Valor Health

DNA-encoded chemical library (DEL) technology provides a time- and cost-efficient method to simultaneously screen billions of compounds for their affinity to a protein target of interest. Here we report its use to identify a novel chemical series of inhibitors of the thioesterase activity of polyketide synthase 13 (Pks13) from Mycobacterium tuberculosis (Mtb). We present three chemically distinct series of inhibitors along with their enzymatic and Mtb whole cell potency, the measure of on-target activity in cells, and the crystal structures of inhibitor-enzyme complexes illuminating their interactions with the active site of the enzyme. One of these inhibitors showed a favorable pharmacokinetic profile and demonstrated efficacy in an acute mouse model of tuberculosis (TB) infection. These findings and assay developments will aid in the advancement of TB drug discovery.

Abstract Coagulation factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are critical to coagulation and platelet aggregation. We leveraged whole-genome sequence data from the Trans-Omics for Precision Medicine (TOPMed) program along with TOPMed-based imputation of genotypes in additional samples to identify genetic associations with circulating FVIII and VWF levels in a single-variant meta-analysis, including up to 45 289 participants. Gene-based aggregate tests were implemented in TOPMed. We identified 3 candidate causal genes and tested their functional effect on FVIII release from human liver endothelial cells (HLECs) and VWF release from human umbilical vein endothelial cells. Mendelian randomization was also performed to provide evidence for causal associations of FVIII and VWF with thrombotic outcomes. We identified associations (P < 5 × 10−9) at 7 new loci for FVIII (ST3GAL4, CLEC4M, B3GNT2, ASGR1, F12, KNG1, and TREM1/NCR2) and 1 for VWF (B3GNT2). VWF, ABO, and STAB2 were associated with FVIII and VWF in gene-based analyses. Multiphenotype analysis of FVIII and VWF identified another 3 new loci, including PDIA3. Silencing of B3GNT2 and the previously reported CD36 gene decreased release of FVIII by HLECs, whereas silencing of B3GNT2, CD36, and PDIA3 decreased release of VWF by HVECs. Mendelian randomization supports causal association of higher FVIII and VWF with increased risk of thrombotic outcomes. Seven new loci were identified for FVIII and 1 for VWF, with evidence supporting causal associations of FVIII and VWF with thrombotic outcomes. B3GNT2, CD36, and PDIA3 modulate the release of FVIII and/or VWF in vitro.

Purpose: The purpose of this research is to investigate the relationships between a number of SDG’s important aspects. This study looks at Islamic business risks, macroeconomics, disclosure related to Corporate Social Responsibility (CSR), and the effect of having female members on the board of directors on the value of the company. Theoretical framework: The theoretical basis is the literature on the relationship between the Sustainable Development Goals (SDGs) and the business practices implemented by corporations. The study's findings indicate that while macroeconomics does not have an impact on female directors' financial performance, it does have an impact on firm value. Female directors and corporate valuation are unaffected by CSR Disclosure, although financial performance is. Sharia business risk has an impact on female directors and firm value but has no impact on firm value itself. Design/methodology/approach: Data was gathered quantitatively. Using the use of partial least squares structural equation modelling, we studied surveying information from 27 samples, and the research period was 5 years, so the total data was 135 data (27x5 years). Findings: According to the findings, the contribution to the SDG's are a. Reduction of Inequalities (SDG 10), b. Poverty Eradication (SDG 1) and Productive Employment (SDG 8), c. Energy Sustainability (SDG 7) and Environmental Protection (SDG 13), d. Quality Education (SDG 4), e. Health and Wellbeing (SDG 3), f. Innovation and Infrastructure (SDG 9), g. Sustainable Water Environment and Clean Water (SDG 6), h. Peace, Justice, and Strong Institutions (SDG 16). The value of the company is impacted by female directors and financial performance. The effects of macroeconomics, CSR disclosure, and sharia business risks on firm value cannot be mitigated by female directors. Financial performance mediates the impact of CSR disclosure and sharia business risk on company value but not the impact of macroeconomics on firm value. Research, Practical &amp; Social implications: This research aimed was to investigate the potential correlation between the adoption of business practices by corporations and the attainment of the Sustainable Development Goals (SDGs). Also, to investigate the connections between various important elements in a networked corporate environment. This study's primary target areas include macroeconomics, Islamic business risks, Corporate Social Responsibility (CSR) disclosure, and the effect of having female directors on the board of directors on corporate value. Originality/value: The study's worth lies in the additional insights it gives into the potential correlation between the adoption of business practices by corporations and the attainment of the Sustainable Development Goals (SDGs).

The role of C‐type natriuretic peptide (CNP) in the regulation of cardiac function in humans remains to be established as previous investigations have been confined to animal model systems. Here, we used well‐characterized engineered cardiac tissues (ECTs) generated from human stem cell‐derived cardiomyocytes and fibroblasts to study the acute effects of CNP on contractility. Application of CNP elicited a positive inotropic response as evidenced by increases in maximum twitch amplitude, maximum contraction slope and maximum calcium amplitude. This inotropic response was accompanied by a positive lusitropic response as demonstrated by reductions in time from peak contraction to 90% of relaxation and time from peak calcium transient to 90% of decay that paralleled increases in maximum contraction decay slope and maximum calcium decay slope. To establish translatability, CNP‐induced changes in contractility were also assessed in rat ex vivo (isolated heart) and in vivo models. Here, the effects on force kinetics observed in ECTs mirrored those observed in both the ex vivo and in vivo model systems, whereas the increase in maximal force generation with CNP application was only detected in ECTs. In conclusion, CNP induces a positive inotropic and lusitropic response in ECTs, thus supporting an important role for CNP in the regulation of human cardiac function. The high degree of translatability between ECTs, ex vivo and in vivo models further supports a regulatory role for CNP and expands the current understanding of the translational value of human ECTs.

