Search Results (4,093)

Background/Objectives: Sacituzumab govitecan (SG) is an antibody–drug conjugate targeting Trop-2 that has demonstrated clinical benefits in randomised trials for patients with metastatic triple-negative breast cancer (mTNBC) and metastatic hormone receptor-positive/HER2-negative (HR+/HER2− mBC) disease. However, real-world data on its effectiveness and safety are limited, especially in patients with poor performance status or central nervous system (CNS) involvement. This study aimed to evaluate the real-world outcomes of SG in these two subtypes. Methods: We conducted a retrospective, multicentre, observational study across three tertiary hospitals in Spain. Patients with mTNBC or HR+/HER2− mBC treated with SG between June 2022 and March 2025 were included. Clinical data, treatment history, adverse events (AEs), and survival outcomes were also recorded. The median progression-free survival (mPFS) and median overall survival (mOS) were estimated using Kaplan–Meier analysis. Univariate and multivariate analyses were performed to identify the factors influencing outcomes. The association between granulocyte colony-stimulating factor (G-CSF) prophylaxis and neutropenia was assessed using Fisher’s exact test. Results: A total of 56 patients were included in this study (33 with mTNBC and 23 with HR+/HER2− mBC). In the mTNBC group, mPFS was 4.0 months (95% CI: 1.94–5.98) and mOS was 11.0 months (95% CI: 4.80–17.12). In the HR+/HER2− mBC group, mPFS was 3.7 months (95% CI: 2.02–5.44) and mOS was 20.2 months (95% CI: 3.9–36.5). Fatigue, neutropenia, and gastrointestinal toxicity were the most common AEs. Primary G-CSF prophylaxis was not associated with a reduced incidence of neutropenia (p = 0.434). Conclusions: In routine practice, SG shows effectiveness comparable to that of randomised trials across both subtypes, with a safety profile consistent with pivotal studies. The observed toxicity profile was consistent with that described in pivotal clinical trials and other studies. The prophylactic use of G-CSF was not associated with an impact on the occurrence of neutropenia, but the incidence of neutropenia was lower than that in clinical trials and other studies that did not administer G-CSF prophylactically. Full article

Background: Trimetazidine is a clinically established cardioprotective agent with anti-ischemic and antioxidant properties, widely used in the management of coronary artery disease. Combining its metabolic and cytoprotective effects with the potent anti-inflammatory activity of profens presents a promising therapeutic strategy. Methods: Five novel trimetazidine–profen hybrid compounds were synthesized using N,N′-dicyclohexylcarbodiimide-mediated coupling and structurally characterized by NMR and high-resolution mass spectrometry. Their antioxidant activity was evaluated by hydroxyl radical scavenging assays (HRSA), and the anti-inflammatory potential was assessed via the inhibition of albumin denaturation (IAD). Lipophilicity was determined chromatographically. Molecular docking and 100 ns molecular dynamics simulations were performed to investigate the binding modes and stability in human serum albumin (HSA) binding sites. The acute toxicity of the hybrid molecules was predicted in silico using GUSAR software. Results: All synthesized hybrids demonstrated varying degrees of biological activity, with compound 3c exhibiting the most potent antioxidant (HRSA IC₅₀ = 71.13 µg/mL) and anti-inflammatory (IAD IC₅₀ = 108.58 µg/mL) effects. Lipophilicity assays indicated moderate membrane permeability, with compounds 3c and 3d showing favorable profiles. Docking studies revealed stronger binding affinities of S-enantiomers, particularly 3c and 3d, to Sudlow sites II and III in HSA. Molecular dynamics simulations confirmed stable ligand–protein complexes, highlighting compound 3c as maintaining consistent and robust interactions. The toxicity results indicate that most hybrids, particularly compounds 3b–3d, exhibit a favorable safety profile compared to the parent trimetazidine. Conclusion: The hybrid trimetazidine–profen compounds synthesized herein, especially compound 3c, demonstrate promising dual antioxidant and anti-inflammatory therapeutic potential. Their stable interaction with serum albumin and balanced physicochemical properties support further development as novel agents for managing ischemic heart disease and associated inflammatory conditions. Full article

