Asymptomatic SARS-CoV-2 infection following first dose mRNA-1273 COVID-19 vaccine in a veterans affairs long term care facility.

An outbreak of SARS-CoV-2 involving four residents of a United States Veterans Affairs long term care facility occurred following administration of the first dose of the mRNA-1273 vaccine (Moderna) to thirty out of 33 residents. Three out of 4 positive cases were partially vaccinated and remained asymptomatic. One of 2 partially vaccinated patients who were tested for anti-spike protein antibodies had detectable levels at the time of diagnosis. The mortality rate was lower compared to a prior outbreak reported in this facility.

Tocilizumab in the treatment of critical COVID-19 pneumonia: A retrospective cohort study of mechanically ventilated patients.

OBJECTIVES: The purpose of this study is to evaluate clinical outcomes in patients with critical COVID-19 pneumonia requiring invasive mechanical ventilation who were treated with tocilizumab DESIGN: Single-center retrospective cohort study SETTING: Stony Brook University Hospital, a 600-bed academic tertiary medical center in Suffolk County, New York PARTICIPANTS: Consecutive patients with COVID-19 confirmed by nasopharyngeal polymerase chain reaction (PCR) who were admitted to Stony Brook University Hospital between March 10 and April 2 2020 and required mechanical ventilation in any intensive care unit during their hospitalization EXPOSURE: Treatment with tocilizumab while intubated MAIN OUTCOME: Overall mortality 30 days from the date of intubation RESULTS: Forty-five patients received tocilizumab compared to seventy controls. Baseline demographic characteristics, inflammatory markers, treatment with corticosteroids, and sequential organ failure assessment (SOFA) scores were similar between the two cohorts. Patients who received tocilizumab had significantly lower Charlson co-morbidity index (2.0 vs 3.0,P = 0.01) than controls. There was a trend towards younger mean age in the tocilizumab exposed group (56.2 vs 60.6; P = 0.09). In logistic regression analysis there was no reduction in mortality associated with receipt of tocilizumab (odds ratio (OR) 1.04; 95% CI, 0.27-3.75). There was no observed increased risk of secondary infection in patients given tocilizumab (28.9 vs 25.7; OR 1.17; 95% CI, 0.51-2.71). CONCLUSION: When controlling for age, severity of illness, and co-morbidities, tocilizumab was not associated with reduction in mortality in this retrospective cohort study of mechanically ventilated patients with COVID-19 pneumonia. Further studies are needed to determine the role of tocilizumab in the treatment of COVID-19.

A randomized clinical efficacy study targeting mPGES1 or EP4 in dogs with spontaneous osteoarthritis.

Canine studies of spontaneous osteoarthritis (OA) pain add valuable data supporting drug treatment mechanisms that may translate to humans. A multicenter, randomized, double-blind, placebo- and active-controlled study was conducted in client-owned dogs with moderate OA pain to evaluate efficacy of LYA, an inhibitor of microsomal prostaglandin E synthase-1 (mPGES1), an EP4 antagonist (LYB), and carprofen, versus placebo. Of 255 dogs screened, 163 were randomized (placebo/LYA/LYB/carprofen: n = 43/39/42/39) and 158 completed treatment. Efficacy versus placebo was assessed using Bayesian mixed-effect model for repeated measure analyses of the Canine Brief Pain Inventory (CBPI) pain interference score (PIS; primary endpoint), pain severity score, and overall impression, as well as the Liverpool Osteoarthritis in Dogs (LOAD) mobility score. The posterior probability that the difference to placebo was <0 at week 2 was 80% for LYA and 54% for LYB for CBPI PIS (both <95% predefined threshold). For secondary endpoints, the posterior probability that the difference to placebo was <0 at week 2 ranged from 89 to 96% for LYA and from 56 to 89% for LYB. The posterior probabilities comparing carprofen to placebo groups were ≥90% for all efficacy endpoints. The proportion of dogs with one or more adverse event was not significantly different from placebo (32.6%) for LYA (35.9%) or carprofen (25.6%), but the rate for LYB (59.5%) was higher versus placebo (P = 0.017). LYA treatment demonstrated consistent improvement in all efficacy measures, suggesting that inhibition of mPGES1 may be an effective treatment for chronic pain associated with OA.

Identification and Mitigation of Reactive Metabolites of 2-Aminoimidazole-Containing Microsomal Prostaglandin E Synthase-1 Inhibitors Terminated Due to Clinical Drug-Induced Liver Injury.

