Specific Endpoints Research Articles

Pragmatic Clinical Trials in Osteoporosis.

In this review, we present the application of pragmatic clinical trials for evaluating interventions in osteoporosis, and we discuss methodological considerations for designing and conducting a pragmatic clinical trial compared with a classical randomized clinical trial. Pragmatic clinical trials are a popular study design testing effectiveness of health interventions and are intended to address the limitations associated with traditional explanatory randomized clinical trials testing efficacy of interventions. To date, only few pragmatic clinical trials have been conducted in osteoporosis. Pragmatic clinical trials are conducted under routine clinical practice setting and are intended to inform policy makers and clinical decisions. Osteoporosis is a chronic disease well-suited to this particular study design given the existence of a clear and specific natural endpoint, namely fracture occurrence, and the availability of several treatments to prevent fractures.

Metabolomic Assessment Reveals Alteration in Polyols and Branched Chain Amino Acids Associated With Present and Future Renal Impairment in a Discovery Cohort of 637 Persons With Type 1 Diabetes.

Background: Improved understanding of the pathophysiology causing diabetic kidney disease (DKD) is imperative. The aim of this study was to uncover associations between serum metabolites and renal outcomes.Methods: Non-targeted serum metabolomics analyses were performed in samples from 637 persons with type 1 diabetes using two-dimensional gas chromatography coupled to time-of-flight mass-spectrometry. Longitudinal data at follow-up (median 5.5 years) on renal events were obtained from national Danish health registries. A composite renal endpoint (n = 123) consisted of estimated glomerular filtration rate (eGFR) decline from baseline (≥30%), progression to end-stage renal disease and all-cause mortality. Metabolites with significant associations (p < 0.05) in any of the cross-sectional analyses with eGFR and albuminuria were analyzed for specific and composite endpoints. Adjustments included traditional cardiovascular risk factors and correction for multiple testing.Results: A data-driven partial correlation analysis revealed a dense fabric of co-regulated metabolites and clinical variables dominated by eGFR. Ribonic acid and myo-inositol were inversely associated with eGFR, positively associated with macroalbuminuria (p < 0.02) and longitudinally associated with higher risk of eGFR decline ≥30% (HR 2.2–2.7, CI [1.3–4.3], p < 0.001). Ribonic acid was associated with a combined renal endpoint (HR 1.8, CI [1.3–2.3], p = 0.001). The hydroxy butyrate 3,4-dihydroxybutanoic acid was cross-sectionally associated with micro- and macroalbuminuria, urinary albumin excretion rate and inversely associated with eGFR (p < 0.04) while branched chain amino acids were associated with eGFR and lower risk of the combined renal endpoint (p < 0.02).Conclusions: Alterations in serum metabolites, particularly polyols and amino acids, were associated with renal endpoints in type 1 diabetes highlighting molecular pathways associated with progression of kidney disease. External validation is needed to further assess their roles and potentials as future therapeutic targets.

State-of-the-art in radiomics of hepatocellular carcinoma: a review of basic principles, applications, and limitations.

Radiomics is a new field in medical imaging with the potential of changing medical practice. Radiomics is characterized by the extraction of several quantitative imaging features which are not visible to the naked eye from conventional imaging modalities, and its correlation with specific relevant clinical endpoints, such as pathology, therapeutic response, and survival. Several studies have evaluated the use of radiomics in patients with hepatocellular carcinoma (HCC) with encouraging results, particularly in the pretreatment prediction of tumor biological characteristics, risk of recurrence, and survival. In spite of this, there are limitations and challenges to be overcome before the implementation of radiomics into clinical routine. In this article, we will review the concepts of radiomics and their current potential applications in patients with HCC. It is important that the multidisciplinary team involved in the treatment of patients with HCC be aware of the basic principles, benefits, and limitations of radiomics in order to achieve a balanced interpretation of the results toward a personalized medicine.

PRO114 EQ-5D UTILITY ESTIMATES FOR PATIENTS WITH SYSTEMIC SCLEROSIS (SSC). INSIGHTS FROM THE FOCUSSCED PHASE III EFFICAY AND SAFETY STUDY OF TOCILIZUMAB.

