Covalent hits and where to find them.

Covalent hits for drug discovery campaigns are neither fantastic beasts nor mythical creatures, they can be routinely identified through electrophile-first screening campaigns using a suite of different techniques. These include biophysical and biochemical methods, cellular approaches, and DNA-encoded libraries. Employing best practice, however, is critical to success.

Ruggedized Self-Propelling Hemostatic Gauze Delivers Low Dose of Thrombin and Systemic Tranexamic Acid and Achieves High Survival in Swine With Junctional Hemorrhage.

Introduction: Hemorrhage is responsible for 91% of preventable prehospital deaths in combat. Bleeding from anatomic junctions such as the groin, neck, and axillae make up 19% of these deaths, and reports estimate that effective control of junctional hemorrhage could have prevented 5% of fatalities in Afghanistan. Hemostatic dressings are effective but are time-consuming to apply and are limited when proper packing and manual pressure are not feasible, such as during care under fire.

Does pharyngoplasty work? Outcomes of 100 consecutive operations over 10 years.

Background: Velopharyngeal insufficiency is a commonly encountered problem in Cleft Surgery, with pharyngoplasty being the mainstay of surgical management. In this study we aim to investigate the indications and outcomes of a single institution's experience and compare to international literature.

Methods: A retrospective review was performed looking at over 100 consecutive primary pharyngoplasty operations for velopharyngeal dysfunction over a 10-year period at a single institution.

A perspective on the discovery of enzyme activators.

Enzyme activation remains a largely under-represented and poorly exploited area of drug discovery despite some key literature examples of the successful application of enzyme activators by various mechanisms and their importance in a wide range of therapeutic interventions. Here we describe the background nomenclature, present the current position of this field of drug discovery and discuss the challenges of hit identification for enzyme activation, as well as our perspectives on the approaches needed to overcome these challenges in early drug discovery.

Percutaneous delivery of self-propelling thrombin-containing powder increases survival from noncompressible truncal hemorrhage in a swine model of coagulopathy and hypothermia.

Background: Noncompressible truncal hemorrhage (NCTH) remains a leading cause of preventable death on the battlefield. Definitively managing severe NCTH requires surgery within the first hour after injury, which is difficult when evacuating casualties from remote and austere environments. During delays to surgery, hemostatic interventions that are performed prehospital can prevent coagulopathy and hemorrhagic shock and increase the likelihood that casualties survive to receive definitive care.

Videoconferencing for Large Animal Trauma Experiments During COVID-19: A Cross-Continent Experience.

Introduction: COVID-19 shutdowns in many research facilities across North America impacted preclinical trauma-related research and development. Shutdown limited the speed and resources available for large animal experiments necessary for advancing medical devices and technologies. However, the pandemic led to the rapid adoption and expansion of videoconferencing in social circles, workplaces, and primary care health settings.

Percutaneous delivery of self-propelling hemostatic powder for managing non-compressible abdominal hemorrhage: a proof-of-concept study in swine.

Introduction: Non-compressible intra-abdominal hemorrhage (NCIAH) is a major cause of preventable death on the battlefield and in civilian trauma. Currently, it can only be definitively managed with surgery, as there are limited strategies for controlling ongoing NCIAH in the prehospital environment. We hypothesized that a self-propelling thrombin-containing powder (SPTP) could increase survival in a swine model of NCIAH when delivered percutaneously into the closed abdomen using an engineered spray system.

Severe upper gastrointestinal bleeding is halted by endoscopically delivered self-propelling thrombin powder: A porcine pilot study.

Hemostatic powders have emerged recently to treat upper gastrointestinal bleeding (UGIB). Previously, we developed a novel self-propelling thrombin powder (SPTP) that effectively manages external pulsatile arterial bleed without compression, by effervescing and carrying thrombin into the wound. Here, we tested if SPTP, sprayed endoscopically, can manage severe UGIB in a live porcine model.

The Use of Acoustic Mist Ionization Mass Spectrometry for High-Throughput Screening.

It is clear from the analysis of the distribution of approved drug targets that enzymes continue to be a major target class for the pharmaceutical industry. The application of high-throughput screens designed to monitor the activity of these enzyme targets, and the ability of test compounds to modulate this activity, is still the predominant hit finding approach in the industry. The widespread use of enzyme activity-based screens has led to the development of several useful guidelines for the development and validation of robust and reliable assays.

High-Throughput Mechanism of Inhibition.

Enzymes represent a significant proportion of the druggable genome and constitute a rich source of drug targets. Delivery of a successful program for developing a modulator of enzyme activity requires an understanding of the enzyme's mechanism and the mode of interaction of compounds. This allows an understanding of how physiological conditions in disease-relevant cells will affect inhibitor potency.

Adult Cleft Palate Repair: It's Worth a Shot.

Repair of cleft palate in the adult population is controversial. We present a case of a 66-year-old woman who underwent secondary cleft palate repair. The patient was born with a cleft palate and at age 15 years underwent palate repair that subsequently broke down.

Efficacy of a Peruvian Botanical Remedy (Sabell A4+) for Treating Liver Disease and Protecting Gastric Mucosal Integrity.

The purpose of this study was to determine the efficacy of a Peruvian botanical formulation for treating disorders of hepatic function and gastric mucosal integrity. The formulation A4+ (Sabell Corporation) contains extracts of rhizome, flower, and leaf. Individually these plants have been used as traditional remedies for liver disease.

Acoustic mist ionization mass spectrometry (AMI-MS) as a drug discovery platform.

