Data-driven scalable pipeline using national agent-based models for real-time pandemic response and decision support.

This paper describes an integrated, data-driven operational pipeline based on national agent-based models to support federal and state-level pandemic planning and response. The pipeline consists of (i) an automatic semantic-aware scheduling method that coordinates jobs across two separate high performance computing systems; (ii) a data pipeline to collect, integrate and organize national and county-level disaggregated data for initialization and post-simulation analysis; (iii) a digital twin of national social contact networks made up of 288 Million individuals and 12.6 Billion time-varying interactions covering the US states and DC; (iv) an extension of a parallel agent-based simulation model to study epidemic dynamics and associated interventions. This pipeline can run 400 replicates of national runs in less than 33 h, and reduces the need for human intervention, resulting in faster turnaround times and higher reliability and accuracy of the results. Scientifically, the work has led to significant advances in real-time epidemic sciences.

The PATRIC Bioinformatics Resource Center: expanding data and analysis capabilities.

The PathoSystems Resource Integration Center (PATRIC) is the bacterial Bioinformatics Resource Center funded by the National Institute of Allergy and Infectious Diseases (https://www.patricbrc.org). PATRIC supports bioinformatic analyses of all bacteria with a special emphasis on pathogens, offering a rich comparative analysis environment that provides users with access to over 250 000 uniformly annotated and publicly available genomes with curated metadata. PATRIC offers web-based visualization and comparative analysis tools, a private workspace in which users can analyze their own data in the context of the public collections, services that streamline complex bioinformatic workflows and command-line tools for bulk data analysis. Over the past several years, as genomic and other omics-related experiments have become more cost-effective and widespread, we have observed considerable growth in the usage of and demand for easy-to-use, publicly available bioinformatic tools and services. Here we report the recent updates to the PATRIC resource, including new web-based comparative analysis tools, eight new services and the release of a command-line interface to access, query and analyze data.

[Similarity between leaves of Nauclea officinalis and stems of Nauclea officinalis].

The study is to develop a method to determine 3 batches leaves of Nauclea officinalis and stems of N. officinalis by HPLC. The differences between strictosamide contents and fingerprints was compared, then chromatographic peak of fingerprints was validated with the assistance of LC-MS. The strictosamide contents in stems of N. officinalis were higher than leaves of N. officinalis. The main chemical composition in leaves of N. officinalis and stems of N. officinalis were alkaloid which revealed by LC-MS. There are 7 chemical compositions were same between them, but the chemical composition in leaves of N. officinalis is more than stems of N. officinalis. This provides a scientific basis for the development of the potential medicinal value of leaves of N. officinalis and the sustainable utilization of N. officinalis.

[Quantitative and qualitative evaluation on tablets of Ginkgo biloba leaves using fingerprint and LC-MS analysis].

A reasonable method for the quality control of tablets of Ginkgo biloba leaves was established in this paper. The total flavonol glycosides and terpene lactones of G. biloba tablets were quantified by HPLC. Totally, 16 batches of the commercially available tablets of G. biloba leaves were determined. Among of them, 2 batches were unqualified in the content of total flavonol glycosides, and 3 batches were unqualified in the content of terpene lactones. A validated HPLC fingerprint method was established to evaluate the commercially available tablets of G. biloba leaves with the assistance of LC-MS. Sixteen batches showed the similarity of 0.763-0.989. There were 31 fingerprint chromatogram peaks were identified as flavonoids compositions by LC-MS. This provides a research idea for the quality control of tablets of G. biloba leaves.

Novel multi-cluster workflow system to support real-time HPC-enabled epidemic science: Investigating the impact of vaccine acceptance on COVID-19 spread.

