The Delayed Presentation and Diagnosis of Youth Wrestling Injuries: A 20-Year Analysis of National Injury Data.

INTRODUCTION: The nature of wrestling may lead athletes to mask injuries with the delayed presentations of youth wrestling-related injuries not being well characterized. METHODS: This descriptive epidemiological study queried the National Electronic Injury Surveillance System database to characterize delayed presentations of wrestling-related injuries in middle and high-school athletes. Data collection consisted of national estimates, demographics, and injury characteristics of patients with delayed (D) presentations (≥1 day) and same-day (S) presentations to US emergency departments after sustaining a wrestling-related injury during the scholastic wrestling season (December to February, 2000 to 2019). RESULTS: Of middle and high-school wrestlers presenting to US emergency departments, 5.6% (95% confidence interval [CI] 4.3% to 7.1%) reported delayed presentations for a total of 1,110 patients (CI, 591 to 1,630) annually. Most commonly (P < 0.001), injuries were sustained on Saturdays in both cohorts (D, 28.2%; CI, 22.4% to 34.8%; S, 29.6%; CI, 24.3% to 35.5%). Patients reporting delayed presentations were less likely to sustain fractures (D, 11.5%; CI, 8.3% to 15.6%; S, 18.9%; CI, 15.0% to 23.5%; P = 0.019) and injuries of the head/neck (D, 20.0%; CI, 16.5 to 24.1%; S, 26.2%; CI, 21.4% to 31.7%; P = 0.011). DISCUSSION: A substantial proportion of adolescent wrestlers report delayed presentations of injuries. This emphasizes the need for vigilance in detecting subtle signs of injury.

Recovery of node of ranvier structure in optic nerve under visual deprivation.

Neural activity can increase the length of nodes of Ranvier (NOR) and slow impulse transmission; however, little is known about the biologically and clinically important recovery process. Sensory deprivation promotes neural plasticity in many phenomena, raising the question of whether recovery of NOR morphology is influenced by sensory deprivation. The results show that NOR gap length recovery in mouse optic nerve was not affected significantly by binocular visual deprivation imposed by maintaining mice in 24 hr dark for 30 days compared to mice recovering under normal visual experience. The findings provide insight into the cellular mechanism of NOR plasticity.

Patella and Trochlea Osteochondritis Dissecans: Demographics and Treatment Paradigms.

OBJECTIVE: Previous research on patellar and trochlear groove osteochondritis dissecans (OCD) is limited by small sample sizes. This study aims to describe the presentation of patients with OCD lesions of the patella and trochlea and characterize the outcomes of operative and nonoperative treatments. METHODS: This retrospective cohort study identified all patients from a single institution from 2008 to 2021 with patellar and/or trochlear OCD lesions. Patients were excluded from the study if surgical records were unavailable or if the patient had knee surgery for a different injury at index surgery or in the 12 months postoperative. Minimum follow-up was 12 months. Outcomes included a return to sports (RTS), pain resolution, radiographic healing, and treatment "success" (defined as full RTS, complete pain resolution, and full healing on imaging). RESULTS: A total of 68 patients (75 knees) were included-45 (60%) with patellar OCD and 30 (40%) with trochlear. Of the patients, 69% were males. The median age at knee OCD diagnosis was 14 years. At the final follow-up, 62% of knees (n = 44) recovered sufficiently to allow a full RTS and 54% of knees (n = 39) had full pain resolution. Of the 46 knees with radiographic imaging at least 1 year apart, 63% had full healing of the lesion. There was no significant difference in RTS, pain resolution, radiographic healing, or overall success when comparing treatments. CONCLUSIONS: This study provides valuable epidemiologic demographic and outcome data regarding the scarcely reported patellar and trochlear OCD. While over half of patients fully returned to sports and reported full pain resolution, a large proportion continued to experience symptoms over a year after presentation. Future research should aim to better define the treatment algorithms for these OCD subtypes. LEVEL OF EVIDENCE: Level III.

Pediatric Fractures Associated With Riding Bicycles: A National 20-year Analysis.

