Search Results (25)

Background: Radioligand therapy with [¹⁷⁷Lu]Lu-PSMA-617 represents an emerging treatment for metastatic castration-resistant prostate cancer (mCRPC). Its clinical positioning relative to standard therapies remains under discussion. Objective: To compare overall survival (OS), radiographic progression-free survival (rPFS), PSA response, and treatment burden across randomised trials evaluating [¹⁷⁷Lu]Lu-PSMA-617 versus androgen receptor pathway inhibitors (ARTA), Cabazitaxel, or standard of care (SOC). Evidence Acquisition: We conducted a meta-analysis of five randomised controlled trials, including 2073 patients with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC). We assessed survival endpoints, baseline comparability, and treatment intensity. Evidence Synthesis: [¹⁷⁷Lu]Lu-PSMA-617 significantly improved rPFS and PSA response. While modest overall, the OS benefit was more pronounced in taxane-naïve populations. Compared with Cabazitaxel, [¹⁷⁷Lu]Lu-PSMA-617 was associated with similar or better survival despite shorter treatment duration and potentially lower cumulative toxicity and cost. Economic modelling suggests it could offer a more sustainable therapeutic option under typical willingness-to-pay thresholds. Conclusions: [¹⁷⁷Lu]Lu-PSMA-617 shows clinical effectiveness and economic value in mCRPC, with potential advantages over Cabazitaxel and ARTA. Its use could be prioritised in early treatment lines. Patient Summary: This study suggests that PSMA-targeted radioligand therapy is at least as effective as other treatments for advanced prostate cancer, with potential benefits in terms of toxicity, duration, and overall cost. Full article

Background/Objectives: A common reason for a pediatrician’s visit is acute tonsillopharyngitis (ATR), which is usually caused by viruses. A dietary supplement comprising Pelargonium sidoides extract, honey, propolis, and zinc was proposed as an effective adjuvant for the management of respiratory tract infections. The study aimed to determine the efficacy of this dietary supplement in conjunction with standard of care (SoC) compared to SoC alone, in a pediatric population affected by ATR. Methods: This open randomized study (registered on ClinicalTrials.gov: NCT 04899401) involved three Romanian sites specialized in pediatric care. The primary endpoints were changes in Tonsillitis Severity Score and the number of patients failing to respond (evaluating the use of ibuprofen or high-dose paracetamol as a rescue medication). One hundred and thirty children, distributed into two groups, were enrolled and treated for six days. Results: The results showed an overall better performance in terms of efficacy of dietary supplement + SoC, compared to SoC alone, with lower total Tonsillitis Severity Score ratings on day 6 (p = 0.002) and lower sub-scores related to erythema and throat pain on day 6. No adverse events were reported. Investigators found compliance to be optimal. Conclusions: The administration of the dietary supplement + SoC in pediatric patients with ATR was found to be safe and superior to the administration of SoC alone in terms of efficacy. The results confirmed that the tested dietary supplement is an optimum effective adjuvant in the treatment of respiratory tract infections and is suitable for the daily clinical practice of pediatricians. Full article

The sophistication of cyberthreats demands more efficient and intelligent tools to support Security Operations Centers (SOCs) in managing and mitigating incidents. To address this, we developed the Security Event Response Copilot (SERC), a system designed to assist analysts in responding to and mitigating security breaches more effectively. SERC integrates two core components: (1) security event data extraction using Retrieval-Augmented Generation (RAG) methods, and (2) LLM-based incident response guidance. This paper specifically utilizes Wazuh, an open-source Security Information and Event Management (SIEM) platform, as the foundation for capturing, analyzing, and correlating security events from endpoints. SERC leverages Wazuh’s capabilities to collect real-time event data and applies a RAG approach to retrieve context-specific insights from three vectorized data collections: incident response knowledge, the MITRE ATT&CK framework, and the NIST Cybersecurity Framework (CSF) 2.0. This integration bridges strategic risk management and tactical intelligence, enabling precise identification of adversarial tactics and techniques while adhering to best practices in cybersecurity. The results demonstrate the potential of combining structured threat intelligence frameworks with AI-driven models, empowered by Wazuh’s robust SIEM capabilities, to address the dynamic challenges faced by SOCs in today’s complex cybersecurity environment. Full article