We present MacKenzie, a HPC-driven multi-cluster workflow system that was used repeatedly to configure and execute fine-grained US national-scale epidemic simulation models during the COVID-19 pandemic. Mackenzie supported federal and Virginia policymakers, in real-time, for a large number of "what-if" scenarios during the COVID-19 pandemic, and continues to be used to answer related questions as COVID-19 transitions to the endemic stage of the disease. MacKenzie is a novel HPC meta-scheduler that can execute US-scale simulation models and associated workflows that typically present significant big data challenges. The meta-scheduler optimizes the total execution time of simulations in the workflow, and helps improve overall human productivity. As an exemplar of the kind of studies that can be conducted using Mackenzie, we present a modeling study to understand the impact of vaccine-acceptance in controlling the spread of COVID-19 in the US. We use a 288 million node synthetic social contact network (digital twin) spanning all 50 US states plus Washington DC, comprised of 3300 counties, with 12 billion daily interactions. The highly-resolved agent-based model used for the epidemic simulations uses realistic information about disease progression, vaccine uptake, production schedules, acceptance trends, prevalence, and social distancing guidelines. Computational experiments show that, for the simulation workload discussed above, MacKenzie is able to scale up well to 10K CPU cores. Our modeling results show that, when compared to faster and accelerating vaccinations, slower vaccination rates due to vaccine hesitancy cause averted infections to drop from 6.7M to 4.5M, and averted total deaths to drop from 39.4K to 28.2K across the US. This occurs despite the fact that the final vaccine coverage is the same in both scenarios. We also find that if vaccine acceptance could be increased by 10% in all states, averted infections could be increased from 4.5M to 4.7M (a 4.4% improvement) and total averted deaths could be increased from 28.2K to 29.9K (a 6% improvement) nationwide.

[Study on chemical constituents from leaves of Naudea officinalis].

OBJECTIVE: To study the chemical constituents of the leaves of Naudea officinalis. METHOD: The chemical constituents were separated by column chromatography and semi-preparative HPLC techniques, and their structures were determined by spectral analysis. RESULT: Five compounds were isolated and identified as strictosamide (1), 10-hydroxy strictosamide (2), kaempferol-3-O-rutinoside (3), rutin (4), pumiloside(5). CONCLUSION: Among these compounds, 2, 3, 4 are isolated from the leaves of Naudea officinalis for the first time.

From 5Vs to 6Cs: Operationalizing Epidemic Data Management with COVID-19 Surveillance.

The COVID-19 pandemic brought to the forefront an unprecedented need for experts, as well as citizens, to visualize spatio-temporal disease surveillance data. Web application dashboards were quickly developed to fill this gap, including those built by JHU, WHO, and CDC, but all of these dashboards supported a particular niche view of the pandemic (ie, current status or specific regions). In this paper, we describe our work developing our own COVID-19 Surveillance Dashboard, available at https://nssac.bii.virginia.edu/covid-19/dashboard/, which offers a universal view of the pandemic while also allowing users to focus on the details that interest them. From the beginning, our goal was to provide a simple visual way to compare, organize, and track near-real-time surveillance data as the pandemic progresses. Our dashboard includes a number of advanced features for zooming, filtering, categorizing and visualizing multiple time series on a single canvas. In developing this dashboard, we have also identified 6 key metrics we call the 6Cs standard which we propose as a standard for the design and evaluation of real-time epidemic science dashboards. Our dashboard was one of the first released to the public, and remains one of the most visited and highly used. Our group uses it to support federal, state and local public health authorities, and it is used by people worldwide to track the pandemic evolution, build their own dashboards, and support their organizations as they plan their responses to the pandemic. We illustrate the utility of our dashboard by describing how it can be used to support data story-telling - an important emerging area in data science.

Evaluating the impact of international airline suspensions on the early global spread of COVID-19.

Global airline networks play a key role in the global importation of emerging infectious diseases. Detailed information on air traffic between international airports has been demonstrated to be useful in retrospectively validating and prospectively predicting case emergence in other countries. In this paper, we use a well-established metric known as effective distance on the global air traffic data from IATA to quantify risk of emergence for different countries as a consequence of direct importation from China, and compare it against arrival times for the first 24 countries. Using this model trained on official first reports from WHO, we estimate time of arrival (ToA) for all other countries. We then incorporate data on airline suspensions to recompute the effective distance and assess the effect of such cancellations in delaying the estimated arrival time for all other countries. Finally we use the infectious disease vulnerability indices to explain some of the estimated reporting delays.

Genetic polymorphisms in the cyclooxygenase-1 and cyclooxygenase-2 genes and risk of colorectal adenoma.