Estimate utilities for SSc patients based on EQ-5D and assess its relation with disease specific trial endpoints. EQ-5D-3L (n = 210) was collected in focuSSced phase 3 randomised controlled trial. Utilities were estimated using the Dolan tariff. Pearson correlation was assessed between EQ-5D scores and Modified Rodnan Skin Score (mRSS), Forced Vital Capacity (FVC) and Health Assessment Questionnaire Disability Index (HAQ-DI) Score. Least Square mean utilities per different mRSS, FVC and HAQ levels were also estimated and assessed. A mixed model with fixed effects was employed in R® (mlmRev package) for the estimation of utilities, adjusting for baseline utility, age, gender, HAQ-DI and mRSS. Correlation of EQ-5D was strong only vs. HAQ-DI changes. Mean utilities of 0.72, 0.63, 0.55 and 0.42 were observed in mRSS score categories of <11, 12-22, 23-33 and >34 respectively. Similarly, mean utilities of 0.81, 0.69, 0.59, 0.44 and 0.21 were observed for the HAQ-DI score categories of <0.5, 0.5 – 1.1, 1.2 – 1.6, 1.6 to 2.0 and >2.1 respectively. For FVC >80%, mean utility was 0.67 while for those below 80% utility dropped to 0.60. These utility trends are consistent with the disease severity as reflected in those disease specific measurements. 70% percent of the utility weights observed, were within the range of 0.5 and 0.85, with only 16% of ceiling effect values and 6% negative. Among the coefficients included in the mixed model, only base-case utility and HAQ-DI score were statistically significant. The adjusted estimated utility was 0.648 (St. Error 0.019) in a cohort with average age of 48 years. The low adjusted utility observed in this young cohort, indicates the major impact of this disease in the quality of life of these patients. EQ-5D measurements were consistent with the severity of SSc as reflected in the disease specific questionnaires.

Outcomes for carotid endarterectomy in nonagenarians

ObjectiveCarotid endarterectomy (CEA) is a well-established procedure with prospective randomized data demonstrating the benefit of stroke prevention. With the aging of the population, there are limited data published for nonagenarians, especially for asymptomatic stenosis. This study investigated 30-day morbidity and mortality as well as late survival in symptomatic and asymptomatic nonagenarians with severe carotid stenosis undergoing CEA. MethodsA retrospective review was conducted of a single vascular surgery group's registry involving multiple hospitals between November 1994 and June 2017 for all primary CEAs of patients ≥90 years old at the time of surgery. The exclusion criterion was redo surgery or bilateral CEAs. Demographic data, sex, symptoms, risk factors, and postoperative complications were analyzed. Survival analysis was conducted using SPSS software (IBM Corp, Armonk, NY) for the specific end point 30-day morbidity or mortality and late survival. ResultsThere were 77 patients (44 male [57%]) who underwent CEA for symptomatic (44 [57%]) and asymptomatic (33 [43%]) internal carotid artery stenosis with a median age of 92 years; 23 women were symptomatic compared with 21 men, and 23 men were asymptomatic compared with 10 women. Symptomatic patients included amaurosis fugax (n = 3), stroke (n = 16), and transient ischemic attack (n = 25). CEAs were performed using the eversion technique under cervical block with selective shunting. The 30-day morbidity included one (2.3%) nonfatal myocardial infarction and one (2.3%) ischemic stroke in the symptomatic group compared with one (3%) patient having a nonfatal myocardial infarction and none with ischemic stroke in the asymptomatic group. One patient of the symptomatic group required return to the operating room for hematoma evacuation. The 30-day mortality was 2.3% in the symptomatic group compared with 6.1% in the asymptomatic group. There was no statistical difference in survival based on sex (P = .444). The symptomatic and asymptomatic groups had similar median survival of 27.7 months and 29.4 months (P = .987), respectively. ConclusionsThe aging population adds increasing difficulty in decision-making for surgical intervention on carotid stenosis. CEA in nonagenarians is associated with reasonably low 30-day rates of ischemic stroke and myocardial infarction in our small study. However, enthusiasm for asymptomatic CEA in this population must be tempered by low survival rates.

