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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.

Recent increase in the number of natural disasters resulting in widespread, long-duration, and costly outages have brought the energy system resilience to the forefront. As system owners and operators seek to improve the system resilience, they often find it challenging to assess the costs and benefits of resilience investments. Costs are fairly well understood and measured, but benefits are less so. There are many resilience metrics that attempt to measure resilience benefit, but the existing methods for calculating metrics and incorporating value of resilience in energy decisions are not easily executed. To address this, we developed a method for modeling the value of resilience that is flexible and scalable across multiple types of models. This article describes a framework for incorporating duration-dependent customer damage functions (CDFs) into grid- and campus-scale planning and operations models. In two case studies, we consider how the duration-dependent value of resilience influences the investment and operation decisions. We find that in both cases, knowledge of the value of lost load provides opportunities to reduce the lifecycle cost of energy through adjusted investment or operational decisions. The primary contribution of this research is to integrate the duration-dependent value of resilience in energy decisions. This study will be useful to grid operators interested in reducing the value of customer losses during grid outages, as well as campus or site owners evaluating resilience investments.

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

BACKGROUND Magnetic resonance imaging (MRI) accuracy after neoadjuvant systemic therapy (NST) for breast cancer varies according to hormone receptor (HR), human epidermal growth factor receptor type-2 (HER2) subtype and Ki-67 proliferation index. Whether MRI accuracy varies by genomic signatures is unknown. We examined the accuracy of MRI in the NEONAB trial (Clinicaltrials.gov #: NCT01830244). AIM To examine the accuracy of MRI to predict pathological response to neoadjuvant therapy for breast cancer in the NEONAB trial. METHODS Patients with stages II-III breast cancer received sequential epirubicin, cyclophosphamide and nab-paclitaxel and trastuzumab if they were HER2+. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated to assess the utility of preoperative MRI to predict pathological complete response (pCR). Bland-Altman plots were used to assess agreement between MRI and pathological assessment of residual disease. RESULTS MRI correctly predicted pCR in 64.1% of the cohort. Sensitivity and specificity were 52% and 78%, respectively; PPV 73% and NPV 58%. MRI predicted pCR most accurately in HER2-positive patients; sensitivity 58%, specificity 100%, PPV 100% and NPV 38%. MRI had higher PPV and NPV in tumours with Ki-67 ≥ 15% than tumours with Ki-67 < 15%, 75% versus 50% and 57.5% versus 50%, respectively. In this study, MRI underestimated residual tumour size by 1.65 mm (limits of agreement: 43.07-39.77 mm). CONCLUSIONS MRI appears more accurate for predicting pCR in HER2+ disease than other subtypes and in cancers with Ki-67 ≥ 15% compared to those with Ki-67 < 15%. Accuracy of MRI in our HR+, RS ≥ 25 cohort is comparable to previous reports of unselected HR+ disease. MRI post-NST should be interpreted in conjunction with HER2 status and Ki-67 index of the primary.

Assistive technology (AT) is an essential facilitator of independence and participation, both for people living with the effects of disability and/or non-communicable disease, as well as people aging with resultant functional decline. The World Health Organization (WHO) recognizes the substantial gap between the need for and provision of AT and is leading change through the Global Cooperation on Assistive Technology (GATE) initiative. Showcasing innovations gathered from 92 global researchers, innovators, users and educators of AT through the WHO GREAT Summit, this article provides an analysis of ideas and actions on a range of dimensions in order to provide a global overview of AT innovation. The accessible method used to capture and showcase this data is presented and critiqued, concluding that "innovation snapshots" are a rapid and concise strategy to capture and showcase AT innovation and to foster global collaboration. Implications for Rehabilitation Focal tools such as ePosters with uniform data requirements enable the rapid sharing of information. A diversity of innovative practices are occurring globally in the areas of AT Products, Policy, Provision, People and Personnel. The method offered for Innovation Snapshots had substantial uptake and is a feasible means to capture data across a range of stakeholders. Meeting accessibility criteria is an emerging competency in the AT community. Substantial areas of common interest exist across regions and globally in the AT community, demonstrating the effectiveness of information sharing platforms such as GATE and supporting the idea of regional forums and networks.