BACKGROUND: Biking is a popular childhood activity with an intrinsic risk of injury. While advocacy groups have promoted protective equipment to help mitigate these risks, trends in the national health burden of fractures associated with biking in the pediatric population have not been explored in depth. METHODS: The National Electronic Injury Surveillance System database was queried between 2001 and 2020 to identify patients aged 18 years or below with fractures presenting to US emergency departments associated with riding bicycles. The patient narratives were analyzed to exclude patients not actively riding bicycles and to note helmet use and collisions with motor vehicles (MVs). RESULTS: A total of 33,955 fractures were identified in the database, representing an estimated 1,007,714 fractures from 2001 to 2020, or 50,331 fractures annually. Linear regression noted a significant decrease in fractures over the period ( R2 =0.899; P <0.001). Most fractures occurred in patients who were male (71.8%, 95% CI: 70.4% to 73.2%), White (53.1%, 46.0% to 60.0%), and aged 10 to 12 (30.6%, 29.6% to 31.7%) or 13 to 15 years (24.8%, 23.4% to 26.2%). Fractures occurred most frequently in the forearm (25.2%, 22.8% to 27.8%), wrist (21.2%, 19.5% to 22.9%), and shoulder (10.5%, 9.7% to 11.3%). Patients who sustained fractures after being struck by a MV were >6 times more likely to be admitted to the hospital (36.0%, 28.6% to 44.2%) compared with patients not struck by a MV (5.4%, 4.3% to 6.8%). When helmet use was recorded in patients with skull fractures, most patients were not wearing helmets at the time of injury (85.7%, 74.6% to 92.5%). CONCLUSIONS: Although the national burden of fractures associated with riding bicycles in pediatric populations has steadily decreased, it remains a significant cause of injury for children. Fractures involving MV more often require hospitalization, and an alarming number of skull fractures are noted in children not wearing helmets. These data support continued efforts to promote consistent helmet use and safer riding environments around MV in all children, but especially among 10- to 15-year-old males. LEVEL OF EVIDENCE: Level III-prognostic.

Removing or Only Moving a Barrier? Screening Applications with US Medical Licensing Examination Step 2CK Instead of Step 1 May Benefit Women but Not Underrepresented Minorities in Orthopaedics.

Most orthopaedic surgery program directors report using a minimum score cutoff for the US Medical Licensing Examination Step 1 examination when evaluating residency applicants. The transition to a Pass/Fail grading system beginning in the 2022-2023 application cycle will alter applicant evaluation in the interview selection process. The impact of this change, particularly on women and underrepresented minority (URM) applicants, remains unclear. This study was designed to evaluate how a shift to screening applications using Step 2 Clinical Knowledge (CK) instead of Step 1 scores could impact selection for residency interviews. Methods: We reviewed all 855 Electronic Residency Application Service applications submitted to the University of Pennsylvania's orthopaedic surgery residency program in the 2020-2021 cycle. Applicant age, sex, medical school of graduation, self-identified race, and permanent zip code were evaluated for association with Step 1 and Step 2CK scores using a 2-sample t test. A multivariable linear regression analysis was conducted to understand the predictive value of demographic features and medical school features on Step 1 and 2CK scores. Results: Multivariable linear regression revealed both Step 1 and 2CK scores were lower for applicants of URM status (Step 1: p < 0.001; Step 2CK: p < 0.001) and from international medical schools (p = 0.043; p = 0.006). Step 1 scores but not Step 2CK scores were lower for applicants who were women (p < 0.001; p = 0.730), ≥30 years of age (p < 0.001; p = 0.079), and from medical schools outside the top 25 in National Institutes of Health (NIH) funding or US News and World Report (USNWR) ranking (p = 0.001; p = 0.193). Conclusions: Conversion of Step 1 grading to Pass/Fail may reduce barriers for groups with lower average Step 1 scores (URM, female, ≥30 years of age, and from institutions with lower NIH funding or USNWR rankings). However, if Step 2CK scores replace Step 1 as a screening tool, groups with lower Step 2CK scores, notably URM applicants, may not experience this benefit. Level of Evidence: Level IV. See Instructions for Authors for a complete description of levels of evidence.

Measuring and modeling the effects of vagus nerve stimulation on heart rate and laryngeal muscles.

