The COVID-19 High-Performance Computing Consortium.

In March of 2020, recognizing the potential of High Performance Computing (HPC) to accelerate understanding and the pace of scientific discovery in the fight to stop COVID-19, the HPC community assembled the largest collection of worldwide HPC resources to enable COVID-19 researchers worldwide to advance their critical efforts. Amazingly, the COVID-19 HPC Consortium was formed within one week through the joint effort of the Office of Science and Technology Policy (OSTP), the U.S. Department of Energy (DOE), the National Science Foundation (NSF), and IBM to create a unique public-private partnership between government, industry, and academic leaders. This article is the Consortium's story-how the Consortium was created, its founding members, what it provides, how it works, and its accomplishments. We will reflect on the lessons learned from the creation and operation of the Consortium and describe how the features of the Consortium could be sustained as a National Strategic Computing Reserve to ensure the nation is prepared for future crises.

Evaluating Emergency Department Utilization for Mobile Mental Health Patients: A Correlational Retrospective Analysis.

BACKGROUND: Patients who have barriers to attending traditional mental health clinics are at risk for psychiatric decompensation, which can lead to inappropriate utilization of emergency departments (EDs). Mobile health clinics have the potential to reduce avoidable ED visits by providing easily accessible care. AIMS: To determine whether psychiatric patients have a significant reduction in ED visits after admission to the mobile mental health clinic (MMHC). METHOD: This study is a replication of a pilot study on the first 43 patients admitted to the MMHC that was conducted soon after the opening. Results of that study were promising. In the current study, health records from a sample of 265 patients from the MMHC were reviewed retrospectively to determine the number of ED visits post admission to the MMHC. ED visits were examined 8 months prior to admission to the MMHC and 8 months after. Descriptive statistics and paired t-tests were used to analyze demographics and determine differences in ED visits pre- and post admission to the MMHC. RESULTS: Findings demonstrated that patients admitted to the MMHC had a significant reduction (p < .05) in ED utilization. There was also a decrease in mean ED visits in patients who received combined treatment, which included medication management and counseling. CONCLUSION: The MMHC is an effective initiative to reduce ED overutilization, thereby decreasing Medicaid costs. Psychiatric care provided directly in the home can promote health and prevent destabilization.

Effect of the LIVESTRONG at the YMCA exercise program on physical activity, fitness, quality of life, and fatigue in cancer survivors.

BACKGROUND: Physical activity (PA) has been linked to a lower risk of developing and dying of cancer, yet many cancer survivors do not exercise. In the current study, the authors evaluated the impact of the LIVESTRONG at the YMCA exercise program, available at Young Men's Christian Associations (YMCAs) across the United States, on PA, fitness, quality of life, fatigue, body composition, serum biomarkers, and program safety in cancer survivors. METHODS: Cancer survivors were recruited through the Yale Cancer Center and the Dana-Farber Cancer Institute and randomized to a 12-week, twice-weekly LIVESTRONG at the YMCA exercise program at YMCAs in Connecticut or Massachusetts or to a control group. Questionnaires, dual-energy x-ray absorptiometry scans, 6-minute walk tests (6MWTs), and a fasting blood draw were completed at baseline and at 12 weeks. Intervention effects were evaluated using mixed model repeated measures analysis, with changes at 12 weeks in PA and 6MWT as the primary endpoints. RESULTS: A total of 186 participants were randomized (95 to the exercise group and 91 to the control group). The majority of patients were diagnosed with AJCC stage I to II cancer and 53% had breast cancer. Participants randomized to the LIVESTRONG at the YMCA program experienced increases in PA (71% exercising at ≥ 150 minutes/week vs 26% of controls; P<.05) and improvements in the 6MWT (group difference: 28.9 meters [95% confidence interval, 0.3-49.0; P = .004]) and quality of life (group difference: 2.6 [95% confidence interval, 0.1-5.0; P = .04]). No adverse events were reported. CONCLUSIONS: The LIVESTRONG at the YMCA exercise program has the potential to impact thousands of survivors across the YMCA network and could lead to improvements in disease and psychosocial outcomes in the growing population of cancer survivors. Cancer 2017;123:1249-1258. © 2016 American Cancer Society.

