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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.

BackgroundSuicide deaths have been increasing for the past 20 years in the USA resulting in 45 979 deaths in 2020, a 29% increase since 1999. Lack of data linkage between entities with potential to implement large suicide prevention initiatives (health insurers, health institutions and corrections) is a barrier to developing an integrated framework for suicide prevention.ObjectivesData linkage between death records and several large administrative datasets to (1) estimate associations between risk factors and suicide outcomes, (2) develop predictive algorithms and (3) establish long-term data linkage workflow to ensure ongoing suicide surveillance.MethodsWe will combine six data sources from North Carolina, the 10th most populous state in the USA, from 2006 onward, including death certificate records, violent deaths reporting system, large private health insurance claims data, Medicaid claims data, University of North Carolina electronic health records and data on justice involved individuals released from incarceration. We will determine the incidence of death from suicide, suicide attempts and ideation in the four subpopulations to establish benchmarks. We will use a nested case–control design with incidence density-matched population-based controls to (1) identify short-term and long-term risk factors associated with suicide attempts and mortality and (2) develop machine learning-based predictive algorithms to identify individuals at risk of suicide deaths.DiscussionWe will address gaps from prior studies by establishing an in-depth linked suicide surveillance system integrating multiple large, comprehensive databases that permit establishment of benchmarks, identification of predictors, evaluation of prevention efforts and establishment of long-term surveillance workflow protocols.

This paper assesses the state-of-the-art for rubber tire wheel tracking of asphalt mixtures in a laboratory setting with emphasis on differentiating moisture damage from rutting. This assessment made use of a comprehensive literature review and roughly 300 experiments conducted over several years with the second generation of the Purdue Laboratory Wheel Tracker (PURWheel). The literature review revealed that direct separation of rutting from moisture damage with physical measurements taken with a rubber tire under otherwise identical conditions is not common practice. Collective analysis of these roughly 300 experiments revealed that second-generation PURWheel protocols offer two specific contributions to the asphalt mixture testing community: (1) a pneumatic rubber tire is used, which is most representative of vehicle traffic; and (2) the effects of moisture damage can be decoupled from rutting by testing under both wet and dry conditions where all other parameters are constant. The analysis was performed on data collected for other purposes, but the data did provide seven manners to evaluate moisture damage and three manners to evaluate variability in the context of standardizing protocols. These 10 evaluations clearly demonstrated the potential of rubber tire wheel tracking to improve characterization of asphalt mixtures beyond what has occurred to date. This paper works toward standardization of protocols for rubber tire wheel tracking in wet and dry conditions, and some discussion is provided on the status and needed advancements toward this eventual goal.

Supplementary Fig. S4 shows the effects of USP36 on DGCR8 ubiquitination and that USP36 SUMOylation of DGCR8 does not depend on its DUB activity.

miRNA biogenesis is a cellular process that produces mature miRNAs from their primary transcripts, pri-miRNAs, via two RNAse III enzyme complexes: the Drosha-DGCR8 microprocessor complex in the nucleus and the Dicer-TRBP complex in the cytoplasm. Emerging evidence suggests that miRNA biogenesis is tightly regulated by posttranscriptional and posttranslational modifications and aberrant miRNA biogenesis is associated with various human diseases including cancer. DGCR8 has been shown to be modified by SUMOylation. Yet, the SUMO ligase mediating DGCR8 SUMOylation is currently unknown. Here, we report that USP36, a nucleolar ubiquitin-specific protease essential for ribosome biogenesis, is a novel regulator of DGCR8. USP36 interacts with the microprocessor complex and promotes DGCR8 SUMOylation, specifically modified by SUMO2. USP36-mediated SUMOylation does not affect the levels of DGCR8 and the formation of the Drosha-DGCR8 complex, but promotes the binding of DGCR8 to pri-miRNAs. Consistently, abolishing DGCR8 SUMOylation significantly attenuates its binding to pri-miRNAs and knockdown of USP36 attenuates pri-miRNA processing, resulting in marked reduction of tested mature miRNAs. Induced expression of a SUMOylation-defective mutant of DGCR8 inhibits cell proliferation. Together, these results suggest that USP36 plays an important role in regulating miRNA biogenesis by SUMOylating DGCR8.Significance:This study identifies that USP36 mediates DGCR8 SUMOylation by SUMO2 and is critical for miRNA biogenesis. As USP36 is frequently overexpressed in various human cancers, our study suggests that deregulated USP36-miRNA biogenesis pathway may contribute to tumorigenesis.

