Similar Exposure Research Articles

Abstract C147: The DNA replication checkpoint inhibitors, ATRN-1051 (WEE1i) and ATRN-119 (ATRi), are potentially well tolerated and effective cancer treatments

Abstract Previous studies have demonstrated WEE1i and ATR inhibitors (ATRi and WEE1i) to be promising cancer therapeutics through synthetic lethality with various cancer associated mutations. However, a key limitation to the use of these inhibitors as cancer therapies in prior clinical trials has been the occurrence of adverse hematological effects, including anemia and thrombocytopenia. Herein, we describe two novel inhibitors, ATRN-1051 (WEE1i) and ATRN-119 (ATRi) that are potentially both effective in tumor suppression in animal models and well tolerated. ATRN-1051 was developed to be both a potent WEE1i and selective for WEE1 over other kinases (PLK1, PLK2 and PLK3). ATRN-1051 has an IC50 of 2.2 nM for WEE1 and limits the proliferation of various cancer cell lines in culture in the 100 nM to 200 nM range. Notably, ATRN-1051 is particularly effective in suppressing the growth of Cyclin E overexpressing cells lines, pinpointing Cyclin E as a potential biomarker for ATRN-1051. In addition, ATRN-1051 has potentially favorable pharmacokinetic properties that permits 3-8 times lower dosing than other clinical WEE1 inhibitors to achieve similar exposure (AUC, 0-24) levels (1). Consistent with the increase selectivity of ATRN-1051 fostering increased tolerability, dose-range finding studies indicate that doses potentially expected to cause significant tumor suppression are hematological well tolerated in mice, with red blood cell and platelet counts remaining in a non-pathogenic range. Importantly, daily oral dosing of ATRN-1051 suppresses the growth of CCNE1-amplified high-grade serous ovarian xenografted tumors over the course of 28 days, providing further evidence of the role of CCNE1-overexpression as a biomarker for ATRN-1051 treatment. Based on these data, ATRN-1051 has entered and is now progressing through IND-enabling studies. As a distinct upstream DNA replication checkpoint inhibitor, ATRN-119 is a macrocyclic ATRi that is highly specific for inhibition of ATR over other phosphatidylinositol kinase-related kinases (PIKKs), such as ATM, DNA-PK, and MTOR, implying the potential for increased tolerability. Supporting this implication, daily dosing of ATRN-119 suppresses tumor growth in xenograft mouse models of colon, pancreatic, and prostate cancers and causes no appreciable loss of body weight or hematologic toxicity. Daily dosing of ATRN-119 in combination with PARP inhibition causes significant tumor reduction in a BRCA2-deficient PDX model of high-grade serous ovarian cancer, again with no appreciable loss of body weight. These findings have led to a biomarker-driven Phase 1/2a clinical trial of ATRN-119 with daily dosing (Simpkins, PI). Together, these findings underscore the promise of ATRN-1051 and ATRN-119 as DNA replication checkpoint inhibitors for the treatment of a variety of cancers. (1) Data from study in A-427 NSCLC xenograft model as reported in Zentalis Corporate Overview, March 2022 Citation Format: Joseph Vacca, Stephen Rocca, Molly Hansbarger, Sonia Ritzmann, Justin Frye, Fiona Simpkins, Eric J. Brown, Oren Gilad. The DNA replication checkpoint inhibitors, ATRN-1051 (WEE1i) and ATRN-119 (ATRi), are potentially well tolerated and effective cancer treatments [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C147.

Cancer Risks among Emergency Medical Services Workers in Ontario, Canada

Objectives Emergency medical services workers, such as paramedics, provide important emergency care and may be exposed to potential carcinogens while working. Few studies have examined the risk of cancer among paramedics demonstrating an important knowledge gap in existing literature. This study aimed to investigate cancer risks among paramedics in a large cohort of Ontario workers. Methods Paramedics were identified in the Occupational Disease Surveillance System (ODSS) from 1996 to 2019. The ODSS was established by linking lost-time worker’s compensation claims to administrative health data, including the Ontario Cancer Registry to identify incident cases of cancer. Cox-proportional hazard models were used to calculate age and sex-adjusted hazard ratios and 95% confidence intervals to estimate the risk of cancer among paramedics compared to all other workers in the ODSS. Results A total of 7240 paramedics were identified, with just over half of the paramedics identifying as male similar to the overall ODSS cohort. Paramedics had a statistically significant elevated risk of any cancer (HR 1.19, 95% CI 1.06–1.34), and elevated risks for melanoma (HR 2.18, 95% CI 1.46–3.26) and prostate cancer (HR 1.73, 95% CI 1.34–2.22). Paramedics had a statistically significant reduced risk for lung cancer (HR 0.48, 95% CI 0.28–0.83). Findings were similar to cancer risks identified in firefighters and police in the same cohort. Conclusions This study contributes valuable findings to understanding cancer risks among paramedics and further supports the existing evidence on the increased risk of cancer among emergency medical services workers. We have observed some similar results for firefighters and police, which may be explained by similar exposures, including vehicle exhaust, shiftwork, and intermittent solar radiation. This can lead to a better understanding of carcinogens and other exposures among paramedics and inform cancer prevention strategies.

