Human Pharmacokinetic and CYP3A Drug-Drug Interaction Prediction of GDC-2394 Using Physiologically Based Pharmacokinetic Modeling and Biomarker Assessment.

Physiologically based pharmacokinetic (PBPK) modeling was used to predict the human pharmacokinetics and drug-drug interaction (DDI) of GDC-2394. PBPK models were developed using in vitro and in vivo data to reflect the oral and intravenous PK profiles of mouse, rat, dog, and monkey. The learnings from preclinical PBPK models were applied to a human PBPK model for prospective human PK predictions. The prospective human PK predictions were within 3-fold of the clinical data from the first-in-human study, which was used to optimize and validate the PBPK model and subsequently used for DDI prediction. Based on the majority of PBPK modeling scenarios using the in vitro CYP3A induction data (mRNA and activity), GDC-2394 was predicted to have no-to-weak induction potential at 900 mg twice daily (BID). Calibration of the induction mRNA and activity data allowed for the convergence of DDI predictions to a narrower range. The plasma concentrations of the 4ß-hydroxycholesterol (4ß-HC) were measured in the multiple ascending dose study to assess the hepatic CYP3A induction risk. There was no change in plasma 4ß-HC concentrations after 7 days of GDC-2394 at 900 mg BID. A dedicated DDI study found that GDC-2394 has no induction effect on midazolam in humans, which was reflected by the totality of predicted DDI scenarios. This work demonstrates the prospective utilization of PBPK for human PK and DDI prediction in early drug development of GDC-2394. PBPK modeling accompanied with CYP3A biomarkers can serve as a strategy to support clinical pharmacology development plans. SIGNIFICANCE STATEMENT: This work presents the application of physiologically based pharmacokinetic modeling for prospective human pharmacokinetic (PK) and drug-drug interaction (DDI) prediction in early drug development. The strategy taken in this report represents a framework to incorporate various approaches including calibration of in vitro induction data and consideration of CYP3A biomarkers to inform on the overall CYP3A-related DDI risk of GDC-2394.

Discovery of TRPA1 Antagonist GDC-6599: Derisking Preclinical Toxicity and Aldehyde Oxidase Metabolism with a Potential First-in-Class Therapy for Respiratory Disease.

Transient receptor potential ankyrin 1 (TRPA1) is a nonselective calcium ion channel highly expressed in the primary sensory neurons, functioning as a polymodal sensor for exogenous and endogenous stimuli, and has been implicated in neuropathic pain and respiratory disease. Herein, we describe the optimization of potent, selective, and orally bioavailable TRPA1 small molecule antagonists with strong in vivo target engagement in rodent models. Several lead molecules in preclinical single- and short-term repeat-dose toxicity studies exhibited profound prolongation of coagulation parameters. Based on a thorough investigative toxicology and clinical pathology analysis, anticoagulation effects in vivo are hypothesized to be manifested by a metabolite─generated by aldehyde oxidase (AO)─possessing a similar pharmacophore to known anticoagulants (i.e., coumarins, indandiones). Further optimization to block AO-mediated metabolism yielded compounds that ameliorated coagulation effects in vivo, resulting in the discovery and advancement of clinical candidate GDC-6599, currently in Phase II clinical trials for respiratory indications.

Hip resurfacing: case closed? A bibliometric analysis of the past 10 years.

