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Abstract Background Despite recent therapeutic advances, combating cancer resistance remains a formidable challenge. The 78-kilodalton glucose-regulated protein (GRP78), a key stress-inducible endoplasmic reticulum (ER) chaperone, plays a crucial role in both cancer cell survival and stress adaptation. GRP78 is also upregulated during SARS-CoV-2 infection and acts as a critical host factor. Recently, we discovered cardiac glycosides (CGs) as novel suppressors of GRP78 stress induction through a high-throughput screen of clinically relevant compound libraries. This study aims to test the possibility that agents capable of blocking stress induction of GRP78 could dually suppress cancer and COVID-19. Results Here we report that oleandrin (OLN), is the most potent among the CGs in inhibiting acute stress induction of total GRP78, which also results in reduced cell surface and nuclear forms of GRP78 in stressed cells. The inhibition of stress induction of GRP78 is at the post-transcriptional level, independent of protein degradation and autophagy and may involve translational control as OLN blocks stress-induced loading of ribosomes onto GRP78 mRNAs. Moreover, the human Na+/K+-ATPase α3 isoform is critical for OLN suppression of GRP78 stress induction. OLN, in nanomolar range, enhances apoptosis, sensitizes colorectal cancer cells to chemotherapeutic agents, and reduces the viability of patient-derived colon cancer organoids. Likewise, OLN, suppresses GRP78 expression and impedes tumor growth in an orthotopic breast cancer xenograft model. Furthermore, OLN blocks infection by SARS-CoV-2 and its variants and enhances existing anti-viral therapies. Notably, GRP78 overexpression mitigates OLN-mediated cancer cell apoptotic onset and suppression of virus release. Conclusion Our findings validate GRP78 as a target of OLN anti-cancer and anti-viral activities. These proof-of-principle studies support further investigation of OLN as a readily accessible compound to dually combat cancer and COVID-19.

Introduction: Fibrolamellar carcinoma (FLC) displays upregulation of several oncogenes, including HER2, and multiple immune-suppressive mechanisms. We investigated the efficacy and safety of the pan-HER tyrosine kinase inhibitor neratinib as monotherapy (SUMMIT phase 2 basket study) or with immune checkpoint and/or mammalian target of rapamycin (mTOR) inhibitors (compassionate-use program) in patients with FLC. Methods: Patients received neratinib 240 mg/day orally in SUMMIT, or as doublet or triplet combinations with pembrolizumab 2 mg/kg intravenously every 3 weeks, nivolumab 240 mg intravenously every 2 weeks, everolimus 7.5 mg/day orally, or sunitinib 37.5 mg/day orally under compassionate use. The primary endpoint in SUMMIT was objective response rate; safety was a secondary endpoint. Results: Fifteen patients with FLC received neratinib monotherapy in SUMMIT. The objective response rate was 5% (95% confidence interval [CI]: 0–21.8) and the disease control rate was 13.3% (95% CI: 1.7–40.5). Upon progression, five had added immune checkpoint inhibitors with or without everolimus or sunitinib. Two additional patients received neratinib-based combinations outside of SUMMIT, for a total of 17 neratinib-treated patients. One patient who received neratinib plus pembrolizumab had a confirmed partial response, one treated with neratinib plus everolimus had stable disease lasting 6 months, and one who received neratinib plus pembrolizumab plus sunitinib had stable disease lasting 16 months. Grade 3/4 adverse events with neratinib monotherapy occurred in 10 (66.7%)/2 (13.3%) patients, respectively. Grade 3 adverse events with neratinib-based combinations were hyperglycemia (n = 1; neratinib plus pembrolizumab), hepatic failure, and anaphylaxis (n = 1 each, neratinib plus pembrolizumab plus everolimus). There were no grade 4 adverse events with combination therapy. Conclusion: In patients with FLC, single-agent neratinib had limited efficacy, but clinical benefit was observed with neratinib in combination with immunotherapy and/or mTOR-targeted agents.

