PillHarmonics: An Orchestrated Pharmacogenetics Medication Clinical Decision Support Service.

Objectives:  Pharmacogenetics (PGx) is increasingly important in individualizing therapeutic management plans, but is often implemented apart from other types of medication clinical decision support (CDS). The lack of integration of PGx into existing CDS may result in incomplete interaction information, which may pose patient safety concerns. We sought to develop a cloud-based orchestrated medication CDS service that integrates PGx with a broad set of drug screening alerts and evaluate it through a clinician utility study.

Seeking and Providing Social Support on Twitter for Trauma and Distress During the COVID-19 Pandemic: Content and Sentiment Analysis.

Background: The COVID-19 pandemic can be recognized as a traumatic event that led to stressors, resulting in trauma or distress among the general population. Social support is vital in the management of these stressors, especially during a traumatic event, such as the COVID-19 pandemic. Because of the limited face-to-face interactions enforced by physical distancing regulations during the pandemic, people sought solace on social media platforms to connect with, and receive support from, one another.

Impact of RBI's monetary policy announcements on government bond yields: evidence from the pandemic.

We investigate how the bond market responded to the Reserve Bank of India's (RBI) monetary policy actions undertaken since the start of the pandemic. Our approach involves combining a narrative analysis of the media coverage together with an event-study framework around RBI's monetary policy announcements. We find that the RBI's actions early in the pandemic were helpful in providing an expansionary impulse to the bond market.

Assessment of Stakeholder Perceptions and Cost of Implementing a Telemedicine Specialty Program at Correctional Facilities in North Carolina.

Background Delivering in-person health care to the more than 1.2 million incarcerated adults can be expensive, logistically challenging, fragmented, and pose security risks. The purpose of this study was to evaluate the implementation of a specialty care telemedicine program in statewide prisons in North Carolina during the COVID-19 pandemic.

Recommendations for design of a mobile application to support management of anxiety and depression among Black American women.

Black American women experience adverse health outcomes due to anxiety and depression. They face systemic barriers to accessing culturally appropriate mental health care leading to the underutilization of mental health services and resources. Mobile technology can be leveraged to increase access to culturally relevant resources, however, the specific needs and preferences that Black women feel are useful in an app to support management of anxiety and depression are rarely reflected in existing digital health tools.

Digital Health Experiences of Incarcerated Populations Using Telemedicine in North Carolina Prisons.

More than 1.2 million adults are incarcerated in the United States and hence, require health care from prison systems. The current delivery of care to incarcerated individualss is expensive, logistically challenging, risk fragmenting care, and pose security risks.

Overcoming the Pregnane X Receptor Liability: Rational Design to Eliminate PXR-Mediated CYP Induction.

The pregnane X receptor (PXR) regulates expression of proteins responsible for all three phases required for the detoxification mechanism, which include CYP450 enzymes, phase II enzymes, and multidrug efflux pumps. Therefore, PXR is a prominent receptor that is responsible for xenobiotic excretion and drug-drug interactions. Pyrimidinone is an antagonist of the calcium sensing receptor (CaSR) and a strong activator of PXR.

Implementation and Evaluation of a Telemedicine Program for Specialty Care in North Carolina Correctional Facilities.

This cross-sectional study evaluates the implementation of a telemedicine program in North Carolina prisons based on responses from individuals who were incarcerated, health care practitioners, and telepresenters.

Correction to Identification of Quinoline-Based RIP2 Kinase Inhibitors with an Improved Therapeutic Index to the hERG Ion Channel.

[This corrects the article DOI: 10.1021/acsmedchemlett.8b00344.

Discovery of Pyrazolocarboxamides as Potent and Selective Receptor Interacting Protein 2 (RIP2) Kinase Inhibitors.

Herein we report the discovery of pyrazolocarboxamides as novel, potent, and kinase selective inhibitors of receptor interacting protein 2 kinase (RIP2). Fragment based screening and design principles led to the identification of the inhibitor series, and X-ray crystallography was used to inform key structural changes. Through key substitutions about the N1 and C5 N positions on the pyrazole ring significant kinase selectivity and potency were achieved.

Structure-Activity and Structure-Conformation Relationships of Aryl Propionic Acid Inhibitors of the Kelch-like ECH-Associated Protein 1/Nuclear Factor Erythroid 2-Related Factor 2 (KEAP1/NRF2) Protein-Protein Interaction.

The KEAP1-NRF2-mediated cytoprotective response plays a key role in cellular homoeostasis. Insufficient NRF2 signaling during chronic oxidative stress may be associated with the pathophysiology of several diseases with an inflammatory component, and pathway activation through direct modulation of the KEAP1-NRF2 protein-protein interaction is being increasingly explored as a potential therapeutic strategy. Nevertheless, the physicochemical nature of the KEAP1-NRF2 interface suggests that achieving high affinity for a cell-penetrant druglike inhibitor might be challenging.

3,5-Disubstituted-indole-7-carboxamides as IKKβ Inhibitors: Optimization of Oral Activity via the C3 Substituent.

IκB kinase β (IKKβ or IKK2) is a key regulator of nuclear factor kappa B (NF-κB) and has received attention as a therapeutic target. Herein we report on the optimization of a series of 3,5-disubstituted-indole-7-carboxamides for oral activity. In doing so, we focused attention on potency, ligand efficiency (LE), and physicochemical properties and have identified compounds and ()- as having robust in vivo activity.

Identification of Quinoline-Based RIP2 Kinase Inhibitors with an Improved Therapeutic Index to the hERG Ion Channel.