Two 2-aminoimidazole-based inhibitors, LY3031207 (1) and LY3023703 (2), of the microsomal prostaglandin E synthase-1 (mPGES-1) enzyme were found to cause drug-induced liver injury (DILI) in humans. We studied imidazole ring substitutions to successfully mitigate reactive metabolite (RM) formation. These studies support the conclusion that RM formation may play a role in the observations of DILI and the consideration of 2-aminoimidazoles as structure alerts, due to the high likelihood of bioactivation to generate RMs.

Analgesic and anti-inflammatory properties of novel, selective, and potent EP4 receptor antagonists.

Prostaglandin (PG) E2 is the key driver of inflammation associated with arthritic conditions. Inhibitors of PGE 2 production (NSAIDs and Coxibs) are used to treat these conditions, but carry significant side effect risks due to the inhibition of all prostanoids that play important physiological function. The activities of PGE 2 are transduced through various receptor sub-types. Prostaglandin E2 type 4 receptor (EP4) is associated with the development of inflammation and autoimmunity. We therefore are interested in identifying novel EP4 antagonists to treat the signs and symptoms of arthritis without the potential side effects of PGE 2 modulators such as NSAIDs and Coxibs. Novel EP4 antagonists representing distinct chemical scaffolds were identified using a variety of in vitro functional assays and were shown to be selective and potent. The compounds were shown to be efficacious in animal models of analgesia, inflammation, and arthritis.

Discovery and characterization of [(cyclopentyl)ethyl]benzoic acid inhibitors of microsomal prostaglandin E synthase-1.

We describe a novel class of acidic mPGES-1 inhibitors with nanomolar enzymatic and human whole blood (HWB) potency. Rational design in conjunction with structure-based design led initially to the identification of anthranilic acid 5, an mPGES-1 inhibitor with micromolar HWB potency. Structural modifications of 5 improved HWB potency by over 1000×, reduced CYP2C9 single point inhibition, and improved rat clearance, which led to the selection of [(cyclopentyl)ethyl]benzoic acid compound 16 for clinical studies. Compound 16 showed an IC80 of 24nM for inhibition of PGE2 formation in vitro in LPS-stimulated HWB. A single oral dose resulted in plasma concentrations of 16 that exceeded its HWB IC80 in both rat (5mg/kg) and dog (3mg/kg) for over twelve hours.

Characterization of 3,3-dimethyl substituted N-aryl piperidines as potent microsomal prostaglandin E synthase-1 inhibitors.

Here we report on novel, potent 3,3-dimethyl substituted N-aryl piperidine inhibitors of microsomal prostaglandin E synthases-1(mPGES-1). Example 14 potently inhibited PGE2 synthesis in an ex vivo human whole blood (HWB) assay with an IC50 of 7nM. In addition, 14 had no activity in human COX-1 or COX-2 assays at 30µM, and failed to inhibit human mPGES-2 at 62.5µM in a microsomal prep assay. These data are consistent with selective mPGES-1-mediated reduction of PGE2. In dog, 14 had oral bioavailability (74%), clearance (3.62mL/(min*kg)) and volume of distribution (Vd,ss=1.6L/kg) values within our target ranges. For these reasons, 14 was selected for further study.

Identification and biological activity of 6-alkyl-substituted 3-methyl-pyridine-2-carbonyl amino dimethyl-benzoic acid EP4 antagonists.

Continued SAR optimization of a series of 3-methylpyridine-2-carbonyl amino-2,4-dimethyl-benzoic acid led to the selection of compound 4f for clinical studies. Compound 4f showed an IC50 of 123nM for inhibition of PGE2-induced TNFα reduction in an ex vivo LPS-stimulated human whole blood assay (showing >10-fold increase over clinical compound CJ-023,423). Pharmacokinetic profile, selectivity and in vivo efficacy comparing 4f to NSAID diclofenac in the monoiodoacetic acid (MIA) pain model and adjuvant induced arthritis (AIA) inflammatory model are included.

Identification and Characterization of Novel Microsomal Prostaglandin E Synthase-1 Inhibitors for Analgesia.

Prostaglandin (PG) E2 plays a critical role in eliciting inflammation. Nonsteroidal anti-inflammatory drugs and selective inhibitors of cyclooxygenase, which block PGE2 production, have been used as key agents in treating inflammation and pain associated with arthritis and other conditions. However, these agents have significant side effects such as gastrointestinal bleeding and myocardial infarction, since they also block the production of prostanoids that are critical for other normal physiologic functions. Microsomal prostaglandin E2 synthase-1 is a membrane-bound terminal enzyme in the prostanoid pathway, which acts downstream of cyclooxygenase 2 and is responsible for PGE2 production during inflammation. Thus, inhibition of this enzyme would be expected to block PGE2 production without inhibiting other prostanoids and would provide analgesic efficacy without the side effects. In this report, we describe novel microsomal prostaglandin E2 synthase-1 inhibitors that are potent in blocking PGE2 production and are efficacious in a guinea pig monoiodoacetate model of arthralgia. These molecules may be useful in treating the signs and symptoms associated with arthritis.

