Despite guideline recommendations to use overactive bladder (OAB) medications in men with benign prostatic enlargement (BPE) presenting with storage symptoms, prescription rates remain low, possibly due to concern about worsening voiding symptoms. We evaluated the impact of OAB medications on safety outcomes in men receiving pharmacotherapy for BPE in a real-world setting. We retrospectively reviewed 899 patients who received α-blockers, 5α-reductase inhibitors, or phosphodiesterase-5 inhibitors between April 2014 and December 2023. We assessed the association between adding antimuscarinics or β3-agonists and acute urinary retention (AUR) using inverse probability of treatment weighting based on propensity scores; missing baseline covariates were handled by multiple imputation. Median follow-up was 28.7 months. At baseline, OAB users had lower PSA (2.5 vs. 3.6 ng/mL), smaller prostate volume (35 vs. 43 mL), and lower post-void residual (PVR) (12 vs. 35 mL) than non-users (all p < 0.001). 5α-reductase inhibitor use was less common in the OAB group (16.1% vs. 23.8%; p = 0.019). AUR incidence did not differ significantly between groups before (log-rank p = 0.054) or after weighting (hazard ratio 1.18; 95% CI 0.38-3.62; p = 0.776). Among OAB-treated patients, baseline AUR was significantly associated with discontinuation due to increased PVR (hazard ratio 9.10; 95% CI 1.81-45.6; p = 0.010). In men with BPE on pharmacotherapy, addition of OAB medications was not associated with increased risk of AUR. Baseline AUR may predict subsequent discontinuation due to elevated PVR, indicating the need for careful monitoring in such patients.
Venous malformations (VMs) are caused by activation of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) and Abelson murine leukemia viral oncogene homolog 1 (c-ABL) pathways. Daily oral administration of rapamycin (RAPA), an mTOR pathway inhibitor, has limited effectiveness in promoting lesion regression in patients with TEK receptor tyrosine kinase (TIE2)-mutated VMs. This may be due to poor bioavailability, frequent dosing requirements, and off-target effects that make maintaining adherence difficult. Recent preclinical studies have shown that combination treatment with RAPA and a c-ABL inhibitor [ponatinib (PON)] resulted in regression of VMs in a murine model; however, daily oral dosing was required. Here, we describe the formulation of polymeric RAPA, which acts as both a polymeric drug and a drug delivery carrier. The polymer was synthesized by polymerization of methacryloylated RAPA and terminated with polyethylene glycol (PEG-pRAPA). PEG-pRAPA self-assembled to form 30-nanometer nanoparticles (PEG-pRAPA NPs) and enabled the encapsulation of PON (PEG-pRAPA@PON NPs). PEG-pRAPA@PON NPs provided sustained release of both PON and PEG-pRAPA in vitro, reducing AKT phosphorylation comparably to free RAPA and PON. In a murine model of VMs, a single intravenous dose of PEG-pRAPA@PON NPs caused 70% VM regression over 20 days and a 6.3-fold reduction in CD31-positive (human-derived) blood vessels. There was no evidence of systemic toxicity or organ dysfunction after treatment. These findings demonstrated that PEG-pRAPA is an effective polymeric drug and drug delivery platform and support the hypothesis that nanoparticle-based pharmacotherapy can be an effective treatment strategy for VMs.
In 2024, a comprehensive framework for the screening, diagnosis, and management of metabolic dysfunction-associated steatotic liver disease (MASLD) was incorporated in the EASL-EASD-EASO clinical practice guidelines. However, physicians often face barriers applying these recommendations in routine clinical care, especially in the Southeastern Europe, Middle East, and Africa (SEEMEA) region. As a multidisciplinary group of physicians involved in MASLD and metabolic dysfunction-associated steatohepatitis (MASH) management, our objective is to provide a practice-oriented roadmap including practical and educational considerations beyond the hepatology field that could improve patient care and support implementation of clinical guidance within the SEEMEA region. This work is informed by a narrative review and expert input obtained through structured discussions, to examine the status quo and identify key gaps in the MASLD/MASH management, unravelling the patient journey from screening and diagnosis to treatment and follow-up. Furthermore, we advise on priorities on screening triggers and, considering the limited availability of vibration-controlled transient elastography (VCTE), discuss alternative approaches to achieve accurate and timely diagnosis. Finally, following the approval of resmetirom and semaglutide 2.4 mg for MASH treatment, we review the evolving pharmacotherapy landscape and propose a "blueprint" for a specialised MASLD clinic, suggesting mandatory and optional facilities for optimised care.