Supplementary Data from NOTCH Signaling Limits the Response of Low-Grade Serous Ovarian Cancers to MEK Inhibition

Supplementary Figure from NOTCH Signaling Limits the Response of Low-Grade Serous Ovarian Cancers to MEK Inhibition

Related Article from A Systems Approach to Analysis of Molecular Complexity in Breast Cancer

In this issue of Clinical Cancer Research, Andre et al. apply high-resolution arrays to elucidate copy number anomalies in breast cancer. They identify distinct copy number anomaly patterns in different breast cancer subtypes that implicate a number of genes as potential therapeutic targets and as potential markers of therapy responsiveness.

Supplementary Data from Pharmacodynamic Markers of Perifosine Efficacy

Purpose: Using reverse phase protein array, we measured protein expression associated with response to primary chemotherapy in patients with advanced-stage, high-grade serous ovarian cancer.Experimental Design: Tumor samples were obtained from 45 patients with advanced high-grade serous cancers from the Gynecology Tumor Bank at the British Columbia Cancer Agency. Treatment consisted of platinum-based chemotherapy following debulking surgery. Protein lysates were prepared from fresh frozen tumor samples, and 80 validated proteins from signaling pathways implicated in ovarian carcinogenesis were measured by reverse phase protein array. Normalization of Ca-125 by the 3rd cycle of chemotherapy was chosen as the primary outcome measure of chemotherapy response. Logistic regression was used for multivariate analysis to identify protein predictors of Ca-125 normalization and Cox regression to test for the association between protein expression and progression-free survival. A significance level of P ≤ 0.05 was used.Results: The mean age at diagnosis was 56.8 years. epidermal growth factor receptor, YKL-40, and several transforming growth factor β (TGF-β) pathway proteins [c-jun–NH2–kinase (JNK), JNK phosphorylated at residues 183 and 185, plasminogen activator inhibitor 1, Smad3, TAZ] showed significant associations with Ca-125 normalization on univariate testing. On multivariate analysis, epidermal growth factor receptor (P < 0.02), JNK (P < 0.01), and Smad3 (P < 0.04) were significantly associated with normalization of Ca-125. Contingency table analysis of pathway-classified proteins revealed that the selection of TGF-β pathway proteins was unlikely because of false discovery (P < 0.007; Bonferroni adjusted).Conclusion: TGF-β pathway signaling likely plays an important role as a marker or mediator of chemoresistance in advanced serous ovarian cancer. On this basis, future studies to develop and validate a useful predictor of treatment failure are warranted. Clin Cancer Res; 16(10); 2852–60. ©2010 AACR.

Purpose: It is critical to develop methods to quantify the early pharmacodynamic effects of targeted therapeutics in vivo to make drug development more efficient and ensure biologically relevant dosing. Furthermore, an ability to identify patients likely to respond to targeted therapeutics would decrease the size, duration, and cost of clinical trials, resulting in more efficient translation to improved patient outcomes. Recent studies suggest that perifosine inhibits the phosphatidylinositol-3′-kinase (PI3K) pathway by preventing cell membrane recruitment of the AKT pleckstrin homology domain.Experimental Design: A novel functional proteomics technology, reverse phase protein array, was used to establish and quantify pharmacodynamic markers of perifosine efficacy.Results: Perifosine selectively prevents AKT recruitment to the membrane and blocks activation of downstream effectors. Perifosine inhibited breast, ovarian, and prostate cancer models. Growth inhibition was associated with apoptosis. Activation of AKT as a consequence of genomic aberrations predicted perifosine efficacy. In cell lines and xenografts, there was a highly statistically significant correlation between the degree of antitumor efficacy of different perifosine doses and quantified down-regulation of phosphorylation of AKT and of its downstream targets, particularly S6.Conclusions: Because of a strong correlation between proportional modulation of PI3K pathway biomarkers and quantified perifosine efficacy, it is likely that early measurement of such pharmacodynamic biomarkers with reverse phase protein array will optimize selection of responding patients and guide perifosine dosing. Furthermore, PI3K pathway activation status may allow baseline selection of patients most likely to respond to perifosine alone or in combination with other therapies.