Discovery of potent aryl-substituted 3-[(3-methylpyridine-2-carbonyl) amino]-2,4-dimethyl-benzoic acid EP4 antagonists with improved pharmacokinetic profile.

Two new series of EP4 antagonists containing a 3-methylaryl-2-carbonyl core have been identified. One series has a 3-substituted-phenyl core, while the other one incorporates a 3-substituted pyridine. Both series led to compounds with potent activity in functional and human whole blood (hWB) assays. In the pyridine series, compound 7a was found to be a highly potent and selective EP4 antagonist, with suitable rat and dog pharmacokinetic profiles.

Discovery and Characterization of 2-Acylaminoimidazole Microsomal Prostaglandin E Synthase-1 Inhibitors.

As part of a program aimed at the discovery of antinociceptive therapy for inflammatory conditions, a screening hit was found to inhibit microsomal prostaglandin E synthase-1 (mPGES-1) with an IC50 of 17.4 µM. Structural information was used to improve enzyme potency by over 1000-fold. Addition of an appropriate substituent alleviated time-dependent cytochrome P450 3A4 (CYP3A4) inhibition. Further structure-activity relationship (SAR) studies led to 8, which had desirable potency (IC50 = 12 nM in an ex vivo human whole blood (HWB) assay) and absorption, distribution, metabolism, and excretion (ADME) properties. Studies on the formulation of 8 identified 8·H3PO4 as suitable for clinical development. Omission of a lipophilic portion of the compound led to 26, a readily orally bioavailable inhibitor with potency in HWB comparable to celecoxib. Furthermore, 26 was selective for mPGES-1 inhibition versus other mechanisms in the prostanoid pathway. These factors led to the selection of 26 as a second clinical candidate.

Discovery of substituted-2,4-dimethyl-(naphthalene-4-carbonyl)amino-benzoic acid as potent and selective EP4 antagonists.

A novel series of EP4 antagonists, based on a quinoline scaffold, has been discovered. Medicinal chemistry efforts to optimize the potency of the initial hit are described. A highly potent compound in a clinically relevant human whole blood assay was identified. Selectivity and pharmacokinetic profiles of this compound are discussed.

Discovery and characterization of a potent and selective EP4 receptor antagonist.

EP4 is a prostaglandin E2 receptor that is a target for potential anti-nociceptive therapy. Described herein is a class of amphoteric EP4 antagonists which reverses PGE2-induced suppression of TNFα production in human whole blood. From this class, a potent and highly bioavailable compound (6) has been selected for potential clinical studies. EP4 binding and functional data, selectivity, and pharmacokinetic properties of this compound are included.

Crystal Structures of mPGES-1 Inhibitor Complexes Form a Basis for the Rational Design of Potent Analgesic and Anti-Inflammatory Therapeutics.

Microsomal prostaglandin E synthase 1 (mPGES-1) is an α-helical homotrimeric integral membrane inducible enzyme that catalyzes the formation of prostaglandin E2 (PGE2) from prostaglandin H2 (PGH2). Inhibition of mPGES-1 has been proposed as a therapeutic strategy for the treatment of pain, inflammation, and some cancers. Interest in mPGES-1 inhibition can, in part, be attributed to the potential circumvention of cardiovascular risks associated with anti-inflammatory cyclooxygenase 2 inhibitors (coxibs) by targeting the prostaglandin pathway downstream of PGH2 synthesis and avoiding suppression of antithrombotic prostacyclin production. We determined the crystal structure of mPGES-1 bound to four potent inhibitors in order to understand their structure-activity relationships and provide a framework for the rational design of improved molecules. In addition, we developed a light-scattering-based thermal stability assay to identify molecules for crystallographic studies.

Defining a mismatch: differences in usage of social networking sites between medical students and the faculty who teach them.