Direct real-world comparisons between osimertinib and second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are lacking, particularly regarding the comparative effectiveness, safety, and economic implications of different treatment sequencing strategies. We emulated a target trial using the TriNetX database to study adults with newly diagnosed metastatic EGFR-mutant non-small cell lung cancer (NSCLC). After 1:1 propensity score matching, 777 patients in the first-line osimertinib arm were compared with 777 patients in the second-generation TKI arm. The primary outcome was overall survival (OS), with secondary outcomes including health care utilization and toxicity. First-line osimertinib demonstrated significantly longer median OS compared with second-generation TKIs (53.4 v 33.2 months; hazard ratio [HR], 0.618). Although sequential therapy (second-generation TKI followed by osimertinib) achieved similar OS, it was associated with significantly higher toxicity. Patients with brain metastases derived greater benefit from osimertinib (HR, 0.563). Osimertinib also significantly reduced rates of hospitalization, intensive care unit admission, and severe infections, generating substantial health care savings ($5.73 million per 1,000 patients) despite higher drug costs. First-line osimertinib provides prolonged OS and meaningful economic benefits over second-generation TKIs. Given the higher toxicity burden of sequential therapy despite similar survival outcomes, our findings support the implementation of first-line osimertinib to optimize patient experience and reduce health care utilization in metastatic EGFR-mutant NSCLC.
Current predictive biomarkers for immune checkpoint inhibitor (ICI)-based therapy in patients with lung adenocarcinoma (LUAD) or lung squamous cell carcinoma (LUSC), such as PD-L1 protein expression or tumor mutation burden, are still suboptimal. We aim to explore immunophenotypic factors as potential biomarkers in this patient population. Clinical, genomic, and transcriptomic data from five patient cohorts, consisting of three publicly available data and two retrospective cohorts, were included. Immune tumor microenvironment (TME) subtype and tertiary lymphoid structure (TLS) signature were evaluated using RNA expression data, and deconvolutional cellular decomposition of tumor samples was performed using the Kassandra algorithm. Survival analysis was performed using a log-rank test and multivariate Cox regression. All statistical analyses were performed using Python version 3.10. In total, 514 patients were included in this analysis. A minority of LUAD (40.8%) had an immune-hot phenotype, which corresponded to better overall survival (OS) and progression-free survival (PFS) than the immune-cold phenotype. TLS-high signature was also associated with a superior ICI response rate and improved PFS, even with multivariate adjustments. Increased T-cell and macrophage infiltration and trafficking were predictive of ICI response. PD-L1 status and KEAP1 or STK11 mutations did not affect the response rates but were associated with poorer OS and PFS. Dynamic and active immune recruitment, indicated by immune-hot TME and high TLS score, was predictive of ICI benefit in patients with LUAD. Further prospective studies are warranted to expand to other treatment combinations with PD-(L)1 inhibitors.
Rheumatoid arthritis (RA) is a complex autoimmune disease, the present study aimed to investigate the effects of cinnamaldehyde (CA) on collagen-induced arthritis (CIA) in rats, with particular attention to changes in intestinal barrier-related features, gut microbiota composition, and fecal short-chain fatty acids (SCFAs). In CIA rats, CA treatment alleviated arthritis-related signs, reduced inflammatory responses, and attenuated joint pathological damage. CA administration was also associated with restoration of intestinal barrier-related features, including restoration of colonic histopathology and mucus layer integrity, as well as increased expression of tight junction proteins. Moreover, CA treatment was associated with altered gut microbiota composition. At the genus level, CA intervention was associated with increased abundance of Akkermansia, Ligilactobacillus, and Ruminococcaceae, which were negatively correlated with arthritis severity. CA treatment was associated with increased fecal SCFA levels in CIA rats. Collectively, these findings indicate that CA administration is associated with normalization of the gut microbiota, enhancement of intestinal barrier function, and amelioration of arthritis symptoms in CIA rats, suggesting that the interplay among gut dysbiosis, intestinal barrier damage, and arthritis may represent a contributing factor in the pathogenesis of RA.
