Search Results (1,741)

Background: Drug–drug interactions (DDIs) may occur when two or more drugs are taken together, leading to undesired side effects or potential synergistic effects. Most clinical effects of drug combinations have not been assessed in clinical trials. Therefore, predicting DDIs can provide better patient management, avoid drug combinations that can negatively affect patient care, and exploit potential synergistic combinations to improve current therapies in women’s healthcare. Methods: A DDI prediction model was built to describe relevant drug combinations affecting reproductive treatments. Approved drug features (chemical structure of drugs, side effects, targets, enzymes, carriers and transporters, pathways, protein–protein interactions, and interaction profile fingerprints) were obtained. A unified predictive score revealed unknown DDIs between reproductive and commonly used drugs and their associated clinical effects on reproductive health. The performance of the prediction model was validated using known DDIs. Results: This prediction model accurately predicted known interactions (AUROC = 0.9876) and identified 2991 new DDIs between 192 drugs used in different female reproductive conditions and other drugs used to treat unrelated conditions. These DDIs included 836 between drugs used for in vitro fertilization. Most new DDIs involved estradiol, acetaminophen, bupivacaine, risperidone, and follitropin. Follitropin, bupivacaine, and gonadorelin had the highest discovery rate (42%, 32%, and 25%, respectively). Some were expected to improve current therapies (n = 23), while others would cause harmful effects (n = 11). We also predicted twelve DDIs between oral contraceptives and HIV drugs that could compromise their efficacy. Conclusions: These results show the importance of DDI studies aimed at identifying those that might compromise or improve their efficacy, which could lead to personalizing female reproductive therapies. Full article

Background: Thyroid eye disease (TED) is a rare autoimmune orbital disorder predominantly associated with Graves’ disease. It is characterized by orbital inflammation, tissue remodeling, and potential visual morbidity. Conventional therapies, particularly systemic glucocorticoids, offer only partial symptomatic relief, failing to reverse chronic structural changes such as proptosis and diplopia, and are associated with substantial adverse effects. This review aims to synthesize recent developments in understandings of TED pathogenesis and to critically evaluate emerging therapeutic strategies. Methods: A systematic literature review was conducted using MEDLINE, Embase, and international clinical trial registries focusing on pivotal clinical trials and investigational therapies targeting core molecular pathways involved in TED. Results: Current evidence suggests that TED pathogenesis is primarily driven by the autoimmune activation of orbital fibroblasts (OFs) through thyrotropin receptor (TSH-R) and insulin-like growth factor-1 receptor (IGF-1R) signaling. Teprotumumab, a monoclonal IGF-1R inhibitor and the first therapy approved by the U.S. Food and Drug Administration for TED, has demonstrated substantial clinical benefit, including improvements in proptosis, diplopia, and quality of life. However, concerns remain regarding relapse rates and treatment-associated adverse events, particularly hearing impairment. Investigational therapies, including next-generation IGF-1R inhibitors, small-molecule antagonists, TSH-R inhibitors, neonatal Fc receptor (FcRn) blockers, cytokine-targeting agents, and gene-based interventions, are under development. These novel approaches aim to address both inflammatory and fibrotic components of TED. Conclusions: Teprotumumab has changed TED management but sustained control and toxicity reduction remain challenges. Future therapies should focus on targeted, mechanism-based, personalized approaches to improve long-term outcomes and patient quality of life. Full article

