Evaluation of deep-learning TSE images in clinical musculoskeletal imaging.

In this study, we compared the fat-saturated (FS) and non-FS turbo spin echo (TSE) magnetic resonance imaging knee sequences reconstructed conventionally (conventional-TSE) against a deep learning-based reconstruction of accelerated TSE (DL-TSE) scans. A total of 232 conventional-TSE and DL-TSE image pairs were acquired for comparison. For each consenting patient, one of the clinically acquired conventional-TSE proton density-weighted sequences in the sagittal or coronal planes (FS and non-FS), or in the axial plane (non-FS), was repeated using a research DL-TSE sequence. The DL-TSE reconstruction resulted in an image resolution that increased by at least 45% and scan times that were up to 52% faster compared to the conventional TSE. All images were acquired on a MAGNETOM Vida 3T scanner (Siemens Healthineers AG, Erlangen, Germany). The reporting radiologists, blinded to the acquisition time, were requested to qualitatively compare the DL-TSE against the conventional-TSE reconstructions. Despite having a faster acquisition time, the DL-TSE was rated to depict smaller structures better for 139/232 (60%) cases, equivalent for 72/232 (31%) cases and worse for 21/232 (9%) cases compared to the conventional-TSE. Overall, the radiologists preferred the DL-TSE reconstruction in 124/232 (53%) cases and stated no preference, implying equivalence, for 65/232 (28%) cases. DL-TSE reconstructions enabled faster acquisition times while enhancing spatial resolution and preserving the image contrast. From these results, the DL-TSE provided added or comparable clinical value and utility in less time. DL-TSE offers the opportunity to further reduce the overall examination time and improve patient comfort with no loss in diagnostic accuracy.

Shunt freedom in slit ventricle syndrome: using paradoxical ventriculomegaly following lumbar shunting to our advantage. Illustrative cases.

BACKGROUND: The authors present two cases of paradoxical ventriculomegaly after lumboperitoneal (LP) shunting in patients with slit ventricle syndrome (SVS). OBSERVATIONS: After placement of an LP shunt, both patients rapidly developed radiographic and clinically symptomatic ventricular enlargement. The then generous ventricular corridors allowed both patients to be treated by endoscopic third ventriculostomy (ETV) with concurrent removal of their LP shunt. The patients then underwent staged increases in their shunt resistance to the maximum setting and remain asymptomatic. LESSONS: The authors suggest that this paradoxical ventriculomegaly may have resulted from a pressure gradient between the shunt systems in the intra- and extraventricular spaces due to a noncommunicating etiology of their hydrocephalus. ETV may successfully exploit this newfound obstructive hydrocephalus and provide resolution of the radiographic and clinical hydrocephalus through allowing for improved communication between the cranial and lumbar cerebrospinal fluid spaces in SVS.

Demographic Predictors of Treatment and Complications for Spinal Disorders: Part 2, Lumbar Spine Trauma.

OBJECTIVE: To study the impact of demographic factors on management of traumatic injury to the lumbar spine and postoperative complication rates. METHODS: Data was obtained from the National Inpatient Sample (NIS) between 2010-2014. International Classification of Diseases, 9th revision, Clinical Modification codes identified patients diagnosed with lumbar fractures or dislocations due to trauma. A series of multivariate regression models determined whether demographic variables predicted rates of complication and revision surgery. RESULTS: A total of 38,249 patients were identified. Female patients were less likely to receive surgery and to receive a fusion when undergoing surgery, had higher complication rates, and more likely to undergo revision surgery. Medicare and Medicaid patients were less likely to receive surgical management for lumbar spine trauma and less likely to receive a fusion when operated on. Additionally, we found significant differences in surgical management and postoperative complication rates based on race, insurance type, hospital teaching status, and geography. CONCLUSION: Substantial differences in the surgical management of traumatic injury to the lumbar spine, including postoperative complications, among individuals of demographic factors such as age, sex, race, primary insurance, hospital teaching status, and geographic region suggest the need for further studies to understand how patient demographics influence management and complications for traumatic injury to the lumbar spine.

