Search Results (87)

Background/Objectives: Inflammatory bowel disease (IBD) patients face elevated gastrointestinal (GI) infection risks due to immune dysregulation and gut dysbiosis. While steroids and immunosuppressants are known to increase infection risk, data on biologics and proton pump inhibitors (PPIs) remain limited, particularly for non-Clostridioides difficile (C.diff) infections. Methods: This retrospective cohort study analyzed 9849 hospitalized IBD patients (2013–2023) from the Northwell Inpatient Database. Patients were categorized into four groups: biologics-only, PPIs-only, both, or neither. GI infections were identified via C.diff PCR, GI PCR, and chart review. Multivariate logistic regression adjusted for demographics, BMI, and IBD type. Results: GI infections occurred in 1.75% of patients, with significantly higher odds in those on biologics alone (OR 21.5, 95% CI 11.7–39.4) or with PPIs (OR 16.6, 95% CI 10.2–26.8) versus untreated patients. Non-C.diff infections were strongly associated with biologics (OR 20.7, 95% CI 10.2–41.9). PPIs alone increased slightly the risk of GI infections (OR 1.6, 95% CI 1.1–2.4). Vedolizumab and adalimumab had the highest infection risks among biologics (26.8% and 22.7%, respectively). Bacterial pathogens, such as E. coli and Salmonella, predominated, with no significant difference in causative agents across treatment groups. Conclusions: Biologic therapy greatly increases GI infection risk in IBD patients independent of PPI use. Clinicians should weigh infection risks when prescribing biologics, particularly in high-risk populations. Further studies are needed to assess risks by biologic subtype and the interplay with PPIs. Full article

Background: Up to one-third of patients with gastroesophageal reflux disease (GERD) have persistent symptoms despite proton-pump inhibitor (PPI) therapy. E-Gastryal^® + MgAlg (Aurora Biofarma, Italy) is a mucosal protective agent that enhances barrier function against acid and non-acidic reflux. This study assessed its efficacy in combination with omeprazole versus omeprazole alone and as maintenance therapy. Methods: Patients with symptomatic GERD and Grade A reflux esophagitis confirmed by endoscopy were randomized to receive omeprazole 20 mg plus E-Gastryal^® + MgAlg or omeprazole 20 mg alone. The primary endpoint was the number of rescue medications used over 28 days. Secondary endpoints included symptom relief and quality-of-life assessments using the Reflux Symptom Index (RSI), Gastroesophageal Reflux Disease Impact Scale (GIS), GERD-Health-Related Quality of Life (GERD-HRQL), and Global Assessment of Performance (IGAP). Results: Ninety-six patients were included. The combination group used significantly fewer rescue medications (mean: 21 vs. 40.9 tablets; p = 0.002). At week 4, the combination group showed greater improvement in RSI, GIS, and GERD-HRQL scores (p < 0.001). Symptom relief was sustained during weeks 5–26 with E-Gastryal^® + MgAlg alone. Conclusions: E-Gastryal^® + MgAlg combined with omeprazole improves symptom control compared to PPI monotherapy. Continued use as maintenance therapy supports its role in long-term GERD management (NCT04130659). Full article

Background: Local audits of Helicobacter pylori (H. pylori) prescriptions and outcomes are necessary to assess guideline awareness among clinicians and treatment effectiveness. Aims: The aims were to investigate first-line prescriptions and effectiveness over a 10-year period in Ireland and evaluate the influence of the 2017 Irish consensus guidelines on these trends. Methods: Data were collected at e-CRF AEG-REDCap from the European Registry on H. pylori management (Hp-EuReg) and quality reviewed from 2013 to 2022. All treatment-naïve cases were assessed for effectiveness by modified intention-to-treat (mITT) analysis. Multivariate analysis was also performed. Results: Data from 1000 patients (mean age 50 ± 15 years; 54% female) were analyzed. Clarithromycin (C) and amoxicillin (A) triple therapy represented 88% of treatments, followed by sequential C, A, and metronidazole (M) therapy (4.3%) and triple C + M (2.7%). Bismuth quadruple therapy was prescribed in 1.7% of cases. Treatment durations of 14, 10, and 7 days accounted for 87%, 4.5%, and 8.5% of prescriptions, respectively. High-, standard-, and low-dose proton pump inhibitors (PPIs; 80 mg, 40 mg, and 20 mg omeprazole equivalent b.i.d.) were used in 86%, 0.9%, and 13% of cases, respectively. The overall eradication rate was 80%, while it was 81% for triple C + A. Good compliance and high-dose PPI were associated with higher overall mITT eradication rates (OR 4.5 and OR 1.9, respectively) and triple C + A eradication rates (OR 4.2 and OR 1.9, respectively). Overall eradication rates increased from 74% pre-2017 to 82% (p < 0.05) by the end of 2022. Similarly, the triple C + A eradication rates increased from 76% to 83% (p < 0.05). Conclusions: While first-line treatment effectiveness improved in clinical practice over time, cure rates remain below 90%. Alternative first-line strategies are required in Ireland. Full article

