Key Safety Research Articles

Tenecteplase for Ischemic Stroke at 4.5 to 24 Hours without Thrombectomy

BackgroundTenecteplase is an effective thrombolytic agent for eligible patients with stroke who are treated within 4.5 hours after the onset of stroke. However, data regarding the effectiveness of tenecteplase beyond 4.5 hours are limited.MethodsIn a trial conducted in China, we randomly assigned patients with large-vessel occlusion of the middle cerebral artery or internal carotid artery who had salvageable brain tissue as identified on perfusion imaging and who did not have access to endovascular thrombectomy to receive tenecteplase (at a dose of 0.25 mg per kilogram of body weight; maximum dose, 25 mg) or standard medical treatment 4.5 to 24 hours after the time that the patient was last known to be well (including after stroke on awakening and unwitnessed stroke). The primary outcome was the absence of disability, which was defined as a score of 0 or 1 on the modified Rankin scale (range, 0 to 6, with higher scores indicating greater disability), at day 90. The key safety outcomes were symptomatic intracranial hemorrhage and death.ResultsA total of 516 patients were enrolled; 264 were randomly assigned to receive tenecteplase and 252 to receive standard medical treatment. Less than 2% of the patients (4 in the tenecteplase group and 5 in the standard-treatment group) underwent rescue endovascular thrombectomy. Treatment with tenecteplase resulted in a higher percentage of patients with a modified Rankin scale score of 0 or 1 at 90 days than standard medical treatment (33.0% vs. 24.2%; relative rate, 1.37; 95% confidence interval, 1.04 to 1.81; P=0.03). Mortality at 90 days was 13.3% with tenecteplase and 13.1% with standard medical treatment, and the incidence of symptomatic intracranial hemorrhage within 36 hours after treatment was 3.0% and 0.8%, respectively.ConclusionsIn this trial involving Chinese patients with ischemic stroke due to large-vessel occlusion, most of whom did not undergo endovascular thrombectomy, treatment with tenecteplase administered 4.5 to 24 hours after stroke onset resulted in less disability and similar survival as compared with standard medical treatment, and the incidence of symptomatic intracranial hemorrhage appeared to be higher. (Funded by the National Natural Science Foundation of China and others; TRACE-III ClinicalTrials.gov number, NCT05141305.)

Safety Leadership: A Catalyst for Positive Safety Climate on Construction Sites

Limited research exists on safety leadership and safety climate in developing countries, despite their established importance in the construction industry. This study addresses this gap by investigating how immediate superiors’ safety leadership behaviours influence safety climate perceptions among construction professionals in southern India. Using a quantitative approach, the study collected valid questionnaire surveys among 279 construction professionals by convenience sampling across various construction sites. The survey revealed that safety leadership significantly and positively predicts five key safety climate factors: management’s commitment to safety, safety equipment and procedures, safety training, communication and openness, and group dynamics and safety culture. These findings highlight the critical role immediate superiors play in shaping safety climate perceptions through their commitment, communication, and employee involvement. This research underscores the importance of investing in safety leadership development to improve safety outcomes, reduce accidents and injuries, and enhance regulatory compliance within the Indian construction industry.

Embedding More Autonomous Safety in MCUs-Based Embedded Systems using Project-Based Learning (case study)

In this research, we present a new technique for learning embedded systems design (ES) that integrates Project-Based Learning (PBL) with conventional face-to-face learning. The PBL course uses a project-based learning approach which offers insights for effective safety feature implementation, concentrates on ES or IoT applications and highlights security in the developed system. This is achieved by using Safety co-processors and Microcontrollers which are secure and cost-effective. Furthermore, the study highlights the key safety modules suitable for integration into MCUs. Additionally, we propose implementing a functional safety layer including a safety co-processor equipped with trusted input/output controllers that contribute to identifying potential failures and increase the system fault tolerance.

Palbociclib plus exemestane with GnRH agonist vs capecitabine in premenopausal patients with HR+/HER2- metastatic breast cancer: Updated survival results of the randomized phase 2 study Young-PEARL.