Untangling Hydrogen Bond Networks with Ion Mobility Spectrometry and Quantum Chemical Calculations: A Case Study on H+XPGG.

Ion mobility spectrometry-mass spectrometry and quantum chemical calculations are used to determine the structures and stabilities of singly protonated XaaProGlyGly peptides: H+DPGG, H+NPGG, H+EPGG, and H+QPGG. The IMS distributions are similar, suggesting the peptides adopt closely related structures in the gas phase. Quantum chemical calculations show that all conformers seen in the experimental spectrum correspond to the cis configuration about the Xaa-Pro peptide bond, significantly different from the behavior seen previously for H+GPGG. Density functional theory and quantum theory of atoms in molecules (QTAIM) investigations uncover a silent drama as a minor conformer not observed in the H+DPGG spectrum becomes the preferred conformer in H+QPGG, with both conformers being coincident in collision cross section. Investigation of the highly coupled hydrogen bond network, replete with CH···O interactions and bifurcated hydrogen bonds, reveals the cause of this effect as well as the absence of trans conformers from the spectra. A series of generalized observations are provided to aid in enzyme and ligand design using these coupled hydrogen bond motifs.

Enhancing Periconceptional Health by Targeting Postpartum Mothers at Rural WIC Clinics.

The overall goal of this pilot quality improvement (QI) intervention was to (1) assess the feasibility of making a WIC (Women, Infants, and Children) systems-level change that added measurement of maternal weight and discussion of maternal health habits into each postpartum maternal and offspring visit in rural clinics in Colorado and (2) assess the impacts of the intervention on maternal diet, physical activity, and weight status. A mixed-method evaluation approach was used involving the collection of quantitative data (HeartSmartMoms usage reports, manual WIC chart reviews [to calculate screening rates], pre-/postsurveys, and weight status [body mass index]) and qualitative data (focus groups and project team meeting minutes). It was determined it is feasible to make a short-term systems-level change; however, many barriers were encountered in doing so, and the results were not sustained. The QI intervention did decrease participants' daily consumption of sugar-sweetened beverages and maternal weight status (controlling for maternal age and language), but did not improve any other eating/physical activity behaviors. Lessons learned and recommendations to improve the implementation of health promotion interventions aimed at improving postpartum maternal health, which can increase health during the periconceptional phase, and in turn, improve the health outcomes for a child, are discussed.

Identifying patterns of obesity risk behavior to improve pediatric primary care.

PURPOSE: To develop profiles of obesity risk behaviors for children and adolescents. DESIGN AND METHODS: Risk assessments were obtained from patients (n = 971) at a school-based health center. Latent class analysis was used to create subgroups based on seven indicators measuring diet, activity, and screen time. RESULTS: Four classes emerged, with 44% classified as the "Healthiest," 8% as the "Least Healthy," 37% as "Mixed Diet/Low Activity/Low Screen Time," and 11% as "Mixed Diet/High Activity/High Screen Time." Several demographic predictors distinguished the classes. PRACTICE IMPLICATIONS: Obesity risk factor profiles may help providers identify strengths and risks, tailor counseling, and plan interventions with families.

P2-quinazolinones and bis-macrocycles as new templates for next-generation hepatitis C virus NS3/4a protease inhibitors: discovery of MK-2748 and MK-6325.

With the goal of identifying inhibitors of hepatitis C virus (HCV) NS3/4a protease that are potent against a wide range of genotypes and clinically relevant mutant viruses, several subseries of macrocycles were investigated based on observations made during the discovery of MK-5172. Quinazolinone-containing macrocycles were identified as promising leads, and optimization for superior cross-genotype and mutant enzyme potency as well as rat liver and plasma concentrations following oral dosing, led to the development of MK-2748. Additional investigation of a series of bis-macrocycles containing a fused 18- and 15-membered ring system were also optimized for the same properties, leading to the discovery of MK-6325. Both compounds display the broad genotype and mutant potency necessary for clinical development as next-generation HCV NS3/4a protease inhibitors.