BACKGROUND: Use of social networking sites (SNS) by medical students is increasing, and some students lack awareness of pitfalls arising from the intersection of social networking and medicine. Many institutions have developed guidelines on using SNS, but they are insufficient for students. Educators need new methods to train students on the appropriate use of this technology, but more information is needed before implementing change. PURPOSES: Differences in SNS usage between students and faculty were examined. The goal was to evaluate four content areas: SNS usage patterns, attitudes regarding activity on SNS, experience with patient interactions online, and awareness of institutional guidelines on use of SNS. METHODS: A cross-sectional survey took place at Feinberg School of Medicine, Northwestern University, in 2012. Participants included all students and a cohort of faculty who teach them in a class on professionalism. RESULTS: The response rate was 42% by students (300/711) and 78% by faculty (31/40). Of the students, 94% use SNS, compared to 48% of faculty. Students were more likely than faculty to display content they would not want patients to see (57% vs. 27%), report seeing inappropriate content on colleagues' SNS profiles (64% vs. 42%), and ignore harmful postings by colleagues (25% vs. 7%). Faculty were more likely than students to have been approached by patients on SNS (53% vs. 3%). Most participants were unlikely to conduct Internet searches on patients. CONCLUSIONS: Students are more likely than faculty to use SNS and use it very differently than faculty. Students would benefit from training on appropriate use of SNS. Topics that should be addressed include editing one's online presence, managing friend requests from patients, dealing with colleagues who post harmful content, conducting Internet searches on patients, and discussion of boundaries to identify potential harms associated with SNS usage. Differences in usage between students and faculty raise questions if faculty are well suited to provide this training.

Economics of Malignant Gliomas: A Critical Review.

PURPOSE: Approximately 18,500 persons are diagnosed with malignant glioma in the United States annually. Few studies have investigated the comprehensive economic costs. We reviewed the literature to examine costs to patients with malignant glioma and their families, payers, and society. METHODS: A total of 18 fully extracted studies were included. Data were collected on direct and indirect costs, and cost estimates were converted to US dollars using the conversion rate calculated from the study's publication date, and updated to 2011 values after adjustment for inflation. A standardized data abstraction form was used. Data were extracted by one reviewer and checked by another. RESULTS: Before approval of effective chemotherapeutic agents for malignant gliomas, estimated total direct medical costs in the United States for surgery and radiation therapy per patient ranged from $50,600 to $92,700. The addition of temozolomide (TMZ) and bevacizumab to glioblastoma treatment regimens has resulted in increased overall costs for glioma care. Although health care costs are now less front-loaded, they have increased over the course of illness. Analysis using a willingness-to-pay threshold of $50,000 per quality-adjusted life-year suggests that the benefits of TMZ fall on the edge of acceptable therapies. Furthermore, indirect medical costs, such as productivity losses, are not trivial. CONCLUSION: With increased chemotherapy use for malignant glioma, the paradigm for treatment and associated out-of-pocket and total medical costs continue to evolve. Larger out-of-pocket costs may influence the choice of chemotherapeutic agents, the economic implications of which should be evaluated prospectively.

Colonoscopy is high yield in spinal cord injury.

OBJECTIVES/BACKGROUND: Colorectal cancer (CRC) can be prevented by routine colonoscopy. CRC screening in special populations, e.g. spinal cord injury and disorders, presents unique barriers and, potentially, a higher risk of complications. We were concerned about potentially higher risks of complications and sought to determine the safety of colonoscopy. METHODS: Retrospective observational design using medical record review for 311 patients who underwent 368 colonoscopies from two large VA SCI centers from 1997-2008. Patient demographics and peri-procedural characteristics, including indication, bowel prep quality, and pathological findings are presented. Descriptive statistics are presented. RESULTS: The population was predominantly male and Caucasian, and 199 (64%) had high-level injuries (T6 or above). Median age at colonoscopy was 61 years (interquartile range 53-69). Just <1/2 of the colonoscopies were diagnostic, usually for evidence of rectal bleeding. Although a majority of colonoscopies were reported as poorly prepped, the proportion that were adequately prepped increased over time (from 3.7 to 61.3%, P = <0.0001). Of the 146 polyps removed, 101 (69%) were adenomas or carcinomas. Ten subjects had 11 complications, none of which required surgical intervention. CONCLUSIONS: Although providing quality colonoscopic care in this population is labor intensive, the data suggests that it appears safe and therapeutically beneficial. The results indicate that the risk of screening is outweighed by the likelihood of finding polyps. Recognition of the benefit of colonoscopy in this population may have improved bowel prep and reporting over time. Spinal cord injury providers should continue to offer screening or diagnostic colonoscopy to their patients when indicated, while being aware of the special challenges that they face.

Results from the first decade of research conducted by the Research on Adverse Drug Events and Reports (RADAR) project.