PURPOSE: Cyclooxygenase (COX) enzymes, COX1 and COX2, are key in converting arachidonic acid (AA) into prostaglandins that have been associated with colorectal carcinogenesis. The aim of our study was to investigate associations of polymorphisms in COX genes, alone and in interaction with exposures known to be related to inflammation and AA metabolism, with risk of colorectal adenomas. MATERIALS AND METHODS: In a community-, colonoscopy-based case-control study with 162 incident, sporadic colorectal adenoma cases and 211 controls, we investigated associations of two promoter polymorphisms (-842 A > G in COX1 and -765 G > C in COX2) and two polymorphisms in the 3'-UTR of COX2 (8473 T > C and 9850 A > G) with risk of adenomas. Multiple logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CI) of colorectal adenoma after adjusting for potential confounders. RESULTS: Overall, there was no evidence for an association between any of the four polymorphisms and colorectal adenomas. However, we found a statistically significant interaction between the COX2 8473 T > C polymorphism and nonsteroidal anti-inflammatory drug (NSAIDs) use (P (interaction) = 0.03): The greatest reduced risk was observed for individuals with the 8473 C variant allele who also regularly used NSAIDs (OR = 0.35, 95% CI 0.16-0.75). CONCLUSION: These results suggest that the C allele of COX2 8473 T > C polymorphism may interact with NSAIDs to reduce risk for colorectal adenoma.

Polymorphism of the cyclin D1 gene, CCND1, and risk for incident sporadic colorectal adenomas.

Cyclin D1, encoded by the CCND1 gene and activated by the adenomatous polyposis coli-beta-catenin-T-cell factor/lymphoid enhancing factor pathway, induces G(1) to S-phase cell cycle transition, promoting cell proliferation. A recently described codon 242, exon 4, G to A single nucleotide polymorphism (A870G) produces a longer half-life cyclin D1. To investigate whether CCND1 genotype influences risk for colorectal adenoma, we genotyped CCND1 by PCR/RFLP on 161 incident sporadic adenoma cases and 213 controls ages 30-74 years in a North Carolina colonoscopy-based case-control study. At least one polymorphic A allele was found in 68% of cases and 60% of controls. Having an A allele was associated with increased risk for adenoma: the age- and sex-adjusted odds ratio (OR) was 1.5 [95% confidence interval (CI) 1.0-2.4], a finding that was stronger for those whose adenomas were multiple (OR 2.9, 95% CI 1.4-6.0), larger (>or=1 cm; OR 2.4, 95% CI 1.2-4.8), had moderate to severe dysplasia (OR 2.1, 95% CI 1.1-3.8), or were in the right side of the colon (OR 3.6, 95% CI 1.3-10.0). Joint risk factor multivariate analyses revealed stronger positive associations among those who were older (>57 years; OR 2.8, 95% CI 1.4-5.5), male (OR 2.8, 95% CI 1.3-5.7), currently smoked (OR 2.7, 95% CI 1.3-5.7), or currently drank alcohol (OR 2.2, 95% CI 1.2-4.2) if they had an A allele and stronger inverse associations among those who used nonsteroidal anti-inflammatory drugs (OR 0.4, 95% CI 0.2-0.9) or had higher calcium intakes (OR 0.4, 95% CI 0.2-0.9) if they had no A allele. These data support the hypothesis that the CCND1 A870G polymorphism may increase risk for colorectal neoplasms.

Effect of modelling slum populations on influenza spread in Delhi.

OBJECTIVES: This research studies the impact of influenza epidemic in the slum and non-slum areas of Delhi, the National Capital Territory of India, by taking proper account of slum demographics and residents' activities, using a highly resolved social contact network of the 13.8 million residents of Delhi. METHODS: An SEIR model is used to simulate the spread of influenza on two different synthetic social contact networks of Delhi, one where slums and non-slums are treated the same in terms of their demographics and daily sets of activities and the other, where slum and non-slum regions have different attributes. RESULTS: Differences between the epidemic outcomes on the two networks are large. Time-to-peak infection is overestimated by several weeks, and the cumulative infection rate and peak infection rate are underestimated by 10-50%, when slum attributes are ignored. CONCLUSIONS: Slum populations have a significant effect on influenza transmission in urban areas. Improper specification of slums in large urban regions results in underestimation of infections in the entire population and hence will lead to misguided interventions by policy planners.