Background: Long COVID (LC) is characterized by persistent symptoms at least 3 months after a SARS-COV-2 infection. LC has been associated with fungal translocation, gut dysfunction, and enhanced systemic inflammation. Currently, there is no approved treatment for this condition. The anti-inflammatory effect of vitamins K2 and D3 was shown to help attenuate the course of acute COVID-19 infection. Objective and hypothesis: This trial aims to investigate the effects of vitamins K2/D3 on LC symptoms, as well as gut and inflammatory markers, in people with established long COVID. Our hypothesis is that by attenuating systemic inflammation, vitamins K2/D3 will improve long COVID symptoms. Methods: This single-site randomized controlled study enrolled adults experiencing ≥2 moderate LC symptoms at least 3 months after a COVID-19 infection. The RECOVER Long COVID Research Index and number and type of LC symptoms were considered. Participants were randomized 2:1 to daily 240 µg K2 (pure MK-7 form) and 2000 UI vitamin D3 or standard of care (SOC) for 24 weeks. The endpoints were changes in symptomatology and in select inflammatory, metabolic, and gut biomarkers at 24 weeks. Results: We enrolled 151 participants (n = 98 received vit K2/D3 and 53 received SOC). The median age was 46 years; 71% were female and 29% were non-white. Baseline demographics were balanced between groups. At 24 weeks, the active treatment group only had a sharp increase in 25(OH) D, indicating good treatment adherence. In the vitamin K2/D3 arm, there was a 7.1% decrease in the proportion who had an LC Index ≥12 (vs. a 7.2% increase in the SOC group; p = 0.01). The average number of LC symptoms remained stable in the vitamin K2/D3 arm but increased in the SOC arm (p = 0.03). Additionally, reductions in oxidized LDL, inflammatory markers sTNF-RI and sCD163, and fungal translocation marker (1,3)-β-d-glucan were observed in the vitamin K2/D3 arm compared to the SOC arm (p < 0.01) over 24 weeks. Conclusions: Vitamins K2/D3 improved the RECOVER Long COVID Index, the number of LC symptoms, and several gut and inflammatory markers. Vitamins K2/D3 provide a promising safe intervention for people suffering from long COVID. Full article

Background/Objectives: Overall survival for patients with Stage 3 pancreatic ductal adenocarcinoma (PDAC) remains limited, with a median survival of 12 to 15 months. Irreversible electroporation (IRE) is a local tumor ablation method that induces cancerous cell death by disrupting cell membrane homeostasis. The DIRECT Registry study was designed to assess the effectiveness and safety of IRE when combined with standard of care (SOC) treatment for Stage 3 PDAC versus SOC alone in a real-world setting after at least 3 months of induction chemotherapy; Methods: Patients with Stage 3 PDAC treated with IRE plus SOC or SOC alone were prospectively enrolled in a multicenter registry study. Enrollment required 3 months of active multi-agent chemotherapy with no progression before enrollment. Endpoints were 30- and 90-day mortality and adverse events (AEs). Results: Eighty-seven IRE and 27 SOC subjects were enrolled in the registry. Mean ages were 64.0 ± 8.4 and 66.4 ± 9.9 years, and mean anterior/posterior tumor diameters were 2.2 ± 0.7 cm and 3.2 ± 1.3 for the IRE and SOC groups respectively (p = 0.0066). All IRE procedures were performed using an open approach. The 90-day all-cause mortality was 5/83 (6.0%) and 2/27 (7.4%) for the IRE and SOC groups, respectively. Two subjects in the IRE group died from treatment-related complications, and one patient in the SOC group died due to chemotherapy-related complications. Conclusions: Initial results from the DIRECT registry study indicate the use of IRE for curative intent tumor ablation in combination with induction chemotherapy has equivalent morbidity and mortality rates when compared to standard-of-care chemotherapy alone. Full article