Discovery of diazepane amide DORAs and 2-SORAs enabled by exploration of isosteric quinazoline replacements.

Dual orexin receptor antagonists (DORAs), or orexin 1 (OX1) and orexin 2 (OX2) receptor antagonists, have demonstrated clinical utility for the treatment of insomnia. Medicinal chemistry efforts focused on the reduction of bioactivation potential of diazepane amide 1 through the modification of the Western heterocycle resulted in the discovery of suvorexant, a DORA recently approved by the FDA for the treatment of insomnia. A second strategy towards reducing bioactivation risk is presented herein through the exploration of monocyclic quinazoline isosteres, namely substituted pyrimidines. These studies afforded potent DORAs with significantly reduced bioactivation risk and efficacy in rodent sleep models. Surprisingly, side products from the chemistry used to produce these DORAs yielded isomeric pyrimidine-containing diazepane amides possessing selective OX2R antagonist (2-SORA) profiles. Additional exploration of these isomeric pyrimidines uncovered potent 2-SORA diazepane amides with sleep efficacy in mouse EEG studies.

Diastereo- and enantioselective three-component coupling approach to highly substituted pyrrolidines.

The enantioselective synthesis of substituted pyrrolidines through a mild Lewis-acid catalyzed three-component coupling reaction between picolinaldehyde, amino acids, and activated olefins is reported. The reaction uses low catalyst loadings of commercially available chiral diamines and copper triflate proposed to self-assemble in conjunction with the chelating aldehydes, 4-substituted-2-picolinaldehydes or 4-methylthiazole-2-carboxaldehyde, to generate a catalyst complex. A model is provided to explain how this complex directs enantioselectivity. This work represents a significant advance in the ease, scope, and cost of producing highly substituted, enantioenriched pyrrolidines.

Mediastinal goiter presenting with ventricular tachycardia.

BACKGROUND: We report a rare case of a mediastinal goiter confined to the thoracic inlet and cavity presenting with ventricular tachycardia as the sole clinical manifestation. METHODS AND RESULTS: The patient did not have any of the typical features of a mediastinal goiter such as neck swelling, dysphagia, or respiratory difficulty, but instead had spontaneous onset of wide-complex tachycardia requiring emergency treatment. This atypical presentation led to initial misinterpretation of imaging studies and delayed diagnosis of the mediastinal mass. The large, completely intrathoracic thyroid goiter abutted the cardiac muscle and required a combined transcervical and median sternotomy approach for removal. The arrhythmia resolved postoperatively. CONCLUSION: To our knowledge, this case represents the first documented presentation of ventricular tachycardia as a unique and sole feature of mediastinal goiter.

Development of macrocyclic inhibitors of HCV NS3/4A protease with cyclic constrained P2-P4 linkers.

A series of macrocyclic compounds containing a cyclic constraint in the P2-P4 linker region have been discovered and shown to exhibit excellent HCV NS3/4a genotype 3a and genotype 1b R155K, A156T, A156V, and D168V mutant activity while maintaining high rat liver exposure. The effect of the constraint is most dramatic against gt 1b A156 mutants where ~20-fold improvements in potency are achieved by introduction of a variety of ring systems into the P2-P4 linker.

Development of potent macrocyclic inhibitors of genotype 3a HCV NS3/4A protease.

A series of macrocyclic compounds containing 2-substituted-quinoline moieties have been discovered and shown to exhibit excellent HCV NS3/4a genotype 3a and genotype 1b R155K mutant activity while maintaining the high rat liver exposure. Cyclization of the 2-substituted quinoline substituent led to a series of tricyclic P2 compounds which also display superb gt3a potency.

Discovery of MK-5172, a Macrocyclic Hepatitis C Virus NS3/4a Protease Inhibitor.