LBA1002 Background: The Young-PEARL study demonstrated improved progression free survival (PFS) (mPFS: 20.1 vs. 14.4 mo.) of exemestane plus palbociclib with ovarian function suppression (OFS) compared to capecitabine in premenopausal patients with HR+/HER2- metastatic breast cancer (mBC). Here we report updated survival outcomes with median follow-up of 54.8 months (data cutoff, November 30, 2023). Methods: Premenopausal women aged 19 years or older with HR+/HER2- BC who had relapsed or progressed during previous tamoxifen therapy were enrolled. One line of previous chemotherapy for mBC was allowed. The primary endpoint was PFS, which was defined as the time from C1D1 to disease progression or death. The key secondary endpoint was overall survival (OS). Other secondary endpoints included objective response rate (ORR) and toxicities. Results: 184 patients were randomly assigned to exemestane plus palbociclib with OFS (n=92) or capecitabine (n=92). Median age was 44.0 years (range, 28-58). Key efficacy and safety are shown in Table. Final analysis was conducted for 174 patients. The updated mPFS was 19.5 mo. (90% CI, 14.3-22.3) for exemestane + palbociclib + OFS compared with 14.0 mo. (90% CI, 11.7-18.7) for capecitabine (HR 0.75, P=0.04). mOS was 54.8 mo. (95% CI, 48.9-77.1) for palbociclib arm and 57.8 mo. (95% CI, 46.3-N/A) for capecitabine arm (HR 1.06, P=0.77). mPFS2 (from the date of 1st PD to 2nd PD) was significantly shorter in palbociclib arm than those of capecitabine arm (7.5 vs. 11.7 mo. P=0.02). Confirmed ORR based on the investigator assessments was 33.3% (95% CI, 23.6-43.1) for palbociclib and 33.7% (95% CI, 23.6-43.9) for capecitabine. Median treatment duration was 18.9 mo. (range 1.6-88.4) in palbociclib and 13.5 mo. (range 0.1-70.8) in capecitabine. In palbociclib arm, 86 (93.5%) experienced grade 3 or more TEAEs, mainly asymptomatic neutropenia (64.1%), compared to 41 (48.2%) patients with grade ≥3 TEAEs in the capecitabine arm, mainly Hand-Foot syndrome and neutropenia (18.8% for each). Conclusions: Young-PEARL study showed exemestane + palbociclib with OFS improves efficacy compared with capecitabine in terms of PFS, which did not lead to an OS benefit for patients with premenopausal HR+/HER2- mBC (median follow-up duration: 54.8 months). The overall safety profile of palbociclib and capecitabine continues to be manageable with longer follow-up. Clinical trial information: NCT02592746 . [Table: see text]

Surface Crystal and Degradability of Shape Memory Scaffold Essentialize Osteochondral Regeneration.

The minimally invasive deployment of scaffolds is a key safety factor for the regeneration of cartilage and bone defects. Osteogenesis relies primarily on cell-matrix interactions, whereas chondrogenesis relies on cell-cell aggregation. Bone matrix expansion requires osteoconductive scaffold degradation. However, chondrogenic cell aggregation is promoted on the repellent scaffold surface, and minimal scaffold degradation supports the avascular nature of cartilage regeneration. Here, a material satisfying these requirements for osteochondral regeneration is developed by integrating osteoconductive hydroxyapatite (HAp) with a chondroconductive shape memory polymer (SMP). The shape memory function-derived fixity and recovery of the scaffold enabled minimally invasive deployment and expansion to fill irregular defects. The crystalline phases on the SMP surface inhibited cell aggregation by suppressing water penetration and subsequent protein adsorption. However, HAp conjugation SMP (H-SMP) enhanced surface roughness and consequent cell-matrix interactions by limiting cell aggregation using crystal peaks. After mouse subcutaneous implantation, hydrolytic H-SMP accelerated scaffold degradation compared to that by the minimal degradation observed for SMP alone for two months. H-SMP and SMP are found to promote osteogenesis and chondrogenesis, respectively, in vitro and in vivo, including the regeneration of rat osteochondral defects using the binary scaffold form, suggesting that this material is promising for osteochondral regeneration.

Roadmap towards safe and sustainable advanced and innovative materials. (Outlook for 2024-2030)

The adoption of innovative advanced materials holds vast potential, contingent upon addressing safety and sustainability concerns. The European Commission advocates the integration of Safe and Sustainable by Design (SSbD) principles early in the innovation process to streamline market introduction and mitigate costs. Within this framework, encompassing ecological, social, and economic factors is paramount. The NanoSafety Cluster (NSC) delineates key safety and sustainability areas, pinpointing unresolved issues and research gaps to steer the development of safe(r) materials. Leveraging FAIR data management and integration, alongside the alignment of regulatory aspects, fosters informed decision-making and innovation. Integrating circularity and sustainability mandates clear guidance, ensuring responsible innovation at every stage. Collaboration among stakeholders, anticipation of regulatory demands, and a commitment to sustainability are pivotal for translating SSbD into tangible advancements. Harmonizing standards and test guidelines, along with regulatory preparedness through an exchange platform, is imperative for governance and market readiness. By adhering to these principles, the effective and sustainable deployment of innovative materials can be realized, propelling positive transformation and societal acceptance.