Supplementary Data from c-Jun-NH2-kinase-1 Inhibition Leads to Antitumor Activity in Ovarian Cancer

Supplementary Table S1 from Functional Proteomic Analysis of Advanced Serous Ovarian Cancer Using Reverse Phase Protein Array: TGF-β Pathway Signaling Indicates Response to Primary Chemotherapy

Purpose: To show the functional, clinical, and biological significance of c-Jun-NH2-kinase (JNK)-1 in ovarian carcinoma.Experimental Design: Analysis of the impact of JNK on 116 epithelial ovarian cancers was conducted. The role of JNK in vitro and in experimental models of ovarian cancer was assessed. We studied the role of N-5-[4-(4-methyl piperazine methyl)-benzoylamido]-2-methylphenyl-4-[3-(4-methyl)-pyridyl]-2-pyrimidine amine (WBZ_4), a novel JNK inhibitor redesigned from imatinib based on targeting wrapping defects, in cell lines and in experimental models of ovarian cancer.Results: We found a significant association of pJNK with progression-free survival in the 116 epithelial ovarian cancers obtained at primary debulking therapy. WBZ_4 led to cell growth inhibition and increased apoptosis in a dose-dependent fashion in four ovarian cancer cell lines. In vivo, whereas imatinib had no effect on tumor growth, WBZ_4 inhibited tumor growth in orthotopic murine models of ovarian cancer. The antitumor effect was further increased in combination with docetaxel. Silencing of JNK-1 with systemically administered siRNA led to significantly reduced tumor weights compared with nonsilencing siRNA controls, indicating that indeed the antitumor effects observed were due to JNK-1 inhibition.Conclusions: These studies identify JNK-1 as an attractive therapeutic target in ovarian carcinoma and that the redesigned WBZ_4 compound should be considered for further clinical development. Clin Cancer Res; 16(1); 184–94

Low-grade serous ovarian carcinoma (LGSOC) is a rare tumor subtype with high case fatality rates in patients with metastatic disease. There is a pressing need to develop effective treatments using newly available preclinical models for therapeutic discovery and drug evaluation. Here, we use multiomics integration of whole-exome sequencing, RNA sequencing, and mass spectrometry–based proteomics on 14 LGSOC cell lines to elucidate novel biomarkers and therapeutic vulnerabilities. Comparison of LGSOC cell line data with LGSOC tumor data enabled predictive biomarker identification of MEK inhibitor (MEKi) efficacy, with KRAS mutations found exclusively in MEKi-sensitive cell lines and NRAS mutations found mostly in MEKi-resistant cell lines. Distinct patterns of Catalogue of Somatic Mutations in Cancer mutational signatures were identified in MEKi-sensitive and MEKi-resistant cell lines. Deletions of CDKN2A/B and MTAP genes were more frequent in cell lines than tumor samples and possibly represent key driver events in the absence of KRAS/NRAS/BRAF mutations. These LGSOC cell lines were representative models of the molecular aberrations found in LGSOC tumors. For prediction of in vitro MEKi efficacy, proteomic data provided better discrimination than gene expression data. Condensin, minichromosome maintenance, and replication factor C protein complexes were identified as potential treatment targets in MEKi-resistant cell lines. This study suggests that CDKN2A/B or MTAP deficiency may be exploited using synthetically lethal treatment strategies, highlighting the importance of using proteomic data as a tool for molecular drug prediction. Multiomics approaches are crucial to improving our understanding of the molecular underpinnings of LGSOC and applying this information to develop new therapies.Significance:These findings highlight the utility of global multiomics to characterize LGSOC cell lines as research models, to determine biomarkers of MEKi resistance, and to identify potential novel therapeutic targets.