Metastatic cancer, characterized by poor survival outcomes and grim prognosis, represents the final stage of malignancy. The current evidence regarding the prophylactic effects of glucagon-like peptide-1 (GLP-1) receptor agonists and sodium–glucose cotransporter 2 (SGLT2) inhibitors on metastatic cancer remains largely unexamined. With a confirmatory approach based on the Cochrane recommendation, we conducted a frequentist-based network meta-analysis (NMA) of randomized controlled trials (RCTs) evaluating such medications. The primary outcome was the incidence of metastatic cancer, while secondary outcomes included safety profiles assessed through dropout rates. The findings were reaffirmed by sensitivity analysis with a Bayesian-based NMA. This NMA of 207,606 participants from 67 RCTs revealed that only efpeglenatide demonstrated a statistically significant reduction in metastatic cancer events compared to controls (odds ratio = 0.26, 95% confidence intervals = 0.09 to 0.70, p = 0.010, number needed to treat = 188.4). Efpeglenatide’s efficacy was not confined to specific cancer types. Safety profiles were comparable across all treatments. These findings indicate that efpeglenatide may possess a broad, systemic preventive effect against metastatic cancers, potentially operating through mechanisms that are not restricted to individual organ systems. Further research is warranted to elucidate the molecular pathways underlying its anti-metastatic properties and to explore its role in preventive oncology. Full article

Background/Objectives: Recurrent meningiomas remain difficult to manage due to the absence of effective systemic therapies and comparatively high treatment failure rates, particularly in high-grade tumors. Stereotactic radiosurgery (SRS) offers a minimally-invasive and precise option, particularly for tumors in surgically complex locations. However, the risks associated with re-irradiation, and recent changes in the WHO classification of CNS tumors highlight the need for more personalized and strategic treatment approaches. This systematic review evaluates the safety, efficacy, and clinical considerations for use of SRS for recurrent meningiomas. Methods: In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a systematic literature search was conducted using the PubMed, Scopus, and Web of Science databases for studies reporting outcomes of SRS in recurrent, pathologically confirmed intracranial meningiomas. Studies were excluded if they were commentaries, reviews, case reports with fewer than three cases, or had inaccessible full text. The quality and risk of bias of the included studies were assessed using the modified Newcastle-Ottawa Scale. Data on patient and tumor characteristics, SRS treatment parameters, clinical outcomes, adverse effects, and statistical analysis results were extracted. Results: Sixteen studies were included. For WHO Grade I tumors, 3- to 5-year progression-free survival (PFS) ranged from 85% to 100%. Grade II meningiomas demonstrated more variable outcomes, with 3-year PFS ranging from 23% to 100%. Grade III tumors had consistently poorer outcomes, with reported 1-year and 2-year PFS rates as low as 0% and 46%, respectively. SRS performed after surgery alone was associated with superior outcomes, with local control rates of 79% to 100% and 5-year PFS ranging from 40.4% to 91%. In contrast, tumors previously treated with radiotherapy, with or without surgery, showed substantially poorer outcomes, with 3- to 5-year PFS ranging from 26% to 41% and local control rates as low as 31%. Among patients with prior radiotherapy, outcomes were particularly poor in Grade II and III recurrent tumors. Toxicity rates ranged from 3.7% to 37%, and were generally higher for patients with prior radiation. Predictors of worse PFS included prior radiation, older age, and Grade III histology. Conclusions: SRS may represent a reasonable salvage option for carefully selected patients with recurrent meningioma, particularly following surgery alone. Outcomes were notably worse in high-grade recurrent meningiomas following prior radiotherapy, emphasizing the prognostic significance of both histological grade and treatment history. Notably, the lack of molecular and genetic data in most existing studies represents a key limitation in the current literature. Future prospective studies incorporating molecular profiling may improve risk stratification and support more personalized treatment strategies. Full article