INTRODUCTION: Hip resurfacing (HR) was introduced as a potential alternative to total hip arthroplasty (THA), indicated predominantly for younger, high demand patients. The modern metal-on-metal implant was popularized in the 1990s and early 2000s and promised greater wear resistance. However, its popularity waned due to increased rates of complications related to metal toxicity including pseudo-tumors as well as the recall of many resurfacing implants. The purpose of this study was to conduct a bibliometric analysis and investigate the current trends in hip resurfacing literature. METHODS: Using the keywords "hip resurfacing," publications between 2012 and 2022 were identified on Web of Science Core Collection of Clarivate Analytics. Results were screened for relevance by three independent reviewers using title, abstract, and full text. The retrieved data were evaluated by the bibliometric method. Included articles were imported into CiteSpace 5.7.R1, 64-bit (Drexel University, Philadelphia, PA, USA), VOSviewer 1.6.15 (Leiden University, Leiden, the Netherlands), and the Online Analysis Platform of Literature Metrology to identify trends in publication. RESULTS: Search terms yielded 1200 results and 724 were included in final analysis. A steady decrease of publications was noted over the past decade with less than 40 articles published in 2020 and 2021. The Journal of Hip Arthroplasty (92), Hip International (74), and Clinical Orthopaedics and Related Research (54) published the most articles. Authors from the United States and the United Kingdom published the most studies. High-frequency keywords in co-occurrence and co-cited cluster analysis were metal-on-metal, metal ions, wear, pseudo-tumor, and revision, demonstrating that long-term concerns have been the focus of most recent studies. CONCLUSION: In conclusion, our bibliometric analysis allowed novel exploration and identification of the current research trends, contributions, and the distribution of publications exploring HR. The understanding of HR and the poor long-term outcomes of some resurfacing implants has improved significantly over the past decade, with the most recent focus on failure rates and long-term complications from metal debris. However, the breadth of literature has steadily declined in the past decade, and ultimately demonstrates the decline of scientific interest and focus on novel areas in hip resurfacing and a potential reached consensus.

First-in-human phase 1 trial evaluating safety, pharmacokinetics, and pharmacodynamics of NLRP3 inflammasome inhibitor, GDC-2394, in healthy volunteers.

Inappropriate and chronic activation of the cytosolic NOD-, LRR-, and pyrin domain-containing 3 (NLRP3) inflammasome, a key component of innate immunity, likely underlies several inflammatory diseases, including coronary artery disease. This first-in-human phase I trial evaluated safety, pharmacokinetics (PKs), and pharmacodynamics (PDs) of oral, single (150-1800 mg) and multiple (300 or 900 mg twice daily for 7 days) ascending doses (SADs and MADs) of GDC-2394, a small-molecule inhibitor of NLRP3, versus placebo in healthy volunteers. The study also assessed the food effect on GDC-2394 and its CYP3A4 induction potential in food-effect (FE) and drug-drug interaction (DDI) stages, respectively. Although GDC-2394 was adequately tolerated in the SAD, MAD, and FE cohorts, two participants in the DDI stage experienced grade 4 drug-induced liver injury (DILI) deemed related to treatment, but unrelated to a PK drug interaction, leading to halting of the trial. Both participants experiencing severe DILI recovered within 3 months. Oral GDC-2394 was rapidly absorbed; exposure increased in an approximately dose-proportional manner with low-to-moderate intersubject variability. The mean terminal half-life ranged from 4.1 to 8.6 h. Minimal accumulation was observed with multiple dosing. A high-fat meal led to delays in time to maximum concentration and minor decreases in total exposure and maximum plasma concentration. GDC-2394 had minimal CYP3A4 induction potential with the sensitive CYP3A4 substrate, midazolam. Exploratory ex vivo whole-blood stimulation assays showed rapid, reversible, and near-complete inhibition of the selected PD biomarkers, IL-1ß and IL-18, across all tested doses. Despite favorable PK and target engagement PD, the GDC-2394 safety profile precludes its further development.

Development of an Amorphous Solid Dispersion Formulation for Mitigating Mechanical Instability of Crystalline Form and Improving Bioavailability for Early Phase Clinical Studies.

