Free Energy Perturbation Approach for Accurate Crystalline Aqueous Solubility Predictions.

Early assessment of crystalline thermodynamic solubility continues to be elusive for drug discovery and development despite its critical importance, especially for the ever-increasing fraction of poorly soluble drug candidates. Here we present a detailed evaluation of a physics-based free energy perturbation (FEP+) approach for computing the thermodynamic aqueous solubility. The predictive power of this approach is assessed across diverse chemical spaces, spanning pharmaceutically relevant literature compounds and more complex AbbVie compounds.

Identification of potent and selective inhibitors of PKR via virtual screening and traditional design.

Protein Kinase RNA-activated (PKR) inhibition is thought to be relevant for immunology due to the potential to reduce macrophage and dendritic cell responses to bacteria and its signaling downstream of TNFα. PKR is also associated with neuroscience indications such as Alzheimer's disease due to its activation by the double stranded DNA (dsDNA) virus HSV1, a virus suggested to be important in the development of AD. Studies exploring the mechanistic role of PKR with existing tool molecules such as the tricyclic oxindole C16 are clouded by the poor selectivity profile of this ATP-competitive, Type I kinase inhibitor.

Neuromotor deficits and altered physiological responses to repeated exertional heat stroke exposures in mice.

Exertional heat stroke (EHS) is a life-threatening illness that can lead to negative health outcomes. Using a "severe" preclinical mouse model of EHS, we tested the hypotheses that one EHS exposure results in altered susceptibility to a subsequent EHS and reduced neuromotor performance. Female C57BL/6 mice underwent two protocols, 2 wk apart, either an EHS trial (EHS) or a sham exercise control trial (EXC).

Self-compassion, body satisfaction, and disordered eating symptoms in male collegiate athletes: A longitudinal analysis.

Male athletes are a subpopulation at risk for developing eating disorders and disordered eating concerns, primarily due to the presence of socioculturally-based factors, including body dissatisfaction. Self-compassion may alleviate this risk by improving body satisfaction. To date, no study has examined longitudinally self-compassion's effect on body satisfaction and, ultimately, disordered eating in male athletes.

Hybrid balloon valvuloplasty for management of severe mitral stenosis in four symptomatic, adult dogs.

Four adult dogs weighing <10 kg presented for the evaluation of severe mitral valve stenosis with clinical signs. Owing to the size of the dogs, a hybrid surgical and interventional approach was utilized for balloon valvuloplasty. A left lateral thoracotomy was performed to allow direct entry through the left atrial wall.

Pre-procedural femoral vessel ultrasound in dogs with patent ductus arteriosus: diameter, image quality and relationship with arterial catheterization.

Introduction: Objectives: Patent ductus arteriosus (PDA) in dogs is often treated via minimally invasive transvascular occlusion using femoral artery access. This study compared ultrasound-derived diameter and image quality of the right femoral artery (RFA) and vein (RFV) in dogs with PDA using a linear ultrasound probe (L-P) and phased-array transthoracic echocardiography probe (TTE-P). The case outcome was assessed.

Prediction of clinically important acquired cardiac disease without an echocardiogram in large breed dogs using a combination of clinical, radiographic and electrocardiographic variables.

Introduction: Large breed (LB) dogs develop dilated cardiomyopathy (DCM) and myxomatous mitral valve disease (MMVD). Echocardiography is required for a definitive diagnosis but is not always available. Our objective was to assess the clinical utility of thoracic radiographs alone and in combination with physical examination and electrocardiography findings for the prediction of clinically important DCM or MMVD in LB dogs.

Correlations between age, body size, sex, and conformation and ultrasound-measured femoral vessel diameter in the dog, with implications for transvascular procedural planning.