Background/objectives: Multiple systemic treatments are available for metastatic castration-resistant prostate cancer (mCRPC), with unclear safety profiles. This study seeks to describe the safety determined in randomized clinical trials of a systemic treatment for mCRPC and whether safety differs by age. Methods: We utilized individual patient data from industry-funded phase 2/3 trials in mCRPC on abiraterone acetate (AA). Vivli, a clinical trial repository site, was used. One investigator independently performed screening. Relative effects of treatment were assessed with frequencies and odds of serious adverse events (SAEs). The Preferred Reporting Items for Systematic Reviews and Meta-analyses guideline was used. Subgroup analysis measured odds of SAEs as modified by age. Results: We identified 14 trials with 4296 patients. The median age of participants was 69 years. Nearly all participants experienced at least one adverse event (98.4% abiraterone, 97.3% standard of care [SOC]). More serious adverse events (grade 3 or 4) and deaths (grade 5) occurred in those receiving SOC (71.8%) compared to abiraterone (64.1%). The most frequent adverse event category was “Musculoskeletal and Connective Tissue Disorders”. The most frequent event types included anemia, back pain, hypertension, fatigue, hypokalemia, and bone pain. The odds of all events were lower in those receiving abiraterone compared to SOC. Odds of a serious musculoskeletal event were lower in older subjects by 22% (OR 0.78; 95% CI 0.63, 0.96). Conclusions: In this IPD meta-analysis, abiraterone acetate provides no greater risk of SAE in those receiving abiraterone than those receiving SOCs. Patients in the RCTs are younger and healthier than those in the general population; consequently, the results of RCTS might not be applied to the general population, especially those under-represented in the RCTs. There is a need to further evaluate abiraterone-related fractures and neuromuscular toxicities (NMTs) as key outcomes to gain insight into risk factors related to these adverse events. A real-world prospective study is warranted to examine the overall risks and benefits associated with treatment. Full article

Background: Durvalumab (anti-PD-L1) in combination with gemcitabine and cisplatin has become the first-line treatment for patients with locally advanced, surgically unresectable, or metastatic biliary tract cancer, following the survival benefit demonstrated in the TOPAZ-1 phase III trial. This study presents real-world data from UK centres in patients who received early access to the regimen via AstraZeneca’s scheme. The aim was to assess the safety and efficacy of this treatment approach in routine clinical practice and compare it to outcomes reported in the TOPAZ-1 trial. Method: This retrospective study included patients with locally advanced, surgically unresectable, or metastatic biliary tract adenocarcinoma who received durvalumab in combination with gemcitabine and cisplatin. Data were collected across ten UK centres. The primary endpoint was progression-free survival (PFS), with secondary endpoints including overall survival (OS), overall response rate (ORR), and safety outcomes, encompassing both chemotherapy and immunotherapy-related adverse events (AEs). Results: A total of 134 patients treated between April 2022 and December 2023 were included. The median follow-up was 12.8 months (95% CI: 11–16.8). The median PFS was 8.83 months (95% CI: 5.73–11.7), closely aligning with the 7.2 months reported in TOPAZ-1 (95% CI: 6.7–7.4). The median OS was 12 months (95% CI: 10.7–13.9), slightly below the 12.8 months observed in TOPAZ-1 (95% CI: 11.1–14.0). The ORR was 29.1% (TOPAZ-1: 26.7%), and the disease control rate was 61.2%. In terms of safety, 64 patients (52.3%) experienced any-grade AEs, and 9 patients (6.8%) had grade 3–4 AEs, representing a lower toxicity profile than TOPAZ-1. Immunotherapy-related AEs occurred in 25 patients (18.7%), with grade 3–4 events in 3%. Conclusions: These real-world findings from UK cancer centres support the outcomes of the TOPAZ-1 trial, demonstrating comparable efficacy and a favourable safety profile for durvalumab combined with gemcitabine-cisplatin as first-line treatment for advanced biliary tract cancer. Full article

