Publication trends in ligament augmentation techniques: current concepts.

Importance: Ligament augmentation techniques (LATs) are surgical procedures, in which an anatomical ligament repair or reconstruction is strengthened with a synthetic material. During the last decade, LATs have increased in prevalence in clinical practice and academic literature. Observing the trends in LAT publications can be used to identify clusters of strong evidence for clinical practice and to highlight areas of the literature which need further development.

Ligament augmentation repair is broadly applied across different orthopaedic subspecialities: an ISAKOS international survey of orthopaedic surgeons.

Objectives: To evaluate how ligament augmentation repair (LAR) techniques are currently used in different anatomic regions in orthopaedic sports medicine, and to identify the most common indications and limitations of LAR.

Methods: We sent survey invitations to 4,000 members of the International Society of Arthroscopy, Knee Surgery and Orthopaedic Sports Medicine society. The survey consisted of 37 questions total, with members only receiving some branching questions specific to their area of specialisation.

Variation of volatile organic compound levels within ambient room air and its impact upon the standardisation of breath sampling.

The interest around analysis of volatile organic compounds (VOCs) within breath has increased in the last two decades. Uncertainty remains around standardisation of sampling and whether VOCs within room air can influence breath VOC profiles. To assess the abundance of VOCs within room air in common breath sampling locations within a hospital setting and whether this influences the composition of breath.

Ulotaront: A TAAR1 Agonist for the Treatment of Schizophrenia.

Ulotaront (SEP-363856) is a trace-amine associated receptor 1 (TAAR1) agonist with 5-HT1A receptor agonist activity in Phase 3 clinical development, with FDA Breakthrough Therapy Designation, for the treatment of schizophrenia. TAAR1 is a G-protein-coupled receptor (GPCR) that is expressed in cortical, limbic, and midbrain monoaminergic regions. It is activated by endogenous trace amines, and is believed to play an important role in modulating dopaminergic, serotonergic, and glutamatergic circuitry.

Ion Mobility Spectrometry Characterization of the Intermediate Hydrogen-Containing Gold Cluster Au(PPh)H.

We employ ion mobility spectrometry and density functional theory to determine the structure of Au(PPh)H (PPh = triphenylphosphine), which was recently identified by high mass resolution mass spectrometry. Experimental ion-neutral collision cross sections represent the momentum transfer between the ionic clusters and gas molecules averaged over the relative thermal velocities of the colliding pair, thereby providing structural insights. Theoretical calculations indicate the geometry of Au(PPh)H is similar to Au(PPh), with three hydrogen atoms bridging two gold atoms and two hydrogen atoms forming single Au-H bonds.

ESI-MS Identification of the Cationic Phosphine-Ligated Gold Clusters Au: Insight into the Gold-Ligand Ratio and Abundance of Larger Clusters.

Triphenylphosphine (PPh)-ligated gold nanoclusters are valuable for a number of potential applications due to their relative ease of synthesis and usefulness in forming advanced cluster architectures. While previous studies have reported cationic PPh-ligated gold clusters with core sizes of Au, Au, and Au, there has not been definitive identification by mass spectrometry of many larger clusters in the Au range. Herein, we survey a polydisperse solution of cationic PPh-ligated gold clusters using high-mass-resolution (/Δ = 60,000) electrospray ionization mass spectrometry (ESI-MS).

Minimal transmission in an influenza A (H3N2) human challenge-transmission model within a controlled exposure environment.

Uncertainty about the importance of influenza transmission by airborne droplet nuclei generates controversy for infection control. Human challenge-transmission studies have been supported as the most promising approach to fill this knowledge gap. Healthy, seronegative volunteer 'Donors' (n = 52) were randomly selected for intranasal challenge with influenza A/Wisconsin/67/2005 (H3N2).

Evaluation of an early discharge from hospital scheme focussing on patients' housing needs: The ASSIST Project.

This study calculated a return on investment of an early discharge from hospital scheme focussing on improved responses to patients' housing needs. The study identified critical success factors of the scheme that will inform potential spread of the intervention to other localities. Financial return on investment based on service costs and benefits were calculated and the critical success factors were identified through interviews with key stakeholders.

CoREST Complex-Selective Histone Deacetylase Inhibitors Show Prosynaptic Effects and an Improved Safety Profile To Enable Treatment of Synaptopathies.