Background: In susceptible hosts, SARS-CoV2-induced hyperinflammation accounts for an increased mortality. The search of adjuvant immunomodulatory therapies has been ongoing ever since the pandemic outbreak. Aim: Our purpose was to evaluate the efficacy of cyclosporin A (CsA) as an add-on therapy to the standard of care (SoC) in patients with severe COVID-19 pneumonia. Methods: We conducted a randomized clinical trial in patients admitted to eight Spanish tertiary hospitals. Patients were stratified into two severity categories and randomized in a 1:1 ratio to receive a corticosteroid-based standard therapy with or without CsA. The primary endpoint was FiO2 recovery by Day 12 without relapses. Results: 109 patients were included and randomized, and 98 of them considered for the mITT population (51 assigned to the CsA + SoC group and 47 to the SoC group). A total of 35 (68.6%) patients from the CsA + SoC group and 32 (71.1%) patients from the SoC group reached the primary endpoint in the mITT analysis. No differences were found after stratification into age groups, in the severity level at admission, or in a combination of both. Overall, the time to FiO2 normalization was 7.4 days vs. 7.9 days in the experimental and control groups, respectively. Global mortality was 8.2%. Severe adverse events were uncommon and equally distributed between arms. Conclusion: The addition of CsA did not show differences over a corticosteroid-based treatment in the clinical course of the included patients. A better identification of candidates who will benefit from receiving immunomodulatory drugs is necessary in future studies. Full article

Introduction. Platinum-based chemotherapy represents the standard of care (SoC) for the first-line treatment of advanced urothelial carcinoma (mUC). The benefit of adding immune checkpoint inhibitors (ICIs) to platinum-based chemotherapy was recently investigated. We performed an individual patient data (IPD) meta-analysis of phase 3 clinical trials comparing ICI-based treatments. Methods. A systematic literature search was conducted on the MEDLINE and CENTRAL databases. The results were filtered by including only reports on clinical trials or randomized clinical trials from 2018 to 2023, including 3047 patients from four clinical trials (EV302, CHECKMATE-901, IMVIGOR130, KEYNOTE-361). An IPD meta-analysis was performed by reconstructing IPD from Kaplan–Meier curves. The primary endpoints were overall survival (OS) and progression-free survival (PFS) of Pembrolizumab + EV compared to experimental arms of the other trials of immunotherapy + chemotherapy. Results. The OS analysis showed an advantage of IPD from EV302 vs. all the other trials. For EV302 vs. KEYNOTE-361, the HR was 0.51; for EV302 vs. IMVIGOR130, the HR was 0.47; and for EV302 vs. CHECKMATE-901, the HR was 0.66 (CI 95% 0.51–0.85). In the PFS analysis, the EV302 arm showed a statistically significant advantage compared to CHECKMATE-901 (HR 0.66) and versus IMVIGOR130 (HR 0.51). Limitations: By using reconstructed IPD curves, it was not possible to adjust patient-level covariates, and the heterogeneity of the included population may have affected the pooled results. Conclusions: The EV302 experimental arm showed better OS and PFS when compared to the other immunochemotherapy combinations. An immunochemotherapy combination strategy at the beginning of treatment in mUC seems to be superior in terms of OS and PFS compared to platinum-based chemotherapy alone. EV–Pembrolizumab resulted to have better outcomes compared to avelumab, rather than other immunochemotherapy combinations. However, given the heterogeneity of these studies, a longer follow up and prospective trials are needed to confirm these data. Full article