P4468Dietary plant derived omega-3 fatty acid alpha linolenic acid prevents age-dependent arterial stiffness and improves outcome after stroke in mice

Abstract Background A fundamental determinant of cardio- and cerebrovascular diseases is vascular aging, characterized by arterial stiffness. Arterial stiffness is an independent predictor of adverse cardio- and cerebrovascular events and mortality. Fish-derived omega-3 fatty acids (n3-FA) have been described to decrease cardiovascular events in high risk populations. Little is known on the effects of the plant-derived n3 FA alpha-linolenic acid (ALA). More insight is urgently needed, because of the low costs and abundant global supply of ALA. Thus, we aimed to investigate the effects of a long-term dietary intervention with ALA on age-dependent arterial stiffness and the magnitude of these effects on a specific vascular endpoint – ischemic stroke – in a mouse model of aging. Methods C57BL/6 wildtype males were either fed an ALA-rich (high ALA, 7.3 g%) or a respective control (0.3 g%) diet for 12 months, starting from 6 months of age. At 9, 15 and 18 months, arterial stiffness was assessed by measuring pulse wave velocity (PWV) in the right common carotid artery using a Vevo 3100 system (VisualSonics, Fig. 1A). At 18 months, ischemic stroke was induced by transient middle cerebral artery occlusion (30 mins/48 h). Stroke size was assessed by triphenyl tetrazolium chloride staining and neurological function by a Bederson based score. Results Arterial stiffness steadily and significantly increased in controls over time, while ALA clearly and effectively prevented it (PWV at 9 vs. 18 months: controls + 95%; p&lt;0,0001 vs. High ALA + 15%; ns) (Fig 1A). Stroke size at 18 months was significantly decreased in ALA-fed animals compared to controls (28.39 mm3 vs. 51.77 mm3 p=0.0017) (Fig. 1B). In line with the morphological changes, controls performed significantly worse neurologically (Fig. 1C). Additionally, post-stroke survival at 48 h was improved in ALA-fed animals compared to controls, with 85% survival compared to 57% (Fig. 1D). Figure 1 Conclusion We demonstrate that long-term dietary supplementation with the plant-derived ALA fully prevents the development of age-dependent arterial stiffness. The magnitude of this effect is clearly reflected in biologically relevant decreased stroke size, improved neurological performance and even post-stroke survival. This study not only demonstrates vasoprotective effects of ALA, but also links them to improved outcome of a specific clinical endpoint. Future analyses will aim at delineating the molecular basis of the observed benefits. This will result in a better understanding of some ambiguous results from clinical trials and likely define the population which benefits from ALA.

5132Effect of PCSK9 inhibitors treatment on acute coronary syndrome and stroke incidence: a metanalysis of currently available clinical trials

Abstract Background Proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitors have demonstrated to induce large reductions in low-density lipoprotein cholesterol (LDLc) and major cardiovascular events but none of the studies was statistically powered to demonstrate reductions in specific endpoints rather than a combined end-point of major cardiovascular events. Methods We performed an intention-to-treat meta-analysis in line with recommendations from the Cochrane Collaboration and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement using currently available studies involving PCSK9 inhibitors. The endpoint assessed were acute coronary syndrome (ACS) and stroke. Results We included 81,544 patients, 41,147 treated with a PSCK9 inhibitors: 17,179 with evolocumab; 13,718 with bococizumab and 10,250 with alirocumab (table 1). A total of 1,316 ACS were registered in the treatment group vs. 1,608 in controls, resulting in 18.0% reduction associated with PCSK9 treatment (figure 1). This result was reproduced exactly in the EBCT althougt a non-significant heterogeneity was detected (p=0.052). Metaregression analyses did not demonstrate the implication of the study (p=0.45), study drugs (p=0.26), age (p=0.89), hypertension (p=0.81) or diabetes (p=0.81) on such result. Results on stroke incidence are presented in figure 2. PCSK9 inhibitors treatment resulted in a 24% reduction of stroke when all studies were analyzed together; heterogeneity was statistically significant (p=0.021) but it was not observed in the EBCT analysis where PCSK9 inhibitors were associated with 24% stroke incidence reduction. Conclusions The meta-analysis of currently available studies demonstrates that PCSK9 inhibitors treatment reduces the incidence of ACS by 18% and stroke by 24%.

YI02.03 Statistical Pitfalls in Clinical Trial Design

YI02.03 Statistical Pitfalls in Clinical Trial Design

The Role of Gastrointestinal-Related Fatty Acid-Binding Proteins as Biomarkers in Gastrointestinal Diseases.