Loop flexibility in human telomeric quadruplex small-molecule complexes.

Quadruplex nucleic acids can be formed at the ends of eukaryotic chromosomes. Their formation and stabilisation by appropriate small molecules can be used as a means of inhibiting the telomere maintenance functions of telomerase in human cancer cells. The crystal structures have been determined for a number of complexes between these small molecules and human telomeric DNA and RNA quadruplexes. The detailed structural characteristics of these complexes have been surveyed here and the variations in conformation for the TTA and UUA loops have been explored. Loop conformations have been classified in terms of a number of discrete types and their distribution among the crystal structures. Sugar conformation and backbone angles have also been examined and trends highlighted. One particular loop class has been found to be most prevalent. Implications for in particular, rational drug design, are discussed.

Randomized trial of a physical activity intervention in women with metastatic breast cancer.

BACKGROUND: Exercise interventions improve fitness, functional capacity, and quality of life in patients with early-stage breast cancer, but to the authors' knowledge there are few data regarding the feasibility or potential benefits of exercise in women with metastatic breast cancer. METHODS: Individuals with metastatic breast cancer were randomized 1:1 to a 16-week moderate-intensity exercise intervention or wait-list control group. Intervention goals included 150 minutes of moderate-intensity aerobic exercise per week. The baseline and 16-week evaluations included a modified Bruce Ramp treadmill test, 7-day Physical Activity Recall interview, and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ C-30) questionnaire. RESULTS: A total of 101 participants were randomized (48 to the intervention group and 53 to the control group). The median age of the participants was 49 years, the median time since the diagnosis of metastatic breast cancer was 1.1 years, and approximately 42% of participants were undergoing chemotherapy at the time of enrollment. Study attrition was higher in the intervention arm (14 participants vs 8 participants; P = .15). Women randomized to the exercise intervention experienced a nonsignificant increase with regard to minutes of weekly exercise (62.4 minutes vs 46.0 minutes; P = .17) and physical functioning (EORTC QLQ C30: 4.79 vs 0.93 [P = .23] and Bruce Ramp Treadmill test: 0.61 minutes vs 0.37 minutes [P = .35]) compared with control participants. CONCLUSIONS: Participation in an exercise intervention did not appear to result in significant improvements in physical functioning in a heterogeneous group of women living with advanced breast cancer. Given the significant benefits of exercise in women with early-stage breast cancer, more work is needed to explore alternative interventions to determine whether exercise could help women with metastatic disease live more fully with fewer symptoms from disease and treatment.

The MIntAct project--IntAct as a common curation platform for 11 molecular interaction databases.

IntAct (freely available at http://www.ebi.ac.uk/intact) is an open-source, open data molecular interaction database populated by data either curated from the literature or from direct data depositions. IntAct has developed a sophisticated web-based curation tool, capable of supporting both IMEx- and MIMIx-level curation. This tool is now utilized by multiple additional curation teams, all of whom annotate data directly into the IntAct database. Members of the IntAct team supply appropriate levels of training, perform quality control on entries and take responsibility for long-term data maintenance. Recently, the MINT and IntAct databases decided to merge their separate efforts to make optimal use of limited developer resources and maximize the curation output. All data manually curated by the MINT curators have been moved into the IntAct database at EMBL-EBI and are merged with the existing IntAct dataset. Both IntAct and MINT are active contributors to the IMEx consortium (http://www.imexconsortium.org).

Structure-dependent binding of arylimidamides to the DNA minor groove.