Runx2 Overexpression Enhances Potency and Counteracts Exhaustion in CD8+ CAR T Cells

Chimeric antigen receptor (CAR) T cells are highly effective in treating B cell malignancies, but 50% of patients eventually relapse, often due to progressive dysfunction of the remaining CAR T cell population. While several others have implicated the bZIP transcription factor (TF) family in CAR T cell exhaustion (Seo et al. Nat Immunol. 2021, Lynn et al. Nature. 2019, Zhang et al. Cancer Cell. 2022), here we reveal a novel role for the TF Runx2 in mediating resistance to exhaustion and enhancing potency of CD8+ CAR T cells (CAR8). We have previously shown that CAR8 derived from naïve or memory T cell subsets maintain functional features of the T cell population from which they were derived (DeGolier et al. ASH. 2021). We predicted that an epigenomic and transcriptomic comparison of CAR8 derived from naïve or memory cells could reveal drivers of T cell differentiation and function. To precisely control T cell antigen experience, and to study T cell persistence in the absence of xenogeneic GvHD, we chose to use a syngeneic murine model, with adoptive transfer of E2A-PBX B cell acute lymphoblastic leukemia treated by anti-murine CD19 CAR T cells (Qin et al. Blood. 2018). We used a well-characterized ovalbumin vaccination model to produce memory T cells with which to generate memory-derived CAR8, and concurrently generated naïve-derived CAR8 from naïve hosts (Ahonen et al. J Exp Med. 2004). Comparative ATACseq of naïve CD8+ T cells to memory CD8+ T cells at 28 days post-vaccination revealed differential chromatin accessibility at target loci for Runx family transcription factors. These differences were maintained upon transduction of these T cell populations with a CAR, and after reinfusion into leukemia-bearing hosts. While the Runx family contains three members, RNAseq analysis uncovered that only Runx2 transcripts were highly enriched in memory over naïve cells prior to CAR-transduction but showed that gene expression levels converged upon CAR transduction and reinfusion. Additionally, broad comparisons of chromatin accessibility and transcriptomic profiles to published datasets showed that naïve-derived CAR8 progressively became more “memory-like”, while memory-derived CAR8 became more “effector-like.” We hypothesized that establishing Runx2 expression in naïve-derived CD8+ CAR T cells (CAR8 ND) could enhance the existing “memory-like” state of these T cells and boost T cell potency and anti-leukemia response. Indeed, overexpression of Runx2 in naïve-derived CAR8 (Runx2-CAR8 ND) strongly enhanced leukemia clearance (p<0.05) in mice treated with a sub-curative 1e5 CAR+ T cell dose. While there was no difference in the PD1+ proportion (p = 0.47), indicating similar activation and/or exposure to target antigen, mice treated with Runx2-CAR8 ND exhibited a lower proportion of PD1+/CD39+ cells (p<0.001) as well as a dramatically reduced proportion of PD1+/TOX+ cells (p<0.001), suggesting that Runx2 overexpression counteracts the differentiation trajectory toward terminal exhaustion. Additionally, Runx2-CAR8 ND showed enhanced T cell proportions in the marrow at 11 days post-CAR infusion (p<0.01), with >2-fold higher levels of Runx2-CAR8 ND compared to control CAR8 ND. Finally, in mice treated with a curative 2e6 CAR+ T cell dose, Runx2-CAR8 ND demonstrated a trend toward increased persistence in the blood at 19 days post-CAR infusion, relative to control CAR8 ND (p = 0.053). In conclusion, a comparison of naïve and memory-derived CD8+ CAR T cells at the epigenetic level revealed Runx2 overexpression in naïve-derived CAR T cells as a novel strategy to enhance the anti-leukemia response. Preliminary findings suggest Runx2-CAR8 ND show enhanced T cell proportions and decreased leukemic burden, as well as favorable exhaustion phenotypes. Future studies will expand our characterization of Runx2-CAR8 ND to better understand the effects of Runx2 on CAR T cell epigenetic profile, function and persistence in the bone marrow microenvironment, as well as test the effects of Runx2 overexpression in human CAR T cells. We anticipate that Runx2 overexpression will prove to be a useful strategy in enhancing the durability of CAR-mediated leukemia remissions.

Real-World Treatment Patterns Among Patients with Myelodysplastic Syndromes Initiating Oral Decitabine and Cedazuridine or Intravenous/Subcutaneous Hypomethylating Agents

Introduction: Hypomethylating agents (HMAs) are recommended standard of care for patients with higher-risk myelodysplastic syndromes (HR-MDS). HMA therapies include intravenous (IV) or subcutaneous (SC) decitabine and azacitidine; however, parenteral administration of HMAs has been associated with increased patient burden. The oral HMA decitabine and cedazuridine (DEC-C) was FDA-approved in July 2020 for the treatment of MDS, and offers an alternative to IV/SC HMAs, with similar pharmacokinetic exposure and response rates compared to IV decitabine. This study examined treatment patterns among patients with MDS receiving oral DEC-C compared with IV/SC HMAs in real-world clinical practice. Methods: This was a retrospective analysis using the US Cerner Enviza claims database; medical and prescription claims data for patients were linked to mortality data from Datavant. Adults aged ≥18 years, who were diagnosed with MDS (ICD-10-CM code D46.x; all risk levels), and who had initiated a HMA (≥1 claim; August 1, 2020─August 31, 2022) were included; index date was defined as the first pharmacy or medical claim for DEC-C or IV/SC HMAs, respectively. Patients had variable follow-up after index and were followed until end of enrollment, death, or end of study. Propensity score matching (PSM; 1:1) was performed to balance for confounding factors (age, sex, acute myeloid leukemia [AML] diagnosis, Charlson Comorbidity Index [CCI] score, and red blood cell [RBC] transfusion); adjusted bivariate analysis was used to compare outcomes between treatment groups. Longitudinal persistence was assessed according to the number of cycles of therapy received during follow-up, where a cycle was defined as either 3-10 days of administration of index IV/SC HMA or 1 claim for oral DEC-C, within a 28-day cycle. Results: Of 1569 patients included, 160 (10.2%) received DEC-C and 1409 (89.8%) received IV/SC HMAs. In the DEC-C cohort, median age was 72.5 years and 66.9% were male; in the IV/SC cohort, median age was 69.0 years and 58.2% were male. Two-thirds of patients newly initiated HMAs during the study period (69.4% for DEC-C and 72.2% for IV/SC HMAs); 30.6% of the DEC-C cohort had switched from prior IV/SC HMA treatment. Both groups had high levels of comorbidity; 55.6% of patients in the DEC-C cohort and 58.4% in the IV/SC HMA cohort had CCI scores of ≥3, and 14.4% and 23.8%, respectively, had an AML diagnosis. During the 6-month pre-index period, half (55.3%) of patients in both groups received RBC transfusions, and one quarter (25.9%) received platelet transfusions. After matching, there were 158 patients in each treatment cohort and all covariates included in the PSM were balanced (standardized mean difference <0.2). Median age was 72.0 years and 74.0 years for the DEC-C and IV/SC HMAs matched cohorts, respectively, and 66.5% and 69.6%, respectively, were male. Mean CCI scores were 3.45 for DEC-C and 3.15 for IV/SC HMA groups and 14.6% and 15.8%, respectively, had an AML diagnosis pre index. Longitudinal persistence was comparable between the matched DEC-C and IV/SC cohorts during the first 6 months post-index, with similar proportions receiving the maximum number of treatment cycles (based on a 28-day cycle) at each month following index (73.8% vs 71.1%, 46.5% vs 48.7%, 28.6% vs 24.8%, for 2, 4, 6 months, respectively; Figure). However, a trend towards improved persistence with DEC-C versus IV/SC HMAs was observed in patients receiving treatment beyond 6 months (25.0% vs 17.0%, 18.5% vs 9.0%, 11.4% vs 7.6%, for 8, 10, 12 months, respectively). Mean time to discontinuation of treatment was also numerically higher for DEC-C compared with the IV/SC HMA group (87.7 vs 82.0 days); however, differences were not statistically significant. Conclusions: This study, which is to our knowledge the largest real-world report of oral DEC-C use to date, reveals similar but high levels of disease burden and comorbidities among patients with MDS receiving oral DEC-C and parenteral HMA therapy. Trends in treatment patterns suggest comparable persistence with oral DEC-C and IV/SC HMAs at early stages of therapy and improved persistence with oral DEC-C beyond 6 months. These data support the consideration of oral DEC-C as an alternative to chronic parenteral HMA therapy, with the potential for oral DEC-C to reduce the treatment burden associated with administration of IV/SC HMAs.