The fatty acid-binding proteins play a major role in intracellular transportation of long-chain fatty acids. Nine fatty acid-binding proteins have been identified, with each having individual tissue-specific functions in addition to regulation of fatty acids. This review focuses on the three fatty acid-binding proteins found in the gastrointestinal tract and discusses their role as diagnostic or disease monitoring markers in neonatal necrotizing enterocolitis, acute mesenteric ischemia, celiac disease, and inflammatory bowel disease. Of these three fatty acid-binding proteins, intestinal fatty acid-binding protein is of the most interest due to its exclusive expression in the gastrointestinal tract. The elevation of intestinal fatty acid-binding protein in blood and urine reflects enterocyte damage, regardless of the underlying cause. The short half-life of intestinal fatty acid-binding protein also means it is a relatively sensitive marker. In contrast, there is currently less evidence to support liver fatty acid-binding protein and ileal bile acid-binding protein as sensitive biomarkers in these conditions. More extensive studies with specific endpoints are required to validate the roles of these fatty acid-binding proteins in gastrointestinal diseases.

Surface water extracts impair gene profiles and differentiation in human mesenchymal stem cells

Low concentrations of pollutants in surface water challenge the assessment of chronic effects on human health. Human bone mesenchymal stem cells (hBMSCs) were employed as a sensitive and relevant in vitro model to evaluate the potential biological effects caused by mixtures of pollutants in surface water. Organic extracts of surface water collected from Hun River inhibited cell viability in a dose-dependent manner. Surface water extracts at noncytotoxic concentrations induced 533 to 1055 differentially expressed genes (DEGs) in hBMSCs after 48 h of exposure. Total of 370 genes were commonly affected by surface water from different sites and accounted for 35–69% of DEGs impaired by individual sample. Pathways related to human diseases, genetic information processing and organismal systems were enriched based on DEGs. Interleukins (IL1B, IL6 and IL8) were affected and involved in most human diseases related pathways. The significantly downregulation of COL1A1 and the variation of rheumatoid arthritis pathway suggested that surface water potentially inhibited osteogenic differentiation of hBMSCs. Clustering analysis and principle component analysis with DEGs distinguish the surface water from tributary and mainstream. The crossing-species comparison of transcriptomic changes identified 923 and 2715 differentially expressed orthologs in hBMSCs and zebrafish, respectively. After the exposure ceased, the followed osteogenic and adipogenic differentiation in hBMSCs for 14 days were inhibited by the treatment of surface water during undifferentiated period, whereas the non-polar fraction exhibited stronger potency in affecting differentiation than the mid to polar fractions. hBMSCs, combining unsupervised transcriptomic technique and specific endpoints test, are promising in screening the health effects of environmental mixtures in surface water.

Validity of hospital ICD-10-GM codes to identify acute liver injury in Germany.

Acute liver injury (ALI) is an important adverse drug reaction. We estimated the positive predictive values (PPVs) of ICD-10-GM codes of ALI used in an international postauthorisation safety study (PASS). Analyses used routine data (2007 to 2016, adults) from a German academic hospital in a cross-sectional design. Two algorithms from the PASS were applied to extract potential cases from the hospital information system: specific end point (A) (discharge diagnosis of liver disease-specific codes) and less specific end point (B) (discharge and outpatient-specific and nonspecific codes suggestive of liver injury). ALI cases were confirmed on the basis of plasma liver enzyme activity elevation. Secondary analysis was performed following exclusion of cases with known cancer, chronic liver, biliary and pancreatic disease, heart failure, and alcohol-related disorders, as applied in the PASS. On the basis of ICD codes: outcome A, 154 cases (143 with case notes and lab data for case verification); outcome B, 485 cases (357 with case notes and lab data). ALI was confirmed in 71 outcome A cases, PPV of 49.7% (95% confidence interval [CI], 41.2%-58.1%), and 100 outcome B cases, PPV of 28.0% (95% CI, 23.4%-33.0%). Applying exclusion criteria increased PPV (95% CI) to 62.7% (50.0%-74.2%) for outcome A and 45.7% (37.2%-54.3%) for outcome B. In safety studies on hepatotoxicity based on routine data using ICD-10-GM discharge codes and when validation of potential cases is not feasible, only the more specific codes should be used to describe ALI, and competing diagnoses for liver injury should be excluded to avoid substantial misclassification.

The registration continuum in clinical science: A guide toward transparent practices.