Adjusting for multiple biases usually involves adjusting for one bias at a time, with careful attention to the order in which these biases are adjusted. A novel, alternative approach to multiple-bias adjustment involves the simultaneous adjustment of all biases via imputation and/or regression weighting. The imputed value or weight corresponds to the probability of the missing data and serves to 'reconstruct' the unbiased data that would be observed based on the provided assumptions of the degree of bias. We motivate and describe the steps necessary to implement this method. We also demonstrate the validity of this method through a simulation study with an exposure-outcome relationship that is biased by uncontrolled confounding, exposure misclassification, and selection bias. The study revealed that a non-biased effect estimate can be obtained when correct bias parameters are applied. It also found that incorrect specification of every bias parameter by +/-25% still produced an effect estimate with less bias than the observed, biased effect. Simultaneous multi-bias analysis is a useful way of investigating and understanding how multiple sources of bias may affect naive effect estimates. This new method can be used to enhance the validity and transparency of real-world evidence obtained from observational, longitudinal studies.

"Mastering Emotions: Feelings, Power, and Slavery in the United States." Slavery & Abolition, 44(1), pp. 215–216

Wildfires cause billions of dollars' worth of damage annually. Even when directly not consumed by fire, damage to structures have been reported and accredited to high temperature exposure and moisture content decreases resulting from a wildfire. It is difficult for insurance professionals to assess whether reported structural component or interior distress was the result of a surrounding wildfire event. A residence surrounded by a mountain wildfire in the western United States became the subject of an investigation into wildfire-related distress. The methodology utilized during this investigation is presented and detailed. Elevated exterior temperatures, and their durations, around the structure are inferred from heat damage to nearby flora, exterior building materials, etc. Heat flow analyses are conducted to determine the interior temperatures at which components were exposed. Thermal effects are modeled on a material-by-material basis to evaluate the effect of the determined temperature increase, and moisture content decrease, on distressed items reported to be wildfire-related. Although closely surrounded by a forest fire, much of the distress attributed to the wildfire was found to not be wildfire-related.

This study describes individual cancer patients' nonuse of extended-release or long-acting (ER/LA) opioids, including periods of gap between opioid doses taken. Secondary analysis of a three-month observational study of prescribed ER/LA opioids monitored using electronic pill caps. Two outpatient oncology clinics of a large health system in the Mid-Atlantic region. Inclusion was based on self-identified African Americans and whites, at least 18 years old, diagnosed with solid tumors or multiple myeloma. For the current analysis, the additional inclusion criterion was prescription of an oral ER/LA opioid for cancer pain to be taken around the clock. The electronic monitoring period for each study participant was partitioned into intervals of days between days with one or more openings (using medication event monitoring systems) representing rates of ER/LA opioid nonuse over consecutive days and over time. Of the sample (N = 109), two-thirds of the cancer patients had some nonuse of prescribed ER/LA opioids, with one in four having nonuse during 31.5-87.5% of their electronic-monitoring periods. Nonuse over periods of five or more, six or more, and seven or more consecutive days occurred for 37.6%, 34.9%, and 30.3% of the participants, respectively. About one in three ambulatory cancer patients in this study had substantial gaps between days of ER/LA opioid use, potentially resulting in risk of overdose depending upon the prescribed ER/LA opioid type, dose, and length of the time the opioid was stopped and resumed at the previous dose. This phenomenon has received little to no attention in the opioid safety discourse.

&lt;div class="htmlview paragraph"&gt;Crash severity is quantified by the change in velocity experienced by a vehicle during an impact along with the time duration over which that change in velocity occurs. Since the values of the input parameters for calculating the change in velocity are not known exactly, there is uncertainty associated with the calculated change in velocity. Accurate evaluation of the crash severity will, therefore, include analysis of the effect that uncertainties in the values of the input parameters have on the calculated change in velocity. Monte Carlo simulation, a statistical technique, enables the reconstructionist to evaluate the effect of uncertainty on the analysis of crash severity.&lt;/div&gt; &lt;div class="htmlview paragraph"&gt;Use of the Monte Carlo simulation technique is beneficial since a reconstructionist can enter a range of values for each input parameter. A probability distribution can be assigned to the range of values, which indicates the likelihood that any value in that range corresponds to the actual value of the parameter. The simulation generates thousands of possible combinations of the input parameters selected from the specified ranges, monitors the results of the combinations and analyzes them statistically. Application of the Monte Carlo technique is intended to improve the legitimacy of crash severity analysis by helping the reconstructionist consider a wide range of possible solutions within the bounds of the imperfect data and report statistically meaningful ranges for the change in velocity.&lt;/div&gt; &lt;div class="htmlview paragraph"&gt;This paper demonstrates the application of the Monte Carlo technique to impact severity analysis using a derived two-dimensional, rigid body, momentum-based impact model. Thorough guidance is given to aid the reconstructionist in integrating the momentum model with the Monte Carlo simulation technique and this method is illustrated with a case study. Since the impact model employs restitution constraints in the normal and tangential directions, the effect of uncertainty in formulating appropriate ranges for the values of the restitution coefficients is discussed.&lt;/div&gt;