Supplementary Data from Multiomics Characterization of Low-Grade Serous Ovarian Carcinoma Identifies Potential Biomarkers of MEK Inhibitor Sensitivity and Therapeutic Vulnerability

Background We tested the hypothesis that inhibitor of apoptosis family (IAP) proteins may be altered in BRCA1-mutated ovarian cancers and that could affect the sensitivity to IAP inhibitors. Methods The levels of IAP proteins were evaluated in human cancers and cell lines. Cell lines were used to determine the effects of IAP inhibitors. The in vivo effects of treatments were evaluated in PDX mouse models. Results Expression of X-linked inhibitor of apoptosis (XIAP) is increased in BRCA1-mutated cancers and high levels are associated with improved patient outcomes after platinum chemotherapy. XIAP overexpression is mediated by NF-kB activation and is associated with an optimisation of PARP. BRCA1-mutated cell lines are particularly sensitive to IAP inhibitors due to an inhibitory effect on PARP. Both a BRCA1-mutated cell line with acquired resistance to PARP inhibitors and one with restored BRCA1 remain sensitive to IAP inhibitors. Treatment with IAP inhibitors restores the efficacy of PARP inhibition in these cell lines. The IAP inhibitor LCL161 alone and in combination with a PARP inhibitor, exhibited antitumour effects in PDX mouse models of resistant BRCA2 and 1-mutated ovarian cancer, respectively. Conclusion A clinical trial may be justified to further investigate the utility of IAP inhibitors.

Treatment of HF or HCl/LiF etched Ti3C2Tz with 0.05 M NaHCO3 before water washing reduces the wastewater generated by 75%. Cryolite is precipated from the spent etching media.

In 2019, the National Health Interview survey found that nearly 59% of adults reported pain some, most, or every day in the past 3 months, with 39% reporting back pain, making back pain the most prevalent source of pain, and a significant issue among adults. Often, identifying a direct, treatable cause for back pain is challenging, especially as it is often attributed to complex, multifaceted issues involving biological, psychological, and social components. Due to the difficulty in treating the true cause of chronic low back pain (cLBP), an over-reliance on opioid pain medications among cLBP patients has developed, which is associated with increased prevalence of opioid use disorder and increased risk of death. To combat the rise of opioid-related deaths, the NIH initiated the Helping to End Addiction Long-TermSM (HEAL) initiative, whose goal is to address the causes and treatment of opioid use disorder while also seeking to better understand, diagnose, and treat chronic pain. The NIH Back Pain Consortium (BACPAC) Research Program, a network of 14 funded entities, was launched as a part of the HEAL initiative to help address limitations surrounding the diagnosis and treatment of cLBP. This paper provides an overview of the BACPAC research program‘s goals and overall structure, and describes the harmonization efforts across the consortium, define its research agenda, and develop a collaborative project which utilizes the strengths of the network. The purpose of this paper is to serve as a blueprint for other consortia tasked with the advancement of pain related science.

In the US, over 200 lives are lost from opioid overdoses each day. Accurate and prompt diagnosis of opioid use disorders (OUD) may help prevent overdose deaths. However, International Classification of Disease (ICD) codes for OUD are known to underestimate prevalence, and their specificity and sensitivity are unknown. We developed and validated algorithms to identify OUD in electronic health records (EHR) and examined the validity of OUD ICD codes.Through four iterations, we developed EHR-based OUD identification algorithms among patients who were prescribed opioids from 2014-2017. The algorithms and OUD ICD codes were validated against 169 independent "gold standard" EHR chart reviews conducted by an expert adjudication panel across four healthcare systems. After using 2014-2020 EHR for validating iteration 1, the experts were advised to use 2014-2017 EHR thereafter.Of the 169 EHR charts, 81 (48%) were reviewed by more than one expert and exhibited 85% expert agreement. The experts identified 54 OUD cases. The experts endorsed all 11 OUD criteria from the Diagnostic and Statistical Manual of Mental Disorders-5, including craving (72%), tolerance (65%), withdrawal (56%), and recurrent use in physically hazardous conditions (50%). The OUD ICD codes had 10% sensitivity and 99% specificity, underscoring large underestimation. In comparison our algorithm identified OUD with 23% sensitivity and 98% specificity.This is the first study to estimate the validity of OUD ICD codes and develop validated EHR-based OUD identification algorithms. This work will inform future research on early intervention and prevention of OUD.