Clinical genomic profiling of tumors identifies therapeutic targets, while germline pharmacogenomics (PGx) guides drug dosing and toxicity avoidance. However, the combined clinical landscape of both somatic and germline actionable variants across cancers has not been comprehensively defined. Tumor and matched germline whole-exome sequencing data were analyzed for 10,302 patients in The Cancer Genome Atlas. Somatic mutations with therapeutic relevance were mapped to US Food and Drug Administration (FDA)-approved targeted drugs using the Oncology Knowledge Base database (levels 1-4). Germline PGx variants were identified using PyPGx and cross-referenced with drug-gene interactions in PharmGKB (levels of clinical annotation 1-2). This enabled construction of an integrated germline-somatic PGx profile per patient. All 10,302 patients (100%) harbored at least one actionable germline PGx variant (median = 3; range = 1-9), including 7,520 (73%) with variants relevant to chemotherapy toxicity or supportive care medications (DPYD, UGT1A1, CYP2C9, and CYP2C19). Somatic profiling revealed 4,312 patients (42%) with at least one actionable mutation matched to an FDA-approved targeted therapy (eg, PIK3CA, KRAS). Across the cohort, 5,275 (51%) patients had more actionable germline variants than somatic mutations, whereas 1,988 (19%) had more actionable somatic mutations. Integrating germline PGx with somatic profiling reveals that actionable germline variants are nearly universal among patients with cancer in our cohort, extending beyond tumor-specific therapy to encompass toxicity and supportive care management. Routine implementation of combined germline and somatic sequencing in oncology could enhance therapeutic precision, minimize adverse effects, and inform individualized treatment decisions.
After musculoskeletal injury, a considerable proportion of patients develop heterotopic ossification (HO), the formation of bone at ectopic sites. Traumatic HO is a disabling condition, potentially resulting in loss of joint function and compression of neurovascular structures. Available treatment options are often unsuccessful, frequently necessitating surgical resection of HO lesions with a high risk of recurrence. Given that myeloid cells, including neutrophils and macrophages, are among the first cell types to infiltrate injured tissue, the present study explored the relationship of extracellular traps (ETs) with HO formation in humans and mice. Human HO sample analysis revealed the presence of different stages of ETosis, which are clinically associated with increased ET concentrations in the blood. Experimentally, genetic impairment of ET resolution through combined DNase1 and DNase1l3 deficiency led to increased traumatic HO in mice, whereas HO was strongly attenuated by additional deletion of the ET generator Padi4. Neutrophil depletion impaired local ET formation, reduced HO formation, and blunted genotype-specific differences in HO outcome. In osteogenic precursors, ETs promoted matrix mineralization, and inhibition of ETosis or degradation of cell-free DNA, a major ET component, resulted in reduced osteogenesis. Pharmacological facilitation of ET clearance by dornase alfa, a US Food and Drug Administration-approved recombinant DNase1, or inhibition of ETs by the PADI4 inhibitor GSK484, resulted in inhibition of traumatic HO formation in mice without adversely affecting systemic bone remodeling. Together, our clinical and experimental findings demonstrate that traumatic HO is mediated by targetable neutrophil-dependent mechanisms, with altered ET formation contributing to these effects.