Predictive Biomarker Analysis from the GBT021601 Survival Study in Townes Sickle Mice

Introduction : Sickle cell disease (SCD) is caused by a single nucleotide mutation in the β-globin gene resulting in sickle hemoglobin (HbS). Red blood cell (RBC) deoxygenation leads to HbS polymerization, RBC sickling and subsequent chronic hemolysis, anemia, vascular endothelial cell activation, vaso-occlusion, and ischemia. SCD is associated with extensive morbidity and markedly reduced survival. GBT021601 is an investigational, second-generation HbS polymerization inhibitor that reduces RBC sickling and anemia, and improves both O 2 delivery and consumption in chronically treated Townes Sickle Cell mice that harbor 2 HbS alleles (SS). Objectives of this 2-part study were to (1) characterize the effects of GBT021601 administered ad libitum on compound exposure and pharmacodynamics (PD), (2) examine the impact of long-term (>24 weeks) treatment with GBT021601 on % reticulocytes and overall survival (OS) of Townes SS mice, and (3) assess the utility of early changes in % reticulocytes as a predictive biomarker of survival in Townes SS mice treated with GBT021601. Methods: In Part 1, 24 male Townes SS mice 8-10 weeks old were split into 3 cohorts (n=8/group) and for 3 weeks were fed standard chow containing 0% (control), 0.05% (low dose), or 0.2% (high dose) of GBT021601. Body weight and food consumption were measured weekly. Mice were bled daily on days 10-21 to determine RBC half-life and on days 10 and 21 for analysis of compound exposure. On day 22 mice were euthanized. Whole blood was collected for analyses of compound exposure, % reticulocytes, Hb levels, RBC numbers, RBC half-life, and RBC deformability. In Part 2, 5-week-old Townes mice (AA and SS genotype; 50% male) were fed either standard chow (AA [n=57] and SS mice [n=54]) or chow containing 0.05% or 0.2% of GBT021601 (SS mice only; n=55 each). Body weight and food consumption were measured weekly. Blood was collected at 1, 14, 31, 43, 55, and 67 weeks of treatment for compound exposure analysis and % reticulocytes. Mice were euthanized when the humane end-point criteria were met or after 72 weeks of treatment, and whole blood was collected for compound exposure and % reticulocyte analyses. Results: GBT021601 in chow was well tolerated during both study parts; food consumption and body weight were unaffected. Outcomes in Part 1 confirmed the same compound exposure/PD trends as mice orally gavaged with GBT021601 as observed by Dufu et al. (Br J Haematol 2023); Hb levels, RBC numbers, and RBC half-life increased, RBC deformability improved, and % reticulocytes decreased. Long-term dosing of GBT021601 in the chow of Townes SS mice revealed similar compound exposure and % reticulocytes as our 3-week dosing study (Part 1) and Dufu et al. In Part 2, Townes SS mice fed GBT021601 chow, achieving compound exposures after 1 week of dosing as depicted in Figure 1, had a longer median survival vs control Townes SS mice (60 vs 56 weeks). In control Townes SS mice, % reticulocytes increased during the first 14 weeks of the study and then plateaued, whereas in Townes SS mice fed GBT021601 there was a dose-dependent sustained reduction in % reticulocytes compared with control Townes SS mice. Reductions in % reticulocytes after 1 week of dosing were greater in Townes SS mice achieving a higher compound exposure (Figure 1), a trend sustained after 14 and 31 weeks of treatment. OS increased in Townes SS mice of the same sex achieving a ≤30% reduction in % reticulocytes vs Townes SS mice with % reticulocytes >30% after 1 week of treatment; P=0.00048 (Figure 2). Multivariate survival analysis, including % reticulocytes at 1 week (categorical variable of ≤30% or >30%) and sex as predictors confirmed significant association of >30% reticulocytes with reduced survival (hazard ratio=1.48, P=0.027 using Cox proportional hazard). Conclusions:Longer-term GBT021601 treatment as part of chow was well tolerated by Townes SS mice, and compound exposure was comparable with studies of a shorter duration of treatment. Early compound exposure was predictive of a long-term survival benefit in Townes SS mice. Early reductions in % reticulocytes were more likely in Townes SS mice with a high GBT021601 exposure and were predictive of a long-term survival benefit. Overall, our findings support the use of GBT021601 to reduce % reticulocytes and improve OS in Townes SS mice and suggest the clinical relevance of early reductions in % reticulocytes as a biomarker to predict long-term survival.