In this work, an amorphous solid dispersion (ASD) formulation was systematically developed to simultaneously enhance bioavailability and mitigate the mechanical instability risk of the selected crystalline form of a development drug candidate, GDC-0334. The amorphous solubility advantage calculation was applied to understand the solubility enhancement potential by an amorphous formulation for GDC-0334, which showed 2.7 times theoretical amorphous solubility advantage. This agreed reasonably well with the experimental solubility ratio between amorphous GDC-0334 and its crystalline counterpart (∼2 times) in buffers of a wide pH range. Guided by the amorphous solubility advantage, ASD screening was then carried out, focusing on supersaturation maintenance and dissolution performance. It was found that although the type of polymer carrier did not impact ASD performance, the addition of 5% (w/w) sodium dodecyl sulfate (SDS) significantly improved the GDC-0334 ASD dissolution rate. After ASD composition screening, stability studies were conducted on selected ASD powders and their hypothetical tablet formulations. Excellent stability of the selected ASD prototypes with or without tablet excipients was observed. Subsequently, ASD tablets were prepared, followed by in vitro and in vivo evaluations. Similar to the effect of facilitating the dissolution of ASD powders, the added SDS improved the disintegration and dissolution of ASD tablets. Finally, a dog pharmacokinetic study confirmed 1.8 to 2.5-fold enhancement of exposure by the developed ASD tablet over the GDC-0334 crystalline form, consistent with the amorphous solubility advantage of GDC-0334. A workflow of developing an ASD formulation for actual pharmaceutical application was proposed according to the practice of this work, which could provide potential guidance for ASD formulation development in general for other new chemical entities.

The Effect of Preoperative Benzodiazepine Usage on Postoperative Opioid Consumption After Hand Surgery: A Multicenter Analysis.

Background Prescription rates of opioids and benzodiazepines have steadily increased in the last decade with the percentage of prescription opioid overdose deaths involving benzodiazepines more than doubling during that time. Orthopaedic surgery is one of the highest-volume opioid prescribing medical specialties, but the effects of benzodiazepine use on orthopaedic surgery patient outcomes are not well understood. The purpose of the study was to utilize the state Prescription Drug Monitoring Program (PDMP) database to investigate if perioperative benzodiazepine use predisposes patients to prolonged opioid use following hand and upper extremity orthopaedic surgery. Methods This study was retrospective and conducted at three urban academic institutions. All patients who underwent carpal tunnel release, thumb basal joint arthroplasty, and distal radius fracture open reduction internal fixation performed by 14 board-certified, fellowship-trained orthopaedic hand and upper extremity surgeons between April 2018 and August 2019, were collected via a database query. All opioid and benzodiazepine prescriptions were collected from three months preoperatively to six months postoperatively. Results In this study, 634 patients met the inclusion criteria presented to one of the three institutions during the 18-month study period. Patients consisted of 276 carpal tunnel releases, 217 distal radius fracture open reduction internal fixations, and 141 thumb basal joint arthroplasties. Benzodiazepine users were 14.6% more likely to fill an additional opioid prescription (p<0.005) and were 10.8% more likely to experience prolonged three to six-month postoperative opioid use (p<0.005). Conclusion This study found that patients who use benzodiazepines are at a higher risk of filling additional opioid prescriptions and prolonged opioid use following hand and upper extremity surgery. Prescribers should take this into account when prescribing opioids after upper extremity orthopaedic surgery.

Overcoming Preclinical Safety Obstacles to Discover (S)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-6-(methylamino)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (GDC-2394): A Potent and Selective NLRP3 Inhibitor.

Inappropriate activation of the NLRP3 inflammasome has been implicated in multiple inflammatory and autoimmune diseases. Herein, we aimed to develop novel NLRP3 inhibitors that could minimize the risk of drug-induced liver injury. Lipophilic ligand efficiency was used as a guiding metric to identify a series of 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazinesulfonylureas. A leading compound from this series was advanced into safety studies in cynomolgus monkeys, and renal toxicity, due to compound precipitation, was observed. To overcome this obstacle, we focused on improving the solubility of our compounds, specifically by introducing basic amine substituents into the scaffold. This led to the identification of GDC-2394, a potent and selective NLRP3 inhibitor, with an in vitro and in vivo safety profile suitable for advancement into human clinical trials.

Social Media Use Among Hand Surgeons.

