Pharmaceutical Stock Price Reactions to Price Constraint Threats and Firm-Level R&D Spending

Political pressure in the United States is again building to constrain pharmaceutical prices either directly or through legalized reimportation of lower-priced pharmaceuticals from foreign countries. This study uses the Clinton Administration's Health Security Act (HSA) of 1993 as a natural experiment to show how threats of price constraints affect firm-level R&D spending. We link events surrounding the HSA to pharmaceutical company stock price changes and then examine the cross-sectional relation between the stock price changes and subsequent unexpected R&D spending changes. Results show that the HSA had significant negative effects on firm stock prices and R&D spending. Conservatively, the HSA reduced R&D spending by $1.6 billion, even though it never became law. If the HSA had passed, and had many small firms not raised capital just prior to the HSA, the R&D effects could have been much larger.

Compatibility Condition in Theory of Solid Mechanics (Elasticity, Structures, and Design Optimization)

The strain formulation in elasticity and the compatibility condition in structural mechanics have neither been understood nor have they been utilized. This shortcoming prevented the formulation of a direct method to calculate stress. We have researched and understood the compatibility condition for linear problems in elasticity and in finite element analysis. This has lead to the completion of the method of force with stress (or stress resultant) as the primary unknown. The method in elasticity is referred to as the completed Beltrami-Michell formulation (CBMF), and it is the integrated force method (IFM) in structures. The dual integrated force method (IFMD) with displacement as the primary unknown has been formulated. IFM and IFMD produce identical responses. The variational derivation of the CBMF yielded the new boundary compatibility conditions. The CBMF can be used to solve stress, displacement, and mixed boundary value problems. The IFM in structures produced high-fidelity response even with a modest finite element model. The IFM has influenced structural design considerably. A fully utilized design method for strength and stiffness limitation has been developed. The singularity condition in optimization has been identified. The CBMF and IFM tensorial approaches are robust formulations because of simultaneous emphasis on the equilibrium equation and the compatibility condition

Precision of Sensitivity in the Design Optimization of Indeterminate Structures

Design sensitivity is central to most optimization methods. The analytical sensitivity expression for an indeterminate structural design optimization problem can be factored into a simple determinate term and a complicated indeterminate component. Sensitivity can be approximated by retaining only the determinate term and setting the indeterminate factor to zero. The optimum solution is reached with the approximate sensitivity. The central processing unit (CPU) time to solution is substantially reduced. The benefit that accrues from using the approximate sensitivity is quantified by solving a set of problems in a controlled environment. Each problem is solved twice: first using the closed-form sensitivity expression, then using the approximation. The problem solutions use the CometBoards testbed as the optimization tool with the integrated force method as the analyzer. The modification that may be required, to use the stiffener method as the analysis tool in optimization, is discussed. The design optimization problem of an indeterminate structure contains many dependent constraints because of the implicit relationship between stresses, as well as the relationship between the stresses and displacements. The design optimization process can become problematic because the implicit relationship reduces the rank of the sensitivity matrix. The proposed approximation restores the full rank and enhances the robustness of the design optimization method

Probabilistic Estimation of Critical Flaw Sizes in the Primary Structure Welds of the Ares I-X Launch Vehicle

The primary structure of the Ares I-X Upper Stage Simulator (USS) launch vehicle is constructed of welded mild steel plates. There is some concern over the possibility of structural failure due to welding flaws. It was considered critical to quantify the impact of uncertainties in residual stress, material porosity, applied loads, and material and crack growth properties on the reliability of the welds during its pre-flight and flight. A criterion--an existing maximum size crack at the weld toe must be smaller than the maximum allowable flaw size--was established to estimate the reliability of the welds. A spectrum of maximum allowable flaw sizes was developed for different possible combinations of all of the above listed variables by performing probabilistic crack growth analyses using the ANSYS finite element analysis code in conjunction with the NASGRO crack growth code. Two alternative methods were used to account for residual stresses: (1) The mean residual stress was assumed to be 41 ksi and a limit was set on the net section flow stress during crack propagation. The critical flaw size was determined by parametrically increasing the initial flaw size and detecting if this limit was exceeded during four complete flight cycles, and (2) The mean residual stress was assumed to be 49.6 ksi (the parent material s yield strength) and the net section flow stress limit was ignored. The critical flaw size was determined by parametrically increasing the initial flaw size and detecting if catastrophic crack growth occurred during four complete flight cycles. Both surface-crack models and through-crack models were utilized to characterize cracks in the weld toe

Borylation–Reduction–Borylation for the Formation of 1,4-Azaborines

This project has received funding from the Leverhulme Trust (grant Number RPG-2022-032) and the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (Grant Agreement No. 769599). M.J.I. and E.Z.-C. also thank the EPSRC Programme Grant “Boron: Beyond the Reagent” (EP/W007517/1) for support.Given the current interest in materials containing 1,4-azaborine units, the development of new routes to these structures is important. Carbonyl directed electrophilic borylation using BBr3 is a facile method for the ortho-borylation of N,N-diaryl-amide derivatives. Subsequent addition of Et3SiH results in carbonyl reduction and then formation of 1,4-azaborines that can be protected in situ using a Grignard reagent. Overall, borylation–reduction–borylation is a one-pot methodology to access 1,4-azaborines from simple precursors.Publisher PDFPeer reviewe