Synaptic dysfunction is a pathological feature in many neurodegenerative disorders, including Alzheimer's disease, and synaptic loss correlates closely with cognitive decline. Histone deacetylases (HDACs) are involved in chromatin remodeling and gene expression and have been shown to regulate synaptogenesis and synaptic plasticity, thus providing an attractive drug discovery target for promoting synaptic growth and function. To date, HDAC inhibitor compounds with prosynaptic effects are plagued by known HDAC dose-limiting hematological toxicities, precluding their application to treating chronic neurologic conditions.

GNE-371, a Potent and Selective Chemical Probe for the Second Bromodomains of Human Transcription-Initiation-Factor TFIID Subunit 1 and Transcription-Initiation-Factor TFIID Subunit 1-like.

The biological functions of the dual bromodomains of human transcription-initiation-factor TFIID subunit 1 (TAF1(1,2)) remain unknown, although TAF1 has been identified as a potential target for oncology research. Here, we describe the discovery of a potent and selective in vitro tool compound for TAF1(2), starting from a previously reported lead. A cocrystal structure of lead compound 2 bound to TAF1(2) enabled structure-based design and structure-activity-relationship studies that ultimately led to our in vitro tool compound, 27 (GNE-371).

Supporting the UN's Sustainable Development Goals: reconceptualising a 'sustainable development assessment tool' for the health and care system in England.

Aim:: As one of the biggest organisations in the world, the National Health Service (NHS) in England can contribute considerably to the United Nations' Sustainable Development Goals (UN's SDGs). In order to optimise this, this study evaluated and reconceptualised a sustainable development assessment tool for health and care settings in England.

Methods:: A quantitative survey and user/expert discussion panels were conducted to evaluate and reconceptualise the existing sustainable development assessment tool used by the NHS in England, the so-called 'Good Corporate Citizenship Assessment Tool', including potential improvements such as the integration of the UN's SDGs.

Sickness presenteeism: measurement and management challenges.

Since work can be restorative to health, attending work when unwell should not be viewed as an inherently negative phenomenon. However, the functional benefits are likely to depend on the health condition, and the psychosocial quality of the work provided. The current study used a workforce survey to explore differences in the pattern of presenteeism and absenteeism by health condition, the association of psychosocial work factors with presenteeism compared to absenteeism, and their interaction to predict health.

GNE-886: A Potent and Selective Inhibitor of the Cat Eye Syndrome Chromosome Region Candidate 2 Bromodomain (CECR2).

The biological function of bromodomains, epigenetic readers of acetylated lysine residues, remains largely unknown. Herein we report our efforts to discover a potent and selective inhibitor of the bromodomain of cat eye syndrome chromosome region candidate 2 (CECR2). Screening of our internal medicinal chemistry collection led to the identification of a pyrrolopyridone chemical lead, and subsequent structure-based drug design led to a potent and selective CECR2 bromodomain inhibitor (GNE-886) suitable for use as an in vitro tool compound.

Inhibition of bromodomain-containing protein 9 for the prevention of epigenetically-defined drug resistance.

Bromodomain-containing protein 9 (BRD9), an epigenetic "reader" of acetylated lysines on post-translationally modified histone proteins, is upregulated in multiple cancer cell lines. To assess the functional role of BRD9 in cancer cell lines, we identified a small-molecule inhibitor of the BRD9 bromodomain. Starting from a pyrrolopyridone lead, we used structure-based drug design to identify a potent and highly selective in vitro tool compound 11, (GNE-375).

Diving into the Water: Inducible Binding Conformations for BRD4, TAF1(2), BRD9, and CECR2 Bromodomains.

The biological role played by non-BET bromodomains remains poorly understood, and it is therefore imperative to identify potent and highly selective inhibitors to effectively explore the biology of individual bromodomain proteins. A ligand-efficient nonselective bromodomain inhibitor was identified from a 6-methyl pyrrolopyridone fragment. Small hydrophobic substituents replacing the N-methyl group were designed directing toward the conserved bromodomain water pocket, and two distinct binding conformations were then observed.

Fragment-Based Discovery of a Selective and Cell-Active Benzodiazepinone CBP/EP300 Bromodomain Inhibitor (CPI-637).

CBP and EP300 are highly homologous, bromodomain-containing transcription coactivators involved in numerous cellular pathways relevant to oncology. As part of our effort to explore the potential therapeutic implications of selectively targeting bromodomains, we set out to identify a CBP/EP300 bromodomain inhibitor that was potent both in vitro and in cellular target engagement assays and was selective over the other members of the bromodomain family. Reported here is a series of cell-potent and selective probes of the CBP/EP300 bromodomains, derived from the fragment screening hit 4-methyl-1,3,4,5-tetrahydro-2H-benzo[b][1,4]diazepin-2-one.

Discovery of Benzotriazolo[4,3-d][1,4]diazepines as Orally Active Inhibitors of BET Bromodomains.

Inhibition of the bromodomains of the BET family, of which BRD4 is a member, has been shown to decrease myc and interleukin (IL) 6 in vivo, markers that are of therapeutic relevance to cancer and inflammatory disease, respectively. Herein we report substituted benzo[b]isoxazolo[4,5-d]azepines and benzotriazolo[4,3-d][1,4]diazepines as fragment-derived novel inhibitors of the bromodomain of BRD4. Compounds from these series were potent and selective in cells, and subsequent optimization of microsomal stability yielded representatives that demonstrated dose- and time-dependent reduction of plasma IL-6 in mice.

Identification of a Benzoisoxazoloazepine Inhibitor (CPI-0610) of the Bromodomain and Extra-Terminal (BET) Family as a Candidate for Human Clinical Trials.

In recent years, inhibition of the interaction between the bromodomain and extra-terminal domain (BET) family of chromatin adaptors and acetyl-lysine residues on chromatin has emerged as a promising approach to regulate the expression of important disease-relevant genes, including MYC, BCL-2, and NF-κB. Here we describe the identification and characterization of a potent and selective benzoisoxazoloazepine BET bromodomain inhibitor that attenuates BET-dependent gene expression in vivo, demonstrates antitumor efficacy in an MV-4-11 mouse xenograft model, and is currently undergoing human clinical trials for hematological malignancies (CPI-0610).

Pharmacological evaluation of a novel phosphodiesterase 10A inhibitor in models of antipsychotic activity and cognition.

In this study, we report the pharmacological effects of a novel PDE10A inhibitor, SEP-39. SEP-39 is a potent (1.0nM) inhibitor of human PDE10A in vitro, with good selectivity (>16000-fold) against other PDEs.

Evolution and synthesis of novel orally bioavailable inhibitors of PDE10A.

The design and synthesis of highly potent, selective orally bioavailable inhibitors of PDE10A is reported. Starting with an active compound of modest potency from a small focused screen, we were able to evolve this series to a lead molecule with high potency and selectivity versus other PDEs using structure-based design. A systematic refinement of ADME properties during lead optimization led to a lead compound with good half-life that was brain penetrant.

Development of methyl isoxazoleazepines as inhibitors of BET.

In this report we detail the evolution of our previously reported thiophene isoxazole BET inhibitor chemotype exemplified by CPI-3 to a novel bromodomain selective chemotype (the methyl isoxazoleazepine chemotype) exemplified by carboxamide 23. The methyl isoxazoleazepine chemotype provides potent inhibition of the bromodomains of the BET family, excellent in vivo PK across species, low unbound clearance, and target engagement in a MYC PK-PD model.

The relative frequencies of causes of widespread ground-glass opacity: a retrospective cohort.

Purpose: The purpose of our study was to determine the relative frequencies of causes of widespread ground-glass opacity (GGO) in an unselected, consecutive patient population and to identify any associated imaging findings that can narrow or reorganize the differential.

Materials And Methods: The study was approved by the center's IRB and is HIPPA compliant. Cases with widespread GGO in the radiology report were identified by searching the Radiology Information System.

A practical synthesis of indoles via a Pd-catalyzed C-N ring formation.

A method for the synthesis of N-functionalized C2-/C3-substituted indoles via Pd-catalyzed C-N bond coupling of halo-aryl enamines is described. The general strategy utilizes a variety of amines and β-keto esters which are elaborated into halo-aryl enamines as latent precursors to indoles. The preferred conditions comprising the RuPhos precatalyst and RuPhos in the presence of NaOMe in 1,4-dioxane tolerate a variety of substituents and are scalable for the construction of indoles in multigram quantities.

Expiratory air trapping on thoracic computed tomography. A diagnostic subclassification.

Rationale: Multiple causes for air trapping as identified by expiratory computed tomography (CT) have been reported, but a unified evaluation schema has never been proposed.

Objectives: It was our purpose to identify imaging features that would help distinguish etiologies of mosaic air trapping.

Methods: Cases with the term "air trapping" in the radiology report in 2010 were identified by searching the Radiology Information System of an academic tertiary care center and associated community hospital.

Discovery, Design, and Optimization of Isoxazole Azepine BET Inhibitors.

The identification of a novel series of small molecule BET inhibitors is described. Using crystallographic binding modes of an amino-isoxazole fragment and known BET inhibitors, a structure-based drug design effort lead to a novel isoxazole azepine scaffold. This scaffold showed good potency in biochemical and cellular assays and oral activity in an in vivo model of BET inhibition.