Background: Recently social media use within healthcare has increased significantly. Today, it is common for patients to browse the Internet, including physicians' social media pages, to learn about their medical conditions and search for providers. The purpose of this study is to analyze the use of social media among hand surgeons, and to compare this use between academic and private surgeons. Methods: Using the American Society for Surgery of the Hand's (ASSH) online directory, all active members practicing within the ten most populated U.S. cities were identified. Social media presence was determined by an Internet search of platforms. Members were stratified by practice model (academic vs. private). Chi-square and t-tests were used to compare categorical and continuous variables, and a multivariable logistic regression was performed for the binary variable practice model. Results: Two hundred and fifty-six hand surgeons were identified with 150 (59%) in academic and 106 (41%) in private practice. For ResearchGate accounts, 51 (82%) were academic and 11 (18%) were private. Mean PubMed publications was 38 for academic and 9 for private. YouTube presence was 69 (70%) in academic and 29 (30%) in private. On multivariable analysis, the odds of having ResearchGate and YouTube presence were higher for academic practice. There was no statistically significant difference by practice type for Facebook, Twitter, LinkedIn, and Instagram. Conclusions: With the recent social media expansion, surgeons have adopted social media platforms to reach patients. While the literature has shown that private practices are more active in social media, our results show they are not more active than academic practices in the ten most populated U.S. cities. Level of Evidence: IV.

Comparative Cost Analysis of Single-use Sterile versus Reprocessed Distal Radius Volar Plate Sets.

Background: With the rise in distal radius fracture (DRF) incidence and treatment through open reduction internal fixation, there are increasing concerns in the current medical cost containment climate. To help reduce costs, manufacturers are introducing sterile packed kits. The purpose of this study is to compare the costs of the single use kit (SK) against conventional reprocessed DRF surgical sets (RS). Methods: A four-year retrospective review at three surgical centers was performed to determine a company's RS average sterilization and processing costs. RS instrumentation cost was estimated by straight-line depreciation from the original purchase price. RS implant costs were calculated from the list price. SK list cost was obtained from the same company. Incidence of surgical delays was estimated by a survey of 23 hand surgeons and cost of delays was obtained from surgical center reports. Sensitivity analysis on delay frequency was performed to assess a range of overall costs. Results: OR delays were estimated at one out of 100 cases, with an average cost of $11 per case. For RS, average instruments, implants, and sterilization costs per case was $47, $2882, and $39. The total RS cost of $2,978 and the SK was $1,667 with a difference of $1,313 per case. Conclusion: RS was found to cost $1,313 more per case than the SK in an ambulatory surgical setting and potentially more cost effective. Ultimately, pricing is highly variable at each center based on negotiated and contractual pricing.

Multiple Opioid Prescribers During the Perioperative Period Increases Opioid Consumption Following Upper Extremity Surgery: A Multicenter Analysis.