BACKGROUND: Reduced heart rate (HR) during vagus nerve stimulation (VNS) is associated with therapy for heart failure, but stimulation frequency and amplitude are limited by patient tolerance. An understanding of physiological responses to parameter adjustments would allow differential control of therapeutic and side effects. To investigate selective modulation of the physiological responses to VNS, we quantified the effects and interactions of parameter selection on two physiological outcomes: one related to therapy (reduced HR) and one related to side effects (laryngeal muscle EMG). METHODS: We applied a broad range of stimulation parameters (mean pulse rates (MPR), intra-burst frequencies, and amplitudes) to the vagus nerve of anesthetized mice. We leveraged the in vivo recordings to parameterize and validate computational models of HR and laryngeal muscle activity across amplitudes and temporal patterns of VNS. We constructed a finite element model of excitation of fibers within the mouse cervical vagus nerve. RESULTS: HR decreased with increased amplitude, increased MPR, and decreased intra-burst frequency. EMG increased with increased MPR. Preferential HR effects over laryngeal EMG effects required combined adjustments of amplitude and MPR. The model of HR responses highlighted contributions of ganglionic filtering to VNS-evoked changes in HR at high stimulation frequencies. Overlap in activation thresholds between small and large modeled fibers was consistent with the overlap in dynamic ranges of related physiological measures (HR and EMG). CONCLUSION: The present study provides insights into physiological responses to VNS required for informed parameter adjustment to modulate selectively therapeutic effects and side effects.

The risk of COVID-19 transmission upon return to sport: a systematic review.

OBJECTIVES: To evaluate COVID-19 transmission rates in athletes upon return to sport (RTS), as well as the effectiveness of preventive and surveillance measures associated with RTS. METHODS: In accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, the PubMed, Embase, and Cochrane Library databases were searched to identify all articles reporting on RTS during COVID-19. Articles were excluded on the basis of the following criteria: (1) non-English text, (2) only abstract available, (3) population not athlete-specific, (4) outcome not RTS-specific, (5) COVID-19 transmission data not quantified, (6) editorial, or (7) review article or meta-analysis. Study characteristics; athlete demographics; COVID-19 preventive, surveillance, and diagnostic measures; COVID-19 transmission outcomes; and RTS recommendations were collected from each included article and analyzed. RESULTS: 10 studies were included in the final analysis, comprising over 97,000 athletes across a wide variety of sports, levels of play, and RTS settings. Of the 10 studies, eight identified low transmission rates and considered RTS to be safe/low risk. Overall, COVID-19 transmission rates were higher in athletes than in contacts, and more prevalent in the greater community than in athletes specifically. The risk of COVID-19 did not appear to be necessarily higher for athletes who played high-contact team sports, shared common facilities, or lived in communities impacted by high transmission rates, provided that rigorous COVID-19 safety and testing protocols were implemented and followed. Mask wearing and physical distancing during active play presented the greatest challenge to athletes. CONCLUSION: Rigorous preventive and surveillance measures can mitigate the risk of COVID-19 transmission in athletes upon RTS. However, the heterogeneity of RTS playing conditions, availability of COVID-19 resources, rise of unforeseen novel variants, and undetermined long-term impact of vaccination on athletes remain a challenge to safe and effective RTS in the era of COVID-19.

Association of Thoracic MRI Findings With Specialty and Training.

STUDY DESIGN: Retrospective. OBJECTIVE: To compare the rate of positive pathology on thoracic MRI ordered by surgical spine specialists to those ordered by nonsurgical spine specialists. METHODS: Outpatient thoracic MRIs from January-March 2019 were evaluated from a single academic health care system. Studies without a known ordering provider, imaging report, or patients with known presence of malignancy, multiple sclerosis, recent trauma, or surgery were excluded (n = 320). Imaging studies were categorized by type of provider placing the order (resident, attending, or advanced practice practitioner) and department. MRIs were deemed positive if they showed relevant pathology that correlated with indication for exam as determined by a radiologist. One-sided chi-squared analysis was performed to determine statistical significance. RESULTS: Overall, our data demonstrated 17.2% of studies with positive pathology. Compared to nonspecialty clinicians, subspecialists showed 35/184 (19.0%) positivity rate versus the non-specialist with 20/136 (14.7%) positivity rate (P = .156). Posthoc analysis demonstrated that surgical specialists who order thoracic MRIs yield significantly higher positivity rates at 19/79 (24.0%) compared to nonsurgical specialists at 36/241 (14.9%) (P < .05). Overall, neurosurgery demonstrated the highest rate of positive thoracic MRIs at 14/40 (35.0%). Comparison between the rate of positivity between physicians and advanced practitioners was insignificant (P > .05). CONCLUSIONS: Clinical diagnosis of symptomatic thoracic spine degenerative disease requires an expert physical exam combined with careful attention to radiology findings. Although the percent of relevant pathology on thoracic MRI is low, our data suggests evaluation by a surgical specialist should precede ordering a thoracic spine MRI.