Background: RSV remains a leading cause of infant hospitalization worldwide, and the recently approved nirsevimab could represent an effective and safe prophylactic strategy to prevent severe infections in the general neonatal population. Objectives: We conducted a retrospective observational monocentric pilot study in a mixed preterm/term birth cohort to add real-world evidence of the efficacy and safety of nirsevimab in preventing severe RSV infection. Methods: We included a total of 2035 consecutive infants admitted to the Neonatal Unit, University Hospital “San Giovanni di Dio e Ruggi d’Aragona”, Salerno, Italy, from November 2024 to April 2025. We evaluated 30-day safety profiles and season-wide RSV infection rates, and the outcomes were also compared to newborns’ birth rate in the two previous seasons (2022–2023 and 2023–2024). Results: After the introduction of nirsevimab, a lower RSV infection rate was reported compared to previous seasons, and no adverse effects were observed. Compared to previous seasons, the clinical outcomes were more favorable, as only one unvaccinated neonate with RSV infection required invasive ventilation. Conclusions: In this real-world analysis, we demonstrated a good short-term safety profile of nirsevimab, as well as a potentially high efficacy in the general neonatal population with lower RSV infection incidence. However, future studies are needed to better assess its long-term safety and season-wide efficacy. Full article

Environmental risk assessment (ERA) for pesticide approval in the context of predatory insects remains inadequate as it often overlooks the influence of agricultural practices. An increasing number of studies have shown that prolonged and synergistic pesticide exposure can elevate insect mortality. However, such effects remain largely unstudied in non-target predatory carabid beetles. The carabid beetle Platynus assimilis was subjected to repeated oral and continuous contact exposure to low doses of prothioconazole (20 g ha⁻¹), lambda-cyhalothrin (0.4 g ha⁻¹), or their combination over a 64-day period. The food consumption rate, body mass, locomotor activity, and mortality were monitored throughout the experiment. All pesticide-treated groups showed significantly increased final mortality, with median lethal times (LT₅₀) of 51.6 days for prothioconazole, 60.3 days for lambda-cyhalothrin, and 12.2 days for their combination. A significant synergistic effect on mortality was observed in the combined treatment group, with the highest synergistic ratio detected 20 days after the first exposure. Pesticide-treated beetles exhibited significant abnormalities in locomotor activity and body mass compared to the untreated group. These findings demonstrate that both time-cumulative mortality and potential synergistic interactions, reflecting field-realistic conditions, must be considered in ERA. Failure to do so may lead to an underestimation of pesticide toxicity to predatory carabids. Full article

Chronic kidney disease (CKD) remains a global health burden, with limited therapeutic options that effectively target the underlying pathophysiology. Nuclear factor erythroid 2-related factor 2 (NRF2), a key regulator of oxidative stress and inflammation, has garnered significant attention as a potential therapeutic target in CKD. Despite encouraging preclinical results, no NRF2-targeted agents have achieved clinical approval for CKD treatment. This review synthesizes emerging evidence showing substantial heterogeneity in NRF2 activity across CKD subtypes, influenced by disease etiology, CKD stage, and rate of disease progression. We elucidate the key therapeutic implications across diverse CKD etiologies and highlight that the therapeutic efficacy of NRF2 activation depends on precise modulation tailored to disease context. Although NRF2 overactivation and the need for stage-dependent modulation are increasingly recognized, this review further delineates the consequences of indiscriminate NRF2 activation, demonstrating that its effects diverge across CKD etiologies and cellular contexts. These insights support a nuanced, context-specific approach to NRF2-targeted strategies and provide a framework to guide future drug development in CKD. Full article

Sedation and anesthesia are essential for ensuring animal welfare during surgical procedures such as hernia repair in swine. However, the number of sedative and anesthetic agents officially approved for livestock use remained limited. This study evaluated the sedative efficacy and serotonergic effects of a romifidine/ketamine/diazepam protocol, with and without the addition of tramadol, in swine undergoing umbilical hernia repair. Sixty-six crossbred Large White swine were randomly allocated to three groups: LL (lidocaine 4 mg/kg by infiltration), LT (lidocaine 2 mg/kg by infiltration + tramadol 2 mg/kg intraperitoneally), and TT (lidocaine2 mg/kg by infiltration + tramadol 4 mg/kg intraperitoneally). The physiological parameters heart rate, arterial pressure, oxygen saturation, rectal body temperature, and respiratory rate were assessed. The depth of intraoperative anesthesia and postoperative sedation was assessed using an ordinal scoring system (0–3). Plasma serotonin (5-HT) concentration was measured at baseline and 24 h post-surgery. Physiological parameters remained within species-specific reference ranges throughout the procedure. Anesthesia depth scores significantly decreased over time in all groups (p ≤ 0.001), with the tramadol-treated groups (LT and TT) showing more prolonged deeper anesthesia. Postoperative sedation was significantly higher in the TT group (p ≤ 0.001). Serotonin concentration decreased in LL, increased in LT, and remained stable in TT. These findings suggest that tramadol may enhance sedation and recovery, potentially through serotonergic modulation. Moreover, serotonin could serve as a physiological marker warranting further investigation in future studies of anesthetic protocols in veterinary medicine. Full article