Daniel Hsiang-Te Tsai,1,2 J Simon Bell,3 Shahab Abtahi,4 Brenda N Baak,5 Marloes T Bazelier,4 Ruth Brauer,6 Adrienne YL Chan,6– 9 Esther W Chan,9– 12 Haoqian Chen,13 Celine SL Chui,9,14,15 Sharon Cook,16 Stephen Crystal,16 Poonam Gandhi,13 Sirpa Hartikainen,17 Frederick K Ho,18 Shao-Ti Hsu,1 Jenni Ilomäki,3 Ju Hwan Kim,19 Olaf H Klungel,4 Marjaana Koponen,17 Wallis CY Lau,6,8,9 Kui Kai Lau,20,21 Terry YS Lum,22 Hao Luo,22 Kenneth KC Man,6,8,9 Jill P Pell,18 Soko Setoguchi,13,23 Shih-Chieh Shao,1,24 Chin-Yao Shen,1 Ju-Young Shin,19,25,26 Patrick C Souverein,4 Anna-Maija Tolppanen,17 Li Wei,6,9 Ian CK Wong,6,8,9,27 Edward Chia-Cheng Lai1 1School of Pharmacy, Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 2Centre for Neonatal and Paediatric Infection, St George’s University of London, London, UK; 3Centre for Medicine Use and Safety, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Melbourne, Australia; 4Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands; 5PHARMO Institute for Drug Outcomes Research, Utrecht, the Netherlands; 6Research Department of Practice and Policy, UCL School of Pharmacy, London, UK; 7Groningen Research Institute of Pharmacy, Unit of Pharmacotherapy, ‐Epidemiology and ‐Economics, University of Groningen, Groningen, the Netherlands; 8Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, Special Administrative Region, People’s Republic of China; 9Laboratory of Data Discovery for Health (D24H), Hong Kong Science Park, Hong Kong, Special Administrative Region, People’s Republic of China; 10Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, Special Administrative Region, People’s Republic of China; 11Department of Pharmacy, the University of Hong Kong-Shenzhen Hospital, Shenzhen, People’s Republic of China; 12The University of Hong Kong Shenzhen Institute of Research and Innovation, Shenzhen, People’s Republic of China; 13Center for Pharmacoepidemiology and Treatment Science (PETS), Institute for Health, Rutgers University, New Brunswick, NJ, USA; 14School of Nursing, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, Special Administrative Region, People’s Republic of China; 15School of Public Health, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, Special Administrative Region, People’s Republic of China; 16Center for Health Services Research, Rutgers University, New Brunswick, NJ, USA; 17Kuopio Research Centre of Geriatric Care and School of Pharmacy, University of Eastern Finland, Kuopio, Finland; 18School of Health and Wellbeing, University of Glasgow, Glasgow, UK; 19School of Pharmacy, Sungkyunkwan University, Suwon, South Korea; 20Division of Neurology, Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, Special Administrative Region, People’s Republic of China; 21State Key Laboratory of Brain and Cognitive Sciences, University of Hong Kong, Hong Kong, Special Administrative Region, People’s Republic of China; 22Department of Social Work and Social Administration, University of Hong Kong, Hong Kong, Special Administrative Region, People’s Republic of China; 23Department of Medicine, Rutgers Robert Wood Johnson Medical School and Pharmacoepidemiology and Treatments Science, Institute for Health, Rutgers University, New Brunswick, NJ, USA; 24Department of Pharmacy, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan; 25Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University, Seoul, South Korea; 26Department of Biohealth Regulatory Science, Sungkyunkwan University, Seoul, South Korea; 27Aston Pharmacy School, Aston University, Birmingham, UKCorrespondence: Edward Chia-Cheng Lai, School of Pharmacy and Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Email edward_lai@mail.ncku.edu.twPurpose: To describe and categorize detailed components of databases in the Neurological and Mental Health Global Epidemiology Network (NeuroGEN).Methods: An online 132-item questionnaire was sent to key researchers and data custodians of NeuroGEN in North America, Europe, Asia and Oceania. From the responses, we assessed data characteristics including population coverage, data follow-up, clinical information, validity of diagnoses, medication use and data latency. We also evaluated the possibility of conversion into a common data model (CDM) to implement a federated network approach. Moreover, we used radar charts to visualize the data capacity assessments, based on different perspectives.Results: The results indicated that the 15 databases covered approximately 320 million individuals, included in 7 nationwide claims databases from Australia, Finland, South Korea, Taiwan and the US, 6 population-based electronic health record databases from Hong Kong, Scotland, Taiwan, the Netherlands and the UK, and 2 biomedical databases from Taiwan and the UK.Conclusion: The 15 databases showed good potential for a federated network approach using a common data model. Our study provided publicly accessible information on these databases for those seeking to employ real-world data to facilitate current assessment and future development of treatments for neurological and mental disorders.Keywords: meta-data, data repository, Neurological and Mental Health Global Epidemiology Network, NeuroGEN