Heterocyclic diamidines are strong DNA minor-groove binders and have excellent antiparasitic activity. To extend the biological activity of these compounds, a series of arylimidamides (AIAs) analogues, which have better uptake properties in Leishmania and Trypanosoma cruizi than diamidines, was prepared. The binding of the AIAs to DNA was investigated by Tm , fluorescence displacement titration, circular dichroism, DNase I footprinting, biosensor surface plasmon resonance, X-ray crystallography and molecular modeling. These compounds form 1:1 complexes with AT sequences in the DNA minor groove, and the binding strength varies with substituent size, charge and polarity. These substituent-dependent structure and properties provide a SAR that can be used to estimate K values for binding to DNA in this series. The structural results and molecular modeling studies provide an explanation for the differences in binding affinities for AIAs.

Advances in Adherence Reporting of Resistance Training in a Clinical Trial during Adjuvant Chemotherapy for Colon Cancer.

PURPOSE: Detailed reporting of individually tailored exercise prescriptions (ExR x ) used in clinical trials is essential to describe feasibility, tolerability, and efficacy of the intervention and to inform translation to clinical care. This article outlines the methodology used to develop a resistance training (RT) ExR x for people with colon cancer receiving chemotherapy and reports adherence to the randomized controlled trial testing the impact of RT on relative dose intensity of chemotherapy and patient-reported toxicities. METHODS: Participants randomized to the exercise arm ( n = 90) were included. To promote muscle hypertrophy, the ExR x was twice-weekly, moderate to heavy loads (65%-85% one-repetition maximum), high sets (3-5), and intermediate repetitions (6-10) of five large multijoint movements with adjustable dumbbells. Attendance (achieved frequency) and adherence (achieved volume) were calculated. Group-based trajectory modeling was used to identify clusters of individuals with similar adherence patterns and compared baseline characteristics across adherence groups. RESULTS: The median attendance was 69.1%. Adherence was 60.6% but higher for those receiving 3 versus 6 months of chemotherapy (80.4 vs 47.4%; P < 0.05 ). Participants engaged in a median of 1.4 d of RT each week, lifting 62% of the one-repetition maximum load, for 3.0 sets and 7.5 repetitions per set. Three distinct adherence groups were identified: 13% "nonstarter," 37% "tapered off," and 50% "consistent exercisers." Females were more likely to be in the nonstarter and tapered-off groups. CONCLUSIONS: This article outlines suggested methods for reporting ExR x of RT in oncology clinical trials and provides insight into the tolerance of ExR x of RT during chemotherapy treatment for colon cancer. These findings aim to foster constructive dialogue and offer a premise for designing future research to elucidate the benefits of exercise during chemotherapy.

Thinking beyond 'outbreak': The contentious politics of the science of early warning and overdose epidemic.

This Commentary on the article, "Early warnings and slow deaths: A sociology of outbreak and overdose" by Tim Rhodes and Kari Lancaster, reflects upon rapid response reflexes invoked in societal responses to 'emergency,' 'epidemic,' 'crisis,' and disasters, all of  which require immediate action with no time to think. Epidemiology has given us machines for producing 'fact' about the 'opioid overdose epidemic' that promote the forgetting of the ways in which apparatuses of social control enact the production of facticity. While facts are supposed to be epistemologically reliable and worthy, the work of Rhodes and Lancaster invites us to de-subscribe to these beliefs and re-member our way towards developing slower, more thorough, and more thoughtful ways of seeing a wider array of "indicators, signals, evidence, and narratives of an ecological kind" (Rhodes and Lancaster 2023; this issue). This Commentary focuses on the practices of 'early warning' in social, political, and economic context.

Capturing heart valve development with Gene Ontology.