(1) Background: Violence against healthcare professionals is becoming a growing concern for healthcare systems and a public health issue, and in Portugal it remains undocumented at a national level, leaving a critical knowledge gap. This scenario compromises the development of effective public policies and evidence-based institutional strategies, which are essential for guiding policymakers in the implementation of preventive measures and appropriate safety protocols to assess the nature, frequency, and key factors contributing to violence against healthcare professionals (doctors and nurses) in clinical settings. (2) Methods: This is a quantitative, descriptive, and cross-sectional study. The sample size was 440 professionals (n = 440). Between January and May 2024, healthcare professionals (physicians and nurses) working in four local health units located in the south of Portugal were invited to participate in this study via institutional e-mail. Data was collected using a structured questionnaire on the healthcare professional’s sociodemographic and work-related characteristics and aspects related to violence towards healthcare professionals in the workplace. Unconditional logistic regression models were fitted to compute crude odds ratios (ORs) and 95% confidence intervals (95%CIs) for the association between sociodemographic and work-related characteristics and violence at work. (3) Results: Nearly 40% of the healthcare professionals sampled reported having been victims of violence in the workplace, and, among these, the majority reported experiencing psychological violence (94.2%), followed by physical violence (46.2%), another type of violence (39.1%), and sexual violence (4.1%). Incidents were mostly occasional (65.5%), occurring during the daytime (51.5%) and on weekdays (84.8%). Healthcare professionals aged between 34 and 55 years old were approximately twice as likely to experience violence compared to those who were 56 years old or older (OR = 2.28; 95%CI 1.33–3.90). Also, those who had been with the organization for more than 4 years (5–7 years: OR = 2.37; 95%CI 1.05–5.37. ≥8 years: OR = 1.87; 95%CI 1.00–3.50), as well as those who worked shifts (OR = 1.84; 95%CI 1.25–2.72), reported incidents of violence more frequently. (4) Conclusions: The low response rate (12.5%) and cross-sectional design limit the generalizability of the results, which should be interpreted considering these methodological limitations. Workplace violence in Portugal is a reality, and it requires solutions. Information related to violent incidents must be comprehensively gathered to understand the full extent of the problem and develop prevention strategies based on potentially changeable risk factors to minimize the negative effects of workplace violence. Full article

Dry powder inhalers (DPIs) are the mainstay in the treatment of obstructive pulmonary diseases. However, the performance of DPI formulations is highly dependent on the used inhaler device and the patient’s inspiratory effort. This study aimed to evaluate and compare the aerosolization behavior of three commercially available capsule-based DPI medications—formoterol (Foradil^®), glycopyrronium (Seebri^® Breezhaler), and tiotropium (Spiriva^®)—delivered using three different capsule-based inhalers (Aerolizer, Breezhaler, and Handihaler), under varying flow conditions. Methods: The aerodynamic performance of each formulation–inhaler combination was assessed using the Next-Generation Impactor (NGI) and Dosage Unit Sampling Apparatus (DUSA) methodology. Fine particle dose (FPD) and aerodynamic particle size distribution (APSD) were determined at fixed flow rates of 15, 30, 60, and 100 L/min, as well as at inhaler-specific flow rates corresponding to a 4 kPa pressure drop. Chromatographic quantification of active ingredients was performed using validated HPLC methods specific to each drug. Results: The FPD values increased consistently with higher flow rates across all tested formulations and inhalers. At a 4 kPa pressure drop, Aerolizer and Breezhaler achieved significantly higher FPDs compared to Handihaler. Notably, in some instances, non-dedicated inhalers produced greater respirable fractions than the originally intended devices. APSD profiles revealed that drug deposition shifted toward smaller NGI stages at higher inspiratory flows, supporting enhanced deep lung delivery potential under optimal conditions. Conclusions: Device resistance, capsule orientation, and piercing mechanics substantially influence drug aerosolization. Although non-dedicated inhalers may offer improved FPDs in vitro, clinical use should adhere to approved drug–device combinations, as these have been validated for efficacy and safety under real-world conditions. Full article

Background/Objectives: Pharmacovigilance aims to identify, assess, and minimize drug risks, with spontaneous reporting playing a central role. However, the high level of underreporting and the varying data quality are limitations that should be minimized through prospective cohort studies. Methods: Spontaneous reports reported to the Drug Commission of the German Medical Association (AkdÄ) over one year were compared with the adverse drug reaction (ADR) cases systematically recorded in hospital emergency departments. The frequencies of the demographic patient characteristics and the odds ratios, as the relationship between suspected and concomitant medication, were calculated. Results: In the spontaneous reports, cases were reported by patients a median of 12 years younger, and the group of older patients was less represented (10.8% versus 27.3% in the prospective cohort study). Within the study, cases with polypharmacy were documented significantly more often (a median of seven drugs [IQR 3;10] versus a median of two drugs [IQR 1;5] in the spontaneous reports). New drugs and drugs discussed in the media were frequently reported as causing ADRs, whereas drugs with an effect on the central nervous system were more often suspected in the emergency department setting. Conclusions: Both sources for ADRs provide complementary information that improves the detection of risk signals. The aim for the future is to further increase the awareness of spontaneous reports and to answer specific questions with the help of structured investigations. It is important to compare and validate the findings of spontaneous reports and investigations in regular intervals to improve drug safety. Full article

