Rapid Affinity and Microsomal Stability Ranking of Crude Mixture Libraries of Histone Deacetylase Inhibitors.

The science of drug discovery involves multiparameter optimization of molecular structures through iterative design-make-test cycles. For medicinal chemistry library synthesis, traditional workflows involve the isolation of each individual compound, gravimetric quantitation, and preparation of a standard concentration solution for biological assays. In this work, we explore ways to expedite this process by testing unpurified library mixtures using a combination of mass spectrometry-based assays for affinity selection and microsomal metabolic stability.

Outcomes of direct oral anticoagulants with aspirin vs warfarin with aspirin: a registry-based cohort study.

Background: For patients anticoagulated with direct oral anticoagulants (DOACs) or warfarin and on aspirin (ASA) for nonvalvular atrial fibrillation and/or venous thromboembolism, it is unclear if bleeding outcomes differ.

Objectives: To assess bleeding rates for ASA with DOACs vs warfarin and one another.

Methods: Registry-based cohort study of patients followed by a 6-center quality improvement collaborative in Michigan using data from 2009 to 2022.

Revolutionizing Glioblastoma Treatment: A Comprehensive Overview of Modern Therapeutic Approaches.

Glioblastoma is the most common malignant primary brain tumor in the adult population, with an average survival of 12.1 to 14.6 months.

Telemedicine Critical Care-Mediated Mortality Reductions in Lower-Performing Patient Diagnosis Groups: A Prospective, Before and After Study.

Objectives: Studies evaluating telemedicine critical care (TCC) have shown mixed results. We prospectively evaluated the impact of TCC implementation on risk-adjusted mortality among patients stratified by pre-TCC performance.

Design: Prospective, observational, before and after study.

Life history optimisation drives latitudinal gradients and responses to global change in marine fishes.

Within many species, and particularly fish, fecundity does not scale with mass linearly; instead, it scales disproportionately. Disproportionate intraspecific size-reproduction relationships contradict most theories of biological growth and present challenges for the management of biological systems. Yet the drivers of reproductive scaling remain obscure and systematic predictors of how and why reproduction scaling varies are lacking.

Large Scale Quantum Chemistry with Tensor Processing Units.

We demonstrate the use of Googles cloud-based Tensor Processing Units (TPUs) to accelerate and scale up conventional (cubic-scaling) density functional theory (DFT) calculations. Utilizing 512 TPU cores, we accomplish the largest such DFT computation to date, with 247848 orbitals, corresponding to a cluster of 10327 water molecules with 103270 electrons, all treated explicitly. Our work thus paves the way toward accessible and systematic use of conventional DFT, free of any system-specific constraints, at unprecedented scales.

Higher OAK (Oral Anticoagulation Knowledge) score at baseline associated with better TTR (Time in Therapeutic Range) in patients taking warfarin.

A lack in patient knowledge of warfarin therapy is associated with poor adherence. This knowledge gap may result in a lower INR Time in Therapeutic Range (TTR). To investigate association between patient anticoagulation knowledge and warfarin control.

Length of Anticoagulation in Provoked Venous Thromboembolism: A Multicenter Study of How Real-World Practice Mirrors Guideline Recommendations.

Background For more than a decade, guidelines have recommended a limited 3 months of anticoagulation for the treatment of provoked venous thromboembolism (VTE). How closely real-world practice follows guideline recommendations is not well described. Methods and Results In our multicenter, retrospective cohort study, we evaluated trends in anticoagulation duration for patients enrolled in the MAQI (Michigan Anticoagulation Quality Improvement Initiative) registry who were receiving anticoagulation for a provoked VTE.

Assessment of an Intervention to Reduce Aspirin Prescribing for Patients Receiving Warfarin for Anticoagulation.

Importance: For some patients receiving warfarin, adding aspirin (acetylsalicylic acid) increases bleeding risk with unclear treatment benefit. Reducing excess aspirin use could be associated with improved clinical outcomes.

Objective: To assess changes in aspirin use, bleeding, and thrombosis event rates among patients treated with warfarin.

Outcomes in patients undergoing periprocedural interruption of warfarin or direct oral anticoagulants.

Background: Differences in clinical outcomes following a temporary interruption of warfarin or a direct oral anticoagulant (DOAC) for a surgical procedure are not well described. Differences in patient characteristics from practice-based cohorts have not typically been accounted for in prior analyses.

Aim: To describe risk-adjusted differences in postoperative outcomes following an interruption of warfarin vs DOACs.

Management strategies following slightly out-of-range INRs: watchful waiting vs dose changes.

Patients' international normalized ratios (INRs) often fall slightly out of range. In these cases, the American College of Chest Physicians (ACCP) guidelines suggest maintaining the current warfarin dose and retesting the INR within the following 2 weeks (watchful waiting). We sought to determine whether watchful waiting or dose changes for slightly out-of-range INRs is more effective in obtaining in-range INRs at follow-up.

Anticoagulation Changes Following Major and Clinically Relevant Nonmajor Bleeding Events in Non-valvular Atrial Fibrillation Patients.

Bleeding events are common complications of oral anticoagulant drugs, including both warfarin and the direct oral anticoagulants (DOACs). Some patients have their anticoagulant changed or discontinued after experiencing a bleeding event, while others continue the same treatment. Differences in anticoagulation management between warfarin- and DOAC-treated patients following a bleeding event are unknown.

Bioactive Modified Non-Wovens as a Novel Approach of Plants Protection against Invasive Slugs.

Invasive slugs generate significant problems in the area of horticultural and agricultural production. Despite the multitude of methods to reduce the pest population, including preventive, mechanical, agrotechnical, cultivation, biological, and chemical treatments, no effective plant protection strategy has been developed so far. In this paper, a solution based on modified non-woven fabric with bioactive molluscicidal properties using the extract of tansy flower, metaldehyde, and abamectin (Vertigo 018 EC) was proposed.