Background Opioid prescribing practices have been an area of interest for orthopedic surgeons in the wake of the opioid epidemic. Previous studies have investigated the effects of a multitude of patient-specific risk factors on prolonged opioid use postoperatively. However, to date, there is a lack of studies examining the effects of multiple prescribers during the perioperative period and their potential contribution to prolonged opioid use postoperatively. This study aimed to investigate if multiple unique opioid prescribers perioperatively predispose patients to prolonged opioid use following upper extremity surgery. Second, we compared opioid prescribing patterns among different medical specialties. Methodology This retrospective study was conducted at three academic institutions. Between April 30, 2018, and August 30, 2019, 634 consecutive patients who underwent one of three upper extremity procedures  were included in the analysis: carpal tunnel release (CTR), basal joint arthroplasty (BJA), or distal radius fracture open reduction and  internal fixation (DRF ORIF). Prescription information was collected using the state Prescription Drug Monitoring Program (PDMP) online database  from a period of three months preoperatively to six months postoperatively. A Google search was performed to group prescriptions by medical specialty.  Dependent outcomes included whether patients filled an additional opioid prescription postoperatively and prolonged opioid use (defined as opioid use three to six months postoperatively). Results In total, 634 patients were identified, including 276 CTRs, 217 DRF ORIFs, and 141 BJAs. This consisted of 196 males (30.9%) and 438 females (69.1%) with an average age of 59.4 years (SD: 14.7 years). By six months postoperatively, 191 (30.1%) patients filled an additional opioid prescription, and 89 (14.0%) experienced prolonged opioid use. In total, 235 (37.1%) patients had more than one unique opioid prescriber during the study period (average 2.5 prescribers). Patients with more than one unique opioid prescriber were significantly more likely to have received overlapping opioid prescriptions (15.7% vs. 0.8%, p<.001), to have filled an additional opioid prescription postoperatively (63.8% vs 10.3%, p<.001), and to have experienced prolonged opioid use postoperatively (35.3% vs 1.5%, p<.001) compared to patients with only one opioid prescriber. Patients with multiple unique prescribers filled more opioid prescriptions compared to those with a single prescriber (2.8 refills vs 1.8 refills, p=.035). Within six months postoperatively, 71.4% of opioid refills were written by non-orthopedic providers. Opioid refills written by non-orthopedic prescribers were written for a significantly greater number of pills (68.4 vs. 27.9, p<.001), for a longer duration (22.2 vs. 6.2 days, p<.001), and for larger total morphine milligram equivalents per prescription (831.4 vs. 169.8, p<.001) compared to those written by orthopedic prescribers. Conclusions Patients with multiple unique opioid prescribers during the perioperative period are at a higher risk for prolonged opioid use postoperatively. Non-orthopedic providers were the highest prescribers of opioids postoperatively, and they prescribed significantly larger and longer prescriptions. Our findings highlight the value of utilizing PDMP databases to help curtail opioid overprescription and potential adverse opioid-related outcomes following upper extremity surgery.

Larger Perioperative Opioid Prescriptions Lead to Prolonged Opioid Use After Hand and Upper Extremity Surgery: A Multicenter Analysis.

INTRODUCTION: The opioid epidemic remains an ongoing public health crisis. The purpose of this study was to investigate whether surgeons' prescribing patterns of the initial postoperative opioid prescription predispose patients to prolonged opioid use after upper extremity surgery. METHODS: This multicenter retrospective study was done at three academic institutions. Patients who underwent carpal tunnel release, basal joint arthroplasty, and distal radius fracture open reduction and internal fixation over a 1.5-year period were included. Opioid prescription data were obtained from the Pennsylvania Prescription Drug Monitoring Program website. RESULTS: Postoperatively, 30.1% of the patients (191/634) filled ≥1 additional opioid prescription, and 14.0% (89/634) experienced prolonged opioid use 3 to 6 months postoperatively. Patients who filled an additional prescription postoperatively were initially prescribed significantly more pills (P = 0.001), a significantly longer duration prescription (P = 0.009), and a significantly larger prescription in total milligram morphine equivalents (P = 0.002) than patients who did not fill additional prescriptions. Patients who had prolonged opioid use were prescribed a significantly longer duration prescription (P = 0.026) than those without prolonged use. CONCLUSION: Larger and longer duration of initial opioid prescriptions predisposed patients to continued postoperative opioid use. These findings emphasize the importance of safe and evidence-based prescribing practices to prevent the detrimental effects of opioid use after orthopaedic surgery.

Investigating the Utility of Humanized Pregnane X Receptor-Constitutive Androstane Receptor-CYP3A4/7 Mouse Model to Assess CYP3A-Mediated Induction.