Transvascular interventional radiology procedures have advanced in veterinary medicine, but basic knowledge about expected vascular size and vascular imaging requires further exploration. A prospective analytical study of 230 client-owned dogs was carried out to investigate correlations between ultrasound-measured femoral artery (FA) and femoral vein (FV) diameter and various morphometric and demographic dog variables, compare ultrasound-measured femoral vessel diameter to diameter predicted by body weight, compare right- and left-sided femoral vessel diameter, and assess measurement repeatability. Internal diameter of the FA and FV was measured with ultrasound bilaterally.

Transesophageal Echocardiography-Guided Extraction from the Right Atrium in a Dog.

• In infection, worms can migrate into the heart. • Clinical signs are caused by hemolysis and and obstruction of blood flow. • Transesophageal echocardiography guides removal of radiolucent foreign objects.

Preventing critical failure. Can routinely collected data be repurposed to predict avoidable patient harm? A quantitative descriptive study.

Objectives: To determine whether sharing of routinely collected health service performance data could have predicted a critical safety failure at an Australian maternity service.

Design: Observational quantitative descriptive study.

Setting: A public hospital maternity service in Victoria, Australia.

Integrated Behavioral Treatment for Veterans With Co-Morbid Chronic Pain and Hazardous Opioid Use: A Randomized Controlled Pilot Trial.

Opioid prescription in the treatment of chronic pain is frequent and carries a risk of increased morbidity and mortality in a clinically significant number of patients, particularly those who are using opioids in a hazardous manner. Few treatment options are available that target both pain-related interference and hazardous opioid use among patients with chronic pain. In military Veterans, this issue is of particular importance as numerous reports indicate continued high rates of opioid prescription for chronic pain, as well as significant opioid-related problems.

Inhibition of Interleukin-23-Mediated Inflammation with a Novel Small Molecule Inverse Agonist of RORt.

Blockade of interleukin (IL)-23 or IL-17 with biologics is clinically validated as a treatment of psoriasis. However, the clinical impact of targeting other nodes within the IL-23/IL-17 pathway, especially with small molecules, is less defined. We report on a novel small molecule inverse agonist of retinoid acid-related orphan receptor (ROR) t and its efficacy in preclinical models of psoriasis and arthritis.

Discovery of novel quinoline sulphonamide derivatives as potent, selective and orally active RORγ inverse agonists.

A high-throughput screen against Inventiva's compound library using a Gal4/RORγ-LBD luciferase reporter gene assay led to the discovery of a new series of quinoline sulphonamides as RORγ inhibitors, eventually giving rise to a lead compound having an interesting in vivo profile after oral administration. This lead was evaluated in a target engagement model in mouse, where it reduced IL-17 cytokine production after immune challenge. It also proved to be active in a multiple sclerosis model (EAE) where it reduced the disease score.

Artificial cardiac pacemaker placement in dogs with a cohort of myocarditis suspects and association of ultrasensitive cardiac troponin I with survival.

Introduction: Artificial cardiac pacemakers (APs) are a common treatment for symptomatic bradyarrhythmias in dogs, some of which may be triggered by underlying myocarditis. Severely elevated cardiac troponin I (cTnI) concentrations support a diagnosis of myocarditis. The association of ultrasensitive-cTnI (US-cTnI) concentration with survival in a large cohort of dogs receiving APs is not described.

Prodrugs for colon-restricted delivery: Design, synthesis, and in vivo evaluation of colony stimulating factor 1 receptor (CSF1R) inhibitors.

The ability to restrict low molecular weight compounds to the gastrointestinal (GI) tract may enable an enhanced therapeutic index for molecular targets known to be associated with systemic toxicity. Using a triazolopyrazine CSF1R inhibitor scaffold, a broad range of prodrugs were synthesized and evaluated for enhanced delivery to the colon in mice. Subsequently, the preferred cyclodextrin prodrug moiety was appended to a number of CSF1R inhibitory active parent molecules, enabling GI-restricted delivery.

Psychological treatments for adults with posttraumatic stress disorder: A systematic review and meta-analysis.

Numerous guidelines have been developed over the past decade regarding treatments for Posttraumatic stress disorder (PTSD). However, given differences in guideline recommendations, some uncertainty exists regarding the selection of effective PTSD therapies. The current manuscript assessed the efficacy, comparative effectiveness, and adverse effects of psychological treatments for adults with PTSD.

