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Abstract Chemoprevention is one of the accessible strategies for preventing, delaying or reversing cancer processing utilizing chemical intervention of carcinogenesis. NAD(P)H quinone oxidoreductase 1 (NQO1) is a xenobiotic metabolizing cytosolic enzyme/protein with important functional properties towards oxidation stress, supporting its ability in detoxification/chemoprotective role. A set of 3,5-diylidene-4-piperidones (as curcumin mimics) bearing alkyl sulfonyl group were synthesized with potential NQO1 induction properties. Compounds 5ab (R = 2-MeOC6H4, R’ = Me) and 5ac (R = 2-MeOC6H4, R’ = Et) are the most promising agents synthesized (% induction of NQO1 = 51.562, 45.793) relative to that of 4’-bromoflavone (4’-BF, reference standard) at 10 µM. LPS-induced iNOS production in RAW264.7 macrophages of the most promising agents discovered (5ab and 5ac) displayed concentration-dependent with comparable activities to the reference anti-inflammatory drug indomethacin. Molecular modeling studies (including QSAR, molecular docking and molecular dynamics) were accessed supporting the observed biological profiles.

Abstract: Children’s Oncology Group study AALL1931 investigated the efficacy and safety of recombinant Erwinia asparaginase (JZP458) in patients with acute lymphoblastic leukemia/lymphoblastic lymphoma and hypersensitivity reactions/silent inactivation to Escherichia coli–derived asparaginases. Each pegylated Escherichia coli asparaginase dose remaining in a patient’s treatment plan was replaced by intramuscular (IM) or IV JZP458 (6 doses) administered Monday/Wednesday/Friday (MWF). Three IM cohorts (1a [25 mg/m2 MWF], n = 33; 1b [37.5 mg/m2 MWF], n = 83; 1c [25/25/50 mg/m2 MWF], n = 51) and 1 IV cohort (25/25/50 mg/m2 MWF, n = 62) were evaluated. The proportion (95% confidence interval [CI]) of patients maintaining nadir serum asparaginase activity (NSAA) levels of ≥0.1 IU/mL at the last 72 (primary end point) and 48 hours during course 1 was 90% (95% CI, 81-98) and 96% (95% CI, 90-100) in IM cohort 1c, respectively, and 40% (95% CI, 26-54) and 90% (95% CI, 82-98) in the IV cohort. Population pharmacokinetic modeling results were comparable with observed data, predicting the vast majority of patients would maintain therapeutic NSAA levels when JZP458 is administered IM or IV 25 mg/m2 every 48 hours, or IM 25/25/50 mg/m2 MWF, or with mixed IM and IV administration (IV/IV/IM 25/25/50 mg/m2 MWF). Drug discontinuation occurred in 23% and 56% of patients in the IM and IV cohorts, respectively; 13% and 33% because of treatment-related adverse events (mainly allergic reactions and pancreatitis). JZP458 achieves therapeutic NSAA levels via multiple IM and IV dosing schedules based on combined observed and modeled data with a safety profile consistent with other asparaginases. This trial was registered at www.ClinicalTrials.gov as #NCT04145531.

Abstract Targeted therapy is preferable over other therapeutics due to its limitation of drawbacks and better pharmaceutical outcomes. VEGF and its receptors have been observed to be hyper-activated in many cancer types and are considered promising targets for assigning anticancer agents. The current study is directed towards synthesis of novel antiproliferative 2-oxoindolin-3-ylidenes incorporating urea function with VEGFR-2 properties. The targeted agents were obtained through a two-step reaction. Addition of the appropriate 1-(acetylphenyl)-3-phenylurea 9a,b to the corresponding isatin 10a–f in ethanol containing a quantitative amount of Et2NH followed by acidic dehydration (AcOH/HCl) afforded the targeted agents 12a–j. Promising antiproliferation properties (MTT assay) were observed for most of the synthesized agents against HCT116 (colon), MCF7 (breast) and PaCa2 (pancreatic) cancer cell lines relative to sunitinib. VEGFR-2 inhibitory properties are consistent with the antiproliferation properties exhibited against the tested cell lines. Compound 12b (R = 4-NHCONHPh, R′ = H; % inhibition = 87.2) is the most promising/potent anti-VEGFR-2 agent synthesized with activity close to that of sunitinib (% inhibition = 89.4) at 10 μM. Molecular docking studies (PDB: 3WZE and 3AGD) support the antiproliferation effects against cancer cell lines tested with VEGFR-2 inhibitory properties. The results are consistent with collaboration of the pharmacophores considered (2-oxoindolyl heterocycle and urea) in improving the bio-properties.