Clinical scientists can use a continuum of registration efforts that vary in their disclosure and timing relative to data collection and analysis. Broadly speaking, registration benefits investigators by offering stronger, more powerful tests of theory with particular methods in tandem with better control of long-run false positive error rates. Registration helps clinical researchers in thinking through tensions between bandwidth and fidelity that surround recruiting participants, defining clinical phenotypes, handling comorbidity, treating missing data, and analyzing rich and complex data. In particular, registration helps record and justify the reasons behind specific study design decisions, though it also provides the opportunity to register entire decision trees with specific endpoints. Creating ever more faithful registrations and standard operating procedures may offer alternative methods of judging a clinical investigator's scientific skill and eminence because study registration increases the transparency of clinical researchers' work. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Behavioral effects of chronic WIN 55,212-2 administration during adolescence and adulthood in mice.

Marijuana, a psychoactive drug that activates cannabinoid-1 (CB1) receptors in the brain, is the most prevalently abused illicit drug among American adolescents and young adults. However, the long-term consequences of adolescent exposure to cannabinoids on the brain and behavior remain poorly understood. In both humans and nonhumans, adolescence is characterized by the maturation of the endocannabinoid neurotransmitter system in the prefrontal cortex and striatum-brain regions that underlie choice and decision making and are densely packed with CB1 receptors. In the current study, the effects of chronic WIN 55,212-2 (a CB1 agonist) exposure during adolescence on reversal learning and delay discounting were compared with those of adult-onset exposure using mice. Mice were administered 3.0 mg/kg/day WIN 55,212-2 or vehicle for 21 days beginning in adolescence (postnatal days 28-49) or adulthood (postnatal days 90-111). For the reversal-learning task, there was no difference in errors or omissions to criterion following a reversal in adolescent-exposed mice but adult-exposed mice showed a delay in beginning the reversal, suggesting that adolescents, but not adults, are resilient to this drug. Adult mice given WIN 55,212-2 in adolescence displayed greater impulsivity in the form of preference for smaller-sooner reinforcers over larger-delayed ones in the delay-discounting procedure, but this was seen to a lesser extent with adult-onset exposure. These data underscore the importance of variables related to the timing and duration of exposure as well as the specific and persistent behavioral endpoints affected by chronic cannabinoid administration. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Morphological features of livers of sexual mature dogs

The article describes the features of the macroscopic and microscopic structure of the liver of mature clinically healthy dogs for the use of anatomical, histological and morphometric methods of research. According to the results of organometallic and cytometric studies, the absolute and relative body mass, the volume of hepatocytes, their nuclei and the nuclear-cytoplasmic ratio were determined. Thus, the absolute weight of the liver in the mature dogs is variable and to a certain extent depends on the blood flow to the organ and is 427.4 ± 21.92 g, the relative weight – 2.69 ± 0.1%. Liver of mature dogs is a compact body of flattened form with sharp lower and lateral edges, with deep cuts, dark red color. The histoarhitectonics of the liver of dogs are constructed with connective tissue and parenchyma. The stroma of the organ is formed by a capsule, on top of which is serous membrane. In the area of the gates of the liver, the connective tissue of the capsule penetrates into the middle of the organ, branching and dividing it into lobules. Then it is formed by the hepatic plates by the intraosseous sinusoid capillaries. Liver plates are specific endpoint of the secretory unit of the liver. It has been found that in the microscopic structure of the liver of the dogs, the interstitial connective tissue is poorly developed, therefore the boundaries between the liver lobules are not sufficient. The liver plates behind the microscopic structure have a radial direction from the center to the periphery. The direction closer to the periphery of the particles is less noticeable, since hepatocytes are located in two rows, between which the sinusoidal space clearly appears. Hepatocytes had an irregular, multifaceted form. Their nuclei, which were mainly in the center of the cell, had little clarity of contours of carriel and well perceived color. During microscopic examination of the liver, it is swollen that hepatocytes of the central and intermediate zones are better perceived by color than the cytoplasm of the cells of the peripheral zone of the liver. According to the analysis of our cytomorphometric studies, hepatocytes of dogs have different sizes, which vary in wide range: from small to large. Whereas the average volume of hepatocytes in mature dogs is 964.72 ± 56.003 μm³; the average volume of their nuclei is 105.13 ± 2.02 microns. The nuclear-cytoplasmic ratio of hepatocytes in dogs of this group is 0.128 ± 0.122.