Teachers report a need for professional development in order to feel more confident and be more effective in providing writing instruction and intensive intervention to support middle school students. This study investigates the impacts of online practice-based professional development (PBPD) and coaching for self-regulated strategy development (SRSD) argumentative writing instruction on teachers’ implementation of the instruction. Using a pre-test–post-test design, the study also examined the effects of the SRSD instruction on students’ argumentative writing from source texts. Five middle school teachers from three regions across the United States participated in the PBPD and implemented SRSD with 55 middle school students with high-incidence disabilities or below-proficient writing skills. Following PBPD, teachers implemented the SRSD argumentative writing instruction with high adherence to dosage, fidelity of implementation, and quality. Student writing was scored for argumentative genre elements, holistic quality, total words written, and transition words. Results demonstrate that students improved on all measures. In addition, students reported feeling confident in their argumentative writing abilities. Teachers and students reported high social validity for the intervention. The benefits found in this research study provide a strong foundation supporting the application of comprehensive online PBPD with follow-up coaching to support teacher implementation of SRSD.

Abstract This phase I, dose-escalation trial evaluates the safety of combining interferon-gamma (IFN-γ) and nivolumab in patients with metastatic solid tumors. Twenty-six patients are treated in four cohorts assessing increasing doses of IFN-γ with nivolumab to evaluate the primary endpoint of safety and determine the recommended phase two dose (RP2D). Most common adverse events are low grade and associated with IFN-γ. Three dose limiting toxicities are reported at the highest dose cohorts. We report only one patient with any immune related adverse event (irAE). No irAEs ≥ grade 3 are observed and no patients require corticosteroids. The maximum tolerated dose of IFN-γ is 75 mcg/m2, however based on a composite of safety, clinical, and correlative factors the RP2D is 50 mcg/m2. Exploratory analyses of efficacy in the phase I cohorts demonstrate one patient with a complete response, and five have achieved stable disease. Pre-planned correlative assessments of circulating immune cells demonstrate intermediate monocytes with increased PD-L1 expression correlating with IFN-γ dose and treatment duration. Interestingly, post-hoc analysis shows that IFN-γ induction increases circulating chemokines and is associated with an observed paucity of irAEs, warranting further evaluation. ClinicalTrials.gov Trial Registration: NCT02614456.

During their quest for growth, adaptation, and survival, cancer cells create a favorable environment through the manipulation of normal cellular mechanisms. They increase anabolic processes, including protein synthesis, to facilitate uncontrolled proliferation and deplete the tumor microenvironment of resources. As a dynamic adaptation to the self-imposed oncogenic stress, cancer cells promptly hijack translational control to alter gene expression. Rewiring the cellular proteome shifts the phenotypic balance between growth and adaptation to promote therapeutic resistance and cancer cell survival. The integrated stress response (ISR) is a key translational program activated by oncogenic stress that is utilized to fine-tune protein synthesis and adjust to environmental barriers. Here, we focus on the role of ISR signaling for driving cancer progression. We highlight mechanisms of regulation for distinct mRNA translation downstream of the ISR, expand on oncogenic signaling utilizing the ISR in response to environmental stresses, and pinpoint the impact this has for cancer cell plasticity during resistance to therapy. There is an ongoing need for innovative drug targets in cancer treatment, and modulating ISR activity may provide a unique avenue for clinical benefit.

The primary aim of this study is to characterize long-term quality of life (QOL) in patients with esophageal and gastroesophageal junction (EGEJ) cancers who underwent curative intent treatment. EGEJ survivors were recruited to participate in a one-time cross-sectional survey study using validated questionnaires assessing QOL. Chart review was conducted for patient demographics and clinical characteristics. Spearman correlation coefficients, Wilcoxon signed-rank test, and Fisher's exact test were used to assess relationships between patient characteristics and long-term outcomes. QOL was relatively high in this sample, as evidenced by high median scores on the functional scales and low median scores in the symptom domains of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30, with an overall median global health score of 75.0 (range 66.7-83.3). Patients using opiates at the time of survey reported lower role functioning ( P = .004), social functioning ( P = .052), and overall global health ( P = .041). Younger patients had significantly higher rates of reflux ( P = .019), odynophagia ( P = .045), choking ( P = .005), and cough ( P = .007). Patients using opiates or of younger age had lower QOL and higher symptoms in this cohort of long-term EGEJ survivors.

