Synthesis of Substituted 2-Pyridones via 6π-Electrocyclization of Dienyl Isocyanates.

A one-pot Curtius rearrangement of dienyl carboxylic acids followed by a 6π-electrocyclization process to form substituted 2-pyridone products has been developed. Dienyl isocyanates generated from aliphatic acids were more reactive than their aromatic counterparts. Additionally, substitution patterns of the carboxylic acids had an impact on the efficiency of the cyclization.

Treatment of Acute Bronchitis and its Impact on Return Emergency Department Visits.

BACKGROUND: Antibiotics are not recommended in healthy, uncomplicated adults for the treatment of acute bronchitis, yet are still often prescribed. No randomized studies have examined whether prescribing antibiotics in the emergency department (ED) impacts hospital return rates. OBJECTIVE: Our aim was to compare hospital return rates between those who were prescribed an antibiotic vs. those who were not prescribed an antibiotic for the treatment of acute bronchitis. METHODS: A retrospective cohort study was completed evaluating patients aged 18-64 years who presented to a community teaching hospital ED with acute bronchitis between January 2017 and December 2019. The primary outcomes were 30-day ED return and hospital admissions from initial ED visit. The rates of ED return or readmitted were compared for patients prescribed an antibiotic for treatment of acute bronchitis vs. those patients who were not prescribed an antibiotic. RESULTS: Of the 752 patients included, 311 (41%) were prescribed antibiotics. Baseline demographics were similar between both groups. Of those prescribed an antibiotic, 26 of 311 (8.4%) returned to the hospital within 30 days compared with 33 of 441 patients (7.5%) who were not prescribed an antibiotic (odds ratio 1.13; 95% confidence interval 0.66-1.92). CONCLUSIONS: There was no association found between antibiotic therapy for treatment of acute bronchitis and return to the hospital.

Analysis of a Consecutive Retrospective Cohort of Strangulation Victims Evaluated by a Sexual Assault Nurse Examiner Consult Service.

OBJECTIVE: The purpose of this study was to review the evaluation of strangulation victims assessed by a sexual assault nurse examiner (SANE) service. The primary objective was to produce observational results on documented injury frequency and secondarily to explore advanced imaging use, outcomes, signs/symptoms, and documentation. METHODS: This was a retrospective analysis of a cohort of 130 consecutive strangled patients over a 42-month period evaluated by a SANE consult service in a metropolitan area. A single investigator extracted medical records for demographics, history, imaging, injuries, disposition, and both presence and documentation of a number of signs/symptoms. A second investigator independently extracted greater than 30% of the total charts with universal agreement. Data were analyzed with descriptive statistics. RESULTS: Patients were primarily female (129:1) and their age averaged 30.6 years. Time from event to presentation varied. There were no major brain or neck injuries detected (0%; 95 confidence interval, 0-2.31), and all patients were discharged in stable condition. Imaging was used in 23 patients (17.7%). Certain signs and symptoms were more common than others, and documentation frequency of signs and symptoms varied. CONCLUSION: In this retrospective cohort of 130 consecutive nonfatally strangled awake patients seen as SANE consults in a single emergency department, there were no major injuries documented. The most common signs or symptoms were neck pain, neck markings, and loss of consciousness. Imaging was used in 17.7% of the patients. Presence or absence of neck pain, neck markings, and altered mental status were most consistently documented. Seizure, subcutaneous emphysema, and carotid bruit were least consistently documented.

Exploring Cost Savings with Specialty Biologic Drugs Administered to Adult Inpatients with Inflammatory Bowel Disease.

Background: Specialty infusion and self-injectable biologic drugs for the treatment of inflammatory bowel disease (IBD) are high-cost medications. When administered to hospital-admitted patients, these medications are not reimbursed on an individual basis but rolled into a per diem payment by most payers in the United States (US). Therefore, choosing to administer these medications in the inpatient setting may reveal negative financial implications for some health care institutions. Selecting an alternative site of care to administer these medications during the clinical management process may lead to cost savings. Objective: Review the clinical necessity of inpatient specialty biologic administrations for the treatment of IBD to identify and quantify potential cost saving opportunities. Methods: Using patient medical records at a US academic medical center, we retrospectively identified inpatient administrations of specialty infusion and self-injectable biologic medications for IBD treatment from June 1, 2016 to May 31, 2017. Guided by a standardized form, an evaluation team consisting of 3 of the investigators determined the clinical necessity of each specialty biologic medication administration within the inpatient setting. Costs and reimbursement rates for administration in both the inpatient and outpatient settings were procured and tabulated. Results: Seventeen inpatient specialty biologic administrations for IBD during the 12 month study period were identified. Of these, 11 administrations were given for the treatment of Crohn's disease (CD) and 6 for ulcerative colitis (UC). The evaluation team determined that 65% of these administrations were clinically necessary as inpatient administrations, and that 35% were not. The sum of the wholesale acquisition costs (WAC) for clinically necessary inpatient biologic administrations totaled $54 737, and the WAC for those administrations deemed not clinically necessary totaled $43 702. Further analysis of administration events revealed that the institution could have realized an estimated $13 817 in additional revenue above the cost of the drug if eligible inpatient biologic administrations had been received in the institution's outpatient clinic setting instead. Conclusion: Administering specialty biologic drugs for the treatment of IBD in the care setting best aligned with existing reimbursement structures may lead to institutional cost savings.

Chemoselective Preparation of Clickable Aryl Sulfonyl Fluoride Monomers: A Toolbox of Highly Functionalized Intermediates for Chemical Biology Probe Synthesis.

Sulfonyl fluoride (SF)-based activity probes have become important tools in chemical biology. Herein, exploiting the relative chemical stability of SF to carry out a number of unprecedented SF-sparing functional group manipulations, we report the chemoselective synthesis of a toolbox of highly functionalized aryl SF monomers that we used to quickly prepare SF chemical biology probes. In addition to SF, the monomers bear an embedded click handle (a terminal alkyne that can perform copper(I)-mediated azide-alkyne cycloaddition). The monomers can be used either as fragments to prepare clickable SF analogues of drugs (biologically active compounds) bearing an aryl ring or, alternatively, attached to drugs as minimalist clickable aryl SF substituents.

Modern advances in heterocyclic chemistry in drug discovery.

New advances in synthetic methodologies that allow rapid access to a wide variety of functionalized heterocyclic compounds are of critical importance to the medicinal chemist as it provides the ability to expand the available drug-like chemical space and drive more efficient delivery of drug discovery programs. Furthermore, the development of robust synthetic routes that can readily generate bulk quantities of a desired compound help to accelerate the drug development process. While established synthetic methodologies are commonly utilized during the course of a drug discovery program, the development of innovative heterocyclic syntheses that allow for different bond forming strategies are having a significant impact in the pharmaceutical industry. This review will focus on recent applications of new methodologies in C-H activation, photoredox chemistry, borrowing hydrogen catalysis, multicomponent reactions, regio- and stereoselective syntheses, as well as other new, innovative general syntheses for the formation and functionalization of heterocycles that have helped drive project delivery. Additionally, the importance and value of collaborations between industry and academia in shaping the development of innovative synthetic approaches to functionalized heterocycles that are of greatest interest to the pharmaceutical industry will be highlighted.

Using Social Media to Teach About and Engage Residents in Evidence-Based Medicine.

BACKGROUND AND OBJECTIVES: Evidence-based medicine (EBM) is an important concept for family medicine and is part of several Accreditation Council for Graduate Medical Education milestones. Social media (SM) has become a cornerstone in most of our lives. Previous studies show the use of SM in medical education is expanding. The objective of this study is to use SM for medical education focusing on teaching EBM through an innovative, engaging video series. METHODS: This quasi-experimental study used pre- and postintervention surveys between May 2022 and June 2022 using the American Board of Family Medicine National Journal Club initiative as a foundation. A total of 196 residents and fellows from various family medicine residency programs were eligible to participate. Surveys consisted of SM usage, EBM engagement, EBM comfort and confidence adapted from a validated tool, and questions about the articles reviewed in the videos. RESULTS: A total of 44 of 196 residents and fellows from various family medicine residency programs participated in the preintervention survey. Most participants identified learning about EBM through residency didactics. The most popular SM platforms were Instagram and YouTube for medical content. Participants were least comfortable on the 10-point scale for critically appraising study methods. Postintervention cumulative scores for knowledge about the journal articles increased from 64% to 85%. CONCLUSIONS: The video series taught EBM concepts and were well received, albeit with a low postintervention response rate. These findings contribute to the evolving landscape of medical education with implications for improving the effectiveness of EBM teaching through SM platforms.

Macrocyclic Retinoic Acid Receptor-Related Orphan Receptor C2 Inverse Agonists.

Macrocyclic retinoic acid receptor-related orphan receptor C2 (RORC2) inverse agonists have been designed with favorable properties for topical administration. Inspired by the unanticipated bound conformation of an acyclic sulfonamide-based RORC2 ligand from cocrystal structure analysis, macrocyclic linker connections between the halves of the molecule were explored. Further optimization of analogues was accomplished to maximize potency and refine physiochemical properties (MW, lipophilicity) best suited for topical application. Compound 14 demonstrated potent inhibition of interleukin-17A (IL-17A) production by human Th17 cells and in vitro permeation through healthy human skin achieving high total compound concentration in both skin epidermis and dermis layers.

Impact of an International Service Trip on Pharmacy and Medical Learners' Attitudes Toward Interprofessional Collaboration.

Objective. The purpose of this study was to evaluate the impact of an interprofessional medical service trip to rural Honduras on pharmacy and medical learners' attitudes toward interprofessional learning.Methods. In this mixed-methods research, 19 participating students and residents from medicine and pharmacy completed the Readiness for Interprofessional Learning Scale (RIPLS) before and after the service trip in fall 2017 and spring 2018. Individual semi-structured interviews were conducted with participants following each trip to better understand which aspects of the experience shaped their interprofessional learning.Results. Following the service trip, a significant improvement was found for the Teamwork & Collaboration subscale and the Negative Professional Identity subscale of the RIPLS. Several themes emerged from interviews, including that face-to-face interaction promotes collaboration; limited resources encourage team-based problem-solving; time together outside of work strengthens interprofessional connections; participating in another profession's patient care activities fosters appreciation of individual roles; interprofessional care takes time; and participants felt a greater desire to pursue interprofessional practice in the future.Conclusion. Interprofessional learning during a medical service trip improved participants' attitudes toward collaboration. This study highlights which aspects of this experience contributed most to interprofessional learning, and our results may guide future efforts to design effective interprofessional education experiences.

Synthesis of 2-Arylpiperidines via Pd-Catalyzed Arylation of Aza-Achmatowicz Rearrangement Products with Arylboronic Acids.

The first Pd-catalyzed arylation of aza-Achmatowicz rearrangement products with arylboronic acids is achieved, providing versatile 2-aryldihydropyridinones for facile synthesis of highly functionalized 2-arylpiperidines. Key to this arylation is the use of non-phosphine-ligand palladium precatalyst. The substrate scope is demonstrated with >26 examples, and the utility of 2-aryldihydropyridinones is illustrated by the synthesis of a small collection of 2-arylpiperidines with substituents or functional groups at any carbon (C2-C6) as well as two NK1 receptor antagonists (+)-CP-999,94 and (+)-L-733,060.

Selective, Small-Molecule Co-Factor Binding Site Inhibition of a Su(var)3-9, Enhancer of Zeste, Trithorax Domain Containing Lysine Methyltransferase.

The first chemical probe to primarily occupy the co-factor binding site of a Su(var)3-9, enhancer of a zeste, trithorax (SET) domain containing protein lysine methyltransferase (PKMT) is reported. Protein methyltransferases require S-adenosylmethionine (SAM) as a co-factor (methyl donor) for enzymatic activity. However, SAM itself represents a poor medicinal chemistry starting point for a selective, cell-active inhibitor given its extreme physicochemical properties and its role in multiple cellular processes. A previously untested medicinal chemistry strategy of deliberate file enrichment around molecules bearing the hallmarks of SAM, but with improved lead-like properties from the outset, yielded viable hits against SET and MYND domain-containing protein 2 (SMYD2) that were shown to bind in the co-factor site. These leads were optimized to identify a highly biochemically potent, PKMT-selective, and cell-active chemical probe. While substrate-based inhibitors of PKMTs are known, this represents a novel, co-factor-derived strategy for the inhibition of SMYD2 which may also prove applicable to lysine methyltransferase family members previously thought of as intractable.

The Path(way) Less Traveled: A Pathway-Oriented Approach to Providing Information about Precision Cancer Medicine on My Cancer Genome.

This perspective describes the motivation, development, and implementation of pathway-based content for My Cancer Genome, an online precision medicine knowledge resource describing clinical implications of genetic alterations in cancer. As researchers uncover more about cancer pathogenesis, we are learning more not only about the specific genes and proteins involved but also about how those genes and proteins interact with others along cell signaling pathways. This knowledge has led researchers and clinicians to begin to think about cancer therapy using a pathway-based approach. To facilitate this approach, My Cancer Genome used a list of more than 800 cancer-related genes to identify 20 cancer-relevant pathways and then created content focused on demonstrating the therapeutic relevance of these pathways.

Identification of a Chemical Probe for Family VIII Bromodomains through Optimization of a Fragment Hit.

The acetyl post-translational modification of chromatin at selected histone lysine residues is interpreted by an acetyl-lysine specific interaction with bromodomain reader modules. Here we report the discovery of the potent, acetyl-lysine-competitive, and cell active inhibitor PFI-3 that binds to certain family VIII bromodomains while displaying significant, broader bromodomain family selectivity. The high specificity of PFI-3 for family VIII was achieved through a novel bromodomain binding mode of a phenolic headgroup that led to the unusual displacement of water molecules that are generally retained by most other bromodomain inhibitors reported to date. The medicinal chemistry program that led to PFI-3 from an initial fragment screening hit is described in detail, and additional analogues with differing family VIII bromodomain selectivity profiles are also reported. We also describe the full pharmacological characterization of PFI-3 as a chemical probe, along with phenotypic data on adipocyte and myoblast cell differentiation assays.

Synthesis of pyrazoles from 1,3-diols via hydrogen transfer catalysis.

1,3-Diols engage in ruthenium-catalyzed hydrogen transfer in the presence of alkyl hydrazines to provide 1,4-disubstituted pyrazoles. Regioselective synthesis of unsymmetrical pyrazoles from ß-hydroxy ketones is also described.