Background Many older people are brought to the Emergency Department (ED) who do not require acute hospital admission but there are risks to these patients if this occurs. The Frailty Intervention Team (FIT) are an interdisciplinary team based in the ED including physiotherapy, occupational therapy, speech and language therapy, dietetics, pharmacy, advanced nurse practitioners, and a geriatric registrar and consultant. They assess frail older patients and suggest alternative care pathways to admission. We aimed to investigate the impact of FIT on admission avoidance, bed days saved and to obtain patient feedback on their experience. Methods Routinely collected data from May 2021 to April 2022 was reviewed retrospectively. An anonymous patient feedback questionnaire was posted to 40 patients randomised from the FIT worklist between January to May 2022. Results 2,025 Comprehensive Geriatric Assessments (CGA) were completed between May 2021 and April 2022. 38% percent of patients were discharged home, 45% of this number had follow-up arranged. 104 patients were transferred directly to an offsite bed, mostly rehabilitation. We estimate we avoided 51 admissions to the acute hospital per month, almost half of these were patients admitted to the hospital and, who we discharged to alternative care pathways or home. The average length of stay in April 2022 was 22 days – by avoiding 615 admissions between May 2021 and April 2022 we have saved 13,530 bed days at an estimated cost saving of almost €11 million. 15 completed questionnaires were returned. 73% were very satisfied with their experience. 87% felt the FIT team helped facilitate their discharge from ED. The main themes identified from open ended questions included thorough assessment, patient centred care and satisfaction with early intervention and discharge. Conclusion A Frailty Intervention Team is a cost effective and patient centred way of avoiding unnecessary admissions for older people presenting to the ED.

Background The Department of Health published new guidance in November 2020 “Vitamin D advice for people aged 65 and older” which recommended that all adults ≥65 years should be supplemented with 15micrograms of Vitamin D daily. 55.5% of adults ≥65 years have insufficient/deficient vitamin D levels in winter (TILDA 2020). The Frailty Intervention Team (FIT) assess frail adults ≥65 years in the Emergency Department using medication review and Comprehensive Geriatric Assessment to identify vitamin D supplementation. The audit aim was to determine if compliance with the new guideline improved since the initial audit in January 2021. Methods All patients who had a medicine reconciliation completed by the FIT Pharmacist in January 2022 were included in a retrospective audit. Patients were identified from the pharmacist’s worklist. Data was collected from a Hospital Clinical System using a Microsoft Excel®. The data recorded included: Age, Sex, Rockwood Clinical Frailty Score (CFS) and vitamin D supplementation. Results The FIT Pharmacist completed 66 medicine reconciliations in January 2022. The mean age (+/-SD) was 82.4 (+/-7.6) years.The male to female ratio was 1:1.75The median CFS was 5 (mildly/moderately frail) with an IQR of 1. 68% (n=45) were prescribed vitamin D. Of those 89% (n=40) were prescribed a supplement containing at least 15micrograms of vitamin D. 32% (n=21) were not prescribed any vitamin D supplementation. 8% (n=5) were prescribed doses lower than 15micrograms of vitamin D. Conclusion Compliance with the new guideline was 61% (n=40) in comparison to 65% (n=39) in the initial audit. The results are reflective of adherence to the new guideline in the community. The policy update and education provided post the initial audit has possibly influenced the prescribing of vitamin D in the acute setting which unless patients are re-presenting will not have been captured in the outcome of this re-audit.