Standard Versus Higher Intensity Anticoagulation for Patients With Mechanical Aortic Valve Replacement and Additional Risk Factors for Thromboembolism.

Current guidelines recommend targeting an international normalized ratio (INR) of 2.5 to 3.5 for patients with mechanical aortic valve replacement (AVR) and additional risk factors for thromboembolic events.

Competition between Ammonia-Oxidizing Archaea and Bacteria from Freshwater Environments.

In the environment, nutrients are rarely available in a constant supply. Therefore, microorganisms require strategies to compete for limiting nutrients. In freshwater systems, ammonia-oxidizing archaea (AOA) and ammonia-oxidizing bacteria (AOB) compete with heterotrophic bacteria, photosynthetic microorganisms, and each other for ammonium, which AOA and AOB utilize as their sole source of energy and nitrogen.

A customized 3D implant to target laser interstitial thermal therapy ablation of a posterior fossa mass.

Laser interstitial thermal therapy (LITT) is a minimally invasive neurosurgical technique that has been demonstrated to successfully ablate intracranial tumors. While LITT for supratentorial lesions can often be straightforward, ablation of infratentorial lesions can be difficult with current targeting technologies and instrumentation. The anatomical difficulty of targeting posterior fossa masses can be further complicated in patients who have had a prior craniectomy or other procedure that removed the bone that is required to set the surgical trajectory.

Concerted evolution of body mass, cell size and metabolic rate among carabid beetles.

Alterations in cell number and size are apparently associated with the body mass differences between species and sexes, but we rarely know which of the two mechanisms underlies the observed variance in body mass. We used phylogenetically informed comparisons of males and females of 19 Carabidae beetle species to compare body mass, resting metabolic rate, and cell size in the ommatidia and Malpighian tubules. We found that the larger species or larger sex (males or females, depending on the species) consistently possessed larger cells in the two tissues, indicating organism-wide coordination of cell size changes in different tissues and the contribution of these changes to the origin of evolutionary and sex differences in body mass.

Discovery of macrocyclic HDACs 1, 2, and 3 selective inhibitors for HIV latency reactivation.

A series of unique macrocyclic HDACs 1, 2, and 3 selective inhibitors were identified with good enzymatic activity and high selectivity over HDACs 6 and 8. These macrocyclic HDAC inhibitors used an ethyl ketone as the zinc-binding group. Compounds 25 and 26 stood out as leads due to their low double-digit nM ECs in the 2C4 cell-based HIV latency reactivation assay.

CT-measured Cortical Volume Ratio Is an Accurate Alternative to Nuclear Medicine Split Scan Ratio Among Living Kidney Donors.

Background: The 125I-iothalamate clearance and 99mTc diethylenetriamine-pentaacetic acid (99mTc-DTPA) split scan nuclear medicine studies are used among living kidney donor candidates to determine measured glomerular filtration rate (mGFR) and split scan ratio (SSR). The computerized tomography-derived cortical volume ratio (CVR) is a novel measurement of split kidney function and can be combined with predonation estimated GFR (eGFR) or mGFR to predict postdonation kidney function. Whether predonation SSR predicts postdonation kidney function better than predonation CVR and whether predonation mGFR provides additional information beyond predonation eGFR are unknown.

Comparison of temporary interruption with continuation of direct oral anticoagulants for low bleeding risk procedures.

Introduction: Limited data is available on the rates of bleeding and thromboembolic events for patients undergoing low bleeding risk procedures while taking direct oral anticoagulants (DOAC).

Methods: Adults taking DOAC in the Michigan Anticoagulation Quality Improvement Initiative (MAQI) database who underwent a low bleeding risk procedure between May 2015 and Sep 2019 were included. Thirty-day bleeding (of any severity), thromboembolic events, and death were compared between DOAC temporarily interrupted and continued uninterrupted groups.

Adverse Events Associated With the Addition of Aspirin to Direct Oral Anticoagulant Therapy Without a Clear Indication.

Importance: It is unclear how many patients treated with a direct oral anticoagulant (DOAC) are using concomitant acetylsalicylic acid (ASA, or aspirin) and how this affects clinical outcomes.

Objective: To evaluate the frequency and outcomes of prescription of concomitant ASA and DOAC therapy for patients with atrial fibrillation (AF) or venous thromboembolic disease (VTE).

Design, Setting, And Participants: This registry-based cohort study took place at 4 anticoagulation clinics in Michigan from January 2015 to December 2019.

Discovery of Ethyl Ketone-Based Highly Selective HDACs 1, 2, 3 Inhibitors for HIV Latency Reactivation with Minimum Cellular Potency Serum Shift and Reduced hERG Activity.

We describe the discovery of histone deacetylase (HDACs) 1, 2, and 3 inhibitors with ethyl ketone as the zinc-binding group. These HDACs 1, 2, and 3 inhibitors have good enzymatic and cellular activity. Their serum shift in cellular potency has been minimized, and selectivity against hERG has been improved.

Synthesis of HDAC Inhibitor Libraries via Microscale Workflow.

An integrated workflow has been established that enables the synthesis, purification, and subsequent biological testing of compound libraries on a microgram scale. This approach utilizes mass directed preparative HPLC in conjunction with charged aerosol detection (CAD) to generate solutions of investigational compounds at high purity and standardized concentrations, facilitating high fidelity biological testing. This new workflow successfully delivered libraries of histone deacetylase (HDAC) inhibitors that afforded biological data consistent with that obtained from standard scale parallel medicinal chemistry techniques.