A new class of HCV NS3/4a protease inhibitors containing a P2 to P4 macrocyclic constraint was designed using a molecular modeling-derived strategy. Building on the profile of previous clinical compounds and exploring the P2 and linker regions of the series allowed for optimization of broad genotype and mutant enzyme potency, cellular activity, and rat liver exposure following oral dosing. These studies led to the identification of clinical candidate 15 (MK-5172), which is active against genotype 1-3 NS3/4a and clinically relevant mutant enzymes and has good plasma exposure and excellent liver exposure in multiple species.

Comparing the Effectiveness of CDSS on Provider's Behaviors to Implement Obesity Prevention Guidelines.

Obesity is a global epidemic demanding the use of clinical decision support tools to help clinicians in the identification, assessment and management of healthy weight gain in children. Over the last decade, numerous systematic reviews have shown that clinical decision support systems (CDSS) have positively impacted clinician's performance for drug ordering/dosing and preventive care reminders. CDSS that are built into the clinician's workflow at the point of care also have a positive impact on provider's performance. There are limited studies that examine CDSS in nursing practice. This paper describes a comparative effectiveness study being conducted in school-based clinics to examine the impact of web-based training with and without a CDSS that contains tailored recommendations. The study involves the use of a CDSS tool focused on cardiovascular risks, HeartSmartKids™. This research is an important example of an interdisciplinary team using information technology to address the global issue of obesity prevention.

Antibacterial properties of additives used in injection immunotherapy.

BACKGROUND: Previous studies have reviewed the safety of preparing and administering allergy injection immunotherapy in a physician's office, and showed no evidence of infectious complications. The current study examines the antimicrobial properties of the common additives used in preparation of multidose immunotherapy vials. METHODS: Vials were prepared with varying concentrations of glycerin (0-25%), phenol (0-0.4%) and combinations of glycerin with phenol. A standard inoculum of Staphylococcus aureus was introduced in each vial and incubated. Optical densities were measured and colony counts were performed at 24 and 48 hours. Follow-up broth microdilution assays were performed using varying inocula of bacteria and the highest concentrations of additives to determine the number of bacteria for which these solutions were bacteriostatic and/or bactericidal. Optical densities were measured and colony counts were performed as in the vial assays. RESULTS: All vials with varying dilutions of glycerin, phenol, and their combination showed bacterial growth with the standard inoculum of Staphylococcus aureus. Visible turbidity and optical density were inversely related to additive concentration. Follow-up microdilution assays with differing concentrations of bacteria demonstrated bactericidal activity with inocula of 1 × 10(3) colony forming units (CFU) of Staphylococcus aureus at clinically used concentrations of glycerin and phenol. CONCLUSION: Higher concentrations of additives show better inhibition of bacterial growth. Solutions containing glycerin showed superior bactericidal activity than those containing only phenol. At concentrations of additives used in preparing allergy immunotherapy vials, antibacterial effects were observed with inoculation of 1 × 10(3) CFU or less of Staphylococcus aureus.

Discovery of MK-1220: A Macrocyclic Inhibitor of Hepatitis C Virus NS3/4A Protease with Improved Preclinical Plasma Exposure.

The discovery of MK-1220 is reported along with the development of a series of HCV NS3/4A protease inhibitors containing a P2 to P4 macrocyclic constraint with improved preclinical pharmacokinetics. Optimization of the P2 heterocycle substitution pattern as well as the P3 amino acid led to compounds with greatly improved plasma exposure following oral dosing in both rats and dogs while maintaining excellent enzyme potency and cellular activity. These studies led to the identification of MK-1220.

Advances in cheminformatics methodologies and infrastructure to support the data mining of large, heterogeneous chemical datasets.