Effects of Visual Deprivation on Remodeling of Nodes of Ranvier in Optic Nerve.

Oligodendrocytes, the myelinating cells of the CNS, promote rapid action potential conduction along axons. Changes in the geometry of gaps between myelin segments, known as nodes of Ranvier, affect the conduction speed of neuronal impulses and can ultimately alter neural synchronization and circuit function. In contrast to synaptic plasticity, much less is known about how neural activity may affect node of Ranvier structure. Recently, perinodal astrocytes have been shown to remodel nodes of Ranvier by regulating thrombin proteolysis, but it is not known whether neural activity influences this process. To test this hypothesis, we used transgenic mice with astrocytic expression of a dominant-negative vesicle-associated membrane protein 2 ([gfap]dnVAMP2) to reduce exocytosis of thrombin inhibitors, modulating astrocytic regulation of paranodal loop attachment to induce nodal remodeling, under normal conditions and in adult mice maintained in darkness from postnatal day 40 (P40) to P70. This mechanism of nodal lengthening proceeded normally following binocular visual deprivation (BVD). The effect of BVD on nodal plasticity in animals with unimpaired astrocyte function has not been previously investigated. We find that when exocytosis from astrocytes was unimpaired, nodal gap length was not altered by BVD in adult mice. We conclude that if perinodal astrocytes participate in activity-dependent myelin remodeling through exocytosis, then, as with synaptic plasticity in the visual system, the process must be driven by alterations in neuronal firing other than those produced by BVD.

Acute Vertebral Fractures in Skiing and Snowboarding: A 20-Year Sex-Specific Analysis of National Injury Data.

Background: The epidemiology of acute vertebral fractures (AVFs) sustained while skiing and snowboarding remains poorly defined in the United States. Hypothesis: It was hypothesized that there would be no significant differences across sex and a greater number of AVFs in younger age groups associated with skiing and snowboarding. Study Design: Descriptive epidemiological study. Methods: The authors utilized the National Electronic Injury Surveillance System to identify patients who were reported in emergency departments in the United States from 2000 to 2019. All patients were noted to have sustained AVFs during skiing or snowboarding. National estimates and demographic analysis were performed. Results: A total of 466 AVFs were identified, or roughly 23.3 AVFs per year. Compared with women, men accounted for the majority of AVFs sustained in both skiing and snowboarding: 67.8% (95% CI, 62.6%-73.0%) during skiing and 82.1% (95% CI, 76.3%-87.8%) during snowboarding. This represented a significantly larger percentage of AVFs while snowboarding compared with skiing (P = .002). Women accounted for 32.2% (95% CI, 27.0%-37.4%) of AVFs while skiing and 17.9% (95% CI, 12.2%-23.7%) while snowboarding, which indicated a significantly larger percentage of AVFs sustained during skiing compared with snowboarding (P = .002). Snowboarders were more likely than skiers to sustain an AVF in the region of the coccyx (21.5% [95% CI, 14.3%-28.7%] vs 11.5% [95% CI, 3.5%-16.9%], respectively; P = .003) and as a result of a fall at ground level (69.2% [95% CI, 62.1%-76.4%] vs 52.8% [95% CI, 43.2%-62.4%], respectively; P = .009). A significant decrease in the number of snowboarding-related AVFs was identified over the 20-year study period: 899 in 2000-2003 versus 283 in 2016-2019 (P < .01). The change in skiing-related AVFs over the study period was not statistically significant (694 vs 462; P = .5). Conclusion: This national study of AVFs sustained while skiing and snowboarding identified critical sex- and age-specific differences in the population at risk, anatomic location of injury, and mechanism of injury. The national data generated from this study over a 20-year period may be utilized to better inform public health injury awareness and prevention initiatives in the rapidly growing sports of skiing and snowboarding.