Coronavirus disease 2019 (COVID-19) causes cardiovascular complications, which contributes to the high mortality rate of the disease. Emerging evidence indicates that aberrant vascular smooth muscle cell (SMC) function is a key driver of vascular disease in COVID-19. While antivirals alleviate the symptoms of COVID-19, it is not known whether these drugs directly affect SMCs. Accordingly, the present study investigated the ability of three approved COVID-19 antiviral drugs to influence SMC function. Treatment of SMCs with remdesivir (RDV), but not molnupiravir or nirmatrelvir, inhibited cell proliferation, DNA synthesis, and migration without affecting cell viability. RDV also stimulated an increase in heme oxygenase-1 (HO-1) expression that was not observed with molnupiravir or nirmatrelvir. The induction of HO-1 by RDV was abolished by mutating the antioxidant responsive element of the promoter, overexpressing dominant-negative NF-E2-related factor-2 (Nrf2), or treating cells with an antioxidant. Finally, silencing HO-1 partly rescued the proliferative and migratory response of RDV-treated SMCs, and this was reversed by carbon monoxide and bilirubin. In conclusion, the induction of HO-1 via the oxidant-sensitive Nrf2 signaling pathway contributes to the antiproliferative and antimigratory actions of RDV by generating carbon monoxide and bilirubin. These pleiotropic actions of RDV may prevent occlusive vascular disease in COVID-19. Full article

Background/Objectives: While ocular albinism (OA) is usually associated with reduced vision, nystagmus, and foveal hypoplasia, there is phenotypic variability in iris and fundus hypopigmentation. Hemizygous pathogenic/likely pathogenic (P/LP) variants in GPR143 at X: 151.56–151.59 have been shown in the literature to be associated with OA. The purpose of this study was to report the case of a Hispanic male with X-linked inherited OA associated with a hemizygous GPR143 variant and to review the literature relating to genotype–phenotype associations with GPR143 and OA. Methods: After consent to an IRB-approved protocol, a 14-year-old Hispanic male patient with OA and his parents underwent whole genome sequencing (WGS) in 2023. Two maternal uncles with nystagmus underwent targeted variant testing in 2024. A literature review of reported GPR143 variants was completed. Results: A male with reduced visual acuity, infantile-onset nystagmus, foveal hypoplasia, and iris hypopigmentation was identified to have the variant GPR143, c.455+3A>G, which was also present in his mother and two affected maternal uncles. This variant has been previously identified in other Hispanic patients of Mexican descent. Additionally, 127 variants were identified in the literature and reported to be associated with OA. All patients had reduced visual acuity (average 0.71 ± 0.23 logMAR), 99% had nystagmus, 97% foveal hypoplasia, 79% fundus hypopigmentation, and 71% iris hypopigmentation. Of those patients with reported optotype best corrected visual acuity (BCVA), eight (9%) had VA from 20/25 to 20/40, 24 (24%) had VA from 20/50 to 20/80, and 63 (67%) had VA from 20/100 to 20/200. The most frequent type of variant was missense (31%, n = 39). Frameshift and nonsense variants were associated with the lowest rates of iris hypopigmentation (50% [n = 11] and 44% [n = 8], respectively; p = 0.0068). Conclusions: This case represents phenotypic variability of GPR143-associated OA and highlights the importance of repeat genetic testing and independent analyses of test results for accurate variant classification, particularly in non-White and Hispanic patients. Further studies in more diverse populations are needed to better develop genotype–phenotype associations for GPR143-associated OA. Full article