This paper proposes a novel physics-based equivalent circuit model of the lithium-ion battery for electric vehicle applications that has comprehensive electrochemical significance and an acceptable level of complexity. Initially, the physics-based extended single particle (ESP) model is improved by adding a correction term to mitigate its voltage bias. Then, the equivalent circuit model based on the improved extended single particle (ECMIESP) model is derived. In this model, the surface state of charge (SOC) of solid particles is approximated using a capacity and multi first-order resistance-capacity equivalent circuits with only two lumped parameters. The overpotential of electrolyte diffusion is approximated using a first-order resistance-capacitance equivalent circuit. The electrochemical reaction overpotential is characterized by a nonlinear resistance. The voltage accuracies of ECMIESP and conventional 2RC equivalent circuit model (ECM2RC) are compared across the entire SOC range under various load profiles. The results demonstrate that the ECMIESP model outperforms ECM2RC model, particularly at low SOC or when the electrochemical reaction overpotential exceeds 50 mV. For instance, the ECMIESP model shows an 820.4 mV reduction in voltage error compared to the ECM2RC model at the endpoint during a 2C constant current discharge test. Lastly, the ECMIESP model was used for SOC estimation with extended Kalman filter, resulting in significantly improved accuracy compared to the conventional ECM2RC model. Therefore, the ECMIESP model has great potential for real-time applications in enhancing voltage and SOC estimation precision. Full article

Physicians are currently finding products for pediatric respiratory diseases of viral etiology to reduce the inappropriate use of antibiotic therapy. This study evaluated PediaFlù (Pediatrica S.r.l.), a dietary supplement already on the market composed of honey, propolis, Pelargonium sidoides extract, and zinc (DSHPP), in children affected by acute tonsillopharyngitis (ATR). The open-label, randomized, and controlled study compared DSHPP + standard of care (SoC) versus SoC alone for six days. Children between 3 and 10 years with an ATR ≤ 48 h, a negative rapid test for beta-hemolytic Streptococcus, or a culture identification of nasal and/or pharyngeal exudates were included. A tonsillitis severity score (TSS) and the number of treatment failures (using ibuprofen or high-dose paracetamol as rescue medication) were the primary endpoints. DSHPP+ SoC showed better performance than SoC alone for TSS sub-scores: throat pain and erythema on day 6 (p < 0.001 and p < 0.05), swallowing (p < 0.01 on day 4), and TSS total score on days 4 and 6 (p < 0.05 and p < 0.001). Only one patient (SoC group) had treatment failure for ibuprofen administration. No adverse events were reported. DSHPP is an optimal adjuvant in the treatment of URTI and could potentially be useful in the daily clinical practice of paediatricians evaluating the correct antibiotic prescription. Full article

(1) Background: A high concentration of sodium chloride on in vitro cell culture leads to reduced SARS-CoV-2 replication. Therefore, our aim was to evaluate the effects of inhaling hypertonic NaCl particles (BREATHOX^®) on the duration of COVID-19-induced acute symptoms. (2) Methods: A prospective, open label, randomized, standard of care-controlled group (SOC) pilot trial compared inhaled oral and nasal administered BREATHOX^® (2.0 mg NaCl, particles size between 1–10 μm), with five or ten inhalations per day for ten days. The primary endpoint was the time to resolve COVID-19-related symptoms. Safety outcomes included adverse clinical and laboratory events. (3) Results: A total of 101 individuals were screened and 98 were randomly assigned to BREATHOX^® ten sessions per day (Group 1; 33 patients), BREATHOX^® five sessions per day (Group 2; 32 patients), or SOC (33 patients), and followed up for 28 days. There was an association with cough frequency after 10 days BREATHOX^® compared to SOC [Group 1: hazard ratio (HR) 2.01, 95% confidence interval (CI) 1.06–3.81; Group 2: HR 2.17, 95% CI 1.17–4.04]. No differences between the groups for the reported symptoms’ resolution time were seen after 28 days. After combining both BREATHOX^® groups, the period to cough resolution 10 days after randomization was significantly lower than in SOC (HR 2.10, 95% CI 1.20–3.67). An adverse event occurred in 30% of Group 1, 36% of Group 2, and 9% in SOC individuals. One patient from SOC had a serious adverse event. Nasal burning, sore or itchy nose, and dry mouth were considered related to BREATHOX^® use and resolved after stopping inhalations. (4) Conclusion: BREATHOX^® inhalation is safe and may be effective in reducing the duration of COVID-19-induced coughing. Full article