Introduction: The normal development of all heart valves requires highly coordinated signaling pathways and downstream mediators. While genomic variants can be responsible for congenital valve disease, environmental factors can also play a role. Later in life valve calcification is a leading cause of aortic valve stenosis, a progressive disease that may lead to heart failure. Current research into the causes of both congenital valve diseases and valve calcification is using a variety of high-throughput methodologies, including transcriptomics, proteomics and genomics. High quality genetic data from biological knowledge bases are essential to facilitate analyses and interpretation of these high-throughput datasets. The Gene Ontology (GO, http://geneontology.org/) is a major bioinformatics resource used to interpret these datasets, as it provides structured, computable knowledge describing the role of gene products across all organisms. The UCL Functional Gene Annotation team focuses on GO annotation of human gene products. Having identified that the GO annotations included in transcriptomic, proteomic and genomic data did not provide sufficient descriptive information about heart valve development, we initiated a focused project to address this issue. Methods: This project prioritized 138 proteins for GO annotation, which led to the curation of 100 peer-reviewed articles and the creation of 400 heart valve development-relevant GO annotations. Results: While the focus of this project was heart valve development, around 600 of the 1000 annotations created described the broader cellular role of these proteins, including those describing aortic valve morphogenesis, BMP signaling and endocardial cushion development. Our functional enrichment analysis of the 28 proteins known to have a role in bicuspid aortic valve disease confirmed that this annotation project has led to an improved interpretation of a heart valve genetic dataset. Discussion: To address the needs of the heart valve research community this project has provided GO annotations to describe the specific roles of key proteins involved in heart valve development. The breadth of GO annotations created by this project will benefit many of those seeking to interpret a wide range of cardiovascular genomic, transcriptomic, proteomic and metabolomic datasets.

Impact of a telephone-based physical activity intervention upon exercise behaviors and fitness in cancer survivors enrolled in a cooperative group setting.

Observational studies demonstrate an association between physical activity and improved outcomes in breast and colon cancer survivors. To test these observations with a large, randomized clinical trial, an intervention that significantly impacts physical activity in these patients is needed. The Active After Cancer Trial (AACT) was a multicenter pilot study evaluating the feasibility of a telephone-based exercise intervention in a cooperative group setting. Sedentary (engaging in <60 min of recreational activity/week) breast and colorectal cancer survivors were randomized to a telephone-based exercise intervention or usual care control group. The intervention was delivered through the University of California at San Diego; participants received ten phone calls over the course of the 16-week intervention. All participants underwent assessment of physical activity, fitness, physical functioning, fatigue and exercise self-efficacy at baseline and after the 16-week intervention. One hundred and twenty-one patients were enrolled through ten Cancer and Leukemia Group B (CALGB) institutions; 100 patients had breast cancer and 21 had colorectal cancer. Participants randomized to the exercise group increased physical activity by more than 100 versus 22% in controls (54.5 vs. 14.6 min, P = 0.13), and experienced significant increases in fitness (increased 6-min walk test distance by 186.9 vs. 81.9 feet, P = 0.006) and physical functioning (7.1 vs. 2.6, P = 0.04) as compared to the control group. Breast and colorectal cancer survivors enrolled in a multicenter, telephone-based physical activity intervention increased physical activity and experienced significant improvements in fitness and physical functioning. Lifestyle intervention research is feasible in a cooperative group setting.

Role of Abl kinase and the Wave2 signaling complex in HIV-1 entry at a post-hemifusion step.

Entry of human immunodeficiency virus type 1 (HIV-1) commences with binding of the envelope glycoprotein (Env) to the receptor CD4, and one of two coreceptors, CXCR4 or CCR5. Env-mediated signaling through coreceptor results in Galphaq-mediated Rac activation and actin cytoskeleton rearrangements necessary for fusion. Guanine nucleotide exchange factors (GEFs) activate Rac and regulate its downstream protein effectors. In this study we show that Env-induced Rac activation is mediated by the Rac GEF Tiam-1, which associates with the adaptor protein IRSp53 to link Rac to the Wave2 complex. Rac and the tyrosine kinase Abl then activate the Wave2 complex and promote Arp2/3-dependent actin polymerization. Env-mediated cell-cell fusion, virus-cell fusion and HIV-1 infection are dependent on Tiam-1, Abl, IRSp53, Wave2, and Arp3 as shown by attenuation of fusion and infection in cells expressing siRNA targeted to these signaling components. HIV-1 Env-dependent cell-cell fusion, virus-cell fusion and infection were also inhibited by Abl kinase inhibitors, imatinib, nilotinib, and dasatinib. Treatment of cells with Abl kinase inhibitors did not affect cell viability or surface expression of CD4 and CCR5. Similar results with inhibitors and siRNAs were obtained when Env-dependent cell-cell fusion, virus-cell fusion or infection was measured, and when cell lines or primary cells were the target. Using membrane curving agents and fluorescence microscopy, we showed that inhibition of Abl kinase activity arrests fusion at the hemifusion (lipid mixing) step, suggesting a role for Abl-mediated actin remodeling in pore formation and expansion. These results suggest a potential utility of Abl kinase inhibitors to treat HIV-1 infected patients.