Postural stability is a complex skill dependent upon the coordination of motor, sensory and cognitive systems. The purpose of this project was therefore to explore how older adults’ balance performance is impacted by increased cognitive load, hearing loss, and simulated vision loss. Twenty-eight older adults between the ages of 50 and 93 years (M = 73.86, SD = 10.43) were tested. Participants underwent standard sensory acuity and cognitive functioning tests. The balance trials varied as a function of cognitive load and visual challenge resulting in five conditions: (1) eyes closed, (2) normal vision clear goggles (NV) (3) simulated low vision (20/80) goggles (LV) (4) LV and math task, (5) NV and math task. Postural stability was assessed with three key center of pressure parameters: total path length (TPL), anterior-posterior amplitude (APA) and medial-lateral amplitude (MLA). A mixed-model ANOVA using hearing acuity as a covariate revealed significant effects of complexity in sway amplitude: (APA: p < .017; MLA: p < .020), while TPL approached significance (p < .074). T-tests revealed significant (p < .05) decreases in balance performance across all 3 centre of pressure parameters when comparing single task NV to dual-task NV, NV vs. eyes closed and single task NV vs. LV dual-task. There were significant positive correlations between hearing acuity and balance (MLA) under single task NV (r = .491) and LV conditions (r = .497). Results suggest the attentional demands from increased cognitive load and sensory loss lead to decreases in older adults’ single- and dual-task balance performance.

Interest in renewable energy-based hybrid systems—which combine multiple renewable energy and/or energy storage technologies—is apparent and growing. Such systems could play an important role in the grid of the future, but our ability to quantify their potential impacts is hindered by (a) the inconsistent treatment of hybrid systems and (b) an incomplete understanding of which aspects of hybridization will have the greatest influence. In this article, we review the literature and propose an organization scheme for utility-scale hybrid systems in which electricity is generated from commercially available, renewable energy technologies, and electricity is the only output. Based on this literature review, we propose three categories for delineating systems that link multiple renewable energy and/or energy storage technologies: co-located resources (locational linkage only), virtual power plants (operational linkage only), and full hybrids (location and operational linkages). Proposing a categorization based on whether the systems involve locational and/or operational linkages reflects the fact that technology combinations do not represent a meaningful delineation. In addition, the categories are ideal for informing model development efforts, by identifying the unique characteristics that must be captured in adequate representations of systems that fall under each category. Our categories can also help inform policy considerations, as they delineate system characteristics that would introduce distinct permitting, siting, interconnection, and policy challenges. Therefore, we believe that our proposed taxonomy will help organize thinking and research efforts in a way that will enable consistent evaluation of the costs, values, and potential of renewable energy-based hybrids.

Electrification of end-use technologies could have important implications for bulk power sector planning, operations, and impacts. By combining previously-defined electrification scenarios with capacity expansion modeling, we evaluate the potential challenges and opportunities associated with electrification. Our scenario analysis reveals that electrification reduces energy consumption and air emissions from across the energy sector, and its impacts on energy system costs are modest due, in part, to the abundance of low-cost resources in the United States.

Mycobacterium haemophilum is a rare isolate of non-tuberculous Mycobacterium which has been reported to affect immunocompromised patients. We report a case of a 32-year-old renal transplant patient with M. haemophilum infection initially involving his left sinus which was treated with appropriate antimicrobial therapy for thirteen months. Two weeks after cessation of antibiotics the infection rapidly recurred in his skin and soft tissues of his hands and feet. This case highlights the difficult diagnostic and therapeutic implications of atypical infections in transplant patients. To our knowledge this is the first reported case of relapsed M. haemophilum infection in a renal transplant recipient.

Copper(I) iodide films were cast onto glass from solution. The CuI films absorb vapor-phase amine and sulfide molecules, producing a range of photoluminescent emission colors. Spectroscopic data suggest the presence of low energy CuI cluster-centered transitions.