Prospective Pharmacokinetic Evaluation of Venetoclax (VEN) in AML Demonstrates Significant and Variable Drug Interactions with Azole Antifungals That Increase Ven Exposure, Reduce Clearance, and Necessitate Re-Evaluation of Dose Adjustments

Background: Venetoclax (VEN) in combination with hypomethylating agents (HMA) or low dose cytarabine (LDAC) is the standard of care for the treatment of newly diagnosed AML in pts aged ≥ 75 yrs. or unfit for intensive chemotherapy. While considered low-intensity, myelosuppression is universal, leading to increased rates of infection in the setting of neutropenia. Antifungal prophylaxis during induction has significantly lowered treatment-related mortality (TRM) attributed to invasive fungal infections (Cornely et al, 2007). Azole antifungals, the treatment of choice, pose significant drug-drug interactions through inhibition of CYP3A4 and p-glycoprotein (P-gp), both responsible for VEN metabolism and clearance. This interaction alters VEN pharmacokinetics (PK), increases its exposure, and therefore requires substantial dose adjustments (Agarwal et al, 2017). We previously showed that dose adjusted VEN plus HMA when used concomitantly with azoles retains efficacy, but still resulted in prolonged myelosuppression (Rausch et al, 2022). Little real-world PK data exists to confirm whether the recommended dose adjustments are appropriate or require further refinement. Methods: Pharmacokinetic analysis was conducted during the induction cycle of the phase II study of cladribine plus LDAC and VEN as previously described (Kadia et al, 2022). VEN was administered on days 1-21 during induction and was dose-adjusted to either 100 mg (later amended to 50 mg), 100 mg, or 400 mg daily when used with posaconazole (posa), voriconazole (vori), or caspofungin (caspo), respectively. Dose adjustments were based on package insert recommendations. Prior to amendment, VEN 100 mg was administered with posa based on previously published PK analysis suggesting a 75% dose reduction of VEN with concomitant posa (Agarwal et al, 2017). Steady state VEN PK analysis was conducted on day 8 and trough levels were collected on days 12 and 16 of cycle 1. Levels obtained with concomitant caspo served as a reference level, assuming no significant interaction between VEN and caspo. VEN levels were analyzed via an institutionally developed liquid chromatography coupled mass spectrometry (LCMS) assay and PK analysis was conducted via non-compartmental method using WinOnlin. Results: Forty patients, median age 68 (range, 61-78), were included for pharmacokinetic analysis. Average VEN AUC (area under the exposure) and Cmax (maximum observed plasma concentration) was higher with concomitant vori or posa than with caspo regardless of dose adjustments. Posa in combination with VEN 100 mg increased average AUC by 103% and Cmax by 63%. Vori with VEN 100 mg increased AUC and Cmax by 77% and 43%, respectively. Among the 3 groups, posa with VEN 50 mg resulted in a VEN AUC and Cmax most similar to that observed with caspo and VEN 400 mg. Concomitant posa delayed VEN clearance by 74% with VEN 50 mg and 79% with VEN 100 mg. As a result, the accumulation index observed with posa was 12.5 + 19.98 with VEN 100 mg, 9.2 + 17.5 with VEN 50 mg, and 3.7 + 1.92 with vori, compared to 1.7 + 0.5 with caspo. Although there was interpatient variability in VEN trough levels, we observed consistent intra-patient trough levels. In addition, significant correlation between VEN AUC and VEN trough levels (p = 1 x 10 -4, r 2 = 0.89) was observed. Conclusions: Despite dose adjustments, VEN AUC is significantly higher among pts receiving azole antifungals compared to those receiving caspo. Posa resulted in more potent inhibition of VEN clearance and greater accumulation compared to vori, despite both agents considered strong CYP3A4 inhibitors. This may be a result of the dual inhibitory effect of posa on both CYP3A4 and P-gp activity or more potent inhibition of CYP3A4. Based on PK evaluation, our data suggest VEN 50 mg with concomitant posa provides more similar drug exposure to VEN 400 mg and may be more appropriate than 70 mg or 100 mg in this setting. Given the high accumulation index observed with posa, PK analyses during cycle 2 are ongoing. While there is inter-patient variability in VEN PK, intra-patient trough levels are consistent, correlate well with VEN AUC, and could be used for therapeutic drug monitoring.

1355. The SARS-CoV-2 Monoclonal Antibody AZD3152 Potently Neutralizes Historical and Emerging Variants and is Being Developed for the Prevention and Treatment of COVID-19 in High-risk Individuals