FDA analysis of immune checkpoint inhibitors in combination with vascular endothelial growth factor tyrosine kinase inhibitors in the second-line treatment of patients with advanced non-small cell lung cancer.

8595 Background: Immune checkpoint inhibitors (ICIs) targeting PD-(L)1 in combination with platinum-based chemotherapy is standard first-line therapy for patients with advanced non-small cell lung cancer (NSCLC). The majority of these patients progress and there remains a high unmet medical need in the second-line setting given the limited FDA approved available therapies. The ICI plus vascular endothelial growth factor tyrosine kinase inhibitor (VEGF TKI) combination, successful across several tumor types, was studied in NSCLC as a potential treatment option. Methods: The FDA identified 3 randomized trials conducted between June 2019 and August 2023, comparing the combination regimen ICI plus VEGF TKI to docetaxel in patients with advanced NSCLC who had progressed on both platinum-based chemotherapy and an ICI. All 3 trials were publicly reported to have not met their primary endpoint. Topline results for key efficacy and safety outcomes from each of the 3 trials were provided by the commercial sponsors. Results: 1317 total patients across 3 trials (LEAP-008, SAPPHIRE and CONTACT-01) were randomized to receive either an ICI plus VEGF TKI or docetaxel. The results are presented (Table). Efficacy parameters demonstrated similar results across trials between arms. There was no clear signal that the combination is more effective than single agent docetaxel. Safety parameters across trials consistently demonstrated higher rates of toxicity with the combination. Conclusions: ICI plus oral VEGF TKI combinations have not demonstrated an advantage over docetaxel in randomized trials of patients with advanced NSCLC. In 2 of the 3 trials, response rate data did not demonstrate superior efficacy compared to docetaxel. Additionally, any observed PFS benefit was small in magnitude. The relatively low efficacy, in combination with the additive toxicity of the regimen, may curtail a potential OS benefit. There remains a high unmet medical need in this patient population and further analysis is necessary to explore potential NSCLC subgroups which may derive benefit. [Table: see text]

Trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM1) in patients (pts) with HER2+ metastatic breast cancer (mBC): Updated survival results of DESTINY-Breast03.

1025 Background: DESTINY-Breast03 (NCT03529110), a randomized, multicenter, open-label, phase 3 study, assessed the efficacy and safety of T-DXd vs T-DM1 in pts with HER2+ mBC treated with ≥1 prior anti-HER2 regimen. Median (m) overall survival (OS) was not reached in either arm at the prior data cutoff (DCO; Jul 25, 2022). We report updated survival results, including efficacy and safety, after median duration of follow-up of 41 mo. Methods: Pts were randomized 1:1 to T-DXd 5.4 mg/kg or T-DM1 3.6 mg/kg once every 3 weeks. Primary endpoint was progression-free survival (PFS) by blinded independent central review (assessed at prior DCO); key secondary endpoint was OS. Other secondary endpoints included objective response rate (ORR), PFS, duration of response (DoR), PFS from time of randomization to progression on next line of therapy or death (PFS2), and safety. All secondary endpoints were based on investigator assessment. Results: 524 pts were randomized (T-DXd, n = 261; T-DM1, n = 263). As of Nov 20, 2023, median duration of follow-up was 43.0 mo (range, 0.0-62.9) for T-DXd and 35.4 mo (range, 0.0-60.9) for T-DM1. mOS (95% CI) was 52.6 mo (48.7-not evaluable [NE]) for T-DXd and 42.7 mo (35.4-NE) for T-DM1 (hazard ratio [HR], 0.73), with 110 (42.1%) and 126 (47.9%) OS events, respectively. OS rate (95% CI) at 36 mo was 67.6% (61.3-73.0%; T-DXd) vs 55.7% (49.2-61.7%; T-DM1). mPFS was 29.0 mo for T-DXd and 7.2 mo for T-DM1; PFS rate (95% CI) at 24 mo was 55.8% (49.1-62.0%; T-DXd) vs 20.6% (15.4-26.4%; T-DM1). mPFS2 was 45.2 mo (T-DXd) vs 23.1 mo (T-DM1). Median treatment duration was 18.2 mo (range, 0.7-56.6) with T-DXd vs 6.9 mo (range, 0.7-55.2) with T-DM1; rates of treatment-emergent adverse events (TEAEs) were consistent with prior DCO. Adjudicated drug-related interstitial lung disease/pneumonitis occurred in 16.7% of pts with T-DXd (4 new events [all grade 2] since prior DCO) vs 3.4% with T-DM1 (1 new event [grade 1]); neither arm had grade 4 or 5 events. Key efficacy and safety results are shown in the table. Conclusions: The superiority of T-DXd over T-DM1 was reinforced in this long-term analysis, as observed by clinically meaningful improvement in OS, PFS, and PFS2, consistent with prior DCO. The safety profile of T-DXd continues to be manageable with no cumulative toxicities observed with longer follow-up. Clinical trial information: NCT03529110 . [Table: see text]

