A novel approach to patient portal activation data to power equity improvements.

BACKGROUND: There are significant disparities in access and utilization of patient portals by age, language, race, and ethnicity. MATERIALS AND METHODS: We developed ambulatory and inpatient portal activation equity dashboards to understand disparities in initial portal activation, identify targets for improvement, and enable monitoring of interventions over time. We selected key metrics focused on episodes of care and filters to enable high-level overviews and granular data selection to meet the needs of health system leaders and individual clinical units. RESULTS: In addition to highlighting disparities by age, preferred language, race and ethnicity, and insurance payor, the dashboards enabled development and monitoring of interventions to improve portal activation and equity. DISCUSSION AND CONCLUSIONS: Data visualization tools that provide easily accessible, timely, and customizable data can enable a variety of stakeholders to understand and address healthcare disparities, such as patient portal activation. Further institutional efforts are needed to address the persistent inequities highlighted by these dashboards.

Regulatory agilities impacting review timelines for Pfizer/BioNTech's BNT162b2 mRNA COVID-19 vaccine: a retrospective study.

The appropriate use of regulatory agilities has the potential to accelerate regulatory review, utilize resources more efficiently and deliver medicines and vaccines more rapidly, all without compromising quality, safety and efficacy. This was clearly demonstrated during the COVID-19 pandemic where regulators and industry rapidly adapted to ensure continued supply of existing critical medicines and review and approve new innovative medicines. In this retrospective study, we analyze the impact of regulatory agilities on the review and approval of Pfizer/BioNTech's BNT162b2 mRNA COVID-19 Vaccine globally using regulatory approval data from 73 country/regional approvals. We report on the critical role of reliance and provide evidence that demonstrates reliance approaches and certain regulatory agilities reduced review times for the COVID-19 vaccine. These findings support the case for more widespread implementation of regulatory agilities and demonstrate the important role of such approaches to improve public health outcomes.

Severe Aortic Valvular Incompetence From IgG4-Related Disease: An Unusual Entity.

IgG4-related disease (IgG4-RD) is a new clinical entity characterized by lymphoplasmacytic lesions rich in IgG4-positive plasma cells. Myocardial involvement is extremely rare and not a typical cardiovascular manifestation of IgG4-RD. We report a rare case of IgG4-RD-associated myocardial mass causing severe aortic incompetence, successfully treated with surgery and corticosteroids. (Level of Difficulty: Intermediate.).

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

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

External Validation of the Breast Cancer Surgery Risk Calculator (BCSRc): A Predictive Model for Postoperative Complications.

BACKGROUND: The breast cancer surgical risk calculator (BCSRc) is a prognostic tool that determines a breast cancer patient's unique risk of acute complications following each possible surgical intervention. When used in the preoperative setting, it can help to stratify patients with an increased complication risk and enhance the patient-physician informed decision-making process. The objective of this study was to externally validate the four models used in the BCSRc on a large cohort of patients who underwent breast cancer surgery. METHODS: The BCSRc was developed by using a retrospective cohort from the National Surgical Quality Improvement Program database from 2005 to 2018. Four models were built by using logistic regression methods to predict the following composite outcomes: overall, infectious, hematologic, and internal organ complications. This study obtained a new cohort of patients from the National Surgical Quality Improvement Program by utilizing participant user files from 2019 to 2020. The area under the curve, brier score, and Hosmer-Lemeshow goodness of fit test measured model performance, accuracy, and calibration, respectively. RESULTS: A total of 192,095 patients met inclusion criteria in the development of the BCSRc, and the validation cohort included 60,144 women. The area under the curve during external validation for each model was approximately 0.70. Accuracy, or Brier scores, were all between 0.04 and 0.003. Model calibration using the Hosmer-Lemeshow statistic found all p-values > 0.05. All of these model coefficients will be updated on the web-based BCSRc platform: www.breastcalc.org . CONCLUSIONS: The BCSRc continues to show excellent external-validation measures. Collectively, this prognostic tool can enhance the decision-making process, help stratify patients with an increased complication risk, and improve expectant management.

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

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

EPOC Comparison Between Resistance Training and High-Intensity Interval Training in Aerobically Fit Women.

