Patient "No-Show" Increases the Risk of 90-Day Complications Following Primary Total Knee Arthroplasty: A Retrospective Cohort Study of 6,776 Patients.

BACKGROUND: Patients who "no-show" (NS) clinical appointments are at a high risk of adverse health outcomes. The objective of this study was to evaluate and characterize the relationship between NS visits prior to primary total knee arthroplasty (TKA) and 90-day complications after TKA. METHODS: We retrospectively reviewed 6,776 consecutive patients undergoing primary TKA. Study groups were separated based on whether patients who NS versus always attended their appointment. A NS was defined as an intended appointment that was not canceled or rescheduled ≤2 hours before the appointment in which the patient did not show. Data collected included total number of follow-up appointments prior to surgery, patient demographics, comorbidities, and 90-day postoperative complications. RESULTS: Patients who have ≥3 NS appointments had 1.5 times increased odds of a surgical site infection (odds ratio (OR) 1.54, P = .002) compared to always attended patients. Patients who were ≤65 years old (OR: 1.41, P < .001), smokers (OR: 2.01, P < .001), and had a Charlson comorbidity index ≥3 (OR: 4.48, P < .001) were more likely to miss clinical appointments. CONCLUSION: Patients who have ≥3 NS appointments prior to TKA had an increased risk for surgical site infection. Sociodemographic factors were associated with higher odds of missing a scheduled clinical appointment. These data suggest that orthopaedic surgeons should consider NS data as an important clinical decision-making tool to assess risk for postoperative complications to minimize complications following TKA.

PA- and NP-led Ommaya clinics to manage leptomeningeal carcinomatosis.

OBJECTIVES: Physician assistants (PAs) and NPs are essential to quality care delivery. The need to demonstrate value and optimize PA and NP roles in neurology subspecialty clinics is unmet. We outline the development of a PA- and NP-led neuro-oncology procedural clinic and provide metrics to support the institutional and clinician value added. METHODS: We designed a PA- and NP-led Geisinger Ommaya Clinic (GOC) to manage leptomeningeal carcinomatosis (LMC) with defined clinician roles and the GOC treatment protocol. A retrospective review of 135 patients (2012-2019) compared survival outcomes for patients treated on the protocol compared with those treated off the protocol. RESULTS: Centralized care in the GOCs minimized shared physician encounters and improved PA and NP autonomy and utility. LMC therapy as part of the GOC protocol improved care continuity and survival outcomes. CONCLUSIONS: PA- and NP-led procedural clinics optimize use of these clinicians and open physician availability for nonprocedural duties. This research highlights the institutional patient and financial benefit while demonstrating the operational and leadership growth potential for PAs and NPs.

Early imaging marker of progressing glioblastoma: a window of opportunity.

PURPOSE: Therapeutic intervention at glioblastoma (GBM) progression, as defined by current assessment criteria, is arguably too late as second-line therapies fail to extend survival. Still, most GBM trials target recurrent disease. We propose integration of a novel imaging biomarker to more confidently and promptly define progression and propose a critical timepoint for earlier intervention to extend therapeutic exposure. METHODS: A retrospective review of 609 GBM patients between 2006 and 2019 yielded 135 meeting resection, clinical, and imaging inclusion criteria. We qualitatively and quantitatively analyzed 2000+ sequential brain MRIs (initial diagnosis to first progression) for development of T2 FLAIR signal intensity (SI) within the resection cavity (RC) compared to the ventricles (V) for quantitative inter-image normalization. PFS and OS were evaluated using Kaplan-Meier curves stratified by SI. Specificity and sensitivity were determined using a 2 × 2 table and pathology confirmation at progression. Multivariate analysis evaluated SI effect on the hazard rate for death after adjusting for established prognostic covariates. Recursive partitioning determined successive quantifiers and cutoffs associated with outcomes. Neurological deficits correlated with SI. RESULTS: Seventy-five percent of patients developed SI on average 3.4 months before RANO-assessed progression with 84% sensitivity. SI-positivity portended neurological decline and significantly poorer outcomes for PFS (median, 10 vs. 15 months) and OS (median, 20 vs. 29 months) compared to SI-negative. RC/V ratio ≥ 4 was the most significant prognostic indicator of death. CONCLUSION: Implications of these data are far-reaching, potentially shifting paradigms for glioma treatment response assessment, altering timepoints for salvage therapeutic intervention, and reshaping glioma clinical trial design.