Vaping Prevention in a Middle School Population Using CATCH My Breath.

INTRODUCTION: The number of teens using electronic cigarettes in the United States has reached epidemic proportions. One in 20 middle school youth currently vapes regularly (Wang et al., 2020), supporting the need for e-cigarette education and prevention programs in this vulnerable population. METHOD: The evidence-based youth vaping prevention program, CATCH My Breath, was implemented and evaluated in a small, private, parochial middle school using a quasi-experimental, within-subjects, longitudinal design. RESULTS: Students' e-cigarette knowledge significantly improved postintervention (p < .001) and was sustained at 3 months follow-up. Attitudes about vaping remained stable after postintervention and at 3 months follow-up (p > .05). Susceptibility toward vaping increased or remained consistent despite increased knowledge (p = .096). DISCUSSION: CATCH My Breath is an effective school-based resource to educate middle school youth about the dangers of vaping. Additional research is needed to evaluate the intervention's impact on e-cigarette attitudes and the measurement of susceptibility in teens.

Physical activity in older adults with metastatic gastrointestinal cancer: a pilot and feasibility study.

Objectives: This study determined the feasibility of delivering a 12-week structured physical activity programme during chemotherapy to older adults recently diagnosed with metastatic gastrointestinal (GI) cancer. Methods: This study used a single-cohort design. Older adults (aged ≥65 years) diagnosed with metastatic oesophageal, gastric, pancreatic or colorectal cancer who planned to initiate chemotherapy were enrolled. The physical activity programme included a combination of aerobic, flexibility, strength and balance modalities delivered by a certified cancer exercise trainer during chemotherapy infusion appointments, then translated and sustained at home by participants. The co-primary endpoints included: (1) accrual of 20 participants in 12 months and (2) physical activity adherence of ≥50%. Results: Between March and October 2018, 29 participants were screened, and 20 were enrolled within 12 months (recruitment rate: 69% (90% CI: 55% to 83%); p<0.001), meeting the first co-primary endpoint. The median age of participants was 73.3 years (IQR: 69.3-77.2). At week 12, 67% (90% CI: 48% to 85%) of participants adhered to ≥50% of the prescribed physical activity (p=0.079 (statistically significant)), meeting the second co-primary endpoint. From baseline to week 12, accelerometer-measured light-intensity and moderate-intensity to vigorous-intensity physical activity increased by 307.4 (95% CI: 152.6 to 462.2; p<0.001) and 25.0 min per week (95% CI: 9.9 to 40.1; p=0.001), respectively. There were no serious or unexpected adverse events. The median overall survival was 16.2 months (8.4-22.4). Conclusion: These results establish the feasibility of a larger scale randomised controlled trial that enrols older adults with metastatic GI cancer and delivers a structured physical activity programme during chemotherapy. Trial registration number: NCT03331406.

Fluorine in medicinal chemistry: ß-fluorination of peripheral pyrrolidines attached to acridine ligands affects their interactions with G-quadruplex DNA.