Chemical exchange saturation transfer (CEST) MRI is a novel technique that allows for the specific imaging of certain molecules that contain exchangeable protons. Neuroimaging is a major contributor to diagnosing and monitoring infections of the central nervous system (CNS). This review focuses on summarizing the current literature surrounding the use of CEST MRI imaging in diagnosing, monitoring, and treating CNS infections. BacCEST is a new technique to detect bacterial infection in organs at profound levels. This technique allows for the specific pathogen causing the infection to be understood, allowing for tailored antibiotic therapies. The bacCEST signal is also directly proportional to the number of bacterial cells; this means it can be used over periods to track response to treatment via cell numbers. The results show that most of the research in this area has focused on infections of the brain parenchyma (e.g., encephalitis) and that most studies investigate the use of CEST in animal models, with a minority exploring the application of CEST to human participants. The common neuroinfectious disease presentations relevant to clinical medicine are also briefly described, as well as the traditional and modern imaging techniques used to visualize them. Full article

Background: Patient motion poses significant challenges for the accurate delivery of radiotherapy. In children undergoing proton beam therapy (PBT), up to 30 treatments under general anesthesia may be required over a period of 6 to 8 weeks. To date, the impact of this many iterative anesthetic exposures on patient outcomes remains unclear. Objective: The primary objective of this study was to assess the impact of iterative anesthesia with propofol-based total intravenous anesthesia (propofol-TIVA) on overall survival. The secondary objective was to assess the association between propofol-TIVA and the occurrence of an unplanned admission or emergency room visit within 30 days of treatment start. Methods: This was a retrospective study of children (≤19 years) who had undergone PBT (with or without anesthesia) for central nervous system disease. The Log-rank test and Cox proportional hazards models were used for analysis. Propensity score matching and E-value analyses were used to adjust for selection bias. Results: The average age of the 461 children included was 9.0 years (SD ± 4.9). The majority, 261/461 (56.6%), were male, and 267/461 (57.9%) had undergone PBT without anesthesia. The group who underwent PBT with propofol-TIVA were younger (4.7 years vs. 12.2 years, p < 0.001) and had higher proportions of patients with treatment interruptions (111/194 [57.2%] vs. 118/267 [44.2%], p = 0.006), chemotherapy history (64/194 [33.0%] vs. 18/267 [6.7%], p < 0.001), concurrent chemotherapy (37/194 [19.1%] vs. 27/267 [10.1%], p = 0.006), and unplanned admissions/emergency room visits (26/194 [13.4%] vs. 1/267 [0.4%], p < 0.001). Overall survival rates (propofol-TIVA vs. no anesthesia) at 1yr (94% vs. 96%), 2 years (88% vs. 90%), and 3 years (88% vs. 89%) were similar between patient groups (p = 0.558). In the multivariable analysis, PBT with propofol-TIVA was associated with increased odds of an unplanned admission/emergency room visit before (OR, 38.311; 95%CI, 5.139–285.580; p < 0.001) and after (OR, 42.012; 95% CI, 5.322–331.632; p < 0.001; E-value = 83.52) propensity score matching. Conclusions: In this retrospective study of children undergoing PBT for central nervous system disease, there was no association between anesthesia exposure with propofol-based total intravenous anesthesia and overall survival. However, PBT with propofol-based total intravenous anesthesia was associated with an increased risk of an unplanned admission/emergency room visit within 30 days of treatment start. Full article