Exposure-response (ER) analyses of efficacy and safety of trastuzumab deruxtecan (T-DXd) to inform dosing recommendation in HER2-mutant non-small cell lung cancer (NSCLC).

e20545 Background: T-DXd, a novel human epidermal growth factor receptor 2 (HER2) targeting antibody drug conjugate, was evaluated at doses of 5.4 and 6.4 mg/kg every three weeks in Phase 1 or 2 trials in HER2 mutant (HER2m) NSCLC subjects, including Destiny-Lung01 (DL-01) and DL-02 trials1,2. ER analyses of key efficacy and safety endpoints were conducted to support the dosing recommendation of T-DXd in HER2m NSCLC. Methods: Exposure-efficacy (EE) analysis was performed using confirmed objective response (cORR) data from HER2m NSCLC in Phase 1-2 trials (N = 181). The dataset included primary analysis data cut from DL-011 and interim analysis data cut from DL-02. Exposure-safety (ES) analyses of T-DXd were performed, using pooled data from 11 Phase 1-3 trials (N = 1850) across tumor types, including DL-01 and DL-02, for safety endpoints of adverse events (AEs) associated with dose reduction or discontinuation, Grade3+ (G3+) AEs, serious AEs, G3+Anemia, G3+neutropenia, G3+thrombocytopenia, adjudicated any grade interstitial lung disease (ILD), and G3+ ILD. cORR and all safety endpoints, except ILD were analyzed by logistic regression; any grade ILD was analyzed by parametric time-to-event analysis. The T-DXd or DXd exposure metric and numerous patient-specific covariates were tested in the analysis. Results: T-DXd exposure had a positive but shallow relationship with cORR. The predicted cORR varied from 57% (95% credible interval (CrI): [36, 77]) to 65% (95% CrI: [41, 84]) across 5th and 95th percentile of T-DXd exposure respectively. No clinically meaningful difference in cORR was estimated across 5.4 and 6.4 mg/kg doses with predicted cORR values of 53% (95% CrI: [44, 60]) and 55% (95% CrI: [47, 62]) at T-DXd doses of 5.4 mg/kg and 6.4 mg/kg, respectively. ES relationships were consistent with previous T-DXd ES analyses in breast cancer (BC). Model-predicted AE rates were lower (up to 9%) in 5.4 mg/kg compared to the 6.4 mg/kg dose. Model-predicted safety at 5.4 mg/kg dose in HER2m NSCLC was similar to the approved dose of 5.4 mg/kg in BC. Conclusions: The ER analyses showed no clinically meaningful difference in efficacy between 5.4 and 6.4 mg/kg doses of T-DXd; and safety events were lower in 5.4 mg/kg, thus supporting the 5.4 mg/kg recommended dose for HER2m NSCLC. These findings were later confirmed based on primary analysis in DL-022 and support the utility of ER analyses in dosing recommendation. Reference: Li BT et al. N Engl J Med 2022;386:241-51 Goto K et al. J Clin Oncol 41:4852-4863. Clinical trial information: NCT03505710 , NCT04644237 .

Institutional review of pediatric oncology patients participating in early phase clinical trials.