INTRODUCTION: In 1998, a multidisciplinary team of investigators initiated the Research on Adverse Drug events And Reports (RADAR) project, a post-marketing surveillance effort that systematically investigates and disseminates information describing serious and previously unrecognized serious adverse drug and device reactions (sADRs). OBJECTIVE: Herein, we describe the findings, dissemination efforts, and lessons learned from the first decade of the RADAR project. METHODS: After identifying serious and unexpected clinical events suitable for further investigation, RADAR collaborators derived case information from physician queries, published and unpublished clinical trials, case reports, US FDA databases and manufacturer sales figures. STUDY SELECTION: All major RADAR publications from 1998 to the present are included in this analysis. DATA EXTRACTION: For each RADAR publication, data were abstracted on data source, correlative basic science findings, dissemination and resultant safety information. RESULTS: RADAR investigators reported 43 serious ADRs. Data sources included case reports (17 sADRs), registries (5 sADRs), referral centers (8 sADRs) and clinical trial reports (13 sADRs). Correlative basic science findings were reported for ten sADRs. Thirty-seven sADRS were described as published case reports (5 sADRs) or published case-series (32 sADRs). Related safety information was disseminated as warnings or boxed warnings in the package insert (17 sADRs) and/or 'Dear Healthcare Professional' letters (14 sADRs). CONCLUSION: An independent National Institutes of Health-funded post-marketing surveillance programme can supplement existing regulatory and pharmaceutical manufacturer-supported drug safety initiatives.

Bisphosphonates and nonhealing femoral fractures: analysis of the FDA Adverse Event Reporting System (FAERS) and international safety efforts: a systematic review from the Research on Adverse Drug Events And Reports (RADAR) project.

BACKGROUND: In the United States, hip fracture rates have declined by 30% coincident with bisphosphonate use. However, bisphosphonates are associated with sporadic cases of atypical femoral fracture. Atypical femoral fractures are usually atraumatic, may be bilateral, are occasionally preceded by prodromal thigh pain, and may have delayed fracture-healing. This study assessed the occurrence of bisphosphonate-associated nonhealing femoral fractures through a review of data from the U.S. FDA (Food and Drug Administration) Adverse Event Reporting System (FAERS) (1996 to 2011), published case reports, and international safety efforts. METHODS: We analyzed the FAERS database with use of the proportional reporting ratio (PRR) and empiric Bayesian geometric mean (EBGM) techniques to assess whether a safety signal existed. Additionally, we conducted a systematic literature review (1990 to February 2012). RESULTS: The analysis of the FAERS database indicated a PRR of 4.51 (95% confidence interval [CI], 3.44 to 5.92) for bisphosphonate use and nonhealing femoral fractures. Most cases (n = 317) were attributed to use of alendronate (PRR = 3.32; 95% CI, 2.71 to 4.17). In 2008, international safety agencies issued warnings and required label changes. In 2010, the FDA issued a safety notification, and the American Society for Bone and Mineral Research (ASBMR) issued recommendations about bisphosphonate-associated atypical femoral fractures. CONCLUSIONS: Nonhealing femoral fractures are unusual adverse drug reactions associated with bisphosphonate use, as up to 26% of published cases of atypical femoral fractures exhibited delayed healing or nonhealing.

Is Illinois heeding the call to regionalize pancreatic surgery?

BACKGROUND AND OBJECTIVES: Recommendations to refer pancreatic procedures to high-volume centers have been in place for a decade. We sought to determine whether regionalization of pancreatic procedures to high-volume centers is occurring in Illinois. METHODS: We compared pancreatic procedures performed in Illinois hospitals from 2000 to 2004 [time period (TP) 1] versus 2005-2009 (TP2) for changes in inpatient mortality and hospital volume. Hospitals were categorized into low- (LVH), intermediate- (IVH), or high-volume (HVH). RESULTS: From TP1 to TP2, there was a 23% increase in absolute case volume (2,232-2,737), despite fewer hospitals performing pancreatic procedures (114-95). In hospital mortality decreased (5.5-3.3%, P < 0.01) and was lowest at HVHs. LVHs and IVHs were associated with a 4.7 and 3.0 higher odds of mortality, respectively (both P < 0.001). Overall, HVHs performed 659 (+73%) more procedures, whereas cumulative procedure volume dropped by 154 cases at LVHs (+1%) and IVHs (-18%). CONCLUSIONS: We observed limited evidence of regionalization of pancreatic procedures in Illinois. The increase in HVH case volume cannot be solely attributed to regionalization, given the corresponding modest decrease seen at non-HVHs. There is opportunity for Illinois hospitals to implement strategies such as selective referral to improve mortality after pancreatic resection.