Orthopaedic Surgery Residency Program Social Media Presence During the COVID-19 Pandemic.

In light of away rotation and in-person interview cancellations for the 2020 to 2021 application cycle, social media has become a popular tool for orthopaedic surgery residency programs to highlight their strengths, curricula, and social life to prospective applicants. The authors sought to explore the proliferation and utilization of 3 popular social media platforms by both orthopaedic surgery departments and residencies. METHODS: Orthopaedic surgery departmental and residency program social media accounts and their creation dates across Facebook, Twitter, and Instagram were identified using a standardized search methodology. Residency Instagram accounts were further evaluated for the number of posts, followers, likes, and comments. Both departments and residency programs were cohorted by affiliation with a US News &World Report (USNWR) top 50 American hospital for orthopaedics or by status as a Doximity top 20 program based on reputation. RESULTS: Across a total of 192 residency programs included for analysis, Instagram was the most popular social media platform (61.5%), followed by Twitter (19.8%) and Facebook (10.4%). Conversely, orthopaedic departments more frequently used Facebook (33.9%) and Twitter (28.1%) over Instagram (17.2%). Of the 118 residency Instagram accounts, 102 (86.4%) were created after the onset of the COVID-19 pandemic. Larger residency programs (≥6 spots/year) and those programs in the Doximity top 20 or affiliated with USNWR top 50 orthopaedic hospitals had a greater number of followers as well as likes and comments per post (p < 0.05 for all). CONCLUSIONS: Given the recruitment challenges faced by residency programs because of the COVID-19 pandemic, Instagram has rapidly become a prominent platform for attracting orthopaedic surgery applicants. These accounts have a large number of followers, particularly for residency programs with higher Doximity reputation rankings.

The current state of animal models in research: A review.

Animal models have provided invaluable information in the pursuit of medical knowledge and alleviation of human suffering. The foundations of our basic understanding of disease pathophysiology and human anatomy can largely be attributed to preclinical investigations using various animal models. Recently, however, the scientific community, citing concerns about animal welfare as well as the validity and applicability of outcomes, has called the use of animals in research into question. In this review, we seek to summarize the current state of the use of animal models in research.

Modulation of neuroinflammation and memory dysfunction using percutaneous vagus nerve stimulation in mice.

BACKGROUND: The vagus nerve is involved in regulating immunity and resolving inflammation. Current strategies aimed at modulating neuroinflammation and cognitive decline, in many cases, are limited and ineffective. OBJECTIVE: We sought to develop a minimally invasive, targeted, vagus nerve stimulation approach (pVNS), and we tested its efficacy with respect to microglial activation and amelioration of cognitive dysfunction following lipopolysaccharide (LPS) endotoxemia in mice. METHODS: We stimulated the cervical vagus nerve in mice using an ultrasound-guided needle electrode under sevoflurane anesthesia. The concentric bipolar needle electrode was percutaneously placed adjacent to the carotid sheath and stimulation was verified in real-time using bradycardia as a biomarker. Activation of vagal fibers was confirmed with immunostaining in relevant brainstem structures, including the dorsal motor nucleus and nucleus tractus solitarius. Efficacy of pVNS was evaluated following administration of LPS and analyses of changes in inflammation and behavior. RESULTS: pVNS enabled stimulation of the vagus nerve as demonstrated by changes in bradycardia and histological evaluation of c-Fos and choline acetyltransferase expression in brainstem nuclei. Following LPS administration, pVNS significantly reduced plasma levels of tumor necrosis factor-α at 3 h post-injection. pVNS prevented LPS-induced hippocampal microglial activation as analyzed by changes in Iba-1 immunoreactivity, including cell body enlargement and shortened ramifications. Cognitive dysfunction following endotoxemia was also restored by pVNS. CONCLUSION: Targeted cervical VNS using this novel percutaneous approach reduced LPS-induced systemic and brain inflammation and significantly improved cognitive responses. These results provide a novel therapeutic approach using bioelectronic medicine to modulate neuro-immune interactions that affect cognition.