Among electromagnetic methods of short-term earthquake prediction, an approach is being actively developed based on the phenomenon of magnetic ultra-low-frequency (ULF) power depression occurring a few days before an earthquake. In particular, a nighttime geomagnetic power depression in the band 0.03–0.05 Hz was observed approximately 5 days before the catastrophic Tohoku 2011 earthquake. To verify the reliability of this method, we performed an extended analysis using data from magnetometer arrays JMA, MAGDAS, PWING, and INTERMAGNET. The selected stations included sites close to the epicenter (

The laws of the public office are based on occupying its positions and the public utilities are running on setting the conditions for experience, competence and good reputation, but this matter is not without the issuance of actions from the employee requiring the administration to take the appropriate action to correct the error in job behavior, which results in withdrawing the hand until the truth emerges and this procedure may be By the rule of law, or it may be a use of the discretionary power of the administration at other times, which must be based on foundations that prevent the administration’s abuse of its authority and guarantee the public interest and the interest of the investigation, so withdrawing the hand means that the employee is cut off from permanence and is prevented from being in his department for a certain period, and it is not a penalty. Discipline,

Background: Children and adolescents with intellectual disabilities commonly experience emotion regulation difficulties. To better understand emotion regulation in this population, the views of their teachers were considered. Methods: Twenty-nine teachers participated in two focus groups. This study utilized qualitative methods to determine if the emotion regulation experiences of this population, as perceived by their teachers, map onto the five domains of the process model of emotion regulation: situation selection, situation modification, attentional deployment, cognitive change, and response modulation. Results: A thematic analysis indicated the data from both focus groups was consistent and mapped onto the five domains of the process model; with several additional themes and sub-themes identified. Conclusions: Perspectives provided by teachers affirmed that the process model of emotion regulation is relevant to children and adolescents with intellectual disabilities. Future research might consider developing the themes identified in this qualitative study into quantitative questionnaire items and validating that measure.

Abstract Cytokine release syndrome (CRS) was associated with teclistamab treatment in the phase I/II MajesTEC‐1 study. Cytokines, especially interleukin (IL)‐6, are known suppressors of cytochrome P450 (CYP) enzymes' activity. A physiologically based pharmacokinetic model evaluated the impact of IL‐6 serum levels on exposure of substrates of various CYP enzymes (1A2, 2C9, 2C19, 3A4, 3A5). Two IL‐6 kinetics profiles were assessed, the mean IL‐6 profile with a maximum concentration (Cmax) of IL‐6 (21 pg/mL) and the IL‐6 profile of the patient presenting the highest IL‐6 Cmax (288 pg/mL) among patients receiving the recommended phase II dose of teclistamab in MajesTEC‐1. For the mean IL‐6 kinetics profile, teclistamab was predicted to result in a limited change in exposure of CYP substrates (area under the curve [AUC] mean ratio 0.87–1.20). For the maximum IL‐6 kinetics profile, the impact on omeprazole, simvastatin, midazolam, and cyclosporine exposure was weak to moderate (mean AUC ratios 1.90–2.23), and minimal for caffeine and s‐warfarin (mean AUC ratios 0.82–1.25). Maximum change in exposure for these substrates occurred 3–4 days after step‐up dosing in cycle 1. These results suggest that after cycle 1, drug interaction from IL‐6 effect has no meaningful impact on CYP activities, with minimal or moderate impact on CYP substrates. The highest risk of drug interaction is expected to occur during step‐up dosing up to 7 days after the first treatment dose (1.5 mg/kg subcutaneously) and during and after CRS.

Currently, there are no resources to support culturally and linguistically diverse (CALD) women with breast cancer to make decisions about undergoing breast reconstruction (BR). This study evaluated the usability and acceptability of decision aids (DAs) for Vietnamese- and Arabic-speaking women. This two-phase qualitative recruited Vietnamese- (Phase 1) and Arabic-speaking (Phase 2) adult (age ≥ 18 years) women who were diagnosed with breast cancer and could read Vietnamese/Arabic. Women participated in either think-aloud telephone interviews (Phase 1) or semi-structured telephone interviews (Phase 2) and provided feedback on the DA. Interviews were audio-recorded, translated, and transcribed from Vietnamese/Arabic to English, and inductive thematic analysis was undertaken. Additionally, Arabic-speaking women completed the Preparation for Decision Making (PrepDM) scale in Round 2. Twenty-five women were recruited in two phases (Phase 1: Vietnamese-speaking women, n = 14; Phase 2: Arabic-speaking, n = 11). Three themes were developed in Phase 1: (1) DA content and reception; (2) linguistic attributes and cultural appropriateness; and (3) factors that improve the DAs’ impact. Three themes were developed in Phase 2: (1) varying perceptions of DA content; (2) linguistic and cultural suitability of information; and (3) impact of DA on decision making. Women from both phases identified areas for improvement: minimising the use of medical terminology, considering the cultural taboos associated with the word ‘breast’, and addressing remaining information gaps. Both language DAs were generally perceived as acceptable and useful in providing information about BR options and prompting women’s reflections about the suitability of BR as part of their treatment. The mean PrepDM score for Arabic-speaking women in Round 2 was 4.8/5 (SD = 0.3). Further work is needed to ensure that culturally adapted DAs take into account the myriad of information needs and health literacy levels. The key role of healthcare professionals in shared decision making among CALD populations should also be considered.