Dry eye disease (DED) is a prevalent and disabling condition. Artificial tears are commonly used but often inadequate for moderate-to-severe cases. Secretagogues such as pilocarpine, cevimeline, and diquafosol offer potential alternatives, though their comparative effectiveness remains unclear. To evaluate the safety and efficacy of these secretagogues versus artificial tears in adults with DED, we searched CENTRAL, PubMed, Scopus, LILACS, ClinicalTrials.gov, and WHO ICTRP without language restrictions. Randomized controlled trials (RCTs) comparing secretagogues to artificial tears were eligible. Data extraction and synthesis were conducted using Covidence and the Cochrane RoB 2 tool, and 19 RCTs (n = 2697) were included. Fifteen were analyzed quantitatively; however, only eight trials evaluating diquafosol were suitable for meta-analysis, as data for pilocarpine and cevimeline were insufficient for quantitative synthesis. GRADE was used to assess evidence certainty. PROSPERO registration: CRD42020218407. Diquafosol significantly improved rose bengal staining at 4 weeks and OSDI scores and TBUT in post-cataract patients at 4 and 12 weeks. However, it increased mild adverse events (RR, 1.81; 95% CI, 1.15–2.84). Evidence for pilocarpine and cevimeline was limited. Diquafosol 3% shows greater efficacy than artificial tears in post-cataract DED but with more side effects. Further research is needed for other secretagogues. Full article

Background/Objectives: Essential tremor (ET) is the most common movement disorder worldwide. It negatively affects patients’ activities of daily living (ADL) and quality of life. Unilateral transcranial magnetic resonance-guided focused ultrasound (tcMRgFUS) thalamotomy has been proven as a highly effective and safe treatment option for patients with refractory ET. The aims of this study are to explore the effectiveness and safety of tcMRgFUS thalamotomy in patients with ET in a real-world setting. Methods: Patients who underwent tcMRgFUS thalamotomy at the University Hospital of Palermo were prospectively enrolled. Scores obtained by Quality of Life in Essential Tremor Questionnaire (QUEST) and The Essential Tremor Rating Assessment Scale (TETRAS) were compared before and after tcMRgFUS thalamotomy. Predictors of tcMRgFUS thalamotomy effectiveness were explored by multivariable Cox regression analyses. All the adverse events (AEs) during and after the procedure were collected. Results: Fifty patients were included (80% male; median age at tcMRgFUS 67.4 years). After procedure, the QUEST score decreased by 46.2%, while TETRAS-ADL and TETRAS Performance (TETRAS-PE) decreased by 52.2% and 51.8%, respectively. Temperature peak and longitudinal lesion diameter positively correlated with the magnitude of QUEST and TETRAS-PE reduction. A higher baseline TETRAS-PE score predicted a good prognosis (HR = HR 6.6 [95% CI: 2.1–21.3]; p = 0.001). AEs were mild to moderate and transient, while permanent AE was observed only in one case. Conclusions: This real-world study confirms the higher effectiveness and the favorable safety profile of tcMRgFUS thalamotomy in patients with ET by reducing the tremor-related interference in quality of life, disability in ADL, and tremor severity. Full article

Accurate prediction of maximum voltage is essential for the safe, efficient, and sustainable design of photovoltaic systems, as it defines the maximum allowable number of modules in series. This study examines how the choice of meteorological year affects voltage estimations in high-power PV systems. A comparison is made between maximum voltage results derived from typical meteorological (TMY) years and those based on inter-hourly historical data. The results reveal notable differences, with TMY often underestimating extreme voltage levels. To address this, the study introduces the Extreme Meteorological Year (EMY) model, which uses historical voltage percentiles to better estimate peak voltages and mitigate overvoltage risk. This model has been applied successfully in real PV plant designs. Its performance is assessed using monitoring data from seven PV projects in different regions. The EMY model demonstrates improved accuracy and safety in predicting maximum voltages compared to traditional datasets. Its percentile-based structure enables adaptation to different design criteria, enhancing reliability and supporting more sustainable photovoltaic deployment. Overall, the study underscores the importance of selecting appropriate meteorological data for voltage prediction and presents EMY as a robust tool for improving PV system design. Full article