The diagnosis and monitoring of eosinophilic esophagitis (EoE), a common pediatric pathology, typically involves invasive procedures such as an upper endoscopy with biopsies, imposing a significant burden on patients and healthcare systems. We aimed to assess miR-21-5p and miR-223-3p levels in pediatric EoE patients and evaluate their as potential non-invasive biomarkers of disease activity and response to treatments. We enrolled 13 children with EoE and 8 controls. Plasma and esophageal mucosa samples from patients were collected at diagnosis and after 8–10 weeks of therapy and compared with control samples. After microRNA(miRNA) extraction, the levels of miR-21-5p and miR-223-3p and their relevant target genes were analyzed. Bioinformatic analysis was used to identify the predicted target genes and pathways that are potentially relevant for disease pathophysiology. Plasma levels of miR-21-5p and miR-223-3p were significantly higher in EoE patients than in the controls, reflecting their levels in esophageal mucosa. The target genes of these miRNAs are involved in key signaling pathways (MAPK, Ras, and FoxO), relevant for EoE pathophysiology. Among these, STAT3 (Signal Transducer and Activator of Transcription 3) and PTEN (Phosphatase and Tensin Homolog), which are significantly downregulated in patient esophageal mucosa, are implicated in eosinophilic gastroenteropathies and autoimmune diseases. Following therapy (proton pump inhibitors and/or fluticasone propionate), plasma and tissue expression of both miRNAs significantly decreased and were no longer different from the controls. These microRNAs may serve as complementary non-invasive EoE markers and reduce the need for endoscopy/biopsies. Full article

Background: Bone marrow (BM) adipocytes play a critical role in the progression of both solid tumor metastases and expansion of hematological malignancies across a spectrum of ages, from pediatric to aging populations. Single-point biopsies remain the gold standard for monitoring BM diseases, including hematologic malignancies, but these are limited in capturing the full complexity of loco-regional and global BM microenvironments. Non-invasive imaging techniques such as Magnetic Resonance Imaging (MRI), Computed Tomography (CT), and Positron Emission Tomography (PET) could provide valuable alternatives for real-time evaluation in both preclinical translational and clinical studies. Methods: We developed a preclinical proton density fat fraction (PDFF) MRI technique for the quantitative assessment of BM composition, focusing on the fat fraction (FF) within mouse femurs. We validated this method using aging mice and young mice subjected to 10 Gy X-ray irradiation, compared to young control mice. Water–fat phantoms with varying fat percentages (0% to 100%) were used to optimize the imaging sequence, and immunohistochemical (IHC) staining with H&E validated equivalent adipose content in the femur BM region. Results: Significant differences in FF were observed across age groups (p = 0.001 for histology and p < 0.001 for PDFF) and between irradiated and control mice (p = 0.005 for histology and p = 0.002 for PDFF). A strong correlation (R²~0.84) between FF values from PDFF-MRI and histology validated the accuracy of the technique. Conclusions: These findings highlight PDFF-MRI’s potential as a non-invasive, real-time, in vivo biomarker for quantitatively assessing the BM fat fraction in preclinical studies, particularly in studies evaluating the effects of aging, disease progression, and cytotoxic cancer therapies, including chemotherapy and radiation. Full article

This study investigates the pH-responsive dissociation mechanism of carbon dot (CD) conjugated with the anticancer peptide proximicin-A (PROXI) using density functional theory (DFT) simulations. The CD@PROXI system, designed for targeted cancer therapy, releases the drug in acidic environments typical of cancer sites. DFT simulations, with the B3LYP-D3BJ functional and 6-311G (d, p) basis set, optimized the conjugate’s geometry under neutral and acidic conditions. The focus was on the pH-sensitive C=N bond, existing in two protonation states. Key parameters evaluated included the HOMO-LUMO gap, bond length, IR spectroscopy, non-covalent interaction (NCI), electron localization function (ELF), density of states (DOSs), and electrostatic potential (ESP). Under neutral pH, the system showed stability with a HOMO-LUMO gap of 3.22 eV, indicating low reactivity. In acidic pH, this gap decreased to 0.40 eV, suggesting higher reactivity and potential for drug release. IR spectroscopy indicated weakened C=N bonds in acidic conditions, with bond length increasing from 1.288 Å to 1.324 Å. NCI analysis revealed increased van der Waals interactions, supporting bond weakening. ELF analysis showed electron localization at reactive sites, while DOS profiles and ESP maps highlighted distinct electronic states and potential dissociation regions in acidic conditions. These findings confirm the potential of CD@PROXI for targeted cancer therapy, with drug release triggered by the acidic tumor microenvironment. Full article

