Bemnifosbuvir, a novel, oral, nonmutagenic, nonteratogenic nucleotide analogue inhibits SARS-CoV-2 replication in vitro. Adults in hospital settings with moderate COVID-19 were randomized 1:1 bemnifosbuvir/placebo. Study amended to two parts after interim analysis; part B enrollment limited owing to evolving standard of care. Although the study ended early and did not meet the primary efficacy end point, bemnifosbuvir was well tolerated and did not contribute to all-cause mortality. Compared with placebo, bemnifosbuvir treatment resulted in 0.61log10 greater viral load mean change on day 2; trend sustained through day 8. Treatment-emergent adverse events were similar in both groups; most were mild/moderate, unrelated to study drug. Our results suggest a potential role for bemnifosbuvir in blunting COVID-19 progression. NCT04396106 (ClinicalTrials.gov).

Taletrectinib (AB-106/DS-6051b) is a next-generation, brain-penetrant, ROS1/ NTRK tyrosine kinase inhibitor (TKI) and has shown clinically meaningful effect and safety profile in ROS1+ Non-Small Cell Lung Cancer (NSCLC) patients in phase 1 studies (Fujiwara et al, Oncotarget 2018; 9(34): 23729-23737; Ou et al, JTO Clin Res Rep. 2020 Oct 21;2(1):100108). Taletrectinib has also demonstrated activity against ROS1 G2032R resistance mutation and CNS metastases in the ongoing phase 2 TRUST study (NCT04395677) in China. Also, taletrectinib has shown preliminary efficacy against NTRK-positive solid tumors in an ongoing phase 2 study (NCT04617054). TRUST-II study (NCT04919811) is a phase 2, global, multicenter, open-label, single-arm multi-cohort study evaluating the efficacy and safety of taletrectinib for ROS1 fusion-positive advanced metastatic NSCLC and other solid tumors. Taletrectinib will be given at 600 mg once daily in 21-day cycle. The patients with ROS1 fusions detected by local tests are eligible to enroll with retrospective confirmation by a central laboratory. The study consists of four cohorts: cohort 1: systemic chemotherapy naïve or ≤ one prior line and ROS1 TKI naïve NSCLC (N=53); cohort 2: previously treated with one ROS1 TKI (crizotinib or entrectinib) and with progression who are either chemotherapy naïve or ≤ one line of platinum and/or pemetrexed based therapy for NSCLC (N=46); cohort 3: ≤ 2 prior ROS1 TKIs and with progression who are either chemotherapy naïve or ≤ 2 lines of platinum and/or pemetrexed based therapy for NSCLC (N=10); and cohort 4: systemic chemotherapy naïve or ≤ 2 prior lines of chemotherapy, but ROS1-TKI naïve ROS1-positive solid tumor other than NSCLC ( N=10). The primary endpoint is objective response rate (ORR) (RECIST v1.1) by independent review committee (IRC) assessment for cohorts 1 and 2. Key secondary endpoints include IRC-assessed duration of response, IRC-assessed intra-cranial ORR, progression free survival (PFS), overall survival (OS), and safety. This study is currently recruiting in Japan, Republic of Korea, and USA. Additional accrual is planned in Canada, China, and European Union. NCT04919811. The authors.

ObjectivesBoth combinations of the PARP inhibitor veliparib plus platinum doublet chemotherapy (CT), and the programmed death receptor-1 (PD-1) inhibitor nivolumab plus CT have demonstrated encouraging efficacy for treatment of non-small cell lung cancer (NSCLC). This phase 1 dose-escalation study (NCT02944396) evaluated the quadruple combination of veliparib with nivolumab and doublet CT in patients with unresectable advanced/metastatic NSCLC. Materials and methodsPatients were enrolled into five dosing cohorts: patients received veliparib 120 mg twice daily (BID) combined with nivolumab 360 mg, carboplatin AUC 6 mg/mL∙min, and paclitaxel 200 mg/m2 (C/PAC) or veliparib 80/120/200/240 mg BID in combination with nivolumab 360 mg, carboplatin AUC 6 mg/mL∙min, and pemetrexed 500 mg/m2 (C/PEM). Primary objective was to identify the recommended phase 2 dose (RP2D) of veliparib + nivolumab + CT. Safety, tolerability, and efficacy of this combination were also assessed. ResultsTwenty-five patients were enrolled: 6 patients received veliparib 120 mg BID + nivolumab + C/PAC and 19 received veliparib (80–240 mg BID) + nivolumab + C/PEM. No dose-limiting toxicities were reported, and the RP2Ds were veliparib 120 mg BID + nivolumab + C/PAC, and veliparib 240 mg BID + nivolumab + C/PEM. The most common any-grade adverse events (AEs) were fatigue (56%), nausea (52%), and anemia (48%). Grade 3/4 AEs included anemia (32%) and neutropenia (24%), and the most frequent serious AE was malignant neoplasm progression (12%). Veliparib exhibited approximately dose proportional kinetics in the dose range 80–240 mg BID combined with nivolumab and C/PEM, with no effects on pemetrexed pharmacokinetics. Overall, the confirmed objective response rate was 40%, and best overall response was 64%. ConclusionVeliparib combined with nivolumab and platinum doublet CT was tolerated in patients with advanced/metastatic NSCLC, and no evidence of drug–drug interaction was observed. Although preliminary, this quadruple therapy may have promising antitumor activity.