Ulcerative colitis (UC), a subtype of inflammatory bowel disease (IBD), is a chronic, relapsing inflammatory condition that significantly impairs the patient’s quality of life. While biologics have transformed disease management, a substantial number of patients remain unresponsive or lose efficacy over time. Tofacitinib (TOFA), an oral Janus kinase (JAK) inhibitor, introduces a novel therapeutic class of small-molecule drugs with a unique oral administration route, offering enhanced patient convenience and broader accessibility compared to parenterally administered biologics. As the first oral treatment approved for moderate to severe UC in years, TOFA acts by modulating the JAK/STAT pathway, influencing critical inflammatory mediators such as IL-6, IL-17, and IFN-γ. However, response rates are variable and appear dose-dependent, with up to 60% of patients showing inadequate therapeutic outcomes. This review represents the first comprehensive synthesis focused specifically on biomarkers of TOFA response in UC. Drawing on multi-omics data—epigenomics, transcriptomics, proteomics, and cellular profiling, we highlight emerging predictors of responsiveness, including CpG methylation signatures (e.g., LRPAP1 and FGFR2), transcriptomic regulators (e.g., REG3A and CLDN3), immune and epithelial cell shifts, and the cationic transporter MATE1. TOFA demonstrates a dual mechanism by modulating immune responses while supporting epithelial barrier restoration. Despite being promising, TOFA’s dose-dependent efficacy and interpatient variability underscore the critical need for non-invasive, predictive biomarkers to guide personalized treatment. As the first review of its kind, this work establishes a basis for precision medicine approaches to optimize the clinical utility of TOFA in UC management. Full article

Background: This study aimed to assess the prevalence of SARS-CoV-2 infection, vaccination, and immune status among a population, both Dentists and University Professors, within a clinical setting at one and at 12 months after COVID-19 vaccination. Methods: A cross-sectional study involving 47 professionals (aged 27–52) was conducted in the University Fernando Pessoa. Participants completed an online survey on SARS-CoV-2 infection status and vaccination, received and provided plasma samples for serological analysis. The protocol was approved by the UFP-Ethics Committee. Anti-S1-RBD SARS-CoV-2 IgM and IgG antibody titration values (AU/mL) were measured, by enzyme-linked-immunosorbent assay (ELISA), with reactive immunoglobulins (Ig) seropositivity for values ≥1 AU/mL. Results: SARS-CoV-2 infection rate increased from 8.5% in July 2021 to 48.9% in June 2022, with 8.5% experiencing reinfection. Vaccination rate was 91.5% by July 2021 and increased slightly to 93.6% by June 2022; 72.3% of the sample received a third dose. IgG seropositivity increased from 91.5% to 95.7% in June 2022. After one-year, significant associations were found between IgG seropositivity and both participant’s age (p = 0.009; <50 years) and vaccine doses (p = 0.003; 1–3 doses) received. Conclusions: SARS-CoV-2 infection rate, vaccination, and IgG seropositivity rates were high and increased over one year. The age and vaccination status were associated with the immunity status at 12th month follow-up. Findings highlight variability in IgG seroprevalence due to multiple influencing factors, which justifies future studies. Full article