Abstract Background EVUSHELD was developed for the prevention and treatment of mild-to-moderate COVID-19 for high-risk individuals. However, the SARS-CoV-2 virus continues to evolve in the presence of natural- and vaccine-acquired immunity, escaping previously authorized antibody therapies such as bebtelovimab and EVUSHELD. AZD3152 was selected to neutralize all known SARS-CoV-2 variants of concern and is being developed to provide immunocompromised individuals with continued protection against SARS-CoV-2. Methods Structural analyses were performed to map the AZD3152 binding site. Neutralization assays were employed to determine the potency of AZD3152 across a panel of historical and emerging SARS-CoV-2 variants. Hamsters were prophylactically administered 6.7-60 mg/kg AZD3152 or a control antibody, then challenged intranasally with 6x103 PFU WA-1 SARS-CoV-2, then monitored for weight loss; lung viral load and pathology were evaluated at days 3 and 7. A 3 week GLP repeat IM and IV dose toxicity study in nonhuman primates (NHP) was performed. Results AZD3152 binds to a conserved epitope on the spike receptor binding domain and blocks ACE2 binding. AZD3152 potently neutralizes authentic viral variants (EC50 range, 8.3 to 110.9 ng/mL) and SARS-CoV-2 pseudoviruses (EC50 range of 3.2 to 25.0 ng/mL), including XBB.1.5. Prophylactic administration of AZD3152 conferred dose-dependent protection to hamsters following challenge. Even at a suboptimal dose of 6.7 mg/kg, < 5% weight loss and 2 logs reduction in lung viral subgenomic RNA were observed. AZD3152 was not associated with any adverse findings in NHP and the no observed-adverse-effect-level was the highest dose tested (150 mg/kg). Toxicokinetics demonstrated similar systemic exposure following IM and IV dosing with bioavailability of 94.9% and half-life range of 15.2-26.5 days by IM. Conclusion These results demonstrate that AZD3152 binds a conserved epitope resulting in broad neutralization of SARS-CoV-2 variants, protects hamsters from disease, and has a favorable safety profile in NHP. Thus, AZD3152 may serve as a next-generation antibody for the prevention and treatment of COVID-19. Disclosures Joseph R Francica, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Yingyun Cai, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Seme Diallo, MS, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Kim Rosenthal, MS, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Kuishu Ren, BS, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Daniel J. Flores, MS, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Andrew Dippel, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Yuling Wu, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Xiaoru Chen, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Erin Cantu, BS, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Rakesh Choudhary, MS, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Michal Sulikowski, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Hibret Adissu, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Nydia van Dyk, MSc, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Vaheh Oganesyan, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Saravanan Rajan, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Patricia C. Ryan, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Yueh-Ming Loo, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Taylor Cohen, PhD, AstraZeneca: Employement|AstraZeneca: Stocks/Bonds Mark T. Esser, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Wade Blair, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds

Photon-counting CT urogram: optimal acquisition potential (kV) determination for virtual noncontrast creation.

To quantitatively and qualitatively compare the degree of iodine removal in the collecting system from PCCT urographic phase-derived virtual noncontrast (VNC) images obtained at 140 kV versus 120 kV. A retrospective PACS search identified adult patients (>18 years) who underwent a PCCT urogram for hematuria from 4/2022 to 4/2023 with available urographic phase-derived VNC images in PACS. Tube voltage (120kV, 140kV), body mass index, CTDIvol, dose length product (DLP), and size-specific dose estimate (SSDE) were recorded. Hounsfield Unit (HU) in both renal pelvises and the urinary bladder on urographic-derived VNC were recorded. Three radiologists qualitatively assessed the degree of iodine removal (renal pelvis, urinary bladder) and diagnostic confidence for urinary stone detection. Continuous variables were compared for 140 kV versus 120 kV with the Wilcoxon rank sum test. A p<.05 indicated statistical significance. 63 patients (34 male; median (Q1, Q3) age: 30 (26, 34) years; 140kV/120kV: 30 patients/33 patients) were included. BMI, CTDIvol, DLP, and SSDE were not different for 140kV and 120kV (all p>.05). Median (Q1, Q3) collecting system HU (renal pelvis and bladder) was 0.9 (-3.6, 4.4) HU at 140kV and 10.5 (3.6, 26.7) HU at 120kV (p=.04). Diagnostic confidence for urinary calculi was 4.6 [1.1] at 140kV and 4.1 [1.4] at 120kV (p=.005). Diagnostic confidence was 5/5 (all readers) in 82.2% (74/90) at 140kV and 59.6% (59/99) at 120kV (p<.001). PCCT urographic phase-derived VNC images obtained at 140kV had better collecting system iodine removal than 120kV with similar patient radiation exposure. With excellent PCCT urographic phase iodine removal at 140kV, consideration can be made to utilize a single-phase CT urogram in young patients.

Exposure of the Cavernous Sinus via the Endoscopic Transorbital and Endoscopic Endonasal Approaches: A Comparative Study

To compare the endoscopic transorbital approach (ETOA) and endoscopic endonasal approach (EEA) in terms of cavernous sinus (CS) exposure. Four cadaveric heads (8 sides) were dissected. The CS was accessed using the EEA and ETOA. Stereotactic measurements of the length of the main structures exposed, angles of attack, depths of surgical corridor, and areas of exposure were obtained and compared between the approaches. An illustrative case is also presented. The endoscopic transorbital approach (ETOA) exposed the lateral and superior compartments of the CS without obstruction by the internal carotid artery (ICA). The EEA exposed all compartments after mobilizing the ICA. Both approaches enabled similar exposure of the cranial nerves. The depth of surgical corridor was significantly shorter with the ETOA (P<0.01). The areas of lateral compartment exposure were similar. As the number of instruments placed into the surgical channel increased, the available angles of attack with the ETOA became smaller and were smaller than those of the EEA. In the clinical case presented, the tumor was successfully removed without complications. The ETOA has the advantages of a sterile surgical channel, short operation time, little patient trauma, short surgical corridor, large exposure area, and interdural pathway; moreover, it allows dissection through the interdural space without entering the neurovascular compartment of the CS. Although the space for manipulation of instruments is limited, the ETOA is suitable for treating selected tumors in the superior and lateral compartments of the CS.

Investigating the Replacement of Carboxylates with Carboxamides to Modulate the Safety and Efficacy of Platinum(II) Thioether Cyanide Scavengers.

Cyanide represents a persistent threat for accidental or malicious misuse due to easy conversion into a toxic gas and access to large quantities through several industries. The high safety index of hydroxocobalamin is a cornerstone quality as a cyanide scavenger. Unfortunately, intravenous infusion of hydroxocobalamin limits the utility in a mass casualty setting. We previously reported platinum(II) [Pt(II)] complexes with trans-directing sulfur ligands as an efficacious alternative to hydroxocobalamin when delivered by a bolus intramuscular injection in mice and rabbits. Thus, to enable Pt(II) as an alternative to hydroxocobalamin, a high safety factor is needed. The objective is to maintain efficacy and mitigate the risk for nephrotoxicity. Platinum amino acid complexes with the ability to form five- or six-membered rings and possessing either carboxylates or carboxamides are evaluated in vitro for cyanide scavenging. In vivo efficacy was evaulated in the zebrafish and mice cyanide exposure models. In addition, Pt(II) complex toxicity and pharmacokinetics were evaluated in a cyanide naive Sprague-Dawley model. Doses for toxicity are escalated to 5x from the efficacious dose in mice using a body surface area adjustment. The results show the carboxamide ligands display a time and pH dependence on cyanide scavenging in vitro and efficacy in vivo. Additionally, exchanging the carboxylate for carboxamide showed reduced indications of renal injury. A pharmacokinetic analysis of the larger bidentate complexes displayed rapid absorption by intramuscular administration and having similar plasma exposure. These findings point to the importance of pH and ligand structures for methionine carboxamide complexes with Pt(II).