Regulation of myelin structure and conduction velocity by perinodal astrocytes.

The speed of impulse transmission is critical for optimal neural circuit function, but it is unclear how the appropriate conduction velocity is established in individual axons. The velocity of impulse transmission is influenced by the thickness of the myelin sheath and the morphology of electrogenic nodes of Ranvier along axons. Here we show that myelin thickness and nodal gap length are reversibly altered by astrocytes, glial cells that contact nodes of Ranvier. Thrombin-dependent proteolysis of a cell adhesion molecule that attaches myelin to the axon (neurofascin 155) is inhibited by vesicular release of thrombin protease inhibitors from perinodal astrocytes. Transgenic mice expressing a dominant-negative fragment of VAMP2 in astrocytes, to reduce exocytosis by 50%, exhibited detachment of adjacent paranodal loops of myelin from the axon, increased nodal gap length, and thinning of the myelin sheath in the optic nerve. These morphological changes alter the passive cable properties of axons to reduce conduction velocity and spike-time arrival in the CNS in parallel with a decrease in visual acuity. All effects were reversed by the thrombin inhibitor Fondaparinux. Similar results were obtained by viral transfection of tetanus toxin into astrocytes of rat corpus callosum. Previously, it was unknown how the myelin sheath could be thinned and the functions of perinodal astrocytes were not well understood. These findings describe a form of nervous system plasticity in which myelin structure and conduction velocity are adjusted by astrocytes. The thrombin-dependent cleavage of neurofascin 155 may also have relevance to myelin disruption and repair.

Discovery of GSK1070916, a potent and selective inhibitor of Aurora B/C kinase.

The Aurora kinases play critical roles in the regulation of mitosis and are frequently overexpressed or amplified in human tumors. Selective inhibitors may provide a new therapy for the treatment of tumors with Aurora kinase amplification. Herein we describe our lead optimization efforts within a 7-azaindole-based series culminating in the identification of GSK1070916 (17k). Key to the advancement of the series was the introduction of a 2-aryl group containing a basic amine onto the azaindole leading to significantly improved cellular activity. Compound 17k is a potent and selective ATP-competitive inhibitor of Aurora B and C with K(i)* values of 0.38 +/- 0.29 and 1.5 +/- 0.4 nM, respectively, and is >250-fold selective over Aurora A. Biochemical characterization revealed that compound 17k has an extremely slow dissociation half-life from Aurora B (>480 min), distinguishing it from clinical compounds 1 and 2. In vitro treatment of A549 human lung cancer cells with compound 17k results in a potent antiproliferative effect (EC(50) = 7 nM). Intraperitoneal administration of 17k in mice bearing human tumor xenografts leads to inhibition of histone H3 phosphorylation at serine 10 in human colon cancer (Colo205) and tumor regression in human leukemia (HL-60). Compound 17k is being progressed to human clinical trials.

An orally active calcium-sensing receptor antagonist that transiently increases plasma concentrations of PTH and stimulates bone formation.

Daily subcutaneous administration of exogenous parathyroid hormone (PTH) promotes bone formation in patients with osteoporosis. Here we describe two novel, short-acting calcium-sensing receptor antagonists (SB-423562 and its orally bioavailable precursor, SB-423557) that elicit transient PTH release from the parathyroid gland in several preclinical species and in humans. In an ovariectomized rat model of bone loss, daily oral administration of SB-423557 promoted bone formation and improved parameters of bone strength at lumbar spine, proximal tibia and midshaft femur. Chronic administration of SB-423557 did not increase parathyroid cell proliferation in rats. In healthy human volunteers, single doses of intravenous SB-423562 and oral SB-423557 elicited transient elevations of endogenous PTH concentrations in a profile similar to that observed with subcutaneously administered PTH. Both agents were well tolerated in humans. Transient increases in serum calcium, an expected effect of increased parathyroid hormone concentrations, were observed post-dose at the higher doses of SB-423557 studied. These data constitute an early proof of principle in humans and provide the basis for further development of this class of compound as a novel, orally administered bone-forming treatment for osteoporosis.