10042 Background: Phase 1 or phase 1/2 trials are a first step in pediatric cancer drug development with a primary objective of evaluating safety and dosing of new therapies or new combinations. They most commonly enroll patients with relapsed/refractory or very rare cancers and currently there is a paucity of information regarding outcomes for pediatric patients enrolled on phase 1/2 trials. Thus, we sought to describe clinical outcomes of pediatric patients enrolled in phase 1 clinical trials over a 9-year period at a single institution. Methods: We queried our clinical trials management system to generate a list of all pediatric patients who were enrolled and treated on phase 1 or phase 1/2 trials from 2011-2019. We reviewed the electronic medical record to collect baseline demographic and clinical data. We also collected key efficacy and safety endpoints post-enrollment including: time to death (if applicable); objective response to trial therapy; duration on therapy; need for dose modification; and occurrence of DLT. Overall survival was calculated using Kaplan-Meier methods. Results: A total of 224 unique patients accounted for 258 enrollments and 253 episodes of treatment on trial. The median age at trial enrollment was 11 years (range 0-27 years) and 56.2% were male. The majority of patients were white (85.7%) and non-Hispanic (88.2%). English was the primary language for 86.3% of patients and 65.8% of patients had private insurance. Solid tumors were the most common malignancy at 41.0%, followed by brain tumors (34.1%), and hematologic malignancies (24.9%). The majority of patients (60%) had metastatic disease at time of first enrollment. Among episodes of treatment, 51.4% received targeted monotherapy. Median overall survival from first enrollment for 210 patients treated with available vital status was 12.8 months. Among episodes of treatment, 25.2% of patients had an objective response to trial therapy. Stratified by disease type, objective response was documented for 52.9% of patients with hematologic malignancies, 20.5% of patients with CNS tumors, and 15.8% of patients with solid tumors. Patients on trials with cytotoxic-only treatment had the highest objective response (47.5%), while patients treated with cytotoxic plus targeted therapies combinations had the lowest rate (18.9%). The median duration of therapy was 1.5 months. Twenty-seven patients (11.0%) required dose modification and 22 patients (9.0%) had DLT. Conclusions: We present clinical outcomes for a recent cohort of pediatric patients treated on early phase clinical trials. We identified differential response rates to phase 1 therapy by disease and trial-type in a single-center cohort treated over the past decade. These data are immediately informative to discussions between providers and patients/parents regarding expected phase 1 trial outcomes.

Sacubitril/Valsartan in Patients With Heart Failure and Deterioration in eGFR to

BackgroundSacubitril/valsartan is a foundational therapy for patients with heart failure. Although current U.S. Food and Drug Administration labeling does not provide guidance regarding initiation or continuation of sacubitril/valsartan in patients with worsening kidney function, guidelines identify estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 as a contraindication to therapy. ObjectivesThis study aims to assess the safety and efficacy of continuing sacubitril/valsartan in patients with deterioration of kidney function below an eGFR of 30 mL/min/1.73 m2. MethodsThe association between a deterioration in eGFR <30 mL/min/1.73 m2, efficacy and safety outcomes, and treatment with sacubitril/valsartan vs renin-angiotensin system inhibitor were evaluated using time updated Cox models in a post hoc parallel trial analyses of PARADIGM-HF and PARAGON-HF. ResultsAmong 8,346 randomized patients in PARADIGM-HF and 4,746 in PARAGON-HF, 691 (8.3%) and 613 (12.9%), respectively, had an eGFR <30 mL/min/1.73 m2 at least once in follow-up. Patients experiencing such deterioration were at higher risk of the primary outcome in both PARADIGM-HF and PARAGON-HF. However, the incidence of the primary outcome remained lower with sacubitril/valsartan vs renin-angiotensin system inhibitor, regardless of deterioration in kidney function in both PARADIGM-HF (Pinteraction = 0.50) and PARAGON-HF (Pinteraction = 0.64). Rates of key safety outcomes were higher among patients experiencing eGFR deterioration; however, rates were similar between treatment groups including among those who remained on treatment. ConclusionsPatients experiencing deterioration of kidney function to a value below eGFR 30 mL/min/1.73 m2 faced high risk of cardiovascular and kidney disease outcomes. Continuation of sacubitril/valsartan was associated with persistent clinical benefit and no incremental safety risk. These data support continuation of sacubitril/valsartan for heart failure treatment even when eGFR declines below this threshold (PARADIGM-HF [Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure], NCT01035255; and PARAGON-HF [Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction], NCT01920711)

Mirikizumab Exposure-Response Relationships in Patients with Moderately-to-Severely Active Ulcerative Colitis in Randomized Phase II and III Studies.