This study aimed to synthesize and characterize AgNPs functionalized with crosslinking polyphenols extracted from grape seed extract (GSE) and green tea leaves (GT), and to evaluate their biocompatibility and their effects on the mechanical and physicochemical properties of demineralized dentin. AgNPs were characterized by TEM, XRD, TGA, and zeta potential analysis to determine particle morphology, crystalline structure, chemical composition, and surface charge. Biocompatibility was assessed using fibroblast cytotoxicity assays. In total, 40 human mid-coronal dentin specimens were randomly assigned to four groups (n=10): Control- (sound dentin), Control+ (pH-cycled dentin without treatment), AgGSE (pH-cycled + AgGSE, 1 min), and AgGT (pH-cycled + AgGT, 1 min). Treated dentin was analyzed by ATR-FTIR, XRD, TGA, and three-point bending tests. Both AgNPs were successfully synthesized and exhibited high biocompatibility. AgGSE demonstrated greater dentin matrix interaction, resulting in significantly higher flexural strength (p≤0.001). In contrast, AgGT induced pronounced remineralization with increased PO4/Amide I ratio (p=0.003) and CO3/PO4 ratios (p=0.007 by TGA; p=0.03 by ATR-FTIR), consistent with carbonated apatite deposition. Green-synthesized AgNPs functionalized with GT or GSE promoted reinforcement and remineralization of demineralized dentin through distinct mechanisms of action. These findings highlight their potential as biocompatible agents for dental therapies.
Traditional methods of ocular drug delivery (i.e.) eye drops, have limited effectiveness, with only ∼ 5% the administered dose reaching deeper ocular tissues due to rapid drainage and barriers like the corneal epithelium and blood-retinal barriers. Alternatives such as ocular implants, gels, microneedles, and iontophoresis can improve bioavailability but often cause patient discomfort, invasiveness, or require specialized equipment. Silicone hydrogel contact lenses are utilized in this study for sustained drug delivery using polydopamine (PDA) coatings combined with curcumin-loaded chitosan nanoparticles (NPs). Optimized PDA coatings, achieved with a 0.1 M dopamine hydrochloride solution 10 h immersion, resulted in a uniform 1-3 μm thickness and functioned as a therapeutic neutral-density. Reaction time influenced nanoparticle distribution. Shorter times (1 h) yield narrower size distributions and reduced aggregation. At a chitosan and tripolyphosphate (TPP) ratio of 2:1, particles averaged 167.3±1.9 nm with a low polydispersity index (PDI) of 0.15-0.25, indicating uniformity. Ethanol minimized aggregation, resulting in a narrower size distribution subsequently and creating a smooth nanocomposite film. Curcumin's anti-inflammatory and antioxidant properties are protected from thermal degradation within chitosan NPs, and the hydrophilic PDA coating further stabilized the lenses. We created a convenient, non-invasive alternative to traditional methods, potentially improving therapeutic outcomes and patient compliance in ocular drug delivery.
To explore factors associated with the use of chloroquine, hydroxychloroquine, and ivermectin for Covid-19 prevention in socioeconomically vulnerable populations in Brazil. A cross-sectional study was conducted using data from the project "Expansion of testing, quarantine, digital health, and telemonitoring strategies to tackle the Covid-19 pandemic in Brazil." Participants were users of 19 primary healthcare units in Salvador (Bahia, BA) and Rio de Janeiro (Rio de Janeiro, RJ) from July 2022 to July 2023. Data were collected via a socioeconomic questionnaire and analyzed using logistic regression to assess factors associated with the use of chloroquine, hydroxychloroquine, or ivermectin for Covid-19 prevention. Multicollinearity was assessed using the generalized variance inflation factor (GVIF), with GVIF^(1/(2*df)) > 5 indicating potential collinearity. Sensitivity analyses were performed using the same backward selection procedure as the main model: excluding "sometimes" responses and stratifying analyses by city (Rio de Janeiro and Salvador). Among 7,505 participants, 11.7% reported using chloroquine, hydroxychloroquine, or ivermectin for Covid-19 prevention. Use was more frequent among people who identified themselves as Brown (ORa = 1.38; 95%CI 1.10-1.75), aged 35-44 (ORa = 1.34; 95%CI 1.03-1.75) or 44-59 (ORa = 1.36; 95%CI 1.06-1.77), evangelical (ORa = 1.32; 95%CI 1.14-1.53), and with comorbidities (ORa = 1.25; 95%CI 1.07-1.47). Having up to two doses of Covid-19 vaccine (ORa = 1.30; 95%CI 1.06-1.59) and being unvaccinated while living with someone with comorbidities (ORa = 10.34; 95%CI 2.27-53.48) also increased the odds of use. GVIF values were low except for city (8.79), due to its interaction with income; the variable was retained for conceptual reasons. Sensitivity analyses yielded results consistent with the main model. The use of ineffective medications for Covid-19 prevention was higher among specific demographic groups, reflecting inequalities in access to information and the influence of religious factors. Scientific communication and community engagement strategies remain essential to combat misinformation.