Introduction Although treatment of obstructive sleep apnoea (OSA) using continuous positive airway pressure (CPAP) reduces blood pressure (BP), adherence to CPAP is often suboptimal. A mandibular advancement device (MAD) is a guideline-endorsed alternative therapy for OSA. Still, there is limited evidence on the relative efficacy between MAD and CPAP on BP reduction. We evaluate whether treatment of moderate-to-severe OSA using MAD can improve BP and other health-related outcomes compared with CPAP.Methods and analysis This is a randomised, controlled, non-inferiority trial conducted. We will recruit 220 Asians with a history of hypertension and high cardiovascular risk for an overnight polysomnography screening. Those with moderate-to-severe OSA (apnoea–hypopnoea index ≥15 events/hour) will be randomised to treatment with either MAD or CPAP in a 1:1 ratio. Stratified by age (60 vs

Abstract Background The Pancreatic Cancer Action Network (PanCAN) Patient Registry is an online, pancreatic cancer‐specific, global registry enabling patients to self‐report sociodemographics, disease/management characteristics, and patient‐reported outcomes (PROs). We sought to describe the creation, user experience, and research potential of the PanCAN Registry. Methods We obtained data to describe (1) the creation of the Registry (questionnaire development, marketing efforts, and regulatory considerations); (2) the user experience (user characteristics and interactions with the registry following inception); and (3) the research potential of the registry (comparing PROs and treatment patterns by age [±65 years] and treatment site [community or academic] for users with de novo metastatic disease). Results The Registry was conceived as part of PanCAN’s strategic plan for a personalized therapy initiative. PanCAN staff and disease expert consultants developed questionnaires hosted on an electronic PRO platform. Users had the option to include their data in research efforts, and the Registry platform received institutional review board approval. From 7/2015 to 12/2020, 2187 patients visited the registry and 1697 (77.6%) completed at least one survey (median age = 64 years [range: 24–90], 47.9% women, 88.7% White, 34.0% metastatic disease). Among patients with metastatic disease (N = 567), 46.0% were ≥65 years old and 67.5% received treatment at community sites. Patients ≥65 years reported feeling less hopeful about the treatment plan (12.4% vs. 24.3%, p = 0.003), and patients treated at community sites reported more frequent treatment breaks of >2 weeks (58.2% vs. 28.1%, p

Purpose: For patients with high-risk bladder cancer (pT3+ or N+), local regional failure remains a challenge after chemotherapy and cystectomy. An ongoing prospective phase 2 trial (NCT01954173) is examining the role of postoperative photon radiation therapy for high-risk patients using volumetric modulated arc therapy. Proton beam therapy (PBT) may be beneficial in this setting to reduce hematologic toxicity. We evaluated for dosimetric relationships with pelvic bone marrow (PBM) and changes in hematologic counts before and after pelvic radiation therapy and explored the potential of PBT treatment plans to achieve reductions in PBM dose. Materials and Methods: All enrolled patients were retrospectively analyzed after pelvic radiation per protocol with 50.4 to 55.8 Gy in 28 to 31 fractions. Comparative PBT plans were generated using pencil-beam scanning and a 3-beam multifield optimization technique. Changes in hematologic nadirs were assessed using paired t test. Correlation of mean nadirs and relative PBM dose levels were assessed using the Pearson correlation coefficient (CC). Results: Eighteen patients with a median age of 70 were analyzed. Mean cell count values after radiation therapy decreased compared with preradiation therapy values for white blood cells (WBCs), absolute neutrophil count (ANC), absolute lymphocyte count (all P < .001), and platelets (P = .03). Increased mean PBM dose was associated with lower nadirs in WBC (Pearson CC − 0.593, P = .02), ANC (Pearson CC –0.597, P = .02), and hemoglobin (Pearson CC –0.506, P = .046), whereas the PBM V30 to V40 correlated with lower WBC (Pearson CC –0.512 to –0.618, P < .05), and V20 to V30 correlated with lower ANC (Pearson CC –0.569 to –0.598, P < .04). Comparative proton therapy plans decreased the mean PBM dose from 26.5 Gy to 16.1 Gy (P < .001) and had significant reductions in the volume of PBM receiving doses from 5 to 40 Gy (P < .001). Conclusion: Increased PBM mean dose and V20 to V40 were associated with lower hematologic nadirs. PBT plans reduced PBM dose and may be a valuable strategy to reduce the risk of hematologic toxicity in these patients.