Clinical induction liability is assessed with human hepatocytes. However, underpredictions in the magnitude of clinical induction have been reported. Unfortunately, in vivo studies in animals do not provide additional insight because of species differences in drug metabolizing enzymes and their regulatory pathways. To circumvent this limitation, transgenic animals expressing human orthologs were developed. The aim of this work was to investigate the utility of mouse models expressing human orthologs of pregnane X receptor, constitutive androstane receptor, and CYP3A4/7 (Tg-Composite) in evaluating clinical induction. Rifampin, efavirenz, and pioglitazone, which were employed to represent strong, moderate, and weak inducers, were administered at multiple doses to Tg-Composite animals. In vivo CYP3A activity was monitored by measuring changes in the exposure of the CYP3A probe substrate triazolam. After the in vivo studies, microsomes were prepared from their livers to measure changes of in vitro CYP3A4 activity. In both in vivo and in vitro, distinction of clinic induction was recapitulated as rifampin yielded the greatest inductive effect followed by efavirenz and pioglitazone. Interestingly, with rifampin, in vivo CYP3A activity was approximately 4-fold higher than in vitro activity. Conversely, there was no difference between in vivo and in vitro CYP3A activity with efavirenz. These findings are consistent with the report that, although rifampin exhibits differential inductive effects between the intestines and liver, efavirenz does not. These data highlight the promise of transgenic models, such as Tg-Composite, to complement human hepatocytes to enhance the translatability of clinical induction as well as become a powerful tool to further study mechanisms of drug disposition. SIGNIFICANCE STATEMENT: Underprediction of the magnitude of clinical induction when using human hepatocytes has been reported, and transgenic models may improve clinical translatability. The work presented here showcases the human orthologs of pregnane X receptor, constitutive androstane receptor, and CYP3A4/7 model, which was able to recapitulate the magnitude of clinical induction and to differentiate tissue-dependent induction observed with rifampin but not with efavirenz. These results not only foreshadow the potential application of such transgenic models in assessing clinical induction but also in further investigation of the mechanism of drug disposition.

Tetrahydrofuran-Based Transient Receptor Potential Ankyrin 1 (TRPA1) Antagonists: Ligand-Based Discovery, Activity in a Rodent Asthma Model, and Mechanism-of-Action via Cryogenic Electron Microscopy.

Transient receptor potential ankyrin 1 (TRPA1) is a nonselective calcium-permeable ion channel highly expressed in the primary sensory neurons functioning as a polymodal sensor for exogenous and endogenous stimuli and has generated widespread interest as a target for inhibition due to its implication in neuropathic pain and respiratory disease. Herein, we describe the optimization of a series of potent, selective, and orally bioavailable TRPA1 small molecule antagonists, leading to the discovery of a novel tetrahydrofuran-based linker. Given the balance of physicochemical properties and strong in vivo target engagement in a rat AITC-induced pain assay, compound 20 was progressed into a guinea pig ovalbumin asthma model where it exhibited significant dose-dependent reduction of inflammatory response. Furthermore, the structure of the TRPA1 channel bound to compound 21 was determined via cryogenic electron microscopy to a resolution of 3 Å, revealing the binding site and mechanism of action for this class of antagonists.

A TRPA1 inhibitor suppresses neurogenic inflammation and airway contraction for asthma treatment.

Despite the development of effective therapies, a substantial proportion of asthmatics continue to have uncontrolled symptoms, airflow limitation, and exacerbations. Transient receptor potential cation channel member A1 (TRPA1) agonists are elevated in human asthmatic airways, and in rodents, TRPA1 is involved in the induction of airway inflammation and hyperreactivity. Here, the discovery and early clinical development of GDC-0334, a highly potent, selective, and orally bioavailable TRPA1 antagonist, is described. GDC-0334 inhibited TRPA1 function on airway smooth muscle and sensory neurons, decreasing edema, dermal blood flow (DBF), cough, and allergic airway inflammation in several preclinical species. In a healthy volunteer Phase 1 study, treatment with GDC-0334 reduced TRPA1 agonist-induced DBF, pain, and itch, demonstrating GDC-0334 target engagement in humans. These data provide therapeutic rationale for evaluating TRPA1 inhibition as a clinical therapy for asthma.

Preclinical Safety Assessment of a Highly Selective and Potent Dual Small-Molecule Inhibitor of CBP/P300 in Rats and Dogs.