Previous research has shown that various modes of exercise may elicit significant increases in resting metabolism for up to 24 hours post-exercise, but typically using untrained or moderately active subjects. The purpose of the present study was to compare excess post-exercise oxygen consumption (EPOC) between circuit-style resistance training (RT) and high-intensity interval training (HIIT) in young, aerobically fit women. During the follicular phase of the menstrual cycle, seven participants reported to the laboratory for evening and morning baseline resting metabolic rate (RMR) measurements via indirect calorimetry. Participants fasted and slept overnight in the laboratory between RMR measurements. Following the morning RMR measurement, participants were randomly assigned to complete either a total-body, circuit-style RT protocol (30 seconds of lifting at 80% 1RM:one minute rest) or treadmill HIIT (30-second run at 90% VO2 max:one minute stationary recovery). RMR was repeated 14 and 24 hours post-exercise. All procedures were replicated during the follicular phase of the next menstrual cycle using the remaining exercise protocol. Resting VO2 was significantly (p<0.05) higher 14 hours after RT (3.8±0.3 ml/kg/min) compared to baseline (3.4±0.3 ml/kg/min), however HIIT showed no significant change (3.7±0.3 ml/kg/min). Both RT and HIIT showed significantly higher energy expenditure 14 hours post-exercise (33±5 and 33±4 kcals/30 minutes, respectively) compared to baseline (30±3 kcal). Neither protocol sustained a RMR change at 24 hours. Based on the magnitude and duration of post-exercise energy expenditure, EPOC responses may be a worthwhile consideration when prescribing exercise for weight maintenance in young, fit women.

On the association between circulating biomarkers and atherosclerotic calcification in a cohort of arterial disease participants.

BACKGROUND AND AIMS: Atherosclerotic calcification is a powerful predictor of cardiovascular disease. This study aims to determine whether circulating levels of a local/systemic calcification inhibitor or a marker of bone formation correlate with measures of coronary or extracoronary calcification. METHODS AND RESULTS: Clinical computed tomography (CT) was performed on 64 arterial disease participants undergoing carotid and lower extremity endarterectomy. Coronary artery calcium (CAC) scores and volumes were acquired from the CT scans (n = 42). CAC scores and volumes were used to derive CAC density scores. Micro-CT was performed on excised carotid (n = 36) and lower extremity (n = 31) plaques to quantify the volume and volume fraction of extracoronary calcification. Circulating levels of dephospho-uncarboxylated Matrix Gla Protein (dp-ucMGP), fetuin-A, carboxylated and uncarboxylated osteocalcin (ucOC) were quantified using commercial immunoassays. Carotid participant CAC density scores were moderately negatively correlated with plasma dp-ucMGP (rs = -0.592, P = 0.008). A weak negative association was found between CAC scores and %ucOC for all participants (rs = -0.335, P = 0.040). Another weak negative correlation was observed between fetuin-A and the volume of calcification within excised carotid specimens (rs = -0.366, P = 0.031). Despite substantial differences in coronary and extracoronary calcium measurements, the levels of circulating biomarkers did not vary significantly between carotid and lower extremity subgroups. CONCLUSION: Correlations identified between circulating biomarkers and measures of coronary and extracoronary calcium were not consistent among participant subgroups. Further research is required to determine the association between circulating biomarkers, coronary and extracoronary calcium.

Structures of active-state orexin receptor 2 rationalize peptide and small-molecule agonist recognition and receptor activation.

Narcolepsy type 1 (NT1) is a chronic neurological disorder that impairs the brain's ability to control sleep-wake cycles. Current therapies are limited to the management of symptoms with modest effectiveness and substantial adverse effects. Agonists of the orexin receptor 2 (OX2R) have shown promise as novel therapeutics that directly target the pathophysiology of the disease. However, identification of drug-like OX2R agonists has proven difficult. Here we report cryo-electron microscopy structures of active-state OX2R bound to an endogenous peptide agonist and a small-molecule agonist. The extended carboxy-terminal segment of the peptide reaches into the core of OX2R to stabilize an active conformation, while the small-molecule agonist binds deep inside the orthosteric pocket, making similar key interactions. Comparison with antagonist-bound OX2R suggests a molecular mechanism that rationalizes both receptor activation and inhibition. Our results enable structure-based discovery of therapeutic orexin agonists for the treatment of NT1 and other hypersomnia disorders.

Correlating Ex Vivo Carotid Calcification Measurements With Cerebrovascular Symptoms: A Proof-of-Concept Study.