Occupational risk assessment of glutaraldehyde through personal air monitoring in a hospital setting.

Glutaraldehyde is a high-efficiency disinfectant that has been included in the protocols of some hospitals for controlling the spread of SARS-CoV-2, together with sodium hypochlorite and quaternary ammonium disinfectants. However, exposure has been poorly studied in workplace settings, despite the association between glutaraldehyde and respiratory diseases and skin conditions in exposed workers. This study evaluated the magnitude of exposure associated with the use of glutaraldehyde in healthcare workers across various work areas of a first level of Hospital-Based Care in Colombia. Workers were classified into similar exposure groups (SEGs) based on work areas and tasks performed, and airborne concentrations of glutaraldehyde were measured in different work areas of each SEG through direct monitoring. The 95th percentile of glutaraldehyde concentrations in all SEGs studied exceeded the TLV-C immediately after use. Cleaning workers and nurses had the highest exposures to glutaraldehyde. Results indicate that workers were overexposed and highlight the need to implement controls to reduce exposure. The high-exposure levels also raise the need to consider glutaraldehyde substitution and adequate use of personal protective equipment (PPE).

Influence of light exposure techniques on in vitro pulp temperature rise during bulk fill composite Class I restorations.

This in vitro study assessed peak temperature and temperature increase (ΔT) within the pulp chamber during different extended photoactivation techniques (EPT-applying similar radiant exposure values) to resin-based composites (RBCs) placed in a Class I cavity preparation in an extracted human lower third molar. A T-type thermocouple was placed in the pulp chamber and connected to a temperature analysis device (Thermes, Physitemp). The tooth was attached to an assembly simulating the in vivo environment (controlled baseline pulp chamber temperature and fluid flow). The real-time pulp chamber temperature was evaluated throughout the photoactivation (Bluephase N, Ivoclar Vivadent) of two bulk-fill RBCs: Tetric N Ceram Bulk Fill (TBF; shade: IVA; Ivoclar Vivadent); Surefill SDR flow + (SDR, shade: Universal; Dentsply Sirona), which were exposed to different curing techniques: 40s-occlusal surface; 20s-occlusal + 10s-buccal + 10s-lingual surfaces; 10s-buccal + 10s + lingual + 20s-occlusal surfaces. Each EPT delivered 42.4J/cm2. Vickers hardness (VHN) was measured on the removed, sectioned RBC restorations at the top and bottom middle areas after curing. ΔT and VHN data were analyzed using 2-way ANOVA followed by Bonferroni post-hoc test (α = 0.05). Peak temperature data were analyzed using one-way ANOVA and Dunnett's post-hoc test (α = 0.05). SDR showed higher ΔT values than TBF (p = 0.008) in some EPTs. Neither technique resulted in ΔT values greater than 5.5 °C. Both composites had acceptable bottom/top hardness ratios (greater than 80%), regardless of the photoactivation technique. The evaluated EPTs may be considered safe as a low-temperature increase was noticed within the pulp chamber.

Using machine learning methods to analyze the association between urinary polycyclic aromatic hydrocarbons and chronic bowel disorders in American adults

The etiology of chronic bowel disorders is multifaceted, with environmental exposure to harmful substances potentially playing a significant role in their pathogenesis. However, research on the correlation between polycyclic aromatic hydrocarbons (PAHs) and chronic bowel disorders remains limited. Using data from the National Health and Nutrition Examination Survey (NHANES) conducted in 2009–2010, we investigated the relationship between 9 PAHs and chronic diarrhea and constipation in U.S. adults. We employed unsupervised methods such as clustering and Principal Component Analysis (PCA) to identify participants with similar exposure patterns. Additionally, we used supervised learning techniques, namely weighted quantile sum (WQS) and Bayesian kernel machine (BKMR) regressions, to assess the association between PAHs and the occurrence of chronic diarrhea and chronic constipation. PCA identified three principal components in the unsupervised analysis, explaining 86.5% of the total PAH variability. The first component displayed a mild association with chronic diarrhea, but no correlation with chronic constipation. Participants were divided into three clusters via K-means clustering, based on PAH concentrations. Clusters with higher PAH exposure demonstrated an increased odds ratio for chronic diarrhea, but no meaningful connection with chronic constipation. In the supervised analysis, the WQS regression underscored a positive relationship between the PAH mixture and chronic diarrhea, with three PAHs significantly impacting the mixture effect. The mixture index showed no correlation with chronic constipation. BKMR analysis illustrated a positive trend in the impact of four specific PAHs on chronic diarrhea, given other metabolites were fixed at their 50th percentiles. Our results suggest a clear association between higher PAH exposure and an increased risk of chronic diarrhea, but not chronic constipation. It also underscores the potential role of specific PAHs in contributing to the risk of chronic diarrhea.