Mirikizumab is a humanized anti-interleukin-23p19 monoclonal antibody being developed for ulcerative colitis (UC) and Crohn's disease. We characterized the relationship of mirikizumab systemic exposure with efficacy and safety end points in patients with UC using phase II (NCT02589665) and III (NCT03518086, NCT03524092) trial data. Exposure-response models were developed for clinical remission, clinical response, endoscopic remission, and change in modified Mayo score following induction (50-1,000 mg i.v. every 4 weeks) and maintenance (200 mg s.c. every 4 or 12 weeks) treatment. These models evaluated observed and pharmacokinetic model-predicted mirikizumab exposures as the exposure measure. Key safety event rates were compared across mirikizumab exposure quartiles in the phase III trial. Mirikizumab efficacy in patients with UC showed an apparent positive association with systemic exposure following both induction and maintenance. However, further analysis found this relationship to be overstated by the presence of confounding factors that were not among the tested patient covariates. While prior biologic experience and baseline disease severity showed statistically significant influences on estimated placebo effect, no patient factors affected the mirikizumab effect parameters in any of the phase III exposure-response models. There was no apparent mirikizumab concentration relationship with any adverse event of special interest. When the phase II and III data and confounding are considered together, efficacy was unlikely to be strongly affected by variation in exposures across individual patients at the phase III dose. Together with the previously demonstrated mirikizumab exposure insensitivity to patient factors, these findings indicate that mirikizumab dose adjustment to patient characteristics is not required.

#2063 Safety and efficacy of vadadustat vs darbepoetin alfa in patients on maintenance dialysis by prespecified subgroups of baseline ESA dose

Abstract Background and Aims Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor approved in Europe, Australia, Japan for the treatment of anemia in patients with dialysis-dependent (DD)-CKD. In the INNO2VATE global phase 3 trials in patients with DD-CKD, including 2 separate trials in patients new to dialysis [NCT02865850] and on maintenance dialysis [NCT02892149], vadadustat was noninferior to the erythropoiesis -stimulating agent (ESA) darbepoetin alfa for cardiovascular safety and hemoglobin efficacy. Among patients with DD-CKD, high ESA dose requirements have been associated with an increased risk of cardiovascular complications. In this secondary analysis, we compared cardiovascular safety and hematological efficacy of vadadustat and darbepoetin alfa across baseline ESA dose categories. Method In the INNO2VATE trials, 3554 patients on maintenance dialysis were randomized 1:1 to vadadustat or darbepoetin alfa, stratified according to geographic region, New York Heart Association heart failure classification, and hemoglobin concentration at trial entry. Data were analyzed for prespecified subgroups of patients categorized by their baseline ESA (epoetin alfa/equivalents) dose: low (&amp;lt;90 U/kg/week), intermediate (90-299 U/kg/week), or high (≥300 U/kg/week). Within these dose subgroups, the key safety endpoint was the first occurrence of an adjudicated major adverse cardiovascular event (MACE: first occurrence of all-cause mortality, nonfatal myocardial infarction [MI], or nonfatal stroke) using a time-to-event analysis. Primary and secondary efficacy endpoints were mean change in hemoglobin concentration from baseline during the primary (weeks 24-36) and secondary (weeks 40-52) evaluation periods, respectively. Results More participants were in the low (vadadustat: n = 916 [53%], darbepoetin alfa: n = 968 [55%]) and intermediate (vadadustat: n = 724 [42%], darbepoetin alfa: n = 693 [39%]) than in the high (vadadustat: n = 102 [6%], darbepoetin alfa: n = 98 [6%]) baseline ESA dose subgroups. Hazard ratios for the occurrence of first MACE between vadadustat and darbepoetin alfa in the 3 baseline ESA dose subgroups were as follows: low dose, 0.99 (95% CI, 0.81 to 1.23); intermediate dose, 0.93 (95% CI, 0.74 to 1.18); and high dose, 0.62 (95% CI, 0.34 to 1.14) (Fig.). Similar results were observed for other key MACE-related endpoints, including all-cause mortality, MACE plus hospitalizations for heart failure or thromboembolic events, cardiovascular MACE (first occurrence of cardiovascular mortality, nonfatal MI, or nonfatal stroke), and cardiovascular death. Mean hemoglobin concentrations increased in both treatment groups throughout the trial period. The least squares mean treatment difference (vadadustat compared to darbepoetin alfa) for change in hemoglobin concentration from baseline to the primary efficacy period was –0.10 g/dL (95% CI, –0.19 to –0.02), –0.20 g/dL (95% CI, –0.30 to –0.09), and –0.39 g/dL (95% CI, –0.67 to –0.11) for the low, intermediate, and high baseline ESA dose subgroups, respectively. Similar results were observed for the secondary efficacy period. Across baseline ESA dose subgroups, the proportion of patients whose average hemoglobin concentration was within target range was similar between the vadadustat and darbepoetin alfa arms during the primary efficacy period (low: odds ratio [OR], 0.89; 95% CI, 0.74, 1.08; intermediate: OR, 0.87; 95% CI, 0.70, 1.09; high: OR, 0.90; 95% CI 0.49, 1.64). Similar results were observed during the secondary efficacy period. Conclusion The cardiovascular safety and efficacy of vadadustat was similar to darbepoetin alfa in patients with DD-CKD irrespective of baseline ESA dose. In patients requiring higher ESA doses at baseline, the risk of MACE was numerically (but not significantly) lower in vadadustat-treated patients. Further investigation is required to confirm or refute this trend.