Novel ATP-competitive kinesin spindle protein inhibitors.

Kinesin spindle protein (KSP), an ATPase responsible for spindle pole separation during mitosis that is present only in proliferating cells, has become a novel and attractive anticancer target with potential for reduced side effects compared to currently available therapies. We report herein the discovery of the first known ATP-competitive inhibitors of KSP, which display a unique activity profile as compared to the known loop 5 (L5) allosteric KSP inhibitors that are currently under clinical evaluation. Optimization of this series led to the identification of biphenyl sulfamide 20, a potent KSP inhibitor with in vitro antiproliferative activity against human cells with either wild-type KSP (HCT116) or mutant KSP (HCT116 D130V). In a murine xenograft model with HCT116 D130V tumors, 20 showed significant antitumor activity following intraperitoneal dosing, providing in vivo proof-of-principle of the efficacy of an ATP-competitive KSP inhibitor versus tumors that are resistant to the other known KSP inhibitors.

Phenylbutyrates as potent, orally bioavailable vitronectin receptor (integrin alphavbeta3) antagonists.

In our continuing efforts to identify small molecule vitronectin receptor antagonists, we have discovered a series of phenylbutyrate derivatives, exemplified by 16, which have good potency and excellent oral bioavailability (approximately 100% in rats). This new series is derived conceptually from opening of the seven-membered ring of SB-265123.

Indole naphthyridinones as inhibitors of bacterial enoyl-ACP reductases FabI and FabK.

Bacterial enoyl-ACP reductase (FabI) is responsible for catalyzing the final step of bacterial fatty acid biosynthesis and is an attractive target for the development of novel antibacterial agents. Previously we reported the development of FabI inhibitor 4 with narrow spectrum antimicrobial activity and in vivo efficacy against Staphylococcus aureus via intraperitoneal (ip) administration. Through iterative medicinal chemistry aided by X-ray crystal structure analysis, a new series of inhibitors has been developed with greatly increased potency against FabI-containing organisms. Several of these new inhibitors have potent antibacterial activity against multidrug resistant strains of S. aureus, and compound 30 demonstrates exceptional oral (po) in vivo efficacy in a S. aureus infection model in rats. While optimizing FabI inhibitory activity, compounds 29 and 30 were identified as having low micromolar FabK inhibitory activity, thereby increasing the antimicrobial spectrum of these compounds to include the FabK-containing pathogens Streptococcus pneumoniae and Enterococcus faecalis. The results described herein support the hypothesis that bacterial enoyl-ACP reductases are valid targets for antibacterial agents.

Discovery of a novel and potent class of FabI-directed antibacterial agents.

Bacterial enoyl-acyl carrier protein (ACP) reductase (FabI) catalyzes the final step in each elongation cycle of bacterial fatty acid biosynthesis and is an attractive target for the development of new antibacterial agents. High-throughput screening of the Staphylococcus aureus FabI enzyme identified a novel, weak inhibitor with no detectable antibacterial activity against S. aureus. Iterative medicinal chemistry and X-ray crystal structure-based design led to the identification of compound 4 [(E)-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide], which is 350-fold more potent than the original lead compound obtained by high-throughput screening in the FabI inhibition assay. Compound 4 has exquisite antistaphylococci activity, achieving MICs at which 90% of isolates are inhibited more than 500 times lower than those of nine currently available antibiotics against a panel of multidrug-resistant strains of S. aureus and Staphylococcus epidermidis. Furthermore, compound 4 exhibits excellent in vivo efficacy in an S. aureus infection model in rats. Biochemical and genetic approaches have confirmed that the mode of antibacterial action of compound 4 and related compounds is via inhibition of FabI. Compound 4 also exhibits weak FabK inhibitory activity, which may explain its antibacterial activity against Streptococcus pneumoniae and Enterococcus faecalis, which depend on FabK and both FabK and FabI, respectively, for their enoyl-ACP reductase function. These results show that compound 4 is representative of a new, totally synthetic series of antibacterial agents that has the potential to provide novel alternatives for the treatment of S. aureus infections that are resistant to our present armory of antibiotics.