Cyclic adenosine monophosphate-response element (CREB)-binding protein (CBP) and EP300E1A-binding protein (p300) are members of the bromodomain and extraterminal motif (BET) family. These highly homologous proteins have a key role in modulating transcription, including altering the status of chromatin or through interactions with or posttranslational modifications of transcription factors. As CBP and p300 have known roles for stimulating c-Myc oncogenic activity, a small-molecule inhibitor, GNE-781, was developed to selectively and potently inhibit the CBP/p300 bromodomains (BRDs). Genetic models have been challenging to develop due to embryonic lethality arising from germline homozygous mutations in either CBP or P300. Hence, the purpose of this study was to characterize the role of dual inhibition of these proteins in adult rats and dogs. Repeat dose toxicity studies were conducted, and toxicologic and pathologic end points were assessed. GNE-781 was generally tolerated; however, marked effects on thrombopoiesis occurred in both species. Evidence of inhibition of erythroid, granulocytic, and lymphoid cell differentiation was also present, as well as deleterious changes in gastrointestinal and reproductive tissues. These findings are consistent with many preclinical (and clinical) effects reported with BET inhibitors targeting BRD proteins; thus, the current study findings indicate a likely important role for CBP/p300 in stem cell differentiation.

Initial Debridement of Dorsal Hand Abscesses in the Operating Room Does Not Improve Outcomes.

Background: Hand infections frequently involve the dorsal aspect of the hand and often develop secondary to some traumatic mechanism. Although Staphylococcus aureus is most commonly isolated, anaerobic and polymicrobial infections are not uncommon. To date, treatment is largely anecdotal, with some surgeons preferring a formal debridement in the operating room, while others opt for an initial debridement at the bedside. The goals of this study were to compare outcomes between treatment modalities and to identify the most common causative organisms. Methods: A 10-year retrospective chart review was conducted to identify adult patients who presented with a dorsal hand infection to a single, level 1, urban trauma center. Demographic data were collected as well as the abscess size, location, duration of symptoms, treatment administered, number of formal debridements, length of hospital stay, and complications. Results: The number of formal debridements was significantly less in the initial bedside debridement group (P < .01), as was the hospital length of stay (P < .01). There was no significant difference in hospital readmissions, complications, or infection due to methicillin-resistant Staphylococcus aureus. There was also no significant difference in abscess size, duration of symptoms, or demographic data including age, sex, comorbidities, intravenous drug use status, and immunocompromised status. Conclusions: An initial debridement of dorsal hand infections at the bedside is at least as effective as formal debridement in the operating room. This decreases number of formal debridements and days in the hospital, without any increase in complications. This permits safe, expeditious, and cost-effective treatment for this common condition.

Disruption of IRE1α through its kinase domain attenuates multiple myeloma.

Multiple myeloma (MM) arises from malignant immunoglobulin (Ig)-secreting plasma cells and remains an incurable, often lethal disease despite therapeutic advances. The unfolded-protein response sensor IRE1α supports protein secretion by deploying a kinase-endoribonuclease module to activate the transcription factor XBP1s. MM cells may co-opt the IRE1α-XBP1s pathway; however, the validity of IRE1α as a potential MM therapeutic target is controversial. Genetic disruption of IRE1α or XBP1s, or pharmacologic IRE1α kinase inhibition, attenuated subcutaneous or orthometastatic growth of MM tumors in mice and augmented efficacy of two established frontline antimyeloma agents, bortezomib and lenalidomide. Mechanistically, IRE1α perturbation inhibited expression of key components of the endoplasmic reticulum-associated degradation machinery, as well as secretion of Ig light chains and of cytokines and chemokines known to promote MM growth. Selective IRE1α kinase inhibition reduced viability of CD138+ plasma cells while sparing CD138- cells derived from bone marrows of newly diagnosed or posttreatment-relapsed MM patients, in both US- and European Union-based cohorts. Effective IRE1α inhibition preserved glucose-induced insulin secretion by pancreatic microislets and viability of primary hepatocytes in vitro, as well as normal tissue homeostasis in mice. These results establish a strong rationale for developing kinase-directed inhibitors of IRE1α for MM therapy.

