Autopsy of a Hemodialysis Machine: Potential for Recycling at the End of the Life Cycle.

Background: Hemodialysis (HD) contributes significantly to healthcare's carbon footprint. Worldwide about 100,000 dialysis machines end their life cycle each year. Our aim was to analyze the composition and the potential for recyclability of two dialysis machines, from the two companies with the largest market share, which had met their end-of-use terms (10-12 years of use according to French regulations).

Potent Long-Acting Inhibitors Targeting the HIV-1 Capsid Based on a Versatile Quinazolin-4-one Scaffold.

Long-acting (LA) human immunodeficiency virus-1 (HIV-1) antiretroviral therapy characterized by a ≥1 month dosing interval offers significant advantages over daily oral therapy. However, the criteria for compounds that enter clinical development are high. Exceptional potency and low plasma clearance are required to meet dose size requirements; excellent chemical stability and/or crystalline form stability is required to meet formulation requirements, and new antivirals in HIV-1 therapy need to be largely free of side effects and drug-drug interactions.

Organ donation by Maastricht-III pediatric patients: Recommendations of the Groupe Francophone de Réanimation et Urgences Pédiatriques (GFRUP) and Association des Anesthésistes Réanimateurs Pédiatriques d'Expression Française (ADARPEF). Part II: Specific organizational and technical considerations.

A panel of pediatric experts met to develop recommendations on the technical requirements specific to pediatric controlled donation after planned withdrawal of life-sustaining therapies (Maastricht category III). The panel recommends following the withdrawal of life-sustaining therapies protocol usually applied in each unit, which may or may not include immediate extubation. The organ retrieval process should be halted if death does not occur within 3 h of life-support discontinuation.

The discovery of BMS-737 as a potent, CYP17 lyase-selective inhibitor for the treatment of castration-resistant prostate cancer.

We report herein, the discovery of BMS-737 (compound 33) as a potent, non-steroidal, reversible small molecule inhibitor demonstrating 11-fold selectivity for CYP17 lyase over CYP17 hydroxylase, as well as a clean xenobiotic CYP profile for the treatment of castration-resistant prostate cancer (CRPC). Extensive SAR studies on the initial lead 1 at three different regions of the molecule resulted in the identification of BMS-737, which demonstrated a robust 83% lowering of testosterone without any significant perturbation of the mineralocorticoid and glucocorticoid levels in cynomologous monkeys in a 1-day PK/PD study.

Organ donation by Maastricht-III pediatric patients: Recommendations of the Groupe Francophone de Réanimation et Urgences Pédiatriques (GFRUP) and Association des Anesthésistes Réanimateurs Pédiatriques d'Expression Française (ADARPEF) Part I: Ethical considerations and family care.

The French Transplant Health Authority (Agence de la Biomédecine) has broadened its organ- and tissue-donation criteria to include pediatric patients whose death is defined by circulatory criteria and after the planned withdrawal of life-sustaining therapies (WLST) (Maastricht category III). A panel of pediatric experts convened to translate data in the international literature into recommendations for organ and tissue donation in this patient subgroup. The panel estimated that, among children aged 5 years or over with severe irreversible neurological injury (due to primary neurological injury or post-anoxic brain injury) and no progression to brain death, the number of potential donors, although small, deserves attention.

Analysis of secondary pharmacology assays received by the US Food and Drug Administration.

Secondary pharmacology studies are a time-efficient and cost-effective method for determining the safety profile of a potential new drug before it enters human trials. The results of these multi-target screens are commonly submitted with Investigational New Drug (IND) applications, but there currently is little guidance on how such information is presented and which targets are chosen for testing. In this study, we expand on our previous analysis of secondary pharmacology reports by manually curating and analyzing all secondary pharmacology results received by the FDA received as part of an IND submission.

Diagnosing, Managing, and Supporting Return to Work of Adults With Rotator Cuff Disorders: Clinical Practice Guideline Methods.