Western pine beetle (Dendroctonus brevicomis LeConte) is a major cause of ponderosa pine (Pinus ponderosa Dougl. ex. Laws.) mortality in western North America. Twenty-first century epidemics are among the largest in history and have affected hundreds of thousands of hectares. We synthesize literature on the chemical ecology of western pine beetle and on efforts to exploit our understanding of the western pine beetle-ponderosa pine system to reduce host tree losses. This literature dates back to the early 20th century and focuses on populations in California and Oregon, U.S., where western pine beetle exerts its largest impacts. Research in the 1960s–1970s yielded an effective semiochemical attractant (exo-brevicomin, frontalin, and myrcene) that helped inform understanding of the biology, ecology, and management of this species. Later, research focused on isolation and identification of semiochemical repellents. To date, Verbenone Plus (acetophenone, (E)-2-hexen-1-ol + (Z)-2-hexen-1-ol, and verbenone) is the only semiochemical repellent demonstrated effective for protecting ponderosa pines from mortality attributed to western pine beetle in multiple studies in Canada and the U.S.

Abstract Purpose To evaluate the diagnostic accuracy of SPECT/CT arthrography in patients with suspected aseptic prosthesis loosening following hip and knee arthroplasty. Methods A retrospective review of 63 SPECT/CT arthrogram studies (36 knees and 27 hips) between February 1, 2013, and July 1, 2018, was conducted. All patients underwent clinical and radiologic evaluation as part of their assessment for persistent pain following hip and knee arthroplasty. The detection of tracer activity along the bone-prosthetic interface on SPECT/CT suggests aseptic loosening. Operative assessment as well as clinical/radiologic follow-up at a minimum of 1 year was used as the reference standard. Results The sensitivity and specificity of SPECT/CT for detection of aseptic loosening was 6/7 (86%) and 55/56 (98%), respectively. This gives a positive predictive value (PPV) of 6/7 (86%), a negative predictive value (NPV) of 55/56 (98%), and a diagnostic accuracy of 61/63 (97%). Conclusion SPECT/CT arthrography has a high diagnostic accuracy (97%) in the evaluation of loosening of both hip and knee arthroplasties in patients with persistent post-procedural pain.

Background: Following a prostate cancer (PC) diagnosis, treatment-related symptoms may result in diminished quality of life (QoL). Improved diet and increased exercise may improve QoL in men with PC. Methods: We conducted a 4-arm pilot randomized trial to assess feasibility and acceptability of a 3-month web-based diet and exercise intervention, among men (>18 years of age) with PC (reported elsewhere). The purpose of this study is to describe the change in QoL measured by surveys (eg, QLQ-C30, PROMIS Fatigue) at enrollment and following the intervention. Men were randomized 1:1:1:1 to increasing levels of web-based behavioral support: Level 1: website; Level 2: Level 1 plus personalized diet and exercise prescription; Level 3: Levels 1-2 plus Fitbit and text messages; Level 4: Levels 1-3 plus 2 30-minute coaching calls. T -tests were used to compare pre-post change in mean QoL scores between each Level and Level 1. Results: Two hundred and two men consented and were randomized (n = 49, 51, 50, 52 for Levels 1-4, respectively). Men were predominantly white (93%), with a median age of 70 years (Intra-quartile Range [IQR]: 65,75) and 3 years (IQR: 1,9) post primary treatment for mostly localized disease (74% with T1-2). There were no meaningful changes in QoL, but there were notable trends. Level 3 participants had small improvements in QLQ-C30 Global Health (5.46; 95% CI: −0.02, 10.95) compared to Level 1. In contrast, Level 2 participants trended toward decreasing Global QoL (−2.31, 95% CI: −8.05, 3.42), which may reflect declines in function (eg, Cognitive: −6.94, 95% CI: −13.76, −0.13) and higher symptom burden (eg, Diarrhea: 4.63, 95% CI: −1.48, 10.74). Conclusions: This short, web-based intervention did not appear to have an impact on PC survivors’ QoL. Most men were several years past treatment for localized disease; the potential for this approach to reduce symptoms and improve QoL in men who have worse health may still be warranted.