Background Inappropriate polypharmacy and ‘Potentially Inappropriate Prescriptions’ (PIP) are associated with increased morbidity and hospitalisation, in particular among frail older persons. A structured medication review, in conjunction with a Comprehensive Geriatric Assessment (CGA), can address PIP. The aim of the study was to review Frail Intervention Team (FIT) pharmacist interventions for frail, older adults presenting to the Emergency Department (ED) and experiencing medication compliance difficulties, polypharmacy and PIP. Methods Patients identified for medication review included those experiencing polypharmacy or medication compliance issues, presenting with a fall, delirium and/or frailty syndromes or complex comorbidities. The medication review process involved completion of medicines reconciliation and medication appropriateness review in accordance with the 7-Steps Medication Review Model (Scottish Government Polypharmacy Model of Care Group, 2018). Pharmacist optimisation recommendations were reviewed by a Consultant Geriatrician or Registrar and discussed with the patient prior to implementation. Results The FIT Pharmacist completed medication reviews for 765 patients between May 2021 and April 2022. The mean age (+/-SD) was 83.1 (+/-7.0) years with a median Clinical Frailty Score (CFS) of 5 (mildly/moderately frail). Medication Optimisation recommendations were actioned in 63% (n=483) of patients reviewed. The most commonly encountered PIP’s included: excessive anti-hypertensive/diuretic therapy, long-term acid-suppression therapy, anticholinergics and long-term prophylactic antimicrobials. Prescribing opportunities identified included: bone protection, laxatives and pain management. Conclusion FIT pharmacist review, in conjunction with the CGA, led to medication optimisation interventions in the frail older adult cohort presenting to the ED. Future studies should examine the impact of medication review on patient outcomes post-discharge.

Camera trap studies have become a popular medium to assess many ecological phenomena including population dynamics, patterns of biodiversity, and monitoring of endangered species. In conjunction with the benefit to scientists, camera traps present an unprecedented opportunity to involve the public in scientific research via image classifications. However, this engagement strategy comes with a myriad of complications. Volunteers vary in their familiarity with wildlife, and thus, the accuracy of user-derived classifications may be biased by the commonness or popularity of species and user-experience. From an extensive multi-site camera trap study across Michigan U.S.A, images were compiled and identified through a public science platform called Michigan ZoomIN. We aggregated responses from 15 independent users per image using multiple consensus methods to assess accuracy by comparing to species identification completed by wildlife experts. We also evaluated how different factors including consensus algorithms, study area, wildlife species, user support, and camera type influenced the accuracy of user-derived classifications. Overall accuracy of user-derived classification was 97%; although, several canid (e.g., Canis lupus, Vulpes vulpes) and mustelid (e.g., Neovison vison) species were repeatedly difficult to identify by users and had lower accuracy. When validating user-derived classification, we found that study area, consensus method, and user support best explained accuracy. To continue to overcome stigma associated with data from untrained participants, we demonstrated their value by showing the accuracy from volunteers was comparable to experts when classifying North American mammals. Our hierarchical workflow that integrated multiple consensus methods lead to more image classifications without extensive training and even when the expertise of the volunteer was unknown. Ultimately, adopting such an approach can harness broader participation, expedite future camera trap data synthesis, and improve allocation of resources by scholars to enhance performance of public participants and increase accuracy of user-derived data.

Readmissions and emergency department (ED) visits after colorectal surgery (CRS) are common, burdensome, and costly. Effective strategies to reduce these unplanned postdischarge health care visits require a nuanced understanding of how and why patients make the decision to seek care. We used a purposefully stratified sample of 18 interview participants from a prospective cohort of adult CRS patients. Thirteen (72%) participants had an unplanned postdischarge health care visit. Participant decision-making was classified by methodology (algorithmic, guided, or impulsive), preexisting rationale, and emotional response to perceived health care needs. Participants voiced clear mental algorithms about when to visit an ED. In addition, participants identified facilitators and barriers to optimal health care use. They also identified tangible targets for health care utilization reduction efforts, such as improved care coordination with streamlined discharge instructions and improved communication with the surgical team. Efforts should be directed at improving postdischarge communication and care coordination to reduce CRS patients’ high-resource health care utilization.