Discovery of [11C]MK-8056: A Selective PET Imaging Agent for the Study of mGluR2 Negative Allosteric Modulators.

Modification of potent, selective metabotropic glutamate receptor 2 negative allosteric modulator (mGluR2 NAM) led to a series of analogues with excellent binding affinity, lipophilicity, and suitable physicochemical properties for a PET tracer with convenient chemical handles for incorporation of a 11C or 18F radiolabel. [11C]MK-8056 was synthesized and evaluated in vivo and demonstrated appropriate affinity, selectivity, and physicochemical properties to be used as a positron emission tomography tracer for mGluR2.

Discovery of MK-8768, a Potent and Selective mGluR2 Negative Allosteric Modulator.

Glutamate plays a key role in cognition and mood, and it has been shown that inhibiting ionotropic glutamate receptors disrupts cognition, while enhancing ionotropic receptor activity is pro-cognitive. One approach to elevating glutamatergic tone has been to antagonize presynaptic metabotropic glutamate receptor 2 (mGluR2). A desire for selectivity over the largely homologous mGluR3 motivated a strategy to achieve selectivity through the identification of mGluR2 negative allosteric modulators (NAMs). Extensive screening and optimization efforts led to the identification of a novel series of 4-arylquinoline-2-carboxamides. This series was optimized for mGluR2 NAM potency, clean off-target activity, and desirable physical properties, which resulted in the identification of improved C4 and C7 substituents. The initial lead compound from this series was Ames-positive in a single strain with metabolic activation, indicating that a reactive metabolite was likely responsible for the genetic toxicity. Metabolic profiling and Ames assessment across multiple analogs identified key structure-activity relationships associated with Ames positivity. Further optimization led to the Ames-negative mGluR2 negative allosteric modulator MK-8768.

Discovery of selective glucocorticoid receptor modulator MK-5932.

A series of partial agonists of the Glucocorticoid Receptor were prepared targeting reduced transactivation activity, while maintaining significant transrepression activity. Incorporation of an ortho-aryl amide produced compounds with the desired in vitro profile. Bioreactors consisting of Suspension cultures of Sf21 cells co expressing a CYP3A4 and NADPH-cytochrome P450 oxireductase were used to prepare the major metabolites of these compounds and revealed that oxidative N-dealkylation provided a pathway for formation of metabolites that were more agonistic than the parent partial agonists. Oxidative N-dealkylation was blocked in a new series of compounds, however oxidation alone was capable of producing full agonist metabolites. Incorporation of an ortho-primary amide and utilization of fluorine to modulate agonism afforded partial agonist MK-5932. Synthesis of the major metabolites of MK-5932 using bioreactor technology revealed that no significant GR-active metabolites were formed. Orally administered MK-5932 displayed anti-inflammatory efficacy in a Rat Oxazolone-induced chronic dermatitis model, while sparing plasma insulin.

Design and Synthesis of Piperazine Sulfonamide Cores Leading to Highly Potent HIV-1 Protease Inhibitors.

Using the HIV-1 protease binding mode of MK-8718 and PL-100 as inspiration, a novel aspartate binding bicyclic piperazine sulfonamide core was designed and synthesized. The resulting HIV-1 protease inhibitor containing this core showed an 60-fold increase in enzyme binding affinity and a 10-fold increase in antiviral activity relative to MK-8718.

Discovery of MK-8718, an HIV Protease Inhibitor Containing a Novel Morpholine Aspartate Binding Group.

A novel HIV protease inhibitor was designed using a morpholine core as the aspartate binding group. Analysis of the crystal structure of the initial lead bound to HIV protease enabled optimization of enzyme potency and antiviral activity. This afforded a series of potent orally bioavailable inhibitors of which MK-8718 was identified as a compound with a favorable overall profile.