Abstract Background/Objective: Prior to the COVID-19 pandemic, our research group initiated a pediatric practice-based randomized trial for the treatment of childhood obesity in rural communities. Approximately 6 weeks into the originally planned 10-week enrollment period, the trial was forced to pause all study activity due to the COVID-19 pandemic. This pause necessitated a substantial revision in recruitment, enrollment, and other study methods in order to complete the trial using virtual procedures. This descriptive paper outlines methods used to recruit, enroll, and manage clinical trial participants with technology to obtain informed consent, obtain height and weight measurements by video, and maintain participant engagement throughout the duration of the trial. Methods: The study team reviewed the IRB records, protocol team meeting minutes and records, and surveyed the site teams to document the impact of the COVID-19 shift to virtual procedures on the study. The IRB approved study changes allowed for flexibility between clinical sites given variations in site resources, which was key to success of the implementation. Results: All study sites faced a variety of logistical challenges unique to their location yet successfully recruited the required number of patients for the trial. Ultimately, virtual procedures enhanced our ability to establish relationships with participants who were previously beyond our reach, but presented several challenges and required additional resources. Conclusion: Lessons learned from this study can assist other study groups in navigating challenges, especially when recruiting and implementing studies with rural and underserved populations or during challenging events like the pandemic.

Summary: The cap-binding protein eukaryotic initiation factor 4E (eIF4E) promotes translation of mRNAs associated with proliferation and survival and is an attractive target for cancer therapeutics. Here, we used Eif4e germline and conditional knockout models to assess the impact of reduced Eif4e gene dosage on B-cell leukemogenesis compared to effects on normal pre-B and mature B-cell function. Using a BCR-ABL-driven pre-B-cell leukemia model, we find that loss of one allele of Eif4e impairs transformation and reduces fitness in competition assays in vitro and in vivo. In contrast, reduced Eif4e gene dosage had no significant effect on development of pre-B and mature B cells or on survival or proliferation of non-transformed B lineage cells. These results demonstrate that inhibition of eIF4E could be a new therapeutic tool for pre-B-cell leukemia while preserving development and function of normal B cells.

Caregiver coaching in early intervention (EI) can lead to positive outcomes for young children with delays and disabilities and their families. In response to the COVID-19 pandemic, some EI providers reported coaching caregivers more frequently. However, EI providers' use of caregiver coaching is inconsistent, and there is a need for more effective personnel preparation in this area. In this qualitative study we explored EI providers' beliefs about what factors contributed to their increased use of caregiver coaching during the pandemic. Participants reported two areas that contributed to their use of caregiver coaching: service delivery (e.g., telepractice, role changes, and caregiver expectations for services) and learning opportunities (e.g., personal growth and reflection, educational resources, and collaboration). Implications include the need for policies that allow and promote access to telepractice services and the importance of using a variety of adult learning strategies when delivering in-service and pre-service preparation related to caregiver coaching.

Temsavir, a compound that inhibits HIV entry by binding envelope (Env), is currently in clinical development. Here, Lai et al. identify a more than 10-fold improved compound and, using lattice engineering, obtain crystal structures that give insights into improved inhibition between small molecules and Env.

The Covid-19 pandemic caused a number of instructors to move to emergency remote teaching. In the process, many instructors worried about being able to replicate the instruction of their face-to-face courses. Instructors can use strategies used by fans to promote engagement with course material, build community, and deploy technology in ways that promote their learning goals and enhance learning in online courses.

A severe outbreak of wildfire across the US Pacific Coast during August 2020 led to persistent fire activity through the end of summer. In late September, Fire Weather Outlooks predicted higher than usual fire activity into the winter in parts of California, with concomitant elevated fire danger in the Southeastern US. To help inform the regional and national allocation of firefighting personnel and equipment, we developed visualizations of resource use during recent late season, high-demand analogs. Our visualizations provided an overview of the crew, engine, dozer, aerial resource, and incident management team usage by geographic area. While these visualizations afforded information that managers needed to support their decisions regarding resource allocation, they also revealed a potentially significant gap between resource demand and late-season availability that is only likely to increase over time due to lengthening fire seasons. This gap highlights the need for the increased assessment of suppression resource acquisition and allocation systems that, to date, have been poorly studied.

Eye injuries due to corneal abrasions, chemical spills, penetrating wounds, and microbial infections cause corneal scarring and opacification that result in impaired vision or blindness. However, presently available eye drop formulations of anti-inflammatory and antibiotic drugs are not effective due to their rapid clearance from the ocular surface or due to drug-related side effects such as cataract formation or increased intraocular pressure. In this article, we presented the development of a dextran sulfate-based polymer wafer (DS-wafer) for the effective modulation of inflammation and fibrosis and demonstrated its efficacy in two corneal injury models: corneal abrasion mouse model and alkali induced ocular burn mouse model. The DS-wafers were fabricated by the electrospinning method. We assessed the efficacy of the DS-wafer by light microscopy, qPCR, confocal fluorescence imaging, and histopathological analysis. These studies demonstrated that the DS-wafer treatment is significantly effective in modulating corneal inflammation and fibrosis and inhibited corneal scarring and opacification compared to the unsulfated dextran-wafer treated and untreated corneas. Furthermore, these studies have demonstrated the efficacy of dextran sulfate as an anti-inflammatory and antifibrotic polymer therapeutic.