Vitamin D receptor gene Tru9I polymorphism and risk for incidental sporadic colorectal adenomas.

AIM: Recent laboratory and epidemiological studies suggest that vitamin D is a potential agent for colorectal cancer prevention. Its function is partially mediated by the vitamin D receptor (VDR). The aim of this study was to investigate whether a novel G (allele "U") >A (allele "u") polymorphism (Tru9I) in the VDR intron 8 region is associated with risk for colorectal adenoma in a colonoscopy-based case-control study. METHODS: Genotyping for a total of 391 subjects was carried out through PCR and restriction fragment length polymorphism. RESULTS: The frequencies of "U" and "u" alleles were 89.3% and 10.7%, respectively. The "Uu" and "uu" genotypes were associated with decreased risk for adenoma (OR, 0.71; 95%CI, 0.40-1.25). The inverse association was more pronounced for multiple adenomas and adenomas that were larger had moderate or greater dysplasia, or were sessile: the odds ratios (ORs) were, 0.51 (95%CI, 0.21-1.24), 0.37 (95%CI, 0.11-1.28), 0.68 (95%CI, 0.33-1.41), and 0.36 (95%CI, 0.13-0.97) respectively. In joint/combined analyses, inverse associations were more obvious among those who had at least one "u" allele and also were younger (OR, 0.60; 95%CI, 0.26-1.37), women (OR, 0.38; 95%CI, 0.17-0.88), did not smoke (OR, 0.39; 95%CI, 0.13-1.23), or took NSAID (OR, 0.38; 95%CI, 0.12-1.25), but no evidence existed for interactions with calcium or vitamin D intake. CONCLUSION: Our findings suggest that the VDR Tru9I polymorphism may be associated with lower risk for colorectal adenoma, particularly in interaction with various risk factors, but not with calcium or vitamin D.

Novel genetic variations of the p53R2 gene in patients with colorectal adenoma and controls.

AIM: p53-inducible ribonucleotide reductase small subunit 2 (p53R2) encodes a 351-amino-acid peptide, which catalyzes conversion of ribonucleoside diphosphates to the corresponding deoxyribonucleotides required for DNA replication and repair. A recent study reported that a point mutation (G/T) in the p53 binding sequence in a colon cancer cell line completely impaired p53R2 protein activity. METHODS: We screened the p53R2 gene coding regions and a regulatory region which contains a p53 binding sequence in 100 patients with colorectal adenoma and 100 control subjects using PCR, cold SSCP, and direct DNA sequencing. RESULTS: Although we did not identify genetic variation in all nine exons, four regulatory-region variants were found, of which three were single nucleotide polymorphisms (SNPs) (nt 1 789 C/G, nt 1 928 A/G, 1 933 T/C), and one was 20 bp insertion which replaced a ATTTT between nt 1831 and 1835. Additionally, we determined the frequency of these p53R2 variants in a recently concluded case-control study of incident sporadic colorectal adenomas (163 cases and 210 controls). CONCLUSION: Although more detailed functional characterizations of these polymorphisms remain to be undertaken, these polymorphic sites may be useful for identifying alleles associated with mis-splicing, additional transcript factors and, more generally, in cancer-susceptibility association studies.

Can hyperbaric oxygen therapy reduce breast cancer treatment-related lymphedema? A pilot study.

OBJECTIVE: Arm lymphedema after surgery or radiation for breast cancer is common, causing pain and limitation of activities. Previous reports of hyperbaric oxygen (HBO) therapy for breast edema led us to consider the use of HBO therapy for arm lymphedema. METHODS: Ten healthy postmenopausal women (age 58 +/- 5.7 years) with persistent (9.4 years +/- 9.1 years) arm lymphedema following breast cancer surgery and radiation (n = 10) plus chemotherapy (n = 7) received 20 HBO treatments (90 minutes at 2.0 ATA five times a week for 4 weeks). End points included changes in upper extremity volume, platelet counts, plasma levels of vascular endothelial growth factor (VEGF), and lymph angiogenic-associated vascular endothelial growth factor-C (VEGF-C). Lymphedema volume (LV) was defined as the volume of the unaffected arm subtracted from the volume of the affected arm. RESULTS: We observed a 38% average reduction in hand lymphedema (-7.4 ml, 11.6 SD, range -30-+8 ml, p = 0.076, 95% confidence interval -15.7-0.9 ml) at the end of HBO, which was independent of changes in body weight. For those who benefited (n = 8), the reduction was persistent from the end of treatment to a final measurement an average of 14.2 months after the last HBO treatment. However, total LV did not change significantly. VEGF-C increased from baseline (p = 0.004) before treatment 20, suggesting HBO had begun to stimulate this growth factor. CONCLUSIONS: Future studies should explore the effects of a greater number of HBO treatments on lymphedema, with more patients.