Background: Concordance with evidence-based medicine (EBM) guidelines is associated with improved clinical outcomes in spine surgery. The North American Spine Society (NASS) has published coverage guidelines on indications for lumbar fusion surgery, with a recent survey demonstrating a 60% concordance rate across its members. GPT-4 is a popular deep learning model that receives knowledge training across public databases including those containing EBM guidelines. There is prior research exploring the potential utility of artificial intelligence (AI) software in adherence with spine surgery practices and guidelines, inviting opportunity to further investigate application in the setting of lumbar fusion surgery with current AI models. Methods: Seventeen well-validated clinical vignettes with specific indications for or against lumbar fusion based on NASS criteria were obtained from a prior published research study. Each case was transcribed into a standardized prompt and entered into GPT-4 to obtain a decision whether fusion is indicated. Interquery reliability was assessed with serial identical queries utilizing the Fleiss’ Kappa statistic. Majority response among serial queries was considered as the final GPT-4 decision. Queries were all entered in separate strings. The investigator entering the prompts was blinded to the NASS-concordant decisions for the cases prior to complete data collection. Decisions by GPT-4 and NASS guidelines were compared with Chi-square analysis. Results: GPT-4 responses for 15/17 (88.2%) of the clinical vignettes were in concordance with NASS EBM lumbar fusion guidelines. There was a significant association in clinical decision-making when determining indication for spine fusion surgery between GPT-4 and NASS guidelines (χ² = 9.75; p

Abstract The ionosphere over Iran is located on the upper edge of equatorial ionization anomaly (EIA). The Equatorial Electrojet (EEJ) as the proxy of temporal evolution of the EIA is explored using the MAGDAS stations near the magnetic equator during quiet and active geomagnetic conditions. The possible impact of EIA on Total Electron Content (TEC) over Iran is investigated. Analyzing data from 140 stations over 7 months, it is found that EEJ influences TEC and its latitudinal penetration. During geomagnetically active days, EEJ's behavior and TEC's latitudinal variations are investigated. Diurnal EEJ patterns and counter electrojets (CEJ) are analyzed, alongside solar wind timing effects on EEJ and TEC using data from stations in Brazil, Peru, the Philippines, and Sri Lanka. Statistical correlations between maximum TEC and parameters extracted from the daily EEJ profile, including EEJdaymax, integrated EEJ (IEEJ), and IEEJdaymax—highlight Iran's position at the EIA's upper edge, indicating high susceptibility to equatorial dynamics. In addition, the Rate of Total Electron Content Index (ROTI) has been analyzed under geomagnetic active conditions. The results demonstrate that ROTI exhibits good agreement with TEC in terms of latitude penetration and the detected gradient in TEC. Employing Artificial Neural Networks (ANN) for local TEC prediction, Iran is segmented into eight regions based on GNSS receiver distribution. Each region's ANN model, trained during the quiet geomagnetic condition, assesses predictability and accuracy. The ANN model demonstrates reliable local TEC forecasting and confirms the direct impact of equatorial dynamics on Iran's ionosphere.

Introduction Routine collection of patient-reported outcome measures (PROMs) has the potential to inform and improve cancer care. It is now feasible for patients to complete PROMs electronically (ePROMs) providing information about their current levels of symptoms, side effects of treatment and other concerns. PROM scores can be tracked over time allowing more timely identification of problems and more appropriate intervention. Studies have reported clear benefits in patient–clinician communication when PROMs are used and trials in the USA and France found patients randomised to complete regular ePROMs reported better health-related quality of life, had fewer unplanned hospital visits and, importantly, significantly better survival than those randomised to usual care. However, information about the effects on health outcomes and, particularly, the cost-effectiveness of incorporating this information into practice is limited.Methods and analysis PROMISE (Patient Reported Outcome Measures in cancer care: a hybrid effectiveness-Implementation trial to optimise Symptom control and health service Experience) is a multicentre, randomised hybrid effectiveness/implementation trial to evaluate the clinical and cost-effectiveness of using ePROMs in routine cancer care to improve patient outcomes. Participants (target sample=572; randomised 1:1 to intervention and control) are adults aged 18 years or older diagnosed with a solid cancer and starting treatment at one of the four study hospitals. The primary outcomes are unplanned hospital presentations and physical/functional well-being at 6 months. We hypothesise that, compared with usual care, patients randomised to use an ePROM tool will have fewer unplanned hospital presentations, report better health-related quality of life and greater satisfaction with their care and that the ePROM tool will be cost-effective. We will also assess implementation and process outcomes consistent with the RE-AIM (Reach Effectiveness Adoption Implementation Maintenance) Framework.Ethics and dissemination This trial has been approved by the Metro South Human Research Ethics Committee (HREC/2020/QMS/67441). Participants provide written informed consent, including consent for record linkage, prior to completing the baseline questionnaire. Study results will be disseminated via peer-reviewed journals and presentations at scientific conferences and clinical meetings.Trial registration number ACTRN12620001290987.