Background: Despite strong guideline recommendations, participation in cardiac rehabilitation (CR) among patients with chronic heart failure (CHF) remains low due to logistical, geographical, and psychosocial barriers. Telerehabilitation may help overcome these limitations by offering remote, structured exercise programs supported by digital technologies. Objective: The TELEREHAB-HF study aims to evaluate the efficacy of an 8-week, home-based cardiac telerehabilitation program compared to standard in-person rehabilitation in patients with CHF. Methods: This is a prospective, controlled cohort study involving 220 adult patients with CHF (NYHA class I–III) clinically stable and on optimized therapy. Participants are assigned to either a telerehabilitation group (remote CR via a digital platform with wearable sensors and real-time physiotherapist supervision) or a standard in-person rehabilitation group. The primary outcome is the change in peak oxygen uptake (VO₂max) at 8 weeks. Secondary outcomes include quality of life, functional performance, biochemical and echocardiographic parameters, and cognitive function, assessed at baseline and at 4, 8, 16, and 24 weeks. Expected Results: We hypothesize that telerehabilitation will be non-inferior to standard CR in improving functional capacity and secondary outcomes, with additional benefits in accessibility and adherence. Data from remote monitoring may also support a translational “rehabilomics” approach to exploring exercise-induced biomarker changes. Conclusions: This study seeks to assess the clinical effectiveness, safety, and feasibility of a home-based telerehabilitation model for CHF, with the goal of informing future strategies for broader implementation and personalized rehabilitation. Trial Registration: ClinicalTrials.gov Identifier: NCT07023536 Full article

Mine roof water inrush represents a prevalent hazard in mining operations, characterized by its concealed onset, abrupt occurrence, and high destructiveness. Since mine water inrush is controlled by multiple factors, rigorous risk assessment in hydrogeologically complex coal mines is critically important for operational safety. This study focuses on the roof water inrush hazard in coal seams of the Banji coal mine, China. The conventional water-conducting fracture zone height estimation formula was calibrated through comparative analysis of empirical models and analogous field measurements. Eight principal controlling factors were systematically selected, with subjective and objective weights assigned using AHP and EWM, respectively. Game theory was subsequently implemented to compute optimal combined weights. Based on this, the vulnerability index model and fuzzy comprehensive evaluation model were constructed to assess the roof water inrush risk in the coal seams. The risk in the study area was classified into five levels: safe zone, relatively safe zone, transition zone, relatively hazardous zone, and hazardous zone. A zoning map of water inrush risk was generated using Geographic Information System (GIS) technology. The results show that the safe zone is located in the western part of the study area, while the hazardous and relatively hazardous zones are situated in the eastern part. Among the two models, the fuzzy comprehensive evaluation model aligns more closely with actual engineering practices and demonstrates better predictive performance. It provides a reliable evaluation and prediction model for addressing roof water hazards in the Banji coal seam. Full article

Road safety in cities is becoming a bigger concern worldwide. As more people own cars and traffic congestion increases on old roads, the risk of accidents also grows, which severely affects victims and their families. In 2023, data from the Société de l’Assurance Automobile du Québec (SAAQ) reported that 380 people died in traffic accidents in Quebec. A study of road accidents in Montreal between 2012 and 2021 looked at the most dangerous locations, times, and traffic patterns. In this paper, we investigate the role of autonomous vehicles (AVs) vs human-driven vehicles (HDVs) in reducing road accidents in mixed traffic situations. The reaction time of human drivers to road accidents at signalized intersections affects safety and is used to compare the difference between the two situations. Microscopic traffic simulation models (MTMs) namely the Krauss car-following model is developed using SUMO to assess the vehicles performance. Case study 1 assesses the effect of reaction time on human-driven vehicles. The findings show that longer reaction times lead to more collisions. Case study 2 looks at autonomous vehicles and how human-driven vehicles interact in mixed traffic. The simulations tested various levels of AV penetration (0%, 25%, 50%, 75%, and 100%) in mixed traffic and found that more AVs on the road improve safety and reduce the number of accidents. Full article