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In this paper, ultra-high-performance concrete (UHPC) and its constituents were evaluated by way of instrumented and non-instrumented mechanical-property tests and imaging techniques. Through image analysis, the average size, per cent area, nearest-neighbour distance and relative number density of each inclusion type were determined. Instrumented mechanical-property testing was conducted to obtain estimates for the relative behaviour of UHPC's various constituents. Different combinations of constituents were produced to measure indirect tensile strength, compressive strength, elastic modulus, Poisson's ratio and overall stress–strain behaviour to failure at early and later ages. Stress–strain behaviour and Poisson's ratio of UHPC aligned well with the literature, while constituents of UHPC also showed linear stress–strain relationships and comparable Poisson's ratios. Tensile behaviour at early and late ages was characterised and was found to be driven by inclusion of fibres. Characterisation of UHPC and its constituents is envisioned to be used to further modelling efforts by basing mathematical relationships on physical measurements.

Adolescence is a critical period of neurocognitive development and increased prevalence of mood pathology. In this cross-sectional study, we replicated developmental patterns of neurocognition and tested whether mood symptoms moderated developmental effects. Participants were 419 adolescents ( n = 246 with current mood disorders) who completed reward-learning and executive-functioning tasks and reported on age, puberty, and mood symptoms. Structural equation modeling revealed a quadratic relationship between puberty and reward-learning performance that was moderated by symptom severity: In early puberty, adolescents reporting higher manic symptoms exhibited heightened reward-learning performance (better maximizing of rewards on learning tasks), whereas adolescents reporting elevated anhedonia showed blunted reward-learning performance. Models also showed a linear relationship between age and executive functioning that was moderated by manic symptoms: Adolescents reporting higher mania showed poorer executive functioning at older ages. Findings suggest neurocognitive development is altered in adolescents with mood pathology and suggest directions for longitudinal studies.

Objective: To study associations between the Minnesota coronavirus disease 2019 (COVID-19) mitigation strategies on incidence rates of acute myocardial infarction (MI) or revascularization among residents of Southeast Minnesota. Methods: Using the Rochester Epidemiology Project, all adult residents of a nine-county region of Southeast Minnesota who had an incident MI or revascularization between January 1, 2015, and December 31, 2020, were identified. Events were defined as primary in-patient diagnosis of MI or undergoing revascularization. We estimated age- and sex-standardized incidence rates and incidence rate ratios (IRRs) stratified by key factors, comparing 2020 to 2015–2019. We also calculated IRRs by periods corresponding to Minnesota’s COVID-19 mitigation timeline: “Pre-lockdown” (January 1–March 11, 2020), “First lockdown” (March 12–May 31, 2020), “Between lockdowns” (June 1–November 20, 2020), and “Second lockdown” (November 21–December 31, 2020). Results: The incidence rate in 2020 was 32% lower than in 2015–2019 (24 vs 36 events/100,000 person-months; IRR, 0.68; 95% CI, 0.62-0.74). Incidence rates were lower in 2020 versus 2015–2019 during the first lockdown (IRR, 0.54; 95% CI, 0.44-0.66), in between lockdowns (IRR, 0.70; 95% CI, 0.61-0.79), and during the second lockdown (IRR, 0.54; 95% CI, 0.41-0.72). April had the lowest IRR (IRR 0.48; 95% CI, 0.34-0.68), followed by August (IRR, 0.55; 95% CI, 0.40-0.76) and December (IRR, 0.56; 95% CI, 0.41-0.77). Similar declines were observed across sex and all age groups, and in both urban and rural residents. Conclusion: Mitigation measures for COVID-19 were associated with a reduction in hospitalizations for acute MI and revascularization in Southeast Minnesota. The reduction was most pronounced during the lockdown periods but persisted between lockdowns.