To present the methods used to develop a clinical practice guideline (CPG) with recommendations endorsed by key stakeholders for assessing, managing, and supporting return to work for adults with rotator cuff disorders. Clinical practice guideline development. A steering committee composed of the research team of this project led the development of this CPG in 5 phases, which followed the standards of the NICE and AGREE II collaborations.

Discovery and Preclinical Profiling of GSK3839919, a Potent HIV-1 Allosteric Integrase Inhibitor.

Allosteric HIV-1 integrase inhibitors (ALLINIs) have been of interest recently because of their novel mechanism of action. Strategic modifications to the C5 moiety of a class of 4-(4,4-dimethylpiperidinyl)-2,6-dimethylpyridinyl ALLINIs led to the identification of a tetrahydroisoquinoline heterocycle as a suitable spacer element to project the distal hydrophobic aryl ring. Subsequent optimization of the aryl substitutions identified as an ALLINI with single-digit nanomolar inhibitory potency and low clearance across preclinical species.

5-Bromo-2-chloro-4-fluoro-3-iodopyridine as a Halogen-rich Intermediate for the Synthesis of Pentasubstituted Pyridines.

The 60 individual halopyridine isomers that contain one bromine, chlorine, fluorine, iodine, and H are valuable potential building blocks in medicinal chemistry research, but surprisingly, there has been only one report on the synthesis of just two of them. Herein, we describe simple syntheses of the unique 5-bromo-2-chloro-4-fluoro-3-iodopyridine () and 3-bromo-6-chloro-4-fluoro-2-iodopyridine () using halogen dance reactions. C6 magnesiation of and its 3-phenyl analogue followed by trapping with electrophiles generated a variety of pentasubstituted pyridines with desired functionalities for further chemical manipulations.

Aggregation and analysis of secondary pharmacology data from investigational new drug submissions at the US Food and Drug Administration.

Secondary pharmacology studies are utilized by the pharmaceutical industry as a cost-efficient tool to identify potential safety liabilities of drugs before entering Phase 1 clinical trials. These studies are recommended by the Food and Drug Administration (FDA) as a part of the Investigational New Drug (IND) application. However, despite the utility of these assays, there is little guidance on which targets should be screened and which format should be used.

The climatic drivers of primary Picea forest growth along the Carpathian arc are changing under rising temperatures.

Climatic constraints on tree growth mediate an important link between terrestrial and atmospheric carbon pools. Tree rings provide valuable information on climate-driven growth patterns, but existing data tend to be biased toward older trees on climatically extreme sites. Understanding climate change responses of biogeographic regions requires data that integrate spatial variability in growing conditions and forest structure.

Tree-ring reconstruction of snow avalanche activity: Does avalanche path selection matter?

In the current context of anthropogenic global warming, one of the purposes of dendrogeomorphic analyses is to provide long and continuous chronologies of mass movements, so as to detect potential trends or shift related to increasing temperatures. However, on documented slopes, the comparison between historical archives and tree-ring records suggests that dendrogeomorphic reconstructions systematically underestimate the natural activity of the process under investigation. In the specific case of snow avalanches, underestimation generally amounts to 50% and the main causes generally given for this difference are related to the magnitude of past events.

Climate-growth relationships in a Larix decidua Mill. network in the French Alps.

A better understanding of the respective role of key climatic variables on tree growth is crucial for an accurate assessment of how ongoing global changes may affect both dynamics and distribution of forest tree species in the future. The aim of this study was (i) to explore growth patterns of European larch (Larix decidua Mill.) through a network of tree-ring chronologies developed for the French Alps and (ii) to identify the main climatic drivers explaining radial growth.

Drug-induced cardiac abnormalities in premature infants and neonates.