Nitric oxide (NO) is a highly reactive gas molecule, exhibiting antimicrobial properties. Because of its reactive nature, it is challenging to store and deliver NO efficiently as a therapeutic agent. The objective of this study was to develop NO-releasing polymeric fibers (NO-fibers), as an effective delivery platform for NO. NO-fibers were fabricated with biopolymer solutions of polyvinyl pyrrolidone (PVP) and ethylcellulose (EC), and derivatives of N-diazeniumdiolate (NONOate) as NO donor molecules, using an electrospinning system. We evaluated in vitro NO release kinetics, along with antimicrobial effects and cytotoxicity in microorganisms and human cell culture models. We also studied the long-term stability of NONOates in NO-fibers over 12 months. We demonstrated that the NO-fibers could release NO over 24 h, and showed inhibition of the growth of Pseudomonas aeruginosa (P. aeruginosa) and methicillin-resistant Staphylococcus aureus (MRSA), without causing cytotoxicity in human cells. NO-fibers were able to store NONOates for over 12 months at room temperature. This study presents the development of NO-fibers, and the feasibility of NO-fibers to efficiently store and deliver NO, which can be further developed as a bandage.

Caregiver coaching is a mutually beneficial practice used by early interventionists (EIs) to build caregivers' confidence and capacities to support their children, which, in turn, leads to EIs gaining knowledge from families and developing new skills (e.g., Douglas et al., 2020; Meadan et al., 2020). Coaches (i.e., EIs) help others (i.e., caregivers) learn to (a) reflect on their actions and (b) create plans to improve their actions (Rush & Shelden, 2020b). EIs who use a coaching framework primarily interact with caregivers, while the caregivers' role is to work directly with their children. This service delivery model differs from traditional services, in which the primary interactions are between EIs and children, with caregivers mainly assuming the role of observer (Campbell & Sawyer, 2007). In this article, we provide guidance for adopting a coaching framework and cover the following topics: (a) rationale for using a caregiver coaching framework; (b) what coaching frameworks exist; (c) considerations when choosing a framework; and (d) how to individualize coaching for families.

Across the globe, aircraft that apply water and suppressants during active wildfires play key roles in wildfire suppression, and these suppression resources can be highly effective. In the United States, US Department of Agriculture Forest Service (USFS) aircraft account for a substantial portion of firefighting expense and higher fatality rates compared to ground resources. Existing risk management practices that are fundamental to aviation safety (e.g., routinely asking, “Is this flight necessary?”) may not be appropriately scaled from a risk management perspective to ensure that the tactical use of aircraft is in clear alignment with a wildfire’s incident strategy and with broader agency and interagency fire management goals and objectives. To improve strategic risk management of aviation assets in wildfire suppression, we present a framework demonstrating a risk-informed strategic aviation decision support system, the Aviation Use Summary (AUS). This tool utilizes aircraft event tracking data, existing geospatial datasets, and emerging analytics to summarize incident-scale aircraft use and guide decision makers through a strategic risk management process. This information has the potential to enrich the decision space of the decision maker and supports programmatic transparency, enhanced learning, and a broader level of accountability.

Because of their value as a socially communicative cue, researchers have strived to understand how the gaze of other people influences a variety of cognitive processes. Recent work in social attention suggests that the use of images of people in laboratory studies, as a substitute for real people, may not effectively test socially communicative aspects of eye gaze. As attention affects many other cognitive processes, it is likely that social attention between real individuals could also affect other cognitive processes, such as memory. However, from previous work alone, it is unclear whether, and if so how, socially communicative eye gaze affects memory. The present studies test the assumption that socially communicative aspects of eye gaze may impact memory by manipulating the eye gaze of a live speaker in the context of a traditional recognition paradigm used frequently in the laboratory. A female (Experiment 1) or male (Experiment 2) investigator read words aloud and varied whether eye contact was, or was not, made with a participant. With both female and male investigators, eye contact improved word recognition only for female participants and hindered word recognition in male participants. When a female investigator prolonged their eye contact (Experiment 3) to provide a longer opportunity to both observe and process the investigator’s eye gaze, the results replicated the findings from Experiments 1 and 2. The findings from Experiments 1–3 suggest that females interpret and use the investigator’s eye gaze differently than males. When key aspects from the previous experiments were replicated in a noncommunicative situation (i.e., when a video of a speaker is used instead of a live speaker; Experiment 4), the memory effects observed previously in response to eye gaze were eliminated. Together, these studies suggest that it is the socially communicative aspects of eye gaze from a real person that influence memory. The findings reveal the importance of using social cues that are communicative in nature (e.g., real people) when studying the relationship between social attention and memory.