BACKGROUND AND PURPOSE: The purpose of this study is to examine the ability of ex vivo derived Agatston, Volume, and Density-Volume calcium scores or calcium density measurements to differentiate between carotid plaques based on preoperative cerebrovascular symptomatology. METHODS: Thirty-eight carotid plaques were acquired from standard endarterectomy. Micro-computed tomography was performed on the ex vivo samples. Image series were downsampled to represent the resolution of clinical multidetector computed tomography. Agatston, Volume, and Density-Volume carotid calcium scores were then calculated using coronary methodologies. The fractions of low- and high-density calcification were also determined. RESULTS: The coronary calcium scores could not differentiate between carotid plaques from asymptomatic versus symptomatic patients. However, plaques from asymptomatic patients contained significantly lower fractions of low-density calcification and higher fractions of high-density calcification. CONCLUSIONS: Screening for carotid calcium density in noncontrast computed tomography could reflect plaque stability.

The use of computed tomography pulmonary angiography in the diagnosis of heart failure in the acute setting.

BACKGROUND: Heart failure is a clinical diagnosis characterised by non-specific symptoms such as dyspnoea, fatigue and oedema. The aim of this pilot study was to investigate what role computed tomography pulmonary angiography could play in supporting a diagnosis of heart failure when a pulmonary embolism has been excluded. METHODS: This was a prospective study using the National Integrated Medical Imaging System to assess the potential of computed tomography pulomary angiography (CTPA) as a diagnostic test for heart failure. Consecutive patients were collected from three hospitals of the University of Limerick Hospital Group. We reviewed 230 consecutive CTPA results for cardiac and lung features. Of these, we confirmed which had heart failure by comparison with brain natriuretic peptide (BNP) and echocardiogram criteria. Exclusion criteria included any patients with a diagnosis of pulmonary embolism. RESULTS: Of these 230 patients, only 24 (10.4%) had both objective and clinical signs of heart failure. The most specific signs were shown to be left ventricular enlargement, left atrial enlargement and right ventricular enlargement, which approximated a specificity of 100% (CI 66.3-100.00%). CTPA was shown to match gold standard echocardiography closely in detecting abnormalities as per chi square; Right ventricular enlargement (value = 5.426 P = 0.02), left atrial enlargement (value = 4.9 P = 0.027) and left ventricular enlargement (value = 5.692 P = 0.017). CONCLUSION: Findings on CTPA which included left ventricular enlargement, left atrial enlargement and right ventricular enlargement were shown to be specific for a diagnosis of heart failure. CTPA should be used by physicians awaiting echocardiography to help guide treatment in cases of suspected heart failure.

Discovery of 4-arylquinoline-2-carboxamides, highly potent and selective class of mGluR2 negative allosteric modulators: From HTS to activity in animal models.

Antagonism of the mGluR2 receptor has the potential to provide therapeutic benefit to cognitive disorders by elevating synaptic glutamate, the primary excitatory neurotransmitter in the brain. Selective antagonism of the mGluR2 receptor, however, has so far been elusive, given the very high homology of this receptor with mGluR3, particularly at the orthosteric binding site. Given that inhibition of mGluR3 has been implicated in undesired effects, we sought to identify selective mGluR2 negative allosteric modulators. Herein we describe the discovery of the highly potent and selective class of mGluR2 negative allosteric modulators, 4-arylquinoline-2-carboxamides, following a successful HTS campaign and medicinal chemistry optimization, showing potent in vivo efficacy in rodent.

Building a Better Approach for the Benefit of Patients: 10 Pillars to Strengthen Regulatory Review Systems Globally.

In the current pharmaceutical regulatory environment, patients continue to benefit from great advances in medical care. Sophisticated regulatory review systems have also evolved to ensure that safe and effective medicines are approved. However, these systems are not optimized in all countries. Gaps in individual regulatory agency capabilities together with duplication in non-value added national regulatory requirements, particularly in low- and middle-income countries (LMICs), can slow down regulatory approvals and therefore impede patient access to new medicines. These gaps exist despite the achievements in both regulatory convergence and harmonization of technical requirements by bodies such as the International Conference on Harmonization (ICH). There is a pressing need to strengthen regulatory review systems in emerging market economies as highlighted by the World Health Organization (WHO). These diverse challenges may seem overwhelming to individual national regulators, in part because of the sheer number of initiatives by multiple stakeholders, combined with a lack of information on concise practical actionable measures that can have a positive impact on review efficiency. This commentary presents 10 pillars that we believe represent the key hallmarks of strong regulatory review systems. Leveraging our internal company expertise at the global, regional, and country level across our entire product portfolio (both innovative and generic), we selected features proven to work in leading regulatory agencies, such as the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA), which are also relevant for other regