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Background: OP-1250 is a small molecule oral complete estrogen receptor antagonist (CERAN) that binds the ligand binding domain of the ER and completely blocks ER-driven transcriptional activity. CDK4/6 inhibitors in combination with endocrine therapy have improved progression free survival and overall survival for patients (pts) with metastatic breast cancer (MBC) in the first- and second-line settings. However, most patients will progress and newer combinations such as with OP-1250 may provide improved clinical outcome. OP-1250 potently inactivates both wild-type ER and mutant forms of ER. The latter confers ligand independent activity and is a mechanism of resistance to standard of care endocrine therapies. In preclinical studies, OP-1250 in combination with palbociclib demonstrated synergistic activity in models of wild-type ER and those containing ESR1 activating mutations, and in models of brain metastasis. A Phase 1/2 monotherapy study of OP-1250 is ongoing in MBC subjects who have received 1 or more prior endocrine therapies (NCT04505826). Monotherapy is well tolerated and the recommended phase 2 dose is 120 mg QD. The aim of this combination trial is to define the maximum tolerated dose (MTD), safety, tolerability, and pharmacokinetics (PK) of OP-1250 in combination with palbociclib. Methods: Eligibility criteria include pts with MBC or locally advanced breast cancer who have received no more than 1 prior line of endocrine therapy (prior CDK4/6 inhibitors and one line of chemotherapy are permitted) and measurable or non-measurable disease. Using a 3+3 design, cohorts are sequentially enrolled, and pts receive escalating doses of OP-1250 orally QD continuously in combination with 125 mg of palbociclib orally for 21 of 28 days. Pts are evaluable for dose limiting toxicities (DLTs) if >75% of both treatments were administered within the first 28-day treatment cycle. Blood is collected for PK on cycle 1 days 1, 2 and cycle 2 days 15, 16 for OP-1250 and cycle 1 day 15 for palbociclib. PK profiles, exposure parameters, and drug-drug interactions (DDIs) are assessed. Pts are monitored for adverse events (AE) and tumor assessments (RECIST 1.1) are conducted every two cycles. Results: As of July 7, 2022, 9 pts were evaluable for DLTs after 28 days of treatment in dose levels 30 mg, 60 mg, and 90 mg of OP-1250 in combination with palbociclib. No DLTs occurred at any of the dose levels. As of May 13, 2022, of the 7 pt safety data set, the most common Grade 1/2 treatment emergent adverse events (TEAE), which occurred in 2 patients, were nausea, gastroesophageal reflux, vomiting, and fatigue. Grade 3 neutropenia occurred in 4 pts and all were attributed to palbociclib by the investigator. No Grade 4 events were observed. OP-1250 was highly bioavailable and showed dose proportional exposure in combination with palbociclib. The single and multiple dose exposure of OP-1250 was consistent with that observed in the monotherapy study, indicating an absence of effect of palbociclib on OP-1250 PK. 90 mg steady-state evaluation is ongoing. Palbociclib concentrations at steady state did not demonstrate a meaningful difference from published exposure parameters for the three dose levels evaluated, indicating an absence of DDI. Conclusions: In the first three cohorts of OP-1250 and palbociclib, the combination was well tolerated and no DLTs occurred. There were no clinically significant DDIs observed between OP-1250 and palbociclib at the doses evaluated and exposure of each drug was consistent with observed monotherapy exposure levels. Dose escalation of OP-1250 continues to 120 mg, to be followed by dose expansion. Updated data will be presented. (NCT05266105) Citation Format: Arlene Chan, Daphne Day, Rina Hui, Nicole McCarthy, Rosalind Wilson, Demiana Faltaos, Morena Shaw, Caitlin Murphy. Preliminary data from a Phase 1b dose escalation study of OP-1250, an oral CERAN, in combination with palbociclib in patients with advanced and/or metastatic estrogen receptor (ER)-positive, HER2-negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-07-15.

This article uses a case study approach to reimagine risk management in education abroad programming. It brings together a group of program partners to explore pre-COVID risk management decision-making during political unrest in Ecuador in 2019. Through continued dialogue and self-directed creative reflection techniques, the partners (a Dean of International Education and Study Abroad Director from a college in the United States, the Executive Director and Resident Director from the program provider, a local participant from the host community, and a student from the semester’s cohort), all of whom are co-authors, overcome geographical distance and language barriers to reflect on their experiences over the entire process. Recognizing that COVID-19 changed how education abroad approaches risk management and responding to how movements for social justice are calling for diverse participation in policy decisions, the authors explore the Ecuador case study as a way to confront their biases and assumptions, as well as those projected in our field. Placing special focus on the colonizing nature of Global North to Global South partnerships, the article calls for a greater conversation of decolonizing risk management, ending with lessons learned and recommendations for enhancing partnerships to better serve students, communities, and institutions of higher education as a collective whole. Abstract in Spanish Este artículo utiliza un estudio de caso para re-imaginar la gestión de riesgos en la programación de educación en el extranjero. Reúne a un grupo de colaboradores de un programa para explorar la toma de decisiones en la gestión de riesgos durante las manifestaciones políticas en Ecuador en octubre del 2019. A través de un diálogo continuo y técnicas autodirigidas de reflexión creativa, los colaboradores (la Decana de Educación Internacional y la Directora de Estudios en el Extranjero de una universidad en Estados Unidos, el Director Ejecutivo y la Directora Residente de la organización proveedora del programa, un participante local de la comunidad anfitriona y una estudiante de intercambio del semestre), todos los cuales son coautores, superan la distancia geográfica y las barreras del idioma para reflexionar sobre sus experiencias durante todo el proceso. Reconociendo que COVID-19 cambió la forma en que la educación en el extranjero aborda la gestión de riesgos y respondiendo a las exigencias de movimientos de justicia social por una participación diversa en las decisiones políticas, los autores exploran el estudio de caso de Ecuador como una forma de confrontar sus sesgos y suposiciones. Con un enfoque especial en los legados colonizadores de las relaciones entre el Norte Global y el Sur Global, el artículo pide una mayor conversación sobre la descolonización de la gestión de riesgos. Finaliza con lecciones aprendidas y recomendaciones para equilibrar las alianzas entre diversos actores y servir mejor a los estudiantes, las comunidades locales y las instituciones de educación superior como un solo colectivo.

Many cognitive assessments include a visual component; however, adults may experience a decline in visual acuity with age. Scores on cognitive assessments of adults with visual impairments are typically lower than adults with normal vision, however, it is unclear if these lower scores are a consequence of cognitive or visual impairment. We measured the impact of simulated visual impairment on a cognitive screening measure. Undergraduate students were administered the Montreal Cognitive Assessment (MoCA) under three vision conditions (20/20, simulated 20/80, simulated 20/200). We found a main effect of vision condition on test performance such that there is a statistically significant difference between scores on the 20/20 and 20/80 conditions and 20/200. However, no differences were observed between 20/80 and 20/200. Participants' performance decreased with simulated impairments. A secondary between-subject analysis was conducted on a sample of older adults with and without vision impairment; no differences were found.

The electric power system has historically been designed to provide reliable energy to loads by using a relatively small number of well-understood generators. The distinction between load, generation, and transmission resources has been quite clear. Most of the responsibility for planning and operating a system—building a highly reliable network from less reliable parts—has been with the system manager, whether that be a utility, a regional market operator, or some similar entity. Given this historical context, many experts were initially perplexed by the rapidly growing popularity of hybrid resources, which combine multiple technologies into a single entity. Rather than depending on a system operator to provide instructions to individual technologies, hybrid resources intentionally take on more operational responsibility by optimizing and scheduling their combined functions. Interconnection queues in many regions reveal a large and growing interest in hybrids, suggesting that project developers and investors see them as providing advantages.

Significance On average, older adults (60+) with normal vision read the International Reading Speed Texts (IReST) 37.8 words per minute slower than the standardized values provided by the IReST manufacturer. When assessing reading speed in older adults, clinicians should bear in mind that the IReST norms do not account for these age-related differences. Purpose The purpose of this study was to validate the IReST in an English-speaking Canadian sample of older adults (60+). Methods Canadian English-speaking older adults (n = 25) read all 10 IReST aloud using the same protocol from the original IReST validation study. Results There were significant differences between the older adult sample and the published IReST values for each text (mean difference, -37.84; 95% confidence interval, -41.34 to -34.34). Conclusions Reading speeds of older (60+) Canadian adults fell outside of the standardized values of the English language IReST. Researchers/clinicians who wish to assess older adults' reading speed using the IReST ought to take this discrepancy into account.