Loss of Dnmt3b function upregulates the tumor modifier Ment and accelerates mouse lymphomagenesis

DNA methyltransferase 3B (Dnmt3b) belongs to a family of enzymes responsible for methylation of cytosine residues in mammals. DNA methylation contributes to the epigenetic control of gene transcription and is deregulated in virtually all human tumors. To better understand the generation of cancer-specific methylation patterns, we genetically inactivated Dnmt3b in a mouse model of MYC-induced lymphomagenesis. Ablation of Dnmt3b function using a conditional knockout in T cells accelerated lymphomagenesis by increasing cellular proliferation, which suggests that Dnmt3b functions as a tumor suppressor. Global methylation profiling revealed numerous gene promoters as potential targets of Dnmt3b activity, the majority of which were demethylated in Dnmt3b–/– lymphomas, but not in Dnmt3b–/– pretumor thymocytes, implicating Dnmt3b in maintenance of cytosine methylation in cancer. Functional analysis identified the gene Gm128 (which we termed herein methylated in normal thymocytes [Ment]) as a target of Dnmt3b activity. We found that Ment was gradually demethylated and overexpressed during tumor progression in Dnmt3b–/– lymphomas. Similarly, MENT was overexpressed in 67% of human lymphomas, and its transcription inversely correlated with methylation and levels of DNMT3B. Importantly, knockdown of Ment inhibited growth of mouse and human cells, whereas overexpression of Ment provided Dnmt3b+/+ cells with a proliferative advantage. Our findings identify Ment as an enhancer of lymphomagenesis that contributes to the tumor suppressor function of Dnmt3b and suggest it could be a potential target for anticancer therapies

IRF4 Is a Suppressor of c-Myc Induced B Cell Leukemia

Interferon regulatory factor 4 (IRF4) is a critical transcriptional regulator in B cell development and function. We have previously shown that IRF4, together with IRF8, orchestrates pre-B cell development by limiting pre-B cell expansion and by promoting pre-B cell differentiation. Here, we report that IRF4 suppresses c-Myc induced leukemia in EμMyc mice. Our results show that c-Myc induced leukemia was greatly accelerated in the IRF4 heterozygous mice (IRF4+/−Myc); the average age of mortality in the IRF4+/−Myc mice was only 7 to 8 weeks but was 20 weeks in the control mice. Our results show that IRF4+/−Myc leukemic cells were derived from large pre-B cells and were hyperproliferative and resistant to apoptosis. Further analysis revealed that the majority of IRF4+/−Myc leukemic cells inactivated the wild-type IRF4 allele and contained defects in Arf-p53 tumor suppressor pathway. p27kip is part of the molecular circuitry that controls pre-B cell expansion. Our results show that expression of p27kip was lost in the IRF4+/−Myc leukemic cells and reconstitution of IRF4 expression in those cells induced p27kip and inhibited their expansion. Thus, IRF4 functions as a classical tumor suppressor to inhibit c-Myc induced B cell leukemia in EμMyc mice

Self-Renewal and Differentiation Capacity of Urine-Derived Stem Cells after Urine Preservation for 24 Hours

The authors would like to thank Karl-Erik Andersson for his valuable comments and Ms. Karen Klein (Research Support Core, Wake Forest School of Medicine) for her editorial assistance with this manuscript.Administrative support: AA. Editorial help: AA. Conceived and designed the experiments: YYZ. Performed the experiments: RL GL YS SB. Analyzed the data: RL GL YS SB XL XZ HL YYZ. Contributed reagents/materials/analysis tools: AA. Wrote the paper: RL GL YYZ.Despite successful approaches to preserve organs, tissues, and isolated cells, the maintenance of stem cell viability and function in body fluids during storage for cell distribution and transportation remains unexplored. The aim of this study was to characterize urine-derived stem cells (USCs) after optimal preservation of urine specimens for up to 24 hours. A total of 415 urine specimens were collected from 12 healthy men (age range 20–54 years old). About 6×104 cells shed off from the urinary tract system in 24 hours. At least 100 USC clones were obtained from the stored urine specimens after 24 hours and maintained similar biological features to fresh USCs. The stored USCs had a “rice grain” shape in primary culture, and expressed mesenchymal stem cell surface markers, high telomerase activity, and normal karyotypes. Importantly, the preserved cells retained bipotent differentiation capacity. Differentiated USCs expressed myogenic specific proteins and contractile function when exposed to myogenic differentiation medium, and they expressed urothelial cell-specific markers and barrier function when exposed to urothelial differentiation medium. These data demonstrated that up to 75% of fresh USCs can be safely persevered in urine for 24 hours and that these cells stored in urine retain their original stem cell properties, indicating that preserved USCs could be available for potential use in cell-based therapy or clinical diagnosis.Yeshttp://www.plosone.org/static/editorial#pee

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection