL-33 release was associated with necroptotic cell death responses. Our results reveal that S. aureus infection-elicited keratinocyte necroptosis contributes to IL-33-mediated type 2 inflammation, which exacerbates the pathogenesis of dry skin.

Immunosuppressive role of BDNF in therapy-induced neuroendocrine prostate cancer.

Prostate stromal cells play a crucial role in the promotion of tumor growth and immune evasion in the tumor microenvironment (TME) through intricate molecular alterations in their interaction with prostate cancer (PCa) cells. While the impact of these cells on establishing an immunosuppressive response and influencing PCa aggressiveness remains incompletely understood. Our study shows that the activation of the leukemia inhibitory factor (LIF)/LIF receptor (LIFR) pathway in both prostate tumor and stromal cells, following androgen deprivation therapy (ADT), leads to the development of an immunosuppressive TME. Activation of LIF/LIFR signaling in PCa cells induces neuroendocrine differentiation (NED) and upregulates immune checkpoint expression. Inhibition of LIF/LIFR attenuates these effects, underscoring the crucial role of LIF/LIFR in linking NED to immunosuppression. Prostate stromal cells expressing LIFR contribute to NED and immunosuppressive marker abundance in PCa cells, while LIFR knockdown in prostate stromal cells reverses these effects. ADT-driven LIF/LIFR signaling induces brain-derived neurotrophic factor (BDNF) expression, which, in turn, promotes NED, aggressiveness, and immune evasion in PCa cells. Clinical analyses demonstrate elevated BDNF levels in metastatic castration-resistant PCa (CRPC) and a positive correlation with programmed death-ligand 1 (PDL1) and immunosuppressive signatures. This study shows that the crosstalk between PCa cells and prostate stromal cells enhances LIF/LIFR signaling, contributing to an immunosuppressive TME and NED in PCa cells through the upregulation of BDNF.

Mild cognitive impairment estimation based on functional near-infrared spectroscopy.

Patients with mild cognitive impairment (MCI) are at a high risk of developing future dementia. However, early identification and active intervention could potentially reduce its morbidity and the incidence of dementia. Functional near-infrared spectroscopy (fNIRS) has been proposed as a noninvasive modality for detecting oxygenation changes in the time-varying hemodynamics of the prefrontal cortex. This study sought to provide an effective method for detecting patients with MCI using fNIRS and the Wisconsin card sorting test (WCST) to evaluate changes in blood oxygenation. The results revealed that all groups with a lower mini-mental state examination grade had a higher increase in HHb concentration during a modified WCST (MCST). The increase in the change in oxygenated hemoglobin concentration in the stroke group was smaller than that in the normal group due to weak cerebrovascular reactivity.

Mucinous cystadenocarcinoma of the breast harbours TRPS1 expressions and PIK3CA alterations.

AIMS: Breast mucinous cystadenocarcinoma (BMCA) is a rare tumour recently recognised as a distinct entity by the World Health Organisation Tumour Classification Series. BMCA is a triple-negative tumour that lacks specific immunohistochemical markers; therefore, distinguishing it from mimickers such as ovarian and pancreatic cystadenocarcinomas requires careful clinicopathological correlation. Due to its rarity, little is known about the molecular alterations that underlie BMCA. METHODS AND RESULTS: In this study, we used immunohistochemical staining methods to investigate TRPS1 (trichorhinophalangeal syndrome type 1) expression in BMCA and compare it to expression in ovarian and pancreatic mucinous cystadenocarcinomas. We also collected tumour samples from three BMCA patients for molecular analysis by MALDI-TOF mass spectrometry, real-time polymerase chain reaction, whole exome sequencing and fluorescence in-situ hybridisation. TRPS1 immunoreactivity was found only in BMCA tumour cells and not in the ovarian and pancreatic counterparts. One of the three BMCA tumours also showed a PIK3CA hot-spot mutation, which was confirmed by whole genome next-generation sequencing (NGS). No KRAS, NRAS, BRAF or AKT mutations were found. CONCLUSIONS: To our knowledge, this is the first demonstration of TRPS1 expression in BMCA patients and the first identification of a PIK3CA hotspot mutation in these tumours. These findings provide insights into the molecular mechanisms underlying BMCA tumorigenesis and suggest a potential drug target for this rare and poorly understood cancer.

Weight growth velocity and growth outcomes in very-low-birth-weight infants developing major morbidities.