Branched polyethyleneimine (PEI), possessing different types of amines—e.g., primary, secondary, and tertiary—in the polymer chains are well known for their antibacterial properties and DNA condensing ability, affording substantial advantages in many biomedical uses, including gene therapy. However, because of PEI’s toxicity, depending on the molecular weight, its widespread biomedical use is hindered. Therefore, in this study, PEIs with different molecular weights—i.e., 600, 1200, and 1800 g/mol—were modified with 1,3-propane sultone, undergoing a sulfobetainization reaction in a single step to attain a zwitterionic structure: sulfobetainized PEI (b-PEI). The sulfobetainization reaction was carried out twice to increase the zwitterionic repeating unit on PEI chains. The increasing number of SO₃⁻ groups on the PEI chains was confirmed by the increased peak intensities around 1160 and 1035 cm⁻¹ on the FT-IR spectrum, which are assigned to symmetric and asymmetric S=O peaks. The elemental analysis results for first- and second- betainization PEIs, abbreviated as b¹-PEI and b²-PEI, respectively, were revealedthe increased wt% of S confirming the successful multiple-sulfobetainization of the PEI chains. Thermal stability analyses of PEIs and their corresponding multiple-sulfobetainized forms showed that multiple-sulfobetainization reactions increased the thermal stability of bare PEI chains. PEIs with lower molecular weights exhibited more antimicrobial properties. As PEI is sulfobetainated, its antimicrobial properties can be further adjusted via sulfobetainization (once or twice), or by adjusting the corresponding solution pH, or by protonating them with different acids with different counter anions. The cell toxicity of PEI on L929 fibroblast cells was slightly increased by increasing the molecular weight of the PEI, but all forms of sulfobetainized PEIs were found to be safe (no toxicity), even at 1000 µg/mL concentrations. Full article

Risk priority number (RPN) is the most commonly used failure risk ranking method among all risk assessment methods. However, the traditional RPN method not only cannot handle incomplete information and hesitation information (such as hesitation information between the $s_5=\mathrm{L}\mathrm{o}\mathrm{w}$ and $s_6=\mathrm{M}\mathrm{o}\mathrm{d}\mathrm{e}\mathrm{r}\mathrm{a}\mathrm{t}\mathrm{e}$) provided by experts, but it also does not consider the objective weights of risk assessment factors. These reasons will lead to biased conclusions, causing decision makers to make wrong judgments. To address the limitations of the traditional RPN technique, the aim of this paper is to propose the flexible RPN assessment method under an uncertain environment. The flexible RPN assessment method is an extension of the traditional RPN technique. The flexible RPN method integrates the traditional RPN method and interval-valued 2-tuple weighted average method, and, simultaneously, considers subjective weights and objective weights. In the numerical verification, this study has adopted the example of stages of treatment planning for proton beam radiation therapy to verify the correctness and validity of the proposed flexible RPN technique. The numerical results show that the proposed flexible RPN technique not only handles the hesitation and incomplete information provided by experts but also considers the subjective and objective weights of risk assessment factors, providing more reasonable ranking results in the risk analysis. Full article

Eosinophilic esophagitis (EoE) is a chronic, immune-mediated inflammatory condition of the esophagus characterized by eosinophilic infiltration, and hallmark symptoms of esophageal dysfunction such as dysphagia and food impaction. Over the past three decades, EoE has been recognized as a distinct clinical entity, distinguished from gastroesophageal reflux disease (GERD) through advancements in diagnostic techniques, particularly endoscopy with biopsy. The rising global prevalence of EoE reflects enhanced diagnostic awareness, evolving criteria, and environmental along with lifestyle changes. The etiology of EoE is multifactorial, involving genetic predispositions, immune dysregulation, the gut microbiome, and environmental triggers, including dietary allergens and aeroallergens. Key mechanisms include a type 2 helper T-cell (Th2)-driven immune response, epithelial barrier dysfunction, and genetic variants such as CAPN14 and TSLP. Chronic inflammation leads to tissue remodeling, fibrosis, and esophageal narrowing, contributing to disease progression and complications. Management strategies have evolved to include dietary elimination, proton pump inhibitors, topical corticosteroids, biologics, and endoscopic interventions for fibrostenotic complications. Emerging therapies targeting cytokines such as interleukin (IL)-4, IL-5, and IL-13, alongside novel diagnostic tools like the esophageal string test and Cytosponge, offer promising avenues for improved disease control and non-invasive monitoring. Long-term surveillance combining endoscopic and histological evaluations with biomarkers and non-invasive tools is critical to optimizing outcomes and preventing complications. Future research should address gaps in understanding the role of the esophageal microbiome, refine therapeutic approaches, and develop personalized strategies to improve disease management and patient quality of life. Full article

Chelation therapy is currently successfully applied to reduce the aluminum burden and its neurodegenerative consequences. In view of a possible application to aluminum chelation therapy, here we have studied the complexation of hydroxybenzoic acids, namely, vanillic, syringic and gallic acids, towards aluminum ion at physiologically relevant conditions as regards temperature (37 °C) and ionic strength (i.e., 0.16 M NaCl). The solubility values and the protonation constants of the hydroxybenzoic acids were primarily assessed to estimate the competition of these acids towards aluminum and H⁺ ions. Then, potentiometric titrations were carried out, and the speciation analysis indicated a pH-dependent complexation occurring at a 1:1 hydroxybenzoic acid-to-aluminum ratio for vanillic and syringic, and 1:1, 2:1 and 3:1 ligand-to-Al(III) ratios for gallic. Gallic acid forms more stable complexes with Al(III) ion than vanillic and syringic acids and could therefore represent a good candidate for being used as sequestering agents for Al(III) ion. Full article