Ledipasvir/Sofosbuvir in Hepatitis C Virus–Infected Children With Hematological Malignancies: A Pharmacokinetic Study

Children with hematological malignancies and chronic hepatitis C virus (HCV) infection are at a higher risk for rapid progression of liver disease and malignancy relapse due to multiple hepatitis flares and chemotherapy interruption. They are therefore potential candidates for microelimination of HCV infection. This study aimed to assess the effect of acute lymphoblastic leukemia (ALL) on the pharmacokinetic (PK) profile of direct-acting antivirals, namely ledipasvir/sofosbuvir (LDV/SOF) and the SOF major metabolite GS-331007. This was a 24-week, prospective, controlled, open-label, 2-arm PK study of patients receiving 45/200 mg once-daily LDV/SOF orally for 12 weeks. Eligible patients were HCV-RNA-positive, treatment-naive children aged 6 to <12 years and/or weighing 17 to <35 kg with genotype 4 chronic HCV infection without cirrhosis. The primary efficacy and safety end points were the achievement of sustained virologic response for all patients with absence of any adverse events leading to permanent discontinuation of the study drug. Steady-state noncompartmental analysis was performed to determine the PK parameters of SOF, GS-331007, and LDV as the primary PK outcome. Dose suitability was based on the 90% CI of exposure geometric mean ratio percentage within 50% to 200% compared with adults. Ten HCV-infected children with ALL (chemotherapy treatment group) and 12 eligible children with no malignancy (control group) were enrolled and completed the study period. All 22 patients achieved the sustained virologic response with no adverse events leading to interruption or permanent discontinuation of the study drug. Compared with the control group, the ALL group patients had similar SOF, GS-331007, and LDV exposure. Compared with adults, the AUCτ of GS-331007 was lower and the AUCτ and Cmax,ss of SOF and the Cmax,ss of LDV were modestly higher in the ALL group (acceptance limit, 50%-200%). However, the observed efficacy and favorable safety profile made these changes not clinically significant. Weight-based dosing of LDV/SOF (45/200 mg) is highly effective and safe among genotype 4 HCV-infected children weighing 17 to <35 kg and diagnosed with ALL undergoing maintenance chemotherapy. The similarity in the drug exposure, efficacy, and safety clinical end points between patients with and without hematological malignancy support their therapeutic equivalence. Further studies with a larger sample size may be required to confirm the safety of LDV/SOF in patients with ALL and to recommend appropriate dosing in children with hematological malignancies, if needed. gov identifier: NCT03903185.

Therapeutic monitoring of pediatric transplant patients with conversion to generic tacrolimus

ObjectiveTherapeutic monitoring during interchange of tacrolimus commercial formulations is essential to ensure similar exposure in transplant patients. However, there are limited data in the pediatric transplant population. This study aims to evaluate exposure, safety and efficacy in maintenance pediatric transplant patients under generic tacrolimus substitution. MethodPediatric patients who underwent interchange of tacrolimus formulations were detected by the Service of Pharmacy and included in this study. Tacrolimus trough levels (C0), laboratory parameters and clinical characteristics were recorded before and after the switch. Statistical analysis was performed using Wilcoxon matched pair t-test. ResultsIn total, 10 patients with kidney, liver, heart and hematopoietic stem cell transplantation received the innovator and switched to the generic product. The median (range) of the C0 normalized by the dose before and after switch was 74.8 [(ng/ml)/(mg/kg)] (13.8-518.4) and 65.1 [(ng/ml)/(mg/kg)] (13.5-723.5), respectively (p>0.05). Tacrolimus dose was 0.070(mg/kg) (0.024-0.461) and 0.069(mg/kg) (0.017-0.571) for the innovator and generic formulation, respectively, with no difference when comparing both values (p>0.05). Laboratory parameters did not change after conversion (p>0.05). Adverse events, acute rejection, death and graft loss were not observed. ConclusionsIn our study population, no significant differences in terms of laboratory parameters, drug exposure and dose were observed. We emphasize the need of close monitoring to ensure a safe interchange, especially in vulnerable populations such as the pediatric.

2 1991 Gulf War Women Veterans: Neurotoxicant Exposures and Cognitive Outcomes

Objective:The women who served in the 19901991 Persian Gulf War (GW) are unique in that they were the first group to have fewer restrictions in terms of military occupations and exposure to combat. Of the nearly 41,000 US troops who were women deployed to the GW, many were serving in frontline positions and were exposed to the same toxicants as their male counterparts. Toxicant exposures such as pesticide sprays and creams, oil well fires, diesel fuels, chemical and biological warfare (CBW) agents and anti-nerve gas (PB) pills have been found to result in cognitive impairments across a range of neuropsychological tests. Our research team has been following cohorts of women who were deployed to the GW and correlated exposures with neuropsychological outcomes. Overall, in small cohorts of women veterans we found that higher levels of exposures to pesticide sprays and creams and CBW are correlated with short-term memory, mood, and motor deficits. These findings were different from those of their male counterparts. In a recently developed data-repository we have compiled larger groups of women veterans to validate our prior findings.Participants and Methods:The current study is an analysis of data from a national bio/data-repository (Boston Biorepository Recruitment and Integrative Network for Gulf War Illness; BBRAIN) which includes key data samples from prior GW studies that have been merged and combined into retrospective datasets. Data include general health and chronic symptom questionnaires, demographics, deployment and self-reported exposure histories (separated into no exposure, fewer than 7 days exposure and greater than or equal to 7 days exposure), as well as key neuropsychological test variables. Three separate datasets were combined to include 62 women. Exposures to chemical alarms, oil well fires, pesticide cream or spray, pesticide fogging, and PB pills were self-reported. Linear regression models were produced for each continuous cognitive outcome, modeled on a given exposure, and controlling for age, education level, PTSD, and other exposures.Results:Of the 62 women, the majority were White (77%). 74% of women surveyed were employed and 55% were married. 63% of women had at least a high school education. Deployed women who had &gt; 7 days of exposure to pesticide sprays, CBW, smoke from oil well fires, and PB pills were more likely to show deficits in the areas of verbal learning and short-term memory (p &lt; .03) and those with exposure to CBW, smoke from oil well fires, pesticides creams and PB pills had more errors on a test of executive functioning (p &lt; .01). These data differ from the findings from cohorts of men.Conclusions:These data validate the findings of our prior studies and add credence to the need for separate analyses for men and women. The unique outcomes may lead to individualized treatments for women veterans that may also help women with similar exposures from other deployments in addition to women with occupational exposures.