PLANNING AND RESPONSE IN THE AFTERMATH OF A LARGE CRISIS: AN AGENT-BASED INFORMATICS FRAMEWORK*

We present a synthetic information and modeling environment that can allow policy makers to study various counter-factual experiments in the event of a large human-initiated crisis. The specific scenario we consider is a ground detonation caused by an improvised nuclear device in a large urban region. In contrast to earlier work in this area that focuses largely on the prompt effects on human health and injury, we focus on co-evolution of individual and collective behavior and its interaction with the differentially damaged infrastructure. This allows us to study short term secondary and tertiary effects. The present environment is suitable for studying the dynamical outcomes over a two week period after the initial blast. A novel computing and data processing architecture is described; the architecture allows us to represent multiple co-evolving infrastructures and social networks at a highly resolved temporal, spatial, and individual scale. The representation allows us to study the emergent behavior of individuals as well as specific strategies to reduce casualties and injuries that exploit the spatial and temporal nature of the secondary and tertiary effects. A number of important conclusions are obtained using the modeling environment. For example, the studies decisively show that deploying ad hoc communication networks to reach individuals in the affected area is likely to have a significant impact on the overall casualties and injuries.

Circadian disruption, Per3, and human cytokine secretion.

Circadian disruption has been linked with inflammation, an established cancer risk factor. Per3 clock gene polymorphisms have also been associated with circadian disruption and with increased cancer risk. Patients completed a questionnaire and provided a blood sample prior to undergoing a colonoscopy (n = 70). Adjusted mean serum cytokine concentrations (IL-6, TNF-alpha, gamma-INF, IL-1ra, IL-1-beta, VEGF) were compared among patients with high and low scores for fatigue (Multidimensional Fatigue Inventory), depressive symptoms (Beck Depression Inventory II), or sleep disruption (Pittsburgh Sleep Quality Index), or among patients with different Per3 clock gene variants. Poor sleep was associated with elevated VEGF, and fatigue-related reduced activity was associated with elevated TNF-alpha concentrations. Participants with the 4/5 or 5/5 Per3 variable tandem repeat sequence had elevated IL-6 concentrations compared to those with the 4/4 genotype. Biological processes linking circadian disruption with cancer remain to be elucidated. Increased inflammatory cytokine secretion may play a role.

APOE, APOE promoter, and Tau genotypes and risk for concussion in college athletes.

OBJECTIVE: To investigate associations of APOE, APOE promoter (G-219T), and tau protein exon 6 polymorphisms (47 and 53) and a history of self-reported concussion in college athletes. DESIGN: Multi-center cross-sectional study. SETTING: Male football and male and female soccer programs at the University of South Carolina, Jacksonville University, Benedict College, and the College of Charleston. PARTICIPANTS: Active 18- to 30-year-old (n = 195) intercollegiate male football players and male and female soccer players during 2001 and 2002. ASSESSMENT OF RISK FACTORS: Written questionnaires and blood or mouthwash samples for DNA for genotyping by RFLP/PCR. MAIN OUTCOME MEASUREMENT: Self-reported history of concussions over the previous 8 years. RESULTS: A statistically significant, nearly 3-fold increase in risk of a history of concussion for those with the APOE promoter G-219T TT genotype relative to the GG genotype (OR, 2.8; 95% CI, 1.1 to 6.9) adjusted for age, sport, school, and years in their primary sport, a finding that was stronger for Cantu grade 2 and 3 concussions. CONCLUSIONS: These results suggest that college athletes with an APOE promoter G-219T TT genotype may be at increased risk for having a history of concussions, especially more severe concussions. Although there was some support for the possibility that the tau 53 polymorphism may be associated with increased risk of prior concussion (OR, 2.1; 95% CI, 0.3 to 14.5), there was no support for an association with APOE genotypes. The results of this cross-sectional study support the need for a prospective study of genetic factors, such as APOE promoter polymorphisms, and the incidence of and sequelae from concussions in college athletes.