The expansion of label free mass spectrometry into early drug discovery was always predicted to provide improvements in data quality and depth with the potential to reduce costs but has previously been limited by throughput. There are several techniques that vary by sample introduction technology or ionization technique that try to address the challenges in this area. In this review, the authors describe the deployment of such a device, combining acoustic mist ionization and time-of-flight mass spectrometry.

Comparison of tranexamic acid plasma concentrations when administered via intraosseous and intravenous routes.

Introduction: There is a lack of information regarding intraosseous (IO) administration of tranexamic acid (TXA). Our hypothesis was that a single bolus IO injection of TXA will have a similar pharmacokinetic profile to TXA administered at the same dose IV.

Methods: Sixteen male Landrace cross swine (mean body weight 27.

Toxicology of a Peruvian botanical remedy to support healthy liver function.

Background: The purpose of these studies was to determine the safety of a botanical treatment for supporting healthy liver function developed in Peru. The formulation, A4+, contains extracts of Curcuma longa L. rhizome (A4R), Cordia lutea Lam.

Development of a Web GIS Application for Visualizing and Analyzing Community Out of Hospital Cardiac Arrest Patterns.

Improving survival rates at the neighborhood level is increasingly seen as a priority for reducing overall rates of out-of-hospital cardiac arrest (OHCA) in the United States. Since wide disparities exist in OHCA rates at the neighborhood level, it is important for public health officials and residents to be able to quickly locate neighborhoods where people are at elevated risk for cardiac arrest and to target these areas for educational outreach and other mitigation strategies. This paper describes an OHCA web mapping application that was developed to provide users with interactive maps and data for them to quickly visualize and analyze the geographic pattern of cardiac arrest rates, bystander CPR rates, and survival rates at the neighborhood level in different U.

Identification of high-risk communities for unattended out-of-hospital cardiac arrests using GIS.

Improving survival rates for out of hospital cardiac arrest (OHCA) at the neighborhood level is increasingly seen as priority in US cities. Since wide disparities exist in OHCA rates at the neighborhood level, it is necessary to locate neighborhoods where people are at elevated risk for cardiac arrest and target these for educational outreach and other mitigation strategies. This paper describes a GIS-based methodology that was used to identify communities with high risk for cardiac arrests in Franklin County, Ohio during the period 2004-2009.

Poisson cluster analysis of cardiac arrest incidence in Columbus, Ohio.

Background: Scarce resources in disease prevention and emergency medical services (EMS) need to be focused on high-risk areas of out-of-hospital cardiac arrest (OHCA).

Objective: Cluster analysis using geographic information systems (GISs) was used to find these high-risk areas and test potential predictive variables.

Methods: This was a retrospective cohort analysis of EMS-treated adults with OHCAs occurring in Columbus, Ohio, from April 1, 2004, through March 31, 2009.

Identifying high-risk geographic areas for cardiac arrest using three methods for cluster analysis.

Objectives:   The objective was to identify high-risk census tracts, defined as those areas that have both a high incidence of out-of-hospital cardiac arrest (OHCA) and a low prevalence of bystander cardiopulmonary resuscitation (CPR), by using three spatial statistical methods.

Methods:   This was a secondary analysis of two prospectively collected registries in the city of Columbus, Ohio. Consecutive adult (≥18 years) OHCA patients, restricted to those of cardiac etiology and treated by emergency medical services (EMS) from April 1, 2004, to April 30, 2009, were studied.

A method for the analysis of ginsenosides, malonyl ginsenosides, and hydrolyzed ginsenosides using high-performance liquid chromatography with ultraviolet and positive mode electrospray ionization mass spectrometric detection.

A high-performance liquid chromatographic separation coupled to diode array absorbance and positive mode electrospray mass spectrometric detection has been developed for the analysis of ginsenosides, malonyl ginsenosides, and hydrolyzed ginsenosides in extracts of Asian ginseng (Panax ginseng) and American ginseng (P. quinquefolius). The method is capable of separating, identifying, and quantifying the predominant ginsenosides found in heated alcoholic extracts of Asian and American ginseng roots routinely sold as nutraceuticals.

Determination of metoprolol, and its four metabolites in dog plasma.

Metoprolol and its metabolites alpha-hydroxymetoprolol, O-desmethylmetoprolol, metoprolol acid and deaminated metoprolol were quantified in dog plasma using an isocratic high-performance liquid chromatographic method (with a BetaBasic Cyano column) with fluorescence detection. A solid phase extraction technique (Oasis HLB, Waters) was used to extract metoprolol and its four metabolites from dog plasma with high recovery rates. The method was shown to be sensitive and reproducible and was used to determine the pharmacokinetic profile of metoprolol in dog.

Effects of theophylline on tracheal mucociliary clearance rates in healthy cats.

Objective: To determine tracheal mucociliary clearance rate (TMCCR) by use of a standard protocol in healthy anesthetized cats and to determine the effect of theophylline on TMCCR in healthy anesthetized cats.

Animals: 6 healthy cats.

Procedure: Cats were anesthetized with propofol, and a droplet of the radiopharmaceutical technetium Tc 99m macroaggregated albumin was placed endoscopically at the carina.

Multifocal retinopathy of Great Pyrenees dogs.

Forty-four related Great Pyrenees dogs were examined ophthalmoscopically. Focal retinal elevations, multiple gray-tan-pink subretinal patches, and discrete areas of tapetal hyper-reflectivity were seen in 19 dogs, ranging from 13 weeks to 10 years of age. These lesions varied in size from focal spots that were barely visible with the indirect ophthalmoscope to areas that were larger than the optic disc.