This study examined profiles of adverse childhood experiences (ACEs) and mental and substance use disorders (MSUDs), and associations between distinct profiles of ACEs and MSUDs. Participants were adults (N = 34, 652) involved in the National Epidemiologic Survey on Alcohol and Related Conditions. Latent class analysis was used to examine both profiles of ten ACEs and ten past year MSUDs. Dual latent class analysis regression was used to examine associations between profiles of ACEs and MSUDs. Given gender differences in ACEs and MSUDs, analyses were conducted separately for females and males. Four profiles of ACEs and three profiles of MSUDs were selected for both genders. The four profiles of ACEs were characterized by the following probabilities: high multiple ACEs, high parental substance abuse, high childhood physical abuse, and low ACEs. The three profiles of MSUDs were characterized by the following probabilities: high multiple MSUDs for females and low MSUDs except alcohol use disorders for males, moderate-to-high major depressive episode, and low MSUDs. When compared to the low ACEs and MSUDs profiles, members in the higher ACEs profiles had 3.71-89.75 times greater odds of also being members in the higher MSUDs profiles. However, more than one-third of members in the high multiple ACEs profiles were also in the low MSUDs profiles. Study findings suggest four profiles of the ACEs widely studied as part of the Adverse Childhood Experiences study and risk and resilience for recent MSUDs among men and women nationally affected by ACEs.

The primary purpose of this research is to examine the impact of estimation methods, actual latent trait distributions, and item pool characteristics on the performance of a simulated computerized adaptive testing (CAT) system. In this study, three estimation procedures are compared for accuracy of estimation: maximum likelihood estimation (MLE), expected a priori (EAP), and Warm's weighted likelihood estimation (WLE). Some research has shown that MLE and EAP perform equally well under certain conditions in polytomous CAT systems, such that they match the actual latent trait distribution. However, little research has compared these methods when prior estimates of. distributions are extremely poor. In general, it appears that MLE, EAP, and WLE procedures perform equally well when using an optimal item pool. However, the use of EAP procedures may be advantageous under nonoptimal testing conditions when the item pool is not appropriately matched to the examinees.

Objectives. This ten-year longitudinal study examines various attributes and demographic characteristics of emergency medical technicians (EMTs) and paramedics to identify factors that influence their careers, to identify trends in emergency medical services (EMS), and to provide data on why individuals report leaving the EMS career field. Methods. A 46-item core survey and a 16-item cross-sectional survey were administered to EMT-basics and EMT-paramedics who were randomly selected and placed in cohort groups stratified by duration of continuous registration at each level and by race. The core survey focused on five broad areas of attributes and demographics, including general, professional, educational, personal, and financial. Case weights were calculated for respondents in each stratum, reflecting the individual's probability of selection. These case weights were adjusted, within strata, for nonresponse. The survey will be administered annually. The cross-sectional survey focused on EMS education. Results. This interim report is descriptive of the overall responses of EMT-basics and EMT-paramedics to core survey items. The demographic characteristics of EMT-basics and EMT-paramedics are described as well as a description of their work activities, working conditions, and job satisfaction Conclusions. The initial EMT and paramedic attribute and demographic data have been collected, analyzed, and reported. The longitudinal nature of this study requires further data collection and analysis to accurately present trends in EMS, as well as correlations and associations between identified attributes and other factors that influence the careers of EMTs and paramedics. Further reports of the findings will be necessary.

AbstractWhat does the work on tax expenditures over, the last decade imply about the better design of evaluations in this area? The tax expenditure evaluations are compared against a simple but sturdy general framework for conducting results evaluations that looks at target populations; the treatment, program, or policy; the response variable; how relative effects are estimated; and what happens when no effects are discovered.

Among the issues facing research on the use of information, are three fundamental questions: What exactly constitutes utilization; What social, political, and related factors influence utilization; and Does the nature of utilization change over time?