Background Biofuels produced from biomass are considered to be promising sustainable alternatives to fossil fuels. The conversion of lignocellulose into fermentable sugars for biofuels production requires the use of enzyme cocktails that can efficiently and economically hydrolyze lignocellulosic biomass. As many fungi naturally break down lignocellulose, the identification and characterization of the enzymes involved is a key challenge in the research and development of biomass-derived products and fuels. One approach to meeting this challenge is to mine the rapidly-expanding repertoire of microbial genomes for enzymes with the appropriate catalytic properties. Results Semantic technologies, including natural language processing, ontologies, semantic Web services and Web-based collaboration tools, promise to support users in handling complex data, thereby facilitating knowledge-intensive tasks. An ongoing challenge is to select the appropriate technologies and combine them in a coherent system that brings measurable improvements to the users. We present our ongoing development of a semantic infrastructure in support of genomics-based lignocellulose research. Part of this effort is the automated curation of knowledge from information on fungal enzymes that is available in the literature and genome resources. Conclusions Working closely with fungal biology researchers who manually curate the existing literature, we developed ontological natural language processing pipelines integrated in a Web-based interface to assist them in two main tasks: mining the literature for relevant knowledge, and at the same time providing rich and semantically linked information.

Fungi produce a wide range of extracellular enzymes to break down plant cell walls, which are composed mainly of cellulose, lignin and hemicellulose. Among them are the glycoside hydrolases (GH), the largest and most diverse family of enzymes active on these substrates. To facilitate research and development of enzymes for the conversion of cell-wall polysaccharides into fermentable sugars, we have manually curated a comprehensive set of characterized fungal glycoside hydrolases. Characterized glycoside hydrolases were retrieved from protein and enzyme databases, as well as literature repositories. A total of 453 characterized glycoside hydrolases have been cataloged. They come from 131 different fungal species, most of which belong to the phylum Ascomycota. These enzymes represent 46 different GH activities and cover 44 of the 115 CAZy GH families. In addition to enzyme source and enzyme family, available biochemical properties such as temperature and pH optima, specific activity, kinetic parameters and substrate specificities were recorded. To simplify comparative studies, enzyme and species abbreviations have been standardized, Gene Ontology terms assigned and reference to supporting evidence provided. The annotated genes have been organized in a searchable, online database called mycoCLAP (Characterized Lignocellulose-Active Proteins of fungal origin). It is anticipated that this manually curated collection of biochemically characterized fungal proteins will be used to enhance functional annotation of novel GH genes. Database URL: http://mycoCLAP.fungalgenomics.ca/

Background Nepal has high unmet need for family planning and low use of intrauterine devices (IUDs). While clients’ attitudes toward the IUD are known in a variety of contexts, little is known about providers’ knowledge and perceptions of the IUD in developing countries. Nepal’s liberal IUD service provision policies allow the opportunity to explore provider knowledge and perceptions across cadres and sectors. This research contributes to an understanding of providers’ IUD perceptions in low-resource environments, and increases evidence for IUD task-sharing and private sector involvement. Methods A questionnaire was administered to 345 nurses and auxiliary nurse midwives (ANMs) affiliated with the private Mahila Swastha Sewa (MSS) franchise, public sector, or private non-franchise sector. All providers had been trained in TCu 380A IUD insertion and removal. The questionnaire captured providers’ IUD experience, knowledge, and perceived barriers to recommendation. Descriptive, multivariate linear, and multinomial logistic regression was conducted, comparing providers between cadre and sector. Results On average, providers answered 21.5 of 35 questions correctly, for a score of 61.4%. Providers scored the lowest on IUD medical eligibility, answering 5.9 of 14 questions correctly. Over 50% of providers were able to name the four side effects most frequently associated with the IUD; however, one-third of all providers found at least one of these side effects unacceptable. Adjusted results show that cadre does not significantly impact provider’s IUD knowledge scores or side effect perceptions. Public sector affiliation was associated with higher knowledge scores regarding personal characteristic eligibility and more negative perceptions of two normal IUD side effects. IUD knowledge is significantly associated with provider’s recent training and employment at multiple facilities, and side effect perceptions are significantly associated with client volume, range of family planning methods, and region. Conclusions Provider knowledge and attitudes towards IUD provision are similar across cadre and sector, supporting WHO task-sharing guidelines and validating Nepal’s family planning policies. However, overall provider knowledge is low. We recommend that providers need to receive further training and support to improve knowledge, manage side effects, and recognize women in periods of high unmet need - such as post-partum or post-abortion women - as suitable candidates for IUDs. Electronic supplementary material The online version of this article (doi:10.1186/s12913-015-0701-y) contains supplementary material, which is available to authorized users.