Orthopaedic Surgery Resident Financial Literacy: An Assessment of Knowledge in Debt, Investment, and Retirement Savings.

Most orthopedic residents carry significant debt and may enter their practice with little knowledge of business management, minimal retirement savings, and overall poor financial literacy. This study aimed to gauge financial literacy, debt, and retirement planning in United States orthopedic surgery residents. Willingness to participate in formalized financial education was also assessed. Eighty-five allopathic orthopedic surgery residents in the United States completed a 14-question anonymous online survey in 2016. The survey assessed demographic data, self-assessed financial knowledge, amount of credit card debt and loans, preparation for retirement, and willingness to participate in formal didactic education on these topics. Most respondents derive their financial knowledge from personal research (51%), whereas only 4 per cent have a formal curriculum. Despite most respondents reporting more than $200,000 in outstanding loans, only 31 per cent create and stick to a budget. Few programs offer retirement advice, and 48 per cent of respondents save $0 toward retirement. Eighty-five per cent of residents expressed interest in learning about personal investment, savings, and retirement planning. Orthopedic surgery residents carry significant debt and do not achieve their high-income potential until disproportionately later in life. Only 4 per cent of residents have formal training in investing, personal finance, or retirement despite a majority who desire such a curriculum. In fact, almost 75 per cent of those surveyed felt less prepared for retirement than their peers outside of medical training. This study suggests a role for formal financial education in the orthopedic curriculum to prepare residents for retirement, improve financial literacy, and enhance debt management.

Optimization of Pan-Pim Kinase Activity and Oral Bioavailability Leading to Diaminopyrazole (GDC-0339) for the Treatment of Multiple Myeloma.

Pim kinases have been targets of interest for a number of therapeutic areas. Evidence of durable single-agent efficacy in human clinical trials validated Pim kinase inhibition as a promising therapeutic approach for multiple myeloma patients. Here, we report the compound optimization leading to GDC-0339 (16), a potent, orally bioavailable, and well tolerated pan-Pim kinase inhibitor that proved efficacious in RPMI8226 and MM.1S human multiple myeloma xenograft mouse models and has been evaluated as an early development candidate.

Preclinical assessment of the ADME, efficacy and drug-drug interaction potential of a novel NAMPT inhibitor.

GNE-617 (N-(4-((3,5-difluorophenyl)sulfonyl)benzyl)imidazo[1,2-a]pyridine-6-carboxamide) is a potent, selective nicotinamide phosphoribosyltransferase (NAMPT) inhibitor being explored as a potential treatment for human cancers. Plasma clearance was low in monkeys and dogs (9.14 mL min-1 kg-1 and 4.62 mL min-1 kg-1, respectively) and moderate in mice and rats (36.4 mL min-1 kg-1 and 19.3 mL min-1 kg-1, respectively). Oral bioavailability in mice, rats, monkeys and dogs was 29.7, 33.9, 29.4 and 65.2%, respectively. Allometric scaling predicted a low clearance of 3.3 mL min-1 kg-1 and a volume of distribution of 1.3 L kg-1 in human. Efficacy (57% tumor growth inhibition) in Colo-205 CRC tumor xenograft mice was observed at an oral dose of 15 mg/kg BID (AUC = 10.4 µM h). Plasma protein binding was moderately high. GNE-617 was stable to moderately stable in vitro. Main human metabolites identified in human hepatocytes were formed primarily by CYP3A4/5. Transporter studies suggested that GNE-617 is likely a substrate for MDR1 but not for BCRP. Simcyp® simulations suggested a low (CYP2C9 and CYP2C8) or moderate (CYP3A4/5) potential for drug-drug interactions. The potential for autoinhibition was low. Overall, GNE-617 exhibited acceptable preclinical properties and projected human PK and dose estimates.