In recent years, there has been an explosion in the availability of publicly accessible chemical information, including chemical structures of small molecules, structure-derived properties and associated biological activities in a variety of assays. These data sources present us with a significant opportunity to develop and apply computational tools to extract and understand the underlying structure-activity relationships. Furthermore, by integrating chemical data sources with biological information (protein structure, gene expression and so on), we can attempt to build up a holistic view of the effects of small molecules in biological systems. Equally important is the ability for non-experts to access and utilize state of the art cheminformatics method and models. In this review we present recent developments in cheminformatics methodologies and infrastructure that provide a robust, distributed approach to mining large and complex chemical datasets. In the area of methodology development, we highlight recent work on characterizing structure-activity landscapes, Quantitative Structure Activity Relationship (QSAR) model domain applicability and the use of chemical similarity in text mining. In the area of infrastructure, we discuss a distributed web services framework that allows easy deployment and uniform access to computational (statistics, cheminformatics and computational chemistry) methods, data and models. We also discuss the development of PubChem derived databases and highlight techniques that allow us to scale the infrastructure to extremely large compound collections, by use of distributed processing on Grids. Given that the above work is applicable to arbitrary types of cheminformatics problems, we also present some case studies related to virtual screening for anti-malarials and predictions of anti-cancer activity.

Discovery of vaniprevir (MK-7009), a macrocyclic hepatitis C virus NS3/4a protease inhibitor.

A new class of HCV NS3/4a protease inhibitors which contain a P2 to P4 macrocyclic constraint was designed using a molecular-modeling derived strategy. Exploration of the P2 heterocyclic region, the P2 to P4 linker, and the P1 side chain of this class of compounds via a modular synthetic strategy allowed for the optimization of enzyme potency, cellular activity, and rat liver exposure following oral dosing. These studies led to the identification of clinical candidate 35b (vaniprevir, MK-7009), which is active against both the genotype 1 and genotype 2 NS3/4a protease enzymes and has good plasma exposure and excellent liver exposure in multiple species.

Evaluation of technology to identify and assess overweight children and adolescents.

PURPOSE: The current obesity epidemic has produced a generation of children that may be the first to have a life expectancy shorter than their parents. To address the obesity epidemic, experts have published recommendations for providers. Research suggests the publication of guidelines may not change provider behavior. DESIGN AND METHODS: This study evaluates computer assistance for implementing obesity guidelines in school-based health centers. RESULTS: Significant improvements in identification and assessment of obesity in children with technology support were noted. PRACTICE IMPLICATIONS: Computer decision support shows promise for promoting the implementation of current recommendations by supporting providers in identifying, assessing, and providing tailored recommendations for children at risk of obesity.

A transient cell-based phenotype assay for hepatitis C NS3/4A protease: application to potency determinations of a novel macrocyclic inhibitor against diverse protease sequences isolated from plasma infected with HCV.

The potential of hepatitis C virus (HCV) to develop antiviral resistance renders phenotypic analysis of viral relapse or breakthrough sequences essential to the clinical evaluation of HCV antivirals. This work describes a transient assay in which clinical NS3/4A sequences are co-expressed in Huh-7 cells with a reporter whose activity is an easily quantifiable measure of protease activity. The utility of the assay was demonstrated in potency evaluations of a novel protease inhibitor against panels of NS3/4A sequences spanning genotypes 1-3. The compound was potent against genotype 1a and 1b protease sequences with sub-nanomolar to low nanomolar EC(50)s, slightly diminished in potency against genotype 2b sequences, but poorly active against genotype 3a sequences. Diverse sequences of the same HCV genotype, however, varied in response to the inhibitor as much as 30-fold, with susceptibility differences not easily attributed to specific amino acid polymorphisms. The results demonstrate the versatility of a novel phenotype assay in the evaluation of a promising new class of NS3/4A inhibitor. The results highlight further the complexity in correlating susceptibility differences with specific sequence polymorphisms, and underscore the value in direct phenotyping of clinical sequences for compound sensitivity. The assay will be useful for monitoring changes in susceptibility due to emergence of resistant virus during clinical studies of protease inhibitors.