RIP2 kinase was recently identified as a therapeutic target for a variety of autoimmune diseases. We have reported previously a selective 4-aminoquinoline-based RIP2 inhibitor and demonstrated its effectiveness in blocking downstream NOD2 signaling in cellular models, rodent in vivo models, and human ex vivo disease models. While this tool compound was valuable in validating the biological pathway, it suffered from activity at the hERG ion channel and a poor PK/PD profile thereby limiting progression of this analog.

Approaches to target tractability assessment - a practical perspective.

The assessment of the suitability of novel targets to intervention by different modalities, small molecules or antibodies, is increasingly seen as important in helping to select the most progressable targets at the outset of a drug discovery project. This perspective considers differing aspects of tractability and how it can be assessed using and experimental approaches. We also share some of our experiences in using these approaches.

Outcomes following the treatment of bicondylar tibial plateau fractures with fine wire circular frame external fixation compared to open reduction and internal fixation: A systematic review.

Purpose: The aim of this study was to determine whether circular frame external fixation provides better outcome and fewer complications when compared to open reduction internal fixation.

Methods: A systematic search was carried out and studies were critically appraised with narrative data synthesis.

Results: The systematic search yielded 131 titles and following a rigorous review only five articles were found to directly compare the two treatment methods.

The Identification and Pharmacological Characterization of 6-(tert-Butylsulfonyl)-N-(5-fluoro-1H-indazol-3-yl)quinolin-4-amine (GSK583), a Highly Potent and Selective Inhibitor of RIP2 Kinase.

RIP2 kinase is a central component of the innate immune system and enables downstream signaling following activation of the pattern recognition receptors NOD1 and NOD2, leading to the production of inflammatory cytokines. Recently, several inhibitors of RIP2 kinase have been disclosed that have contributed to the fundamental understanding of the role of RIP2 in this pathway. However, because they lack either broad kinase selectivity or strong affinity for RIP2, these tools have only limited utility to assess the role of RIP2 in complex environments.

DNA-Encoded Library Screening Identifies Benzo[b][1,4]oxazepin-4-ones as Highly Potent and Monoselective Receptor Interacting Protein 1 Kinase Inhibitors.

The recent discovery of the role of receptor interacting protein 1 (RIP1) kinase in tumor necrosis factor (TNF)-mediated inflammation has led to its emergence as a highly promising target for the treatment of multiple inflammatory diseases. We screened RIP1 against GSK's DNA-encoded small-molecule libraries and identified a novel highly potent benzoxazepinone inhibitor series. We demonstrate that this template possesses complete monokinase selectivity for RIP1 plus unique species selectivity for primate versus nonprimate RIP1.

An efficient and highly diastereoselective synthesis of GSK1265744, a potent HIV integrase inhibitor.

A novel synthesis of GSK1265744, a potent HIV integrase inhibitor, is described. The synthesis is highlighted by an efficient construction of the densely functionalized pyridinone core as well as a highly diastereoselective formation of the acyl oxazolidine moiety. The latter exploits the target molecule's ability to chelate to Mg(2+), a key feature in the integrase inhibitor's mechanism of action.

RIP3 induces apoptosis independent of pronecrotic kinase activity.

Receptor-interacting protein kinase 3 (RIP3 or RIPK3) has emerged as a central player in necroptosis and a potential target to control inflammatory disease. Here, three selective small-molecule compounds are shown to inhibit RIP3 kinase-dependent necroptosis, although their therapeutic value is undermined by a surprising, concentration-dependent induction of apoptosis. These compounds interact with RIP3 to activate caspase 8 (Casp8) via RHIM-driven recruitment of RIP1 (RIPK1) to assemble a Casp8-FADD-cFLIP complex completely independent of pronecrotic kinase activities and MLKL.

Druggability Assessment of Allosteric Proteins by Dynamics Simulations in the Presence of Probe Molecules.

Druggability assessment of a target protein has emerged in recent years as an important concept in hit-to-lead optimization. A reliable and physically relevant measure of druggability would allow informed decisions on the risk of investing in a particular target. Here, we define "druggability" as a quantitative estimate of binding sites and affinities for a potential drug acting on a specific protein target.

Lengthening z-osteotomy of the fibula to correct persistent talar shift following open reduction internal fixation of ankle fractures.

Background: In cases where ankle fracture union has been compromised by persistent syndesmotic diastasis following open reduction internal fixation, both external rotation and shortening of the fibula have been identified as prominent features.

Objective: This study reports a technique that uses a z-osteotomy to achieve both lengthening and internal rotation of the fibula to correct persistent talar shift following ankle fracture fixation.

Methods: Four patients with persistent talar shift following open reduction internal fixation for an ankle fracture received z-osteotomy of the fibula to achieve both lengthening and internal rotation.

Exposure to noise in orthopaedic theatres--do we need protection?

Aim: To detect noise levels, generated by high-powered tools in orthopaedic theatres at varying distances from the operating site, and its impact on hearing in staff and patients.

Methods: Sound-level meter was used to measure the sound level generated by various high-powered tools in routine orthopaedic procedures, at varying distances from the operating site. These recorded noise levels were compared against the UK noise safety guidelines.

Nucleobase-directed amyloid nanotube assembly.

Cytosine nucleobases were successfully incorporated into the side chain of the self-assembling amyloid peptide fragment HHQALVFFA to give ccAQLVFFA. At a pH range of 3-4, where cytosine is expected to be partially protonated, small-angle X-ray scattering analyses revealed the nucleobase peptide assembles to be well-defined nanotubes with an outer diameter of 24.8 nm and wall thicknesses of 3.