The Cardiac Safety Research Consortium (CSRC) is a transparent, public-private partnership that was established in 2005 as a Critical Path Program and formalized in 2006 under a Memorandum of Understanding between the United States Food and Drug Administration and Duke University. Our continuing goal is to advance paradigms for more efficient regulatory science related to the cardiovascular safety of new therapeutics, both in the United States and globally, particularly where such safety questions add burden to innovative research and development. This White Paper provides a summary of discussions by a cardiovascular committee cosponsored by the CSRC and the US Food and Drug Administration (FDA) that initially met in December 2014, and periodically convened at FDA's White Oak headquarters from March 2015 to September 2016.

Structural Transformation of LiFePO during Ultrafast Delithiation.

The prolific lithium battery electrode material lithium iron phosphate (LiFePO) stores and releases lithium ions by undergoing a crystallographic phase change. Nevertheless, it performs unexpectedly well at high rate and exhibits good cycling stability. We investigate here the ultrafast charging reaction to resolve the underlying mechanism while avoiding the limitations of prevailing electrochemical methods by using a gaseous oxidant to deintercalate lithium from the LiFePO structure.

Pilot Investigation of 2 Nondiet Approaches to Improve Weight and Health.

Context • Weight loss and maintenance are associated with many health benefits, but long-term maintenance of weight loss remains elusive for many people. Overweight individuals are at higher risk than normal-weight individuals for stress-induced overeating. The use of stress-management tools in a weight loss program might decrease the physiological stress that fuels overeating and improve posttreatment maintenance of weight loss Objective • The study intended to compare the differences in outcomes between 2 approaches to achieving weight loss and changes in health-stress reduction and intuitive eating (IE)-during a 14-wk period.

Rehabilitation of symptomatic atraumatic degenerative rotator cuff tears: A clinical commentary on assessment and management.

Study Design: Clinical Commentary.

Introduction: Atraumatic rotator cuff (RC) disease, is one of the most common cause of shoulder pain, which encompasses a continuum from tendinopathy to full thickness cuff tears. Extrinsic, intrinsic and environmental factors have been implicated in the pathophysiology of this disorder, affecting the clinical presentation of symptoms including pain and irritability.

Regulatory Forum Review*: Utility of in Vitro Secondary Pharmacology Data to Assess Risk of Drug-induced Valvular Heart Disease in Humans: Regulatory Considerations.

Drug-induced valvular heart disease (VHD) is a serious side effect linked to long-term treatment with 5-hydroxytryptamine (serotonin) receptor 2B (5-HT) agonists. Safety assessment for off-target pharmacodynamic activity is a common approach used to screen drugs for this undesired property. Such studies include in vitro assays to determine whether the drug is a 5-HT agonist, a necessary pharmacological property for development of VHD.

Preclinical QT safety assessment: cross-species comparisons and human translation from an industry consortium.

Introduction: In vivo models have been required to demonstrate relative cardiac safety, but model sensitivity has not been systematically investigated. Cross-species and human translation of repolarization delay, assessed as QT/QTc prolongation, has not been compared employing common methodologies across multiple species and sites. Therefore, the accurate translation of repolarization results within and between preclinical species, and to man, remains problematic.

Anticipated classes of new medications and molecular targets for pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) remains a life-limiting condition with a major impact on the ability to lead a normal life. Although existing therapies may improve the outlook in some patients there remains a major unmet need to develop more effective therapies in this condition. There have been significant advances in our understanding of the genetic, cell and molecular basis of PAH over the last few years.

Biochemical and transcriptional profiling to triage additional activities in a series of IGF-1R/IR inhibitors.

Therapeutic development of a targeted agent involves a series of decisions over additional activities that may be ignored, eliminated or pursued. This paper details the concurrent application of two methods that provide a spectrum of information about the biological activity of a compound: biochemical profiling on a large panel of kinase assays and transcriptional profiling of mRNA responses. Our mRNA profiling studies used a full dose range, identifying subsets of transcriptional responses with differing EC(50)s which may reflect distinct targets.