Bictegravir/Emtricitabine/Tenofovir Alafenamide for HIV-1: What is the Hidden Potential of This Emerging Treatment?

Bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) is a single-tablet antiretroviral therapy regimen. B/F/TAF has become a popular treatment choice because of its small tablet size, high barrier to resistance, favorable tolerability, and limited drug-drug interaction profile. Continued research on B/F/TAF has revealed additional potential for this regimen. This review presents recent literature supporting the use of B/F/TAF as an option for consolidating therapy and maintaining virologic suppression in individuals despite M184V/I mutations. Additionally, children are a unique patient population with limited antiviral options. Standard dose B/F/TAF has demonstrated similar drug exposure in children and adolescents as adults, and low-dose B/F/TAF is approved for children living with HIV greater than two years of age and weighing at least 14 kg. Data supporting this recommendation is described in this review. Finally, despite a lack of prospective data, B/F/TAF may have a role in the future of pre- and post-exposure prophylaxis. This review discusses these discoveries and the continued exploration of the hidden potential of B/F/TAF.

Grassland extensification enhances nest densities of ground‐nesting wild bees

Abstract Ground‐nesting wild bees provide essential pollination services in agroecosystems, but they are jeopardized by intensive agricultural management. To mitigate such negative impacts, agri‐environment schemes have been implemented. While the success of enhancing floral food resources is relatively well studied, the role of agri‐environmental schemes in providing suitable nesting habitat remains underexplored. We studied the effectiveness of meadow extensification according to the Swiss agri‐environment scheme in promoting nesting of ground‐nesting bees. Using a paired design, we quantified their nests during four rounds (March–June) in pairs of nine randomly selected extensively (i.e. no fertilizer input, postponed first mowing) and nine intensively managed meadows with similar soil properties, slope, exposure and landscape context. Nest numbers and vegetation characteristics were surveyed in areas of 250 m2. Vegetation properties were also assessed in 0.5 × 0.5 m plots around nest locations and randomly selected locations without nests within each meadow to assess their role as drivers of nesting incidence (nest presence/absence) at this plot scale. We found substantially higher nest numbers of ground‐nesting bees in extensively (mean ± SE per sampling round = 46.8 ± 14.2) compared to intensively managed meadows (0.8 ± 0.3; no nests in three of nine intensively managed meadows). Extensively managed meadows harboured nests of several dominant crop pollinator species, including aggregations of, for example, Lasioglossum malachurum contributing to high nest densities in some of them. Number of nests was negatively related to grass cover and vegetation height, which were lower in extensively compared to intensively managed meadows. Plot‐level nesting incidence increased with bare ground and moss cover, and decreased with grass cover. Synthesis and applications. Our study shows that extensively managed meadows are better nesting habitats for ground‐nesting bees than intensively managed meadows, if reduced management intensity is associated with altered vegetation characteristics such as reduced grass cover and vegetation height, and small‐scale availability of bare ground, driving these effects. This highlights that maintaining and promoting extensive management of meadows can promote ground‐nesting wild bees, including dominant crop pollinators, not only by enhancing floral resources but also by improving nesting opportunities in agroecosystems.

The extent of perceived exposure to economic crime in public and private business: Survey research in Norway

Half of all finance and insurance firms in Norway report that they are exposed to economic crime, particularly fraud, every year. On the other hand, only eighteen percent in public administration and defense perceive similar exposure to economic crime. However, the estimated fraction of unreported, non-registered economic crime in the country is ninety-four percent. These numbers are some of the results from surveys conducted in Norway in 2005, 2010, and 2023. This article applies the main economic crime categories of fraud, theft, manipulation, and corruption as used by scholars to study the survey results. The corruption category shows the largest gap between perceived exposure and police statistics. Comparison to white-collar crime research indicates higher frequency of theft at the street level and higher frequency of manipulation at the upper echelon. Comparison to future surveys in other countries is encouraged.

Exposure to sunlight and allergic morbidity in children (Pollution and Asthma Risk: an Infant Study)

Abstract Background Sunlight relationship with allergies is poorly studied in children. Thus, we examined how early exposure to solar radiation is associated with allergic morbidity in the PARIS birth cohort. Methods This study dealt with children who attended at least one of the two health check-ups: 18 months (n = 2012) and 8/9 years (n = 1080). Early exposure (prenatal and during the first year of life) to solar radiation was assessed using meteorological data (solar radiation, temperature, relative humidity). Children with similar exposure trajectories were grouped by longitudinal and multidimensional cluster analysis. Association of solar radiation exposure with allergic morbidity (i.e. allergic sensitisation at 18 months and 8/9 y., current asthma, rhinitis, and eczema at 8/9 y.) was quantified by multivariable logistic regression models adjusted for potential confounders. The effect modification of maternal vitamin D (VitD) supplementation during pregnancy was also tested. Results Four exposure trajectories were found. The trajectory with the highest exposure to early solar radiation had a reduced risk of sensitisation at 8/9 y. compared to the trajectory with the lowest exposure (p = 0.06). This association was statistically significant in the VitD supplemented subgroup. Solar radiation during pre- and post-natal period was significantly associated with a lower risk of sensitisation at 8/9 y. (for ↗IQR, aOR: 0.47; 95%CI: 0.25-0.87 and 0.84;0.70-1.00, respectively). Increased prenatal exposure to solar radiation was significantly associated with a lower asthma risk at 8/9 y. (for ↗IQR, 0.32; 0.10-0.96). Conclusions Early sunlight exposure may reduce the risk of sensitisation and asthma in school-aged children, especially in those prenatally exposed to VitD intake. These findings highlight the importance of VitD in preventing allergic diseases in children, either through supplementation or sunlight exposure. Key messages • Pre-natal and early postnatal exposure to sunlight could reduce the risk of sensitisation and asthma among school-aged children. • The association may be explained by vitamin D immunomodulatory effect, highlighting its importance in preventing allergic diseases in children through supplementation or sunlight exposure.