Keeping an adequate glycemic control is a major global challenge. Approximately 42% of individuals achieve the recommended HbA1c targets. To compare glycemic control in 2 independent cohorts of patients with type 2 diabetes mellitus treated before and during the COVID-19 pandemic in primary care in Mexico City. Analytical observational study; records of 3598 patients with 2 HbA1c determinations (2562 pre-pandemic and 1036 pandemic) from 213 health units were analyzed. Means, proportions, and t and chi-squared tests were calculated; metabolic control was defined as HbA1c ≤ 8%. Mean HbA1c was 9.1% in both groups in the first measurement; at the last measurement, it was lower in the pre-pandemic group (8.0% vs. 8.3%; p < 0.001). The percentage of controlled patients increased from 38.5% to 58.5% pre-pandemic and from 37.8% to 54.2% during the pandemic (p = 0.017). Dual oral therapy achieved the greatest increase in control (22.5% pre-pandemic, 28.3% pandemic); isolated insulin therapy and absence of pharmacological treatment were less effective under pandemic conditions. The pandemic was associated with lower glycemic control; however, regimens with 1 or 2 oral antidiabetic agents retained their effectiveness. Ensuring continuity of care, drug supply, and support for lifestyle measures will be crucial in future crises. mantener el control glucémico adecuado es un gran reto a nivel mundial. Alrededor del 42% de las personas alcanzan los objetivos de HbA1c recomendados. comparar el control glucémico en 2 grupos independientes de pacientes con diabetes mellitus tipo 2 atendidos antes y durante la pandemia de COVID-19 en el primer nivel de atención de la Ciudad de México. estudio observacional analítico; se analizaron los registros de 3598 pacientes con 2 determinaciones de HbA1c (2562 prepandemia y 1036 pandemia) de 213 unidades de salud. Se calcularon medias, proporciones y pruebas t y chi cuadrada; el control metabólico se definió como HbA1c ≤ 8%. en promedio la HbA1c en la primera medición fue 9.1% en ambos grupos; en la última medición fue menor en el grupo prepandemia (8.0% frente a 8.3%; p < 0.001). El porcentaje de pacientes controlados pasó de 38.5% a 58.5% prepandemia y de 37.8% a 54.2% en pandemia (p = 0.017). La terapia dual oral logró el mayor incremento de control (22.5% en prepandemia, 28.3% en pandemia); la insulinoterapia aislada y la ausencia de fármacos fueron menos eficaces bajo condiciones pandémicas. la pandemia se asoció con menor control glucémico; sin embargo, esquemas con 1 o 2 antidiabéticos orales conservaron efectividad. Asegurar continuidad asistencial, abasto de medicamentos y apoyo en medidas de estilo de vida será crucial en futuras crisis.