Background: Complications occurring during the first postoperative year after lung transplantation increase the risk of long-term mortality. These events often lead to prolonged and repeated hospitalizations. We sought to assess the relationship between days outside the hospital or hospital-free days (HFD) during the first post-transplant year among 1-year survivors and subsequent retransplant-free survival. Methods: In a single-center study, we derived total inpatient days (initial transplant episode, readmission, and emergency room/observation) from the electronic medical record of lung transplant recipients who survived 1 year. The cohort was divided into HFD quartiles and Kaplan-Meier curves of subsequent transplant-free survival were compared with log-rank analysis. A Cox proportional hazards model was used to test the association of HFD with outcome and adjusted for selected variables. Results: Among 238 patients, 42 deaths and 2 retransplants occurred after a median of 3.6 years post-transplant. The median HFD was 341 (interquartile range: 324, 348). Estimated transplant-free survival at 3 and 5 years post-transplant in the lowest quartile of HFD (79% and 56%, respectively) was considerably worse compared with the first quartile (98% and 94%; p

Background: Donor-derived cell-free DNA (dd-cfDNA) is a nonspecific plasma biomarker for tissue injury that has been validated for monitoring acute rejection (AR) after lung transplantation (LT). However, no studies to date have focused specifically on single lung transplantation (SLT). Herein, we report the performance of dd-cfDNA in detecting AR in SLT from 6 academic centers that implemented this biomarker surveillance in their standard of practice (SOP). Methods: dd-cfDNA test results were corrected for SLT by an algorithm in the Clinical Laboratory Improvement Amendments (CLIA) laboratory to permit comparison against the same 1.0% threshold used in double-lung transplant. Investigators reviewed patient SOP electronic medical record clinical data to assign test results into cohorts based on clinical allograft health status. To avoid ambiguity in interpretation, samples drawn after a prior AR or infection event or without histopathologic confirmation of AR were excluded from further analysis. Diagnostic cohorts included AR (N=25 samples), healthy (STABLE, N=137), allograft infection (INFXN, N=41), chronic lung allograft dysfunction (CLAD, N=7), and “OTHER” types of graft injury (N=12). Results: The study included a total of 257 dd-cfDNA results from 103 SLT patients with one patient excluded due to active cancer. Samples were drawn a median of 233 days (interquartile range: 96-489) after SLT. Laterality for SLT (R vs L) and median dd-cfDNA fraction in AR and STABLE cohort were not statistically different. The median dd-cfDNA fraction was elevated with AR (1.8%) and INFXN (1.1%) vs STABLE (0.46%; p

Abstract Pulmonary hypertension (PH) is a frequent complication of chronic lung disease (CLD). However, PH is difficult to diagnose early since accompanying symptoms overlap and are similar to those of the underlying CLD. In most cases the PH is mild to moderate and therefore physical signs may be absent or subtle. This consensus paper provides insight into the clues that might suggest the presence of occult PH in patients with CLD. An overview of current diagnostic tools and emerging diagnostic technologies is provided as well as guidance for the work‐up and diagnosis of PH in patients with CLD.

Summary: The increasing prevalence of antibiotic resistance demands the discovery of antibacterial chemical scaffolds with unique mechanisms of action. Phenotypic screening approaches, such as the use of reporters for bacterial cell stress, offer promise to identify compounds while providing strong hypotheses for follow-on mechanism of action studies. From a collection of ∼1,800 Escherichia coli GFP transcriptional reporter strains, we identified a reporter that is highly induced by cell envelope stress—pPromrcsA-GFP. After characterizing pPromrcsA-GFP induction, we assessed a collection of bioactive small molecules for reporter induction, identifying 24 compounds of interest. Spontaneous suppressors to one compound in particular, MAC-0452936, mapped to the gene encoding the essential prolipoprotein diacylglyceryl transferase, lgt. Lgt inhibition by MAC-0452936 inhibition was confirmed through genetic, phenotypic, and biochemical approaches. The oxime ester, MAC-0452936, represents a useful small molecule inhibitor of Lgt and highlights the potential of using pPromrcsA-GFP as a phenotypic screening tool.