Background: Patients with esophageal cancer (EC) have high rates of malnutrition due to tumor location and treatment-related toxicity. Various strategies are used to improve nutritional status in patients with EC including oral and enteral support. Methods: We conducted a retrospective analysis to determine the impact of malnutrition and prophylactic feeding jejunostomy tube (FJT) placement on toxicity and outcomes in patients with localized EC who were treated with neoadjuvant chemoradiation therapy (nCRT) followed by esophagectomy. Results: We identified 125 patients who were treated with nCRT between 2002 and 2014. Weight loss and hypoalbuminemia occurred frequently during nCRT and were associated with multiple adverse toxicity outcomes including hematologic toxicity, nonhematologic toxicity, grade ≥3 toxicity, and hospitalizations. After adjusting for relevant covariates including the specific nCRT chemotherapy regimen received and the onset of toxicity, there were no significant associations between hypoalbuminemia, weight loss, or FJT placement and relapse-free survival (RFS) or overall survival (OS). FJT placement was associated with less weight loss during nCRT (p = 0.003) but was not associated with reduced toxicity or improved survival. Conclusions: Weight and albumin loss during nCRT for EC are important factors relating to treatment toxicity but not RFS or OS. While pretreatment FJT placement may reduce weight loss, it may not impact treatment tolerance or survival.

Research Highlights: Our results suggest that weather is a primary driver of resource orders over the course of extended attack efforts on large fires. Incident Management Teams (IMTs) synthesize information about weather, fuels, and order resources based on expected fire growth rather than simply reacting to observed fire growth. Background and Objectives: Weather conditions are a well-known determinant of fire behavior and are likely to become more erratic under climate change. Yet, there is little empirical evidence demonstrating how IMTs respond to observed or expected weather conditions. An understanding of weather-driven resource ordering patterns may aid in resource prepositioning as well as forecasting suppression costs. Our primary objective is to understand how changing weather conditions influence resource ordering patterns. Our secondary objective is to test how an additional risk factor, evacuation, as well as a constructed risk metric combining fire growth and evacuation, influences resource ordering. Materials and Methods: We compile a novel dataset on over 1100 wildfires in the western US from 2007−2013, integrating data on resource requests, detailed weather conditions, fuel and landscape characteristics, values at risk, fire behavior, and IMT expectations about future fire behavior and values at risk. We develop a two-step regression framework to investigate the extent to which IMTs respond to realized or expected weather-driven fire behavior and risks. Results: We find that IMTs’ expectations about future fire growth are influenced by observed weather and that these expectations influence resource ordering patterns. IMTs order nearly twice as many resources when weather conditions are expected to drive growth events in the near future. However, we find little evidence that our other risk metrics influence resource ordering behavior (all else being equal). Conclusion: Our analysis shows that incident management teams are generally forward-looking and respond to expected rather than recently observed weather-driven fire behavior. These results may have important implications for forecasting resource needs and costs in a changing climate.

Wildland fire occurrence is highly variable in time and space, and in the United States where total area burned can vary substantially, acquiring resources (firefighters, engines, aircraft, etc.) to respond to fire demand is an important consideration. To determine the composition and scale of this set of suppression resources managers may utilize data produced by past supply and demand information. The key challenge with this approach is that there is currently no clear system of record to track suppression resource supply and demand, and there are potential pitfalls within existing systems that may provide misleading information regarding the true levels of resource scarcity. In this manuscript, we investigate the issue of resource scarcity by examining two key resources that operations personnel have identified as both high value and scarce: type 1 firefighting crews and large airtankers. We examine data from the Resource Ordering and Status System and analyze the level of resource scarcity indicated by these data over the 2014−2018 fire seasons. We focus on data metrics with potential utility for managers responsible for annual national-level decisions regarding crew and airtanker acquisition; some of these metrics are already used to inform such decisions. We examine the limitations of each metric and suggest new metrics that could more accurately reflect true resource use and scarcity. Such metrics could lead to a substantially improved decision-making process.