Children with acute gastroenteritis-associated vomiting discharged from emergency departments (EDs) have improved outcomes when provided with ondansetron for home use. However, only one-third of children who present with significant vomiting experience ongoing vomiting after discharge. To identify characteristics associated with 3 or more vomiting episodes among pediatric patients within 24 hours of ED discharge. This nonprespecified secondary analysis of a randomized clinical trial of children aged 6 months to less than 18 years presenting to EDs between September 14, 2019, and June 27, 2024, with acute gastroenteritis-associated vomiting and who were followed up for 7 days. A prognostic score was derived using generalized linear mixed models across 10 imputed datasets. Data analysis was performed between May 9, 2025, and February 13, 2026. The primary outcome was 3 or more episodes of vomiting within 24 hours of ED discharge. Secondary outcomes included unscheduled health care revisits, intravenous fluid administration, and hospitalization within 7 days after the ED visit. Of 1030 children enrolled, 977 had follow-up data available and were included in this analysis (median age, 47.0 months [IQR, 22.1-80.1 months]; 493 [50.5%] girls; 925 [89.8%] with complete follow-up data). Eighty of 927 children (8.6%) had 3 or more episodes of vomiting in the 24 hours after ED discharge. In unadjusted analysis, only age 6 months to less than 2 years was associated with ongoing vomiting after discharge (odds ratio [OR], 2.17; 95% CI, 1.37-3.43). In multivariable regression analysis, variables associated with postdischarge vomiting included age 6 months to less than 2 years, symptom duration of 24 to 48 hours, or 10 or more vomiting episodes in the 24 hours preceding the ED visit. In a predictive model, a score of 4 points or more was associated with a 13.6% (95% CI, 9.9%-18.1%) probability of 3 or more vomiting episodes within 24 hours of ED discharge, with a sensitivity of 0.50 (95% CI, 0.39-0.61) and specificity of 0.70 (95% CI, 0.67-0.73). Children with 3 or more vomiting episodes within 24 hours of discharge, compared with those without, were more likely to have an unscheduled health care visit (33 of 80 [41.3%] vs 65 of 846 [7.7%]; difference, 33.6%; 95% CI, 22.6%-44.5%), receive intravenous fluids (9 of 80 [11.3%] vs 15 of 846 [1.8%]; difference, 9.5%; 95% CI, 2.5%-16.5%), and be hospitalized (5 of 80 [6.2%] vs 9 of 846 [1.1%]; difference, 5.2%; 95% CI, -0.2% to 10.5%) within 7 days of discharge. In this analysis of children presenting for ED care with vomiting, younger children and those unwell for 24 to 48 hours with 10 or more episodes of vomiting at presentation were more likely to have persistent vomiting after discharge. Based on these findings, these children are most likely to benefit from being provided ondansetron for home administration. ClinicalTrials.gov Identifier: NCT03851835.
3,4-Methylenedioxymethamphetamine (MDMA), widely misused for its euphoric and stimulant properties, induces overt neurotoxicity in rodents and non-human primates and is associated with profound neurochemical and structural brain alterations. Its deleterious effects are primarily mediated through oxidative stress, neuroinflammatory responses, and apoptotic pathways. Glutathione, a crucial endogenous antioxidant, has been proposed as a potential neuroprotective agent capable of mitigating MDMA-induced cerebral damage.Sixty adult male Wistar rats were randomly assigned to six experimental groups and administered oral treatments for 56 days: MDMA (5 mg/kg or 15 mg/kg), glutathione (15 mg/kg), or their combinations. After treatment, brain tissues were harvested and evaluated for oxidative stress biomarkers (8-OHdG, MDA, GPx, GSH, GST, SOD), pro-inflammatory cytokines (MPO, NF-κB, TNF-α), ion transport enzymes (Na⁺/K⁺ ATPase, Ca²⁺ ATPase), neurotransmitter levels (dopamine, serotonin, AChE), and the apoptotic marker caspase-3. Histological analysis of the hippocampus was conducted to assess structural integrity. MDMA administration led to significant elevations in MDA and 8-OHdG, reductions in antioxidant enzymes (GPx, GST, GSH, SOD), upregulation of inflammatory mediators (MPO, NF-κB, TNF-α), and disruption of ion homeostasis via altered Na⁺/K⁺ ATPase and Ca²⁺ ATPase activities. Neurotransmitter imbalances were observed, characterized by increased AChE and serotonin levels and decreased dopamine. Caspase-3 activity was markedly elevated, indicating enhanced apoptosis. Co-administration of glutathione at low MDMA doses ameliorated these effects, restoring antioxidant defenses, suppressing inflammation, and preserving hippocampal architecture. However, its protective efficacy was notably diminished at higher MDMA concentrations. Glutathione confers partial neuroprotection against MDMA-induced neurotoxicity, particularly under moderate exposure conditions. Its antioxidative capacity contributes to the restoration of redox equilibrium and cellular integrity. Nonetheless, under high-dose MDMA exposure, the therapeutic potential of glutathione is limited, suggesting the necessity for complementary interventions targeting excitotoxicity and mitochondrial dysfunction.