To test the antitumor effect and safety of peptide-based anticancer vaccination in dogs with hemangiosarcoma undergoing the standard of care (SOC; surgery and doxorubicin), canine hemangiosarcoma cells were infected with Salmonella typhi Ty21a to release immunogenic endoplasmic reticulum stress-related peptides into the extracellular milieu via CX43 hemichannels opening. The infected tumor cell secretome constituted the vaccine. Following the SOC, dogs with biologically aggressive hemangiosarcoma were vaccinated a total of five times, once every 3 weeks, and were followed up with serial imaging. A retrospective population of dogs undergoing the SOC alone served as controls. The primary endpoints were the time to progression (TTP) and overall survival (OS), and the secondary endpoints were toxicity and immune responses. A total of 28 dogs were vaccinated along with the SOC, and 32 received only the SOC. A tumor-specific humoral response along with a vaccine-specific T-cell response was observed. Toxicity did not occur. The TTP and OS were significantly longer in vaccinated versus unvaccinated dogs (TTP: 195 vs. 160 days, respectively; p = 0.001; OS: 276 vs. 175 days, respectively; p = 0.002). One-year survival rates were 35.7% and 6.3% for vaccinated and unvaccinated dogs, respectively. In dogs with hemangiosarcoma undergoing the SOC, the addition of a peptide-based vaccine increased the TTP and OS, while maintaining a safe profile. Moreover, vaccinated dogs developed a tumor-specific response, supporting the feasibility of future phase three studies. Full article

Epidemiological data suggest that the severe acute respiratory syndrome coronavirus 2 infection rate is higher in women than in men, but the death rate is lower, while women (>50 years) on menopausal hormone therapy (MHT) have a higher survival rate than those not on MHT. Classical oral estrogen enhances the synthesis of coagulation markers and may increase the risk of thromboembolic events that are common in coronavirus disease 2019 (COVID-19). The favorable hemostatic profile of estetrol (E4) might be suitable for use in women who are receiving estrogen treatment and contract COVID-19. A multicenter, randomized, double-blind, placebo-controlled, phase 2 study (NCT04801836) investigated the efficacy, safety, and tolerability of E4 versus placebo in hospitalized patients with moderate COVID-19. Eligible postmenopausal women and men (aged ≥ 18 years old) were randomized to E4 15 mg or placebo, once daily for 21 days, in addition to the standard of care (SoC). The primary efficacy endpoint of improvement in COVID-19 (percentage of patients recovered at day 28) between the placebo and E4 arms was not met. E4 was well tolerated, with no safety signals or thromboembolic events, suggesting that postmenopausal women can safely continue E4-based therapy in cases of moderate COVID-19 managed with SoC. Full article

People with Type 2 diabetes mellitus (T2DM) are reported to have a high prevalence of metabolic syndrome (MetS), which increases their risk of cardiovascular events. Our aim was to determine the effect of physical activity (PA) on metabolic syndrome markers in people with T2DM. The study design was a systematic review and meta-analysis of randomised controlled trials evaluating the effect of PA on MetS in adults with T2DM. Relevant databases including SPORTdiscus, Cochrane Central Register of Controlled Trials, CINAHL, MEDLINE, PsycINFO, EMBASE, SocINDEX were searched up to August 2022. Primary endpoints were changes in MetS markers (blood pressure, triglyceride, high-density lipoprotein, fasting blood sugar, and waist circumference) after an exercise intervention. Using a random effect model with 95% confidence interval (CI), the mean difference between intervention groups and control groups were calculated. Twenty-six articles were included in the review. Overall, aerobic exercise had a significant effect on waist circumference (Mean Difference: −0.34 cm, 95% CI: −0.84, −0.05; effect size: 2.29, I² = 10.78%). The effect sizes on blood pressure, triglyceride, high-density lipoprotein, fasting blood sugar were not statistically significant. No significant differences were found between exercise and control group following resistance training. Our findings suggest that aerobic exercise can improve waist circumference in people with T2DM and MetS. However, both aerobic and resistance exercise produced no significant difference in the remaining MetS markers. Larger and higher-quality studies are required to determine the full effects of PA on MetS markers in this population. Full article