Combination of yeast-based in vitro screens with high-performance thin-layer chromatography as a novel tool for the detection of hormonal and dioxin-like compounds

The combination of classic in vitro bioassays with high-performance thin-layer chromatography (HPTLC) is a promising technique to directly link chemical analysis of contaminants to their potential adverse biological effects. With respect to endocrine disruption, much work is focused on estrogenicity. While a direct combination of HPTLC and the yeast estrogen screen is already developed, it is well accepted that further endocrine effects are relevant for monitoring environmental wellbeing. Here we show that non-estrogenic specific biological endpoints, (partly) related to the endocrine system, can also be addressed by combining respective yeast reporter gene assays with HPTLC to support effect-directed analysis (EDA). These are: androgenicity (YAS), thyroidogenicity (YTS), dioxin-like effects (YDS), effects on the vitamin D (YVS) and the retinoic acid receptor (YRaS). A proof of principle is demonstrated within this study by the characterization of dose-dependent responses to different model compounds for the respective receptors with and without chromatographic development of the HPTLC-plate. Limits of quantification (LOQ) for several model compounds were determined, e.g. 37 pg for testosterone (p-YAS), 0.476 ng for β-naphthoflavone (p-YDS) and 1.02 ng for calcipotriol hydrate (p-YVS) with chromatographic development. The LOQ for p-YTS and p-YRaS were 10.16 pg for 3,3’,5-triiodothyroacetic acid (p-YTS) and 0.41 pg for tamibarotene (p-YRaS), without chromatographic separation. Furthermore, we challenged the developed methodology using environmental samples, demonstrating an elimination efficiency of androgenic activity from municipal wastewater by a wastewater treatment plant between 99.4 and 100%. We anticipate our methodology to substantially broaden the spectrum of specific endpoints combined with HPTLC for an efficient and robust screening of environmental samples to guide a subsequent in-depth EDA.

Abstract LB-112: Unraveling biology and identifying targets with functional genomics approaches using lentiarray crispr libraries

Abstract The ability of CRISPR/Cas9, to efficiently and precisely edit a cell’s DNA and introduce a complete genetic knockout, while minimizing off-target effects, offers an improved approach to target identification. Identifying and validating targets that underlie disease mechanisms still remains a significant challenge in the drug discovery and development process. The transcription factor NF-κB is a crucial player in many aspects of cancer initiation and progression. Here we demonstrate a knock-out screening approach that utilizes an arrayed CRISPR library to interrogate the impact of individual gene knock-outs on the NF-κB pathway in a cervical carcinoma cell line as measured by a functional cell-based assay. We describe the library design concepts, the assay development, screening results and validation of specific identified hits. We tested the approach using a library that targets the human kinome and developed a loss-of-function assay using CellSensor™ NF-κB-bla ME-180 cell line, which stably expresses Cas9. The CellSensor™ reporter assay enables easy identification of genomic targets associated with the NF-κB pathway. We elucidate the key factors in developing a robust assay including both transduction and assay optimization to achieve the highest levels of transduction efficiency and assay window. Using the optimized parameters, we screened the LentiArray CRISPR human kinome library that targets &amp;gt;800 kinases and demonstrate how we followed-up on and validated a subset of the identified hits. The hits were further validated by confirming nucleotide(s) deletion/ insertion in target DNA and additional screening using target specific siRNA and chemical compounds. The ability to scale this approach through the generation of genome wide CRISPR libraries, coupled with the use of lentiviral delivery methods enables high-throughput (HTP) loss-of-function screens to be performed rapidly and identify genes whose activity is important for the specific endpoint being measured. These screenings can provide a wealth of data on the normal functioning of a target and in turn, should yield better validated targets for progression into full drug discovery. Ultimately, the hits from the HTP screenings can be followed up by using CRISPR technology to generate animal knockout models that would support translating the screen to the pre-clinical trials. This in turn could provide better correlation to the clinical setting and thereby reduce candidate drug attrition. Citation Format: Chetana M. Revankar, Julia Braun, Jian-Ping Yang, Justin Wetter, Tufan Gokirmak, Namritha Ravinder, Jon Chesnut, David Piper. Unraveling biology and identifying targets with functional genomics approaches using lentiarray crispr libraries [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-112.

Systematic Review on Polyphenol Intake and Health Outcomes: Is there Sufficient Evidence to Define a Health-Promoting Polyphenol-Rich Dietary Pattern?