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Supplementary Table 1 List of antibodies, reagents and kits used in the study Supplementary Table 2 List of primers used in the study Supplementary Table 3 Comprehensive literature search of angiogenic regulators in HCC Supplementary Table 4 Correlation of 178 genes related to angiogenesis in HCC with SULF2 expression in human HCC microarray gene analysis

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Existing antiangiogenic approaches to treat metastatic hepatocellular carcinoma (HCC) are weakly effectual, prompting further study of tumor angiogenesis in this disease setting. Here, we report a novel role for sulfatase 2 (SULF2) in driving HCC angiogenesis. Sulf2-deficient mice (Sulf2 KO) exhibited resistance to diethylnitrosamine-induced HCC and did not develop metastases like wild-type mice (Sulf2 WT). The smaller and less numerous tumors formed in Sulf2 KO mice exhibited a markedly lower microvascular density. In human HCC cells, SULF2 overexpression increased endothelial proliferation, adhesion, chemotaxis, and tube formation in a paracrine fashion. Mechanistic analyses identified the extracellular matrix protein periostin (POSTN), a ligand of αvβ3/5 integrins, as an effector protein in SULF2-induced angiogenesis. POSTN silencing in HCC cells attenuated SULF2-induced angiogenesis and tumor growth in vivo. The TGFβ1/SMAD pathway was identified as a critical signaling axis between SULF2 and upregulation of POSTN transcription. In clinical HCC specimens, elevated levels of SULF2 correlated with increased microvascular density, POSTN levels, and relatively poorer patient survival. Together, our findings define an important axis controlling angiogenesis in HCC and a mechanistic foundation for rational drug development. Cancer Res; 77(3); 632–45. ©2016 AACR.

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Supplementary Figure 1 Schematic representation of experimental design for HCC carcinogenesis in mice. Supplementary Figure 2 Loss of Sulf2 impairs tumor growth and incidence in DEN-model of HCC carcinogenesis. Supplementary Figure 3 Conditioned media from SULF2-transfected HCC cells promotes endothelial cells viability and adhesion. Supplementary Figure 4 In silico analysis of HCC-angiogenic factors. Supplementary Figure 5 Expression of POSTN in Sulf2 knockout or wild type animals.

Supplementary Figures

Purpose: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, with high mortality and a lack of targeted therapies. To identify and prioritize druggable targets, we performed genome analysis together with genome-scale siRNA and oncology drug profiling using low-passage tumor cells derived from a patient with treatment-resistant HPV-negative HNSCC.Experimental Design: A tumor cell culture was established and subjected to whole-exome sequencing, RNA sequencing, comparative genome hybridization, and high-throughput phenotyping with a siRNA library covering the druggable genome and an oncology drug library. Secondary screens of candidate target genes were performed on the primary tumor cells and two nontumorigenic keratinocyte cell cultures for validation and to assess cancer specificity. siRNA screens of the kinome on two isogenic pairs of p53-mutated HNSCC cell lines were used to determine generalizability. Clinical utility was addressed by performing drug screens on two additional HNSCC cell cultures derived from patients enrolled in a clinical trial.Results: Many of the identified copy number aberrations and somatic mutations in the primary tumor were typical of HPV(−) HNSCC, but none pointed to obvious therapeutic choices. In contrast, siRNA profiling identified 391 candidate target genes, 35 of which were preferentially lethal to cancer cells, most of which were not genomically altered. Chemotherapies and targeted agents with strong tumor-specific activities corroborated the siRNA profiling results and included drugs that targeted the mitotic spindle, the proteasome, and G2–M kinases WEE1 and CHK1. We also show the feasibility of ex vivo drug profiling for patients enrolled in a clinical trial.Conclusions: High-throughput phenotyping with siRNA and drug libraries using patient-derived tumor cells prioritizes mutated driver genes and identifies novel drug targets not revealed by genomic profiling. Functional profiling is a promising adjunct to DNA sequencing for precision oncology. Clin Cancer Res; 24(12); 2828–43. ©2018 AACR.

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Background Larger within‐patient variability of lipid levels has been associated with increased risk of cardiovascular disease (CVD); however, measures of lipid variability require ≥3 measurements and are not currently used clinically. We investigated the feasibility of calculating lipid variability within a large electronic health record–based population cohort and assessed associations with incident CVD. Methods and Results We identified all individuals ≥40 years of age who resided in Olmsted County, MN, on January 1, 2006 (index date), without prior CVD, defined as myocardial infarction, coronary artery bypass graft surgery, percutaneous coronary intervention, or CVD death. Patients with ≥3 measurements of total cholesterol, low‐density lipoprotein cholesterol, high‐density lipoprotein cholesterol, or triglycerides during the 5 years before the index date were retained. Lipid variability was calculated using variability independent of the mean. Patients were followed through December 31, 2020 for incident CVD. We identified 19 652 individuals (mean age 61 years; 55% female), who were CVD‐free and had variability independent of the mean calculated for at least 1 lipid type. After adjustment, those with highest total cholesterol variability had a 20% increased risk of CVD (Q5 versus Q1 hazard ratio, 1.20 [95% CI, 1.06–1.37]). Results were similar for low‐density lipoprotein cholesterol and high‐density lipoprotein cholesterol. Conclusions In a large electronic health record–based population cohort, high variability in total cholesterol, high‐density lipoprotein cholesterol, and low‐density lipoprotein cholesterol was associated with an increased risk of CVD, independent of traditional risk factors, suggesting it may be a possible risk marker and target for intervention. Lipid variability can be calculated in the electronic health record environment, but more research is needed to determine its clinical utility.

While recent efforts to catalogue Earth’s microbial diversity have focused upon surface and marine habitats, 12–20 % of Earth’s biomass is suggested to exist in the terrestrial deep subsurface, compared to ~1.8 % in the deep subseafloor. Metagenomic studies of the terrestrial deep subsurface have yielded a trove of divergent and functionally important microbiomes from a range of localities. However, a wider perspective of microbial diversity and its relationship to environmental conditions within the terrestrial deep subsurface is still required. Our meta-analysis reveals that terrestrial deep subsurface microbiota are dominated by Betaproteobacteria, Gammaproteobacteria and Firmicutes , probably as a function of the diverse metabolic strategies of these taxa. Evidence was also found for a common small consortium of prevalent Betaproteobacteria and Gammaproteobacteria operational taxonomic units across the localities. This implies a core terrestrial deep subsurface community, irrespective of aquifer lithology, depth and other variables, that may play an important role in colonizing and sustaining microbial habitats in the deep terrestrial subsurface. An in silico contamination-aware approach to analysing this dataset underscores the importance of downstream methods for assuring that robust conclusions can be reached from deep subsurface-derived sequencing data. Understanding the global panorama of microbial diversity and ecological dynamics in the deep terrestrial subsurface provides a first step towards understanding the role of microbes in global subsurface element and nutrient cycling.

Background Cognitive impairment and low health literacy are prevalent in patients with heart failure (HF). Low health literacy is associated with poor health outcomes, such as frequent re-hospitalizations and increased mortality. Little is known about the relationships among cognitive impairment, health literacy, and health outcomes (HF rehospitalization and cardiac death). Objective To explore the associations among cognitive impairment, health literacy, and cardiac event-free survival in patients with HF. Methods This was a longitudinal study of 614 rural patients with HF (male 59%, age 66±13 NYHA class III/IV: 35%). Cognitive function was measured using the Mini-Cog test. Health literacy was measured by the Short Test of Functional Health Literacy in Adults. HF hospitalizations and cardiac mortality were followed at least 2 years and obtained by patient interview, medical record review, and death certificate review. Chi-squares, t-tests, ANOVA, Kaplan-Meier with log rank tests, logistic and Cox regressions were used for data analysis. Results Two hundred and seven patients (34%) had cognitive impairment. Compared to those without cognitive impairment, patients with cognitive impairment were 2.77 times more likely to have low health literacy (P Conclusion Patients with cognitive impairment with low health literacy were at high risk of experiencing a cardiac event. Interventions need to be developed to target high risk patients with cognitive impairment and low health literacy, such as older, low-income patients, to alleviate poor outcomes in patients with HF. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): NIH/NHLBI