Introduction: Durvalumab following chemoradiotherapy (CRT) for non-small cell lung cancer stage III has become the standard of care (SoC) in the past few years. With this regimen, 5-year overall survival (OS) has risen to 43%. Therefore, adequate pulmonary function (PF) after treatment is paramount in long-term survivors. In this respect, carbon monoxide diffusing capacity (DL_CO), which represents the alveolar compartment, seems to be a suitable measure for residual lung capacity. The aim of the current analysis was to correlate DL_CO with pneumonitis and radiation dose. Patients and methods: One hundred and twelve patients with histologically confirmed NSCLC III treated between 2015/10 and 2022/03 were eligible for this study. Patients received two cycles of platinum-based induction chemotherapy followed by high-dose radiotherapy (RT). As of 2017/09, durvalumab maintenance therapy was administered for one year. The clinical endpoints were based on the thresholds jointly published by the European Respiratory Society (ERS) and the American Thoracic Society (ATS). Pre-treatment DL_CO of 60% was correlated to the incidence of pneumonitis, whereas the post-treatment DL_CO decline of 10% was related to radiation dose. Results: Patients with a pre-treatment DL_CO < 60% had a higher probability of pneumonitis (n = 98; r = 0.175; p-value 0.042), which could be reproduced in the subgroup of patients who did not receive durvalumab (n = 40; r = 0.288; p-value 0.036). In these individuals, the decline in DL_CO ≥ 10% depended significantly on the size of the lung volume receiving between 45% and 65% (V_65–45%) of the total radiation dose (r = 0.354; p-value = 0.020) and V_{20 Total Lung} (r = 0.466; corrected p-value = 0.042). Conclusions: The current analysis revealed that DL_CO is a predictor for clinically relevant pneumonitis and a monitoring tool for post-treatment lung function as it correlates with radiation dose. This underlines the importance of peri-treatment lung function testing. Full article

Background. The aim of the study was to assess the effect of baricitinib on 28-day all-cause mortality and the progression of respiratory failure in patients needing transfer to the intensive care unit (ICU) with COVID-19 pneumonia treated with high-flow oxygen therapy. Methods. This retrospective study included hospitalized patients with COVID-19 pneumonia treated with high-flow oxygen non-invasive ventilation receiving standard of care (SOC) or SOC in addition to baricitinib. Data on patients’ characteristics, pro-inflammatory markers, D dimer, and National Early Warning Score 2 (NEWS2) values were collected and compared between groups. The primary endpoint was 28-day all-cause in-hospital mortality and the secondary outcome was transfer to the ICU. Results. The study included 125 patients. The primary outcome was observed in 44.8% of them: 27% in the baricitinib group vs. 62% in the SOC group, p < 0.001. Transfer to the ICU ward was significantly lower in the baricitinib group: 29% vs. 81%, p < 0.001. A significant improvement was observed when the baricitinib group was compared to SOC in procalcitonin, CRP, D-dimer, neutrophil-to-lymphocyte ratio values, and NEWS2. Conclusion. Treatment with baricitinib in addition to SOC was associated with reduced mortality and a lower prevalence of transfer to the ICU in hospitalized patients with COVID-19 pneumonia treated with high-flow oxygen non-invasive therapy. Full article