Background: There has been a reduction in successful H. pylori eradication rates recently, which is largely attributed to increasing antibiotic resistance. In areas of high dual clarithromycin and metronidazole resistance such as ours, Maastricht VI/Florence guidelines recommend bismuth quadruple therapy (BQT) as first line of therapy; however, the availability of bismuth was poor in Ireland until recently. Similarly, tetracycline, a component of BQT, is restricted locally, with doxycycline (D) being approved and reimbursed for most indications. Aims: To assess the efficacy of BQT-D therapy for H. pylori eradication in an Irish cohort. Methods: All patients testing positive for H. pylori in three Irish referral centres by urea breath test, stool antigen, or histology were treated prospectively with BQT-D (bismuth subcitrate 120 mg QDS, metronidazole 400 mg TDS, doxycycline 100 mg BD and esomeprazole 40 mg BD) for 14 days. Eradication was evaluated with a urea breath test (UBT) >4 weeks after therapy cessation or by stool antigen testing, as available. Outcomes were recorded and analysed according to demographics and H. pylori treatment history of the patients. Results: 217 patients completed post-eradication testing. Of which, 124 (57%) were female, with a mean age 52 years. 180 patients (83%) were treatment-naïve. A total of 165/180 (92%) of the treatment-naïve patients had successful eradication. There was no association between eradication and gender or age in this cohort (p = 0.3091, p = 0.962 respectively). A total of 29 patients received this therapy as second-line therapy, of which 22 (76%) had successful eradication. Eight patients received the regimen as rescue therapy, with seven (88%) having successful eradication. No serious adverse events were reported. Eleven individuals (6.5%) commented on the complicated nature of the regimen, with 11 tablets being taken at five intervals daily. Conclusions: BQT-D as first-line therapy for H. pylori infection is highly effective in a high dual-resistance population, achieving >90% eradication. BQT-D as a second-line treatment performed less well. Our data support BQT-D as a first-line treatment. Full article

Background/Objectives: Vedolizumab is a gut-selective anti-integrin monoclonal antibody approved for the treatment of inflammatory bowel disease (IBD). While clinical trials have demonstrated a favorable safety profile, real-world studies are essential for identifying rare adverse events (AEs) and evaluating post-marketing safety. This study assessed vedolizumab’s safety in a real-world cohort and supported the detection of potential safety signals. Methods: A retrospective chart review was conducted on adult IBD patients treated with vedolizumab at a tertiary center in the Republic of Serbia between October 2021 and August 2022. Data included demographics, AEs, and newly reported extraintestinal manifestations (EIMs). Exposure-adjusted incidence rates were calculated per 100 patient-years (PYs). Disproportionality analysis using the FDA Adverse Event Reporting System (FAERS) was performed to identify safety signals, employing reporting odds ratios (RORs) and proportional reporting ratios (PRRs) for AEs also observed in the cohort. Prior IBD therapies and reasons for discontinuation were evaluated. Results: A total of 107 patients (42.1% Crohn’s disease, 57.9% ulcerative colitis) were included, with a median vedolizumab exposure of 605 days. There were 92 AEs (56.51/100 PYs), most frequently infections (23.95/100 PYs), gastrointestinal disorders (4.30/100 PYs), and skin disorders (4.30/100 PYs). The most frequently reported preferred terms (PTs) included COVID-19, COVID-19 pneumonia, nephrolithiasis, and nasopharyngitis. Arthralgia (12.90/100 PYs) was the most frequent newly reported EIM. No discontinuations due to vedolizumab AEs occurred. FAERS analysis revealed potential signals for events not listed in prescribing information but observed in the cohort: nephrolithiasis, abdominal pain, diarrhea, malaise, cholangitis, gastrointestinal infection, blood pressure decreased, weight decreased, female genital tract fistula, respiratory symptom, and appendicectomy. Most patients had received three prior therapies, often stopping one due to AEs. Conclusions: Vedolizumab demonstrated a favorable safety profile in the IBD cohort. However, FAERS-identified signals, such as nephrolithiasis, gastrointestinal infections, and decreased blood pressure, warrant further investigation in larger, more diverse populations. Full article

Immune checkpoint inhibitors (ICIs) are approved in at least one line of therapy for most patients with advanced non-small cell lung cancer (NSCLC) without EGFR/ALK alterations and have improved survival for a subset of patients. Adjuvant, neoadjuvant, and perioperative therapy for resectable NSCLC carries the hope of more broadly increased cure rates for patients with resectable lung cancers. This review summarizes the current state of multimodality management, including ICIs, for resectable NSCLC. A literature search of PubMed and Scopus identified phase II and III clinical trials including ICIs in patients with resectable NSCLC. No level 1 evidence guides the clinician in choosing between the available neoadjuvant and perioperative approaches. Full article