A comprehensive review of safety audits: ensuring workplace safety and compliance in Zimbabwe

Safety audits are systematic evaluations of an organisation’s safety management system, policies, procedures, and practices to identify potential hazards and assess compliance with relevant regulations and standards. This article provides a comprehensive review of safety audits, focusing on their role in ensuring workplace safety and compliance in Zimbabwe. A comprehensive search was conducted across various databases, including PubMed, Science Direct, Scopus, Google Scholar, and Sage Publications, to gather relevant articles. The relevance of the literature to the topic being studied was assessed by utilising abstracts and key words such safety audits and safety standards. The article examines multiple research studies carried out on the topic and presents a comprehensive summary of the present condition of safety audits in Zimbabwe. The findings indicated that the objective of safety audits is to proactively identify areas for improvement and implement corrective actions to prevent accidents, injuries, and occupational illnesses. The study indicates types of safety audits including compliance audits and management system audits. The article delves into the key components of safety audit processes, benefits of safety audits and challenges and limitations of safety audits in Zimbabwe. The article concludes by emphasising the importance of continuous improvement in safety audits.

Potential of mixed oxide fuel for higher fissile conversion ratio in light water reactors

The prospect of adopting various mixed oxide fuels to increase the conversion ratio (CR) of conventional LWRs has been explored in this study. The Westinghouse AP1000 fuel assembly (FA) was taken as the reference design. While the geometry of the FA was kept the same, five assembly models were constructed utilizing different MOX fuels in the fuel rods. Depleted UO2 was mixed with PuO2 for the first model, the next two models featured a combination of UO2 with ThO2, the fourth one utilized a mixture of PuO2 and ThO2, and the final model employed a combination of UO2, PuO2, and ThO2. Depletion analysis of these fuel assembly models was then carried out using the lattice physics code Dragon 5. The burnup-dependent infinite multiplication factor and reactivity were determined and a significant improvement in cycle length was observed at the end of the burnup period because of fertile to fissile conversion. A higher fast fission rate was obtained for plutonium-based fuel models compared to the reference, whereas the thorium-based fuel models demonstrated higher thermal fission rates. The linear reactivity model (LRM) was utilized to calculate fuel cycle performance for a three-batch refueling scheme. The three fuel models utilizing PuO2 achieved improved discharge burnup and cycle length, and required lower charge fuel mass to obtain the same thermal power. All of the five proposed models attained higher conversion ratios compared to the reference, while the highest increment in CR was obtained for the last model utilizing all three oxides. The CR of conventional UO2 fuel in AP1000 was 0.64, whereas it was calculated to be 0.73 for Model 5. Key safety parameters including the fuel and moderator temperature coefficients of reactivity and the effective delayed neutron fraction of the models were also determined. Finally, the isotopic evolution of minor actinides and fission product poisons of the models were analyzed as a function of burnup and compared with the reference.

Abstract PS08-04: Multicenter retrospective cohort study of the sequential use of the antibody-drug conjugates (ADCs) trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan (SG) in patients with HER2-low metastatic breast cancer (MBC)

Abstract PS08-04: Multicenter retrospective cohort study of the sequential use of the antibody-drug conjugates (ADCs) trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan (SG) in patients with HER2-low metastatic breast cancer (MBC)

Lebanese medical students' attitudes towards patient safety and medical error disclosure: A cross-sectional study.

To assess Lebanese medical students' attitudes towards patient safety and medical error disclosure. This was a cross-sectional study involving medical students from seven different medical schools in Lebanon. The participants completed the Attitudes to Patient Safety Questionnaire (APSQ-III) online, which consists of 26 items across nine key patient safety domains. Items were scored from 1 (strongly disagree) to 5 (strongly agree). Demographic data were also collected. Of the 549 students enrolled in the study, 325 (59%) were female and 224 (41%) were male. More than half (287, 52%) were aged between 20 and 22 years and 95% were Lebanese. The overall attitude of students towards patient safety was positive (3.59 ± 0.85) with the most positive attitudes in the domains of 'Team functioning' followed by 'Working hours as an error cause'. More positive attitudes were perceived among male students in the domains of 'Professional incompetence as an error cause' and 'Disclosure responsibility' whereas more positive attitudes were seen in female students in the domain of 'Working hour as an error cause'. Older medical students had more positive attitudes in the domain of 'Team functioning' than younger students. Medical students in Lebanon had an overall positive attitude towards patient safety. These findings may be used to guide improvements in patient safety education and enhance patient-centred care in medical institutions in Lebanon.