BACKGROUND: Extrauterine growth restriction (EUGR) is common in very-low-birth-weight-infants and may be associated with poor neurodevelopment. The growth velocity of preterm infants is increasing over decades, but the relationship between growth velocity, EUGR, and morbidities of preterm infants remains unknown. METHODS: A total of 263 infants born between 2012 and 2020, with birthweight <1500 g and gestational age of 24-33 weeks, were included. Birthweight and weight on day of evaluation point (corrected gestational age 36 weeks or discharged, whenever comes first) were converted to age-specific and gender-specific Z-scores and analyzed by multivariable modeling. The average growth velocity was calculated by the exponential model. RESULTS: Average growth velocity from birth to the evaluation point was 11.8 ±â€¯0.3 g/kg/day. The maximum growth velocity from birth to week 8 postnatal occurred at week 4 postnatal (16.4 ±â€¯0.9 g/kg/day). Infants with smaller birth weight, higher gestational age, and indication of intestinal surgery or those who need more days to achieve full enteral feeding were more favorable to have a weight lower than the 10th centile at the evaluation point. By contrast, most comorbidities of prematurity did not affect either lower age-specific weight Z-scores on the evaluation point or larger change in weight Z-score between birth and evaluation point. CONCLUSION: EUGR was associated with gestational age and birth weight. Infants with moderate-to-severe bronchopulmonary dysplasia, high-grade intraventricular hemorrhage, or retinopathy of prematurity tend to have slower growth velocity at 3-5 weeks postnatal, but these did not contribute to EUGR.

Tumor-derived interleukin-1 receptor antagonist exhibits immunosuppressive functions and promotes pancreatic cancer.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDA) is a pernicious disease characterized by an immunosuppressive milieu that is unresponsive to current immunotherapies. Interleukin-1 receptor antagonist (IL-1Ra) is a natural anti-inflammatory cytokine; however, its contribution to cancer pathogenesis and immunosuppression remains elusive. In this research, we investigated the role and mechanism of IL-1Ra in malignant progression of PDA. RESULTS: Through analyzing clinical dataset and examining the pathological tumor tissues and serum samples, we have demonstrated that IL-1Ra expression is elevated in human PDA and positively associated with malignant progression of PDA. To study the biological function of IL-1Ra in tumors, we generated a set of mouse pancreatic cancer cell lines with a knockout (KO) of the Il1rn gene, encoding IL-1Ra, and compared the tumor growth rates in immune-competent and immune-deficient mice. We found that the Il1rn KO cells exhibited greater tumor inhibition in immune-competent mice, highlighting the crucial role of a functional immune system in Il1rn KO-mediated anti-tumor response. Consistently, we found an increase in CD8+ T cells and a decrease in CD11b+Ly6G- immunosuppressive mononuclear population in the tumor microenvironment of Il1rn KO-derived tumors. To monitor the inhibitory effects of IL-1Ra on immune cells, we utilized a luciferase-based reporter CD4+ T cell line and splenocytes, which were derived from transgenic mice expressing ovalbumin-specific T cell receptors in CD8+ T cells, and mice immunized with ovalbumin. We showed that IL-1Ra suppressed T cell receptor signaling and inhibited antigen-specific interferon-γ (IFN-γ) secretion and cytolytic activity in splenocytes. CONCLUSIONS: Our findings illustrate the immunosuppressive properties of the natural anti-inflammatory cytokine IL-1Ra, and provide a rationale for considering IL-1Ra-targeted therapies in the treatment of PDA.

Intermittent Oxygen Supply Facilitates Codegradation of Trichloroethene and Toluene by Anaerobic Consortia.

Biodegradation is commonly employed for remediating trichloroethene- or toluene-contaminated sites. However, remediation methods using either anaerobic or aerobic degradation are inefficient for dual pollutants. We developed an anaerobic sequencing batch reactor system with intermittent oxygen supply for the codegradation of trichloroethylene and toluene. Our results showed that oxygen inhibited anaerobic dechlorination of trichloroethene, but dechlorination rates remained comparable to that at dissolved oxygen levels of 0.2 mg/L. Intermittent oxygenation engendered reactor redox fluctuations (-146 to -475 mV) and facilitated rapid codegradation of targeting dual pollutants, with trichloroethene degradation constituting only 27.5% of the noninhibited dechlorination. Amplicon sequencing analysis revealed the predominance of Dehalogenimonas (16.0% ± 3.5%) over Dehalococcoides (0.3% ± 0.2%), with ten times higher transcriptomic activity in Dehalogenimonas. Shotgun metagenomics revealed numerous genes related to reductive dehalogenases and oxidative stress resistance in Dehalogenimonas and Dehalococcoides, as well as the enrichment of diversified facultative populations with functional genes related to trichloroethylene cometabolism and aerobic and anaerobic toluene degradation. These findings suggested that the codegradation of trichloroethylene and toluene may involve multiple biodegradation mechanisms. Overall results of this study demonstrate the effectiveness of intermittent micro-oxygenation in aiding trichloroethene-toluene degradation, suggesting the potential for the bioremediation of sites with similar organic pollutants.