Heart failure (HF) remains a major cause of morbidity and mortality worldwide. Large language models (LLMs) such as ChatGPT are emerging as potential clinical decision support tools, but their adherence to specialty guidelines is not well characterised. To evaluate the accuracy and guideline concordance of ChatGPT-5 in managing real-world HF scenarios compared with the 2023 European Society of Cardiology (ESC) and 2022 American College of Cardiology (ACC)/American Heart Association (AHA)/Heart Failure Society of America (HFSA) recommendations. Thirty-eight anonymised HF clinical vignettes spanning reduced, mildly reduced, and preserved ejection fraction phenotypes and varied New York Heart Association (NYHA) classes were presented to ChatGPT-5. Two board-certified cardiologists independently graded each response for concordance with guideline recommendations using a 4-point scale (3 = fully concordant, 2 = partially concordant, 1 = discordant, 0 = unsafe/harmful). Discrepancies were adjudicated by a third reviewer. Descriptive statistics summarised performance and inter-rater agreement. Of the 38 responses, 20 (53%) were fully concordant, 4 (11%) partially concordant, 8 (21%) discordant, and 6 (16%) unsafe/harmful. Most inaccuracies involved vague drug titration guidance, incomplete device therapy recommendations, or omission of guideline-directed medical therapy (GDMT). Unsafe suggestions occurred in complex device or advanced therapy decisions. Inter-rater agreement was high. ChatGPT-5 showed moderate concordance with ESC and ACC/AHA/HFSA HF guidelines, indicating potential value as a tool for knowledge synthesis and preliminary clinical support. However, its outputs require expert validation, and safe clinical integration will depend on future models incorporating guideline-based frameworks, real-time data, and rigorous physician oversight.
Membrane oxygenator exchange can be a frequent requirement during extracorporeal membrane oxygenation (ECMO). In low-income health systems, the scarcity and cost of disposables pose significant challenges to timely exchanges. We describe a 48-year-old woman placed on veno-venous ECMO for refractory hypoxemic respiratory failure secondary to pneumonia. Within 30 min, the oxygenator developed thrombosis, characterized by a transmembrane pressure gradient of 229 mmHg. A total of 10 mg of recombinant tissue plasminogen activator (rt-PA) was administered through the premembrane port. Sixty minutes after infusion, the gradient decreased to 116 mmHg, with subsequent improvement in oxygenation. No bleeding occurred. The patient was successfully weaned from ECMO and discharged from the ICU without complications. Low-dose rtPA instillation into a failing oxygenator can postpone exchange and represents a viable salvage strategy for resource-limited ECMO programs.
This study aimed to investigate the microorganisms isolated, antimicrobial resistance patterns, clinical profiles, and therapeutic approaches in adult acute dacryocystitis cases requiring multidisciplinary management, and to present epidemiological data from Turkey. We retrospectively analyzed adult patients referred from a tertiary ophthalmology hospital to the infectious diseases (ID) specialist between January 2022 and April 2025. Clinical and microbiological data were obtained from electronic medical records. Pathogen identification and susceptibility testing were performed using routine microbiological methods, and the results were interpreted according to applicable standard criteria. Sixty-eight patients were included (mean age: 54.9 years; 79.4% female). Of the 68 included patients, 49 underwent microbiological sampling when indicated and sufficient material was available; 38 (77.6%) had positive cultures, yielding 49 isolates. Staphylococcus aureus (n = 12) was the most frequent isolate. Pseudomonas aeruginosa and Enterobacteriaceae were the leading Gram-negative pathogens. All tested Gram-positive isolates were susceptible to vancomycin. Susceptibility to other antibiotics varied across pathogen groups. All fungal isolates were Candida species. Prior antibiotic exposure was not associated with lower culture positivity in this sample. In adult acute dacryocystitis, culture-based therapy is essential, particularly for complex or nonresponsive cases. This study presents local epidemiological data and may help guide empirical therapy and support individualized antimicrobial management.