Common polymorphisms in 5-lipoxygenase and 12-lipoxygenase genes and the risk of incident, sporadic colorectal adenoma.

BACKGROUND: Lipoxygenases (LOX) are major enzymes that metabolize arachidonic acid to hydroxyl-eicosatetraenoic acids and leukotrienes, which have been implicated in inflammation and colorectal cancer risk. Polymorphisms in LOX genes may influence their function and/or expression and, thus, may modify the risk for colorectal adenoma. The authors investigated the associations of 3 polymorphisms (2 in 5-LOX, -1708 guanine-->adenine and 21 cytosine-->thymine; and 1 in 12-LOX, arginine 261 glutamine [Arg261Gln]) in LOX genes with the risk of colorectal adenoma and also explored possible interactions of these polymorphisms with several inflammation-pathway or arachidonic acid metabolism-pathway related factors with the risk of colorectal adenoma. METHODS: By using data from a community-based, case-control study of incident, sporadic colorectal adenoma that included 162 cases and 211 controls, the authors constructed multiple logistic regression models to estimate the odds ratios (OR) and 95% confidence intervals (95% CI) of colorectal adenoma after adjusting for potential confounders. RESULTS: Overall, there were no significant associations of the 2 5-LOX polymorphisms with the risk of colorectal adenoma. However, there was an inverse association between the Arg261Gln polymorphism in 12-LOX and colorectal adenoma (OR, 0.63; 95% CI, 0.40-1.00). A significant interaction also was observed between the 12-LOX polymorphism (Arg261Gln) and the use of nonsteroidal anti-inflammatory drugs (P(interaction) = .02). CONCLUSIONS: The current results suggested that polymorphisms of LOX genes may act independently or with other factors to affect the risk of colorectal adenoma. Further studies will be needed to confirm these findings. Cancer 2007 (c) 2007 American Cancer Society.

The PPAR{gamma} Pro12Ala polymorphism and risk for incident sporadic colorectal adenomas.

Peroxisome proliferator-activated receptor gamma (PPARgamma), a member of the nuclear hormone receptor superfamily initially shown to be a key regulator of fat cell differentiation, can inhibit cell growth and induce apoptosis in colon cell lines. There are heterozygous loss of function mutations in the gene encoding PPARgamma in tumors from approximately 10% of human colon cancer patients. A common structural polymorphism has been detected in the PPARgamma gene at codon 12 (Pro12Ala). We investigated the hypothesis that the PPARgamma Pro12Ala polymorphism is associated with colorectal adenoma risk in a recently concluded case-control study of incident sporadic colorectal adenomas (163 cases and 212 controls). The multivariate-adjusted odds ratio (OR) for incident sporadic colorectal adenoma was 0.65 (95% CI 0.39-1.09) for those with the Pro12Ala or Ala12Ala genotype compared with those with the Pro12Pro genotype. Multivariate-adjusted inverse associations with the Ala12 variant were more pronounced among those who were female (OR 0.36, 95% CI 0.18-0.75) or did not take non-steroidal anti-inflammatory drugs (OR 0.38, 95% CI 0.14-1.00). Marginally significant results were observed among those with a lower waist:hip ratio (OR 0.52, 95% CI 0.24-1.12) or a lower body mass index (OR 0.46, 95% 0.20-1.05). Smoking was a very strong risk factor (OR 2.34, 95%CI 1.37-4.02) for colorectal adenoma among those with the wild-type (Pro12Ala) genotype, but not those with the Ala12 variant (OR 0.86, 95%CI 0.35-2.09). Larger studies are needed to validate these results, which suggest that the PPARgamma Pro12Ala polymorphism may interact with other factors to protect against colorectal adenoma.