Laryngopharyngeal reflux disease (LPRD) is a prevalent upper airway disorder characterized by inflammation and epithelial damage due to the backflow of gastric contents. Current treatments, primarily proton pump inhibitors (PPIs), often show variable efficacy, necessitating the exploration of alternative or adjunctive therapies. This study investigates the therapeutic potential of a mixture of Hedera helix and Coptidis rhizome (HHCR) in mitigating the pathophysiological mechanisms of LPRD. Using an in vitro model of human pharyngeal epithelial cells exposed to acidic conditions, we observed that acid exposure significantly increased the expression of adenosine A3 receptor (adenosine A3) and matrix metalloproteinase-7 (MMP-7), leading to E-cadherin cleavage and compromised epithelial integrity. Treatment with the HHCR mixture effectively suppressed adenosine A3 expression and MMP-7 activity, thereby reducing E-cadherin cleavage and preserving cellular cohesion. These results highlight the HHCR mixture’s ability to modulate the adenosine A3–MMP-7–E-cadherin pathway, suggesting its potential as a valuable adjunctive therapy for LPRD, particularly for patients unresponsive to conventional PPI treatment. This study provides new insights into the molecular interactions involved in LPRD and supports further clinical evaluation of HHCR as a complementary treatment option. Full article

Background and purpose: Proton therapy has been shown to provide dosimetric benefits in comparison with IMRT when treating prostate cancer with whole pelvis radiation; however, the optimal proton beam arrangement has yet to be established. The aim of this study was to evaluate three different intensity-modulated proton therapy (IMPT) beam arrangements when treating the prostate bed and pelvis in the postoperative setting. Materials and Methods: Twenty-three post-prostatectomy patients were planned using three different beam arrangements: two-field (IMPT₂B) (opposed laterals), three-field (IMPT₃B) (opposed laterals inferiorly matched to a posterior–anterior beam superiorly), and four-field (IMPT₄B) (opposed laterals inferiorly matched to two posterior oblique beams superiorly) arrangements. The prescription was 50 Gy radiobiological equivalent (GyE) to the pelvis and 70 GyE to the prostate bed. Comparisons were made using paired two-sided Wilcoxon signed-rank tests. Results: CTV coverages were met for all IMPT plans, with 99% of CTVs receiving ≥ 100% of prescription doses. All organ at risk (OAR) objectives were met with IMPT₃B and IMPT₄B plans, while several rectum objectives were exceeded by IMPT₂B plans. IMPT₄B provided the lowest doses to OARs for the majority of analyzed outcomes, with significantly lower doses than IMPT₂B +/− IMPT₃B for bladder V30–V50 and mean dose; bowel V15–V45 and mean dose; sigmoid maximum dose; rectum V40–V72.1, maximum dose, and mean dose; femoral head V37–40 and maximum dose; bone V40 and mean dose; penile bulb mean dose; and skin maximum dose. Conclusion: This study is the first to compare proton beam arrangements when treating the prostate bed and pelvis. four-field plans provided better sparing of the bladder, bowel, and rectum than 2- and three-field plans. The data presented herein may help inform the future delivery of whole pelvis IMPT for prostate cancer. Full article

The use of charged particle radiotherapy is currently increasing, but combination therapy with DNA repair inhibitors remains to be exploited in the clinic. The high-linear energy transfer (LET) radiation delivered by charged particles causes clustered DNA damage, which is particularly effective in destroying cancer cells. Whether the DNA damage response to this type of damage is different from that elicited in response to low-LET radiation, and if and how it can be targeted to increase treatment efficacy, is not fully understood. Although several preclinical studies have reported radiosensitizing effects when proton or carbon ion irradiation is combined with inhibitors of, e.g., PARP, ATR, ATM, or DNA-PKcs, further exploration is required to determine the most effective treatments. Here, we examine what is known about repair pathway choice in response to high- versus low-LET irradiation, and we discuss the effects of inhibitors of these pathways when combined with protons and carbon ions. Additionally, we explore the potential effects of DNA repair inhibitors on antitumor immune signaling upon proton and carbon ion irradiation. Due to the reduced effect on healthy tissue and better immune preservation, particle therapy may be particularly well suited for combination with DNA repair inhibitors. Full article