Design strategies to address kinetics of drug binding and residence time.

The kinetics of drug binding and drug residence time are recognized to be important in the clinical effectiveness of drug candidates. In most cases a long residence time of the drug-target complex results in an extended duration of pharmacodynamic activity, even when systemic concentrations of drug have been notably reduced through elimination routes. Hence, if selective for target, long residence times can increase the duration of drug efficacy in vivo and can significantly diminish the potential for off-target-mediated toxicities.

Emerging technologies for metabolite generation and structural diversification.

Multiple technologies have emerged for structural diversification and efficient production of metabolites of drug molecules. These include expanded use of enzymatic and bioorganic transformations that mimic biological systems, biomimetic catalysis and electrochemical techniques. As this field continues to mature the breadth of transformations is growing beyond simple oxidative processes due in part to parallel development of more efficient catalytic methods for functionalization of unactivated scaffolds.

PTSD as a mediator between lifetime sexual abuse and substance use among jail diversion participants.

Objective: Many of the individuals with serious mental illness involved in the criminal justice system have experienced interpersonal victimization, such as sexual abuse, and have high rates of alcohol and drug use disorders. Little attention has been paid to the prevalence of posttraumatic stress disorder (PTSD) and its potential role in the substance misuse of offenders with mental illness.

Methods: The study used a path analytic framework to test the hypothesis that PTSD mediates the relationship between sexual abuse and level of alcohol and drug use among individuals (N=386) with mental illness enrolled in a multisite (N=7) jail diversion project.

Joint mobilization acutely improves landing kinematics in chronic ankle instability.

Purpose: The objective of this study is to examine the acute effect of ankle joint mobilizations akin to those performed in everyday clinical practice on sagittal plane ankle joint kinematics during a single-leg drop landing in participants with chronic ankle instability (CAI).

Methods: Fifteen participants with self-reported CAI (defined as <24 on the Cumberland Ankle Instability Tool) performed three single-leg drop landings under two different conditions: 1) premobilization and, 2) immediately, postmobilization. The mobilizations performed included Mulligan talocrural joint dorsiflexion mobilization with movement, Mulligan inferior tibiofibular joint mobilization, and Maitland anteroposterior talocrural joint mobilization.

Perceived coercion among jail diversion participants in a multisite study.

Objective: Although jail diversion is considered an appropriate and humane response to the disproportionately high volume of people with mental illness who are incarcerated, little is known regarding the perceptions of jail diversion participants, the extent to which they feel coerced into participating, and whether perceived coercion reduces involvement in mental health services. This study addressed perceived coercion among participants in postbooking jail diversion programs in a multisite study and examined characteristics associated with the perception of coercion.

Methods: Data collected in interviews with 905 jail diversion participants from 2003 to 2005 were analyzed with random-effects proportional odds models.

S1P(1) receptor agonists: Assessment of selectivity and current clinical activity.

Interest in sphingosine-1-phosphate (S1P)(1) receptor agonists has increased steadily since the discovery that the mechanism of action of fingolimod (FTY-720)-induced lymphopenia is linked to the S1P GPCR family. Fingolimod is an agonist at four out of the five S1P family receptors. Adoptive cell transfer experiments and selective S1P(1) receptor agonists provided evidence that the S1P(1) receptor is the main target responsible for trapping lymphocytes in secondary lymphoid tissue.

Criminal justice involvement, behavioral health service use, and costs of forensic assertive community treatment: a randomized trial.

Jail diversion and forensic community treatment programs have proliferated over the past decade, far outpacing evidence regarding their efficacy. The current study reports findings from a randomized clinical trial conducted in California for frequent jail users with serious mental illness that compares a forensic assertive community treatment (FACT) intervention with treatment as usual (TAU). Outcomes are reported at 12 and 24 months post-randomization for criminal justice outcomes, behavioral health services and costs.