Comparative X-ray structure studies reveal that C-F bond incorporation into the peripheral pyrrolidine moieties of the G-quadruplex DNA binding ligand BSU6039 leads to a distinct pyrrolidine ring conformation, relative to the non-fluorinated analogue, and with a different binding mode involving reversal of the pyrrolidinium N(+)-H orientation.

Paediatric lateral condyle fracture with a posterolateral elbow dislocation: an atypical injury in a preadolescent.

Paediatric lateral condyle fractures of the distal humerus are common but a concomitant elbow dislocation is rare. Typically, paediatric orthopaedic surgeons will treat lateral condyle fractures with pin or metaphyseal single-screw fixation and supplementary immobilisation for several weeks. These techniques sacrifice the early stability and mobilisation necessary to avoid stiffness after a complex elbow fracture-dislocation. We present an 11-year-old boy who sustained a traumatic posterolateral elbow dislocation with lateral condyle and coronoid fractures. Due to advanced skeletal age, both paediatric and adult treatment principles were applied to this rare injury. After initial closed reduction, open reduction and internal fixation of the distal humerus lateral condyle with divergent partially threaded compression screws was performed. Motion was initiated in 2 weeks and the patient regained almost full motion by 3 months. At 1.5-year follow-up, the affected limb carrying angle was unaffected and the patient had no functional limitations.

International Nursing Collaboration to Establish the Philippine Quit Line: Using a Conceptual Model for Partnership and Sustainability in Global Health.

ABSTRACT: Tobacco use remains the single most preventable cause of death and disability worldwide. In the Philippines, 28.3% of the people are current tobacco smokers, which is one of the highest smoking rates in Asia. The World Health Organization estimates that 10 Filipinos die every day from cancer, stroke, and lung and heart disease caused by cigarette smoke and approximately 24 million Filipinos are exposed to secondhand smoke in the home. Although there are quit lines in all 50 U.S. states and territories, there was no access to this smoking cessation program in the Philippines before the initiation of the international collaboration described in this article. In 2012, a Filipino-American nurse with extensive quit line expertise initiated collaboration between the United States and Philippine smoking cessation experts to plan the creation of a quit line at the Lung Center of the Philippines. The Conceptual Model for Partnership and Sustainability in Global Health was used as a foundation for the planning, implementation, and evaluation of the Philippine Quit Line project, which was funded in 2017 by the World Health Organization and the Philippine Department of Health. This funding and other outcomes related to nursing education about tobacco addictions in the Philippines suggest that the Partnership and Sustainability in Global Health Model can provide a blueprint for international collaboration on health projects that are rooted in real collaborative and sustainable partnerships.

Improving laboratory quality and capacity through leadership and management training: Lessons from Zambia 2016-2018.

BACKGROUND: Competent leadership and management are imperative for delivering quality laboratory services; however, few laboratory managers receive job-specific training in organisational management and leadership. OBJECTIVE: To develop and evaluate participants' competencies in organisational leadership and management as measured through learner and laboratory quality improvement assessments. METHODS: This professional development programme employed a mentored, blended learning approach, utilising in-person didactic and online training, with the practical application of a capstone project in the laboratories. Programme impact was evaluated through a series of pre- and post-laboartory assessments using the Stepwise Laboratory Improvement Process Towards Accreditation checklist, as well as learner-competency assessments through online quizzes and discussions. RESULTS: From 2016 to 2018, 31 managers and quality officers from 16 individual laboratories graduated from the programme having completed capstone projects addressing areas in the entire laboratory testing process. Laboratories increased their compliance with the International Organization for Standardization 15189 standard and all but two laboratories significantly increased their accreditation scores. Two laboratories gained three stars, two laboratories gained two stars, and five laboratories gained one star. Five laboratories subsequently achieved International Organization for Standardization 15189 accreditation in 2019. CONCLUSION: This programme taught leadership theory to laboratory managers and allowed them to implement leadership and management practices in the laboratory setting. Programmes such as this complement existing laboratory quality management training programmes such as Strengthening Laboratory Management Toward Accreditation.