Background/Objectives: Inflammatory bowel disease (IBD) is characterized by chronic relapsing and remitting inflammation of the gastrointestinal tract. Fecal microbiota transplantation (FMT) has emerged as an FDA-approved treatment for recurrent Clostridioides difficile infections (CDIs), with promising potential in patients with IBD. This manuscript aimed to provide a comprehensive and updated review of the available literature on fecal microbiota transplantation, its clinical use in IBD in general, as well as in patients with IBD and CDI. Methods: An extensive literature search was performed from October 2024 to March 2025. All publications available within PubMed, Medline, Embase, Google Scholar, and Cochrane databases were reviewed. All original articles, case reports, review articles, systematic reviews, and meta-analyses were included. Qualitative and quantitative data were both extracted. Discussion: Intestinal microbiota is an integral part of the human body, and dysbiosis (an imbalance in the gut’s microbial community) has been linked with several pathologies. Dysbiosis in IBD is marked by reduced beneficial bacteria and increased pro-inflammatory pathogens, contributing to mucosal damage and immune dysregulation. FMT has emerged as a solution to dysbiosis, with the first case recorded in 1917. FMT has been successful in treating patients with CDI. The diagnostic value of the gut microbiome is currently being explored as a possible therapeutic approach to IBD. Several studies have assessed FMT in patients with IBD and CDI with promising results in both ulcerative colitis (UC) and Crohn’s disease (CD) but varying efficacy based on administration routes, donor selection, and processing methods. In the context of recurrent CDI in patients with IBD, FMT demonstrates a high cure rate and potential benefit in concurrently improving IBD activity. However, risks such as IBD flare-ups post-FMT remain a concern. Conclusions: FMT holds promising potential in the management of CDI in patients with IBD. By restoring microbial diversity and correcting dysbiosis, FMT offers a novel, microbiota-targeted alternative to conventional therapies. While data support its efficacy in improving disease remission, variability in outcomes underscores the need for standardized protocols and additional large-scale, controlled studies. Continued research efforts into donor selection, treatment regimens, and long-term safety will be critical to optimizing FMT’s role in IBD and CDI care as well as improving patient outcomes. Full article

Background/Objectives: Antimicrobial consumption (AMC) surveillance and antimicrobial stewardship (AMS) constitute effective strategies to combat the increasing antimicrobial resistance rates worldwide. Post-Soviet countries (Armenia, Azerbaijan, Belarus, Estonia, Georgia, Kazakhstan, Kyrgyzstan, Latvia, Lithuania, Moldova, the Russian Federation, Tajikistan, Turkmenistan, Ukraine, and Uzbekistan) implemented various elements of AMC surveillance and AMS to different extents. The limited quantity and quality of data from post-Soviet countries make it difficult to assess health system performance; therefore, this region is a blind spot in global AMR monitoring. This systematic review assesses and characterises AMC surveillance and AMS implementation in post-Soviet countries. Methods: Evidence was compiled via a search in PubMed, Google Scholar, Embase, CyberLeninka, and Scopus. The eligibility criteria included AMC surveillance- and AMS-related papers in human health within defined regions and timelines. Some literature from the official websites of international and national health organisations was included in the search. Results: As a result of the searches, screening, and critical appraisal, three peer-reviewed publications and 31 documents were selected for analysis. Eleven out of fifteen countries with updated national action plans for combating antimicrobial resistance have defined AMC surveillance and AMS as strategic objectives. All 15 examined countries submitted antimicrobial consumption data to international networks and reported the existence of approved laws and regulations on antibiotic sales. However, disparities exist in the complexity of monitoring systems and AMS implementation between high-income and low-income countries in the region. Conclusions: This review provides key insights into the existing AMC surveillance and AMS implementation in former Soviet countries. Although the approach of this review lacks quantitative comparability, it provides a comprehensive qualitative framework for national-level AMC surveillance and AMS system assessment. Full article