In December 2023, the U.S. Food and Drug Administration approved gene-editing therapies as sickle cell disease treatments. Such approvals for gene-editing not only mark radical scientific innovations for populations living with sickle cell disease (SCD) across the United States but also generate an expectation of a potential cure-the end or eradication of an illness and its effects. This essay, however, cautions against framing gene-editing therapy as a "cure" for SCD. Our argument illustrates that, even if gene editing is proven to permanently normalize the hematologic function of the body, there are other painful aspects of SCD that gene editing is unable to transform. Scientific researchers and health care practitioners could benefit from further bioethical consideration of the effects of using curative language with regards to SCD. The curative framing can easily generate misunderstandings in patient-provider communication and elicit unrealistic expectations. Raising awareness about the importance of how gene-editing therapies for SCD are described and about the need to discuss their limitations can prevent further harm.
Circulating tumor DNA (ctDNA)-based minimal residual disease (MRD) detection has become a strong prognostic stratification factor in postoperation non-small cell lung cancer (NSCLC). Here, we sought to investigate the guiding potential of MRD in informing adjuvant therapy (AT) decisions. Patients with stage IA to IIIB NSCLC who had undergone confirmed R0 resection were enrolled. Blood samples were collected 1 month after surgery before initiation of AT (landmark) and longitudinally every 3-6 months since surgery. Postoperative AT was conducted according to the guideline recommendations, and regular radiographical examinations were recommended for relapse surveillance. MRD detection was conducted using the MinerVa platform (Genecast Precision Diagnostic Co., Ltd. Wuhan, China) using a tumor-informed strategy based on a fixed next-generation sequencing panel spanning 769 cancer-related genes. One hundred sixty-five patients were included in this study, with 35 (21.2%) relapses. At landmark, positive MRD was associated with shorter disease-free survival (DFS) than negative MRD (P < .001, hazard ratio, 12.0). MRD was an independent risk factor for shorter DFS, irrespective of the disease stage and high-risk factors. In the case of negative landmark MRD, there was no significant difference between the DFS of (1) those who received AT and those who did not in stage IB patients with high-risk factors (P = .974), (2) epidermal growth factor receptor (EGFR)-mutant patients with or without adjuvant chemotherapy before adjuvant targeted therapy (P = .502), and (3) EGFR/ALK wild-type with or without adjuvant immunotherapy (P = .534). Clearance of ctDNA during AT was associated with a better prognosis than persistently detected ctDNA (P < .001). ctDNA-based MRD stratifies prognosis after curative resection in NSCLC, with MRD negativity indicating limited benefit from treatment in selected patients and ctDNA clearance reflecting improved outcomes. These findings support the clinical utility of MRD-guided adjuvant treatment strategies.
Magnetic particles have significant potential as novel theranostics due to the relative ease of surface modification for targeting molecules or regions of diseased tissues, coupled with remote in vivo manipulation using an exogenous magnetic field. Employing magnetic particles within the eye is hindered by the lack of safety studies. In particular, our lab has developed peptide-conjugated iron-oxide magnetic particles that target and liberate pseudoexfoliation materials from anterior lens capsules under a rotating magnetic field. Further application of such a mode of therapy may hold the key to reducing the incidence of open-angle glaucoma but requires an evaluation of its potential cytotoxic effects on delicate ocular tissue like the cornea, where a disruption of the endothelial cells can cause blindness. To this end, the effects of peptide-conjugated magnetic particles in a low-frequency rotating magnetic field on cultured porcine corneal endothelial cell monolayers was characterized using membrane integrity assessments for cell viability, metabolic activity assay, and ZO-1 immunocytochemical staining. It was observed that magnetic particles under the influence of this magnetic field had no significant immediate or delayed effect on membrane integrity or metabolic activity of corneal endothelial cell monolayers in culture. Moreover, the expression of the ZO-1 tight junction protein was maintained in the monolayers following magnetic treatment. All results support the safe application of 1-µm magnetic particles (0.2 µg/µL) and a rotating magnetic field (5.5 Hz and 0.5 T) for up to 3 hours as a novel therapy for pseudoexfoliation glaucoma.