Growing evidence support association between polyphenol intake and reduced risk for chronic diseases, even if there is a broad debate about the effective amount of polyphenols able to exert such protective effect. The present systematic review provides an overview of the last 10-year literature on the evaluation of polyphenol intake and its association with specific disease markers and/or endpoints. An estimation of the mean total polyphenol intake has been performed despite the large heterogeneity of data reviewed. In addition, the contribution of dietary sources was considered, suggesting tea, coffee, red wine, fruit and vegetables as the main products providing polyphenols. Total flavonoids and specific subclasses, but not total polyphenols, have been apparently associated with a low risk of diabetes, cardiovascular events and all-cause mortality. However, large variability in terms of methods for the evaluation and quantification of polyphenol intake, markers and endpoints considered, makes it still difficult to establish an evidence-based reference intake for the whole class and subclass of compounds. Nevertheless, the critical mass of data available seem to strongly suggest the protective effect of a polyphenol-rich dietary pattern even if further well targeted and methodologically sound research should be encouraged in order to define specific recommendations.

Can tools contribute to integration in MSP? A comparative review of selected tools and approaches

The role of tools and approaches is currently much debated in maritime spatial planning (MSP). Past evaluation has mainly concentrated on decision support tools and the tangible outputs these can provide for MSP, but little attention has so far been been given to the soft or indirect benefits tool use can have in MSP. This paper assesses the potential benefits of tool use in the context of four common integration challenges in MSP. Drawing on case study material from the Baltic Sea region, the paper reviews the potential contribution of five selected tools and approaches to multi-level and transboundary, policy and sector, stakeholder and knowledge integration. Specific end points are defined for each integration challenge, including general desired outcomes of integrated MSP processes as a template for assessment. Our review shows that the selected tools play different roles in moving towards the various end points of MSP integration. There is an important difference between the potential of each tool, or its inherent capacity, and how it is applied, e.g. in a participative or non-participative setting. Another lesson is that some integration benefits can be achieved by the tools alone, while others – often secondary benefits - depend on how the outcomes of tool use are taken up by the subsequent MSP process. Although the nature of a tool does restrict its potential contribution to MSP integration challenges, the secondary “soft” benefits that can be achieved through certain styles of application and good links to the MSP process can add important integration benefits up and beyond the tool itself. The results presented here may also be relevant to other types of spatial planning and conservation management.

Treatment of Cardiorenal Syndrome.

The treatment of cardiorenal syndrome is as complex as the various mechanisms underlying its pathophysiology. Randomized controlled data typically focus on the treatment of heart failure with cardiac specific endpoints and a lack of worsening renal function used as a surrogate for efficacy. When heart failure is considered the inciting event, the acute state is managed with vasodilators, inotropic support, and decongestion; whereas neurohormonal axis inhibition is more commonly applied to chronic state. A recent shift in thought process regarding the interplay of cardiac and renal dysfunction suggests that renal congestion may be the primary driver of worsening renal function.

In Vivo Force Application Reveals a Fast Tissue Softening and External Friction Increase during Early Embryogenesis

SummaryDuring development, cell-generated forces induce tissue-scale deformations to shape the organism [1, 2]. The pattern and extent of these deformations depend not solely on the temporal and spatial profile of the generated force fields but also on the mechanical properties of the tissues that the forces act on. It is thus conceivable that, much like the cell-generated forces, the mechanical properties of tissues are modulated during development in order to drive morphogenesis toward specific developmental endpoints. Although many approaches have recently emerged to assess effective mechanical parameters of tissues [3, 4, 5, 6, 7, 8], they could not quantitatively relate spatially localized force induction to tissue-scale deformations in vivo. Here, we present a method that overcomes this limitation. Our approach is based on the application of controlled forces on a single microparticle embedded in an individual cell of an embryo. Combining measurements of bead displacement with the analysis of induced deformation fields in a continuum mechanics framework, we quantify material properties of the tissue and follow their changes over time. In particular, we uncover a rapid change in tissue response occurring during Drosophila cellularization, resulting from a softening of the blastoderm and an increase of external friction. We find that the microtubule cytoskeleton is a major contributor to epithelial mechanics at this stage. We identify developmentally controlled modulations in perivitelline spacing that can account for the changes in friction. Overall, our method allows for the measurement of key mechanical parameters governing tissue-scale deformations and flows occurring during morphogenesis.