PURPOSE This study examined the effectiveness of the LuxIQ, the Apple iPad and a smart bulb in assessing optimal colour and illumination to facilitate reading in younger, older and visually impaired adults. METHODS Participants read standardised texts at baseline (normal lighting/no device), then using the Apple iPad, LuxIQ and smart bulb, with their normal vision (20/20 condition) and using a simulated reduction in visual acuity/contrast sensitivity (20/80 condition). Visually impaired participants followed the same procedure used in the 20/80 condition. RESULTS There was a significant interaction between condition and device in younger, F(1.5, 43.51) = 30.41, p

Drug development is a term used to define the entire process of bringing a new drug or device to market. It is an integrated, multidisciplinary endeavor that includes drug discovery, chemistry and pharmacology, nonclinical safety testing, manufacturing, clinical trials, and regulatory submissions. This report summarizes presentations of a workshop entitled “Drug Development 101,” held at the 39th Annual Meeting of the American College of Toxicology in West Palm Beach, Florida. The workshop was designed to provide an introductory overview of drug development. Experienced scientists from industry and government provided overviews of each area, with a focus on safety assessment, and described some of the challenges that can arise. The role of chemistry and manufacturing was discussed in the context of early- and late-stage product development and approaches to assess, control, and limit impurities. The toxicologic assessment was emphasized in early-phase development, from the selection of a candidate drug through the determination of a first-in-human starting dose. Clinical trial development was discussed in the context of regulatory requirements and expectations. The final topic of issues and considerations in the review processes of different types of submissions to Food and Drug Administration included advice for best practices in authoring good Investigational New Drug and New Drug Application/Biologic License Application submissions and interacting effectively with regulatory reviewers.

This study used a multiple probe design to evaluate the effects of a teacher-implemented video-schedule intervention on the mathematical skills and untargeted challenging behaviors of five elementary-school students with autism. Results indicated that the intervention was effective in improving participants' academic performance, and a decrease in the level of challenging behaviors and stereotypy was observed for participants following the introduction of intervention. Additionally, academic gains generalized across academic problems and to a small group setting, suggesting that this technology-based intervention is an efficient use of instructional time. Future research targeting a variety of academic skills and examining intervention implementation by additional practitioners (e.g., teaching assistants) is warranted.

Hepatocellular carcinoma (HCC) is a leading cause of death in patients with cirrhosis and has a rising mortality rate in the United States.

PURPOSE This study examined how optimal colour/illumination conditions and the efficacy of the iPad, LuxIQ and Smart Bulb varied as a function of print size in younger, older and visually impaired adults. METHODS Participants with visual impairments and simulated low vision (SLV) read the MNRead using the iPad, LuxIQ and Smart Bulb. RESULTS In the impairment condition at 1.20 logMAR, the iPad (M = 9.49, 95% CI [3.18, 19.42]) and LuxIQ (M = 15.95, 95% CI [9.54, 24.86]) improved the reading speeds. At 0.80 logMAR (SLV), all devices improved reading speeds of older adults (iPad (M = 28.70, 95% CI [14.65, 42.51]); LuxIQ (M = 49.63, 95% CI [30.04, 69.68]); Smart Bulb (M = 23.11, 95% CI [3.33, 42.11])), but in younger adults only the LuxIQ (M = 13.04, 95% CI [3.21, 21.27]) did so. In the impairment condition, the iPad (M = 5.54, 95% CI [0.31, 12.13]) and LuxIQ (M = 13.90, 95% CI [7.88, 23.49]) improved reading speeds. In the SLV condition, age was a significant predictor of reading speed at 1.20 logMAR (F3,164 = 10.74, p

As the electricity sector evolves, and as all energy types (thermal, electric, chemical, etc.) become more coupled, there has been increased interest to develop and deploy hybrid energy systems (HES). This work focuses on fully integrated HES, where there are multiple energy sources and multiple energy products, often coupled through a storage buffer. A significant amount of the available literature on this work describes technology pathways for fully integrated HES; however, it is unclear how financial institutions should treat these systems. Fully integrated HES represent an increase in complexity from their stand-alone counterparts, but they also potentially mitigate financial risk and provide value to the energy system, which has not yet been accounted for in financing mechanisms that could help to enable such systems. This paper provides some examples of fully integrated HES and proposes principles to help adapt financing to adequately capture the value of such systems.