Adaptation of the World Health Organization (WHO) Safe Surgery Checklist for Use With Cesarean Sections: Implementation and Outcomes With the Safe Cesarean Section Checklist.

Introduction The World Health Organization (WHO) Safe Surgery Checklist significantly decreases morbidity and mortality in regular operating room cases. However, significant differences in workflow and processes exist between regular operating room cases and cesarean sections performed on the labor and delivery unit. The aim of this study is to adapt the WHO Safe Surgery Checklist for the labor and delivery unit and cesarean sections to improve communication and patient safety. Methods A multidisciplinary team consisting of all major stakeholders reviewed and revised the WHO Safe Surgery Checklist making it more applicable to cesarean section operations. The new Safe Cesarean Section Checklist was tested and then integrated into the electronic medical record and utilized on the labor and delivery unit. A specific cesarean section safety attitudes questionnaire was developed, validated, and administered prior to and one year after implementation. Results Usage of the Safe Cesarean Section Checklist was greater than 95% after initial implementation.Significant improvements were reported by the staff on the cesarean section attitudes questionnaire for several key areas including the feeling that all necessary information was available at the beginning of the procedure, decreases in communication breakdowns and delays, and fewer issues related to not knowing who was in charge during the procedure. Discussion Implementation of the Safe Cesarean Section Checklist was successfully adopted by the staff, and improvements in staff perceptions of several key safety issues on our unit were demonstrated. Additional studies should be undertaken to determine if clinical outcomes from this intervention are comparable to those seen with the use of the WHO Safe Surgery Checklist.

Development and application of Tractebel's multi-physics simulation capacity for advanced reactor safety evaluation

This paper provides a comprehensive overview of Tractebel’s current capabilities in transient simulation of Pressurized Water Reactors (PWRs) using multi-physics approaches. It highlights the use of advanced, industry-grade simulation tools and methodologies to tackle practical engineering and licensing studies for PWRs. The paper first introduces the dedicated coupling environment and its recent advancements, which have culminated in the CERES Multiphysics platform. It then delves into three key safety application areas where Tractebel’s multi-physics simulation capabilities are applied, with a focus on system transient analysis:•Small Modular Reactor (SMR) R&D Activities: Tractebel’s contribution to the Horizon 2020 McSAFER project is discussed.•Plant Safety Analyses: The paper discusses studies conducted within the framework of the WENRA RL DEC-A safety analyses.•Plant Operational Support: The paper details how multi-physics simulations are used to justify plant restarts after outages as a preventive measure against potential technical specification violations.The paper also outlines future developments aimed at enhancing and applying these multi-physics simulation capabilities to support new plant designs, including SMRs.

Integrating Safety Practices into the Supply Chain for Sustainable Development in Malaysia's Building Construction Sites

The construction industry plays a vital role in driving sustainable development in Malaysia. However, the sector is also associated with various safety risks and challenges. Safety practices on building construction sites are crucial for the well-being of workers and the overall success of construction projects. This research employs a quantitative approach with descriptive analysis to the extent of the Integration of Safety Practices into the Supply Chain. Utilizing mean and standard deviation calculations, the study analyses rates, compliance levels and other key safety indicators across firms in the construction sectors. Addressing safety concerns at every stage of the supply chain, from sourcing raw materials to final project delivery, stakeholders can mitigate risks, minimize accidents and create a secure working environment. In the context of sustainable development, incorporating safety practices into the supply chain aligns with Malaysia's commitment to achieve the United Nations' Sustainable Development Goals. Specifically, it contributes to SDG 8 (Decent Work and Economic Growth) and SDG 11 (Sustainable Cities and Communities). By prioritizing safety, the construction industry can foster a culture of well-being and productivity, attract skilled workers, and promote responsible business practices. Key safety practices that can be integrated into the supply chain include rigorous supplier vetting, ensuring the use of certified and safe construction materials, implementing proper handling and storage procedures, and conducting regular safety training for all workers involved. Additionally, leveraging technology such as Internet of Things (IoT) devices, wearables, and real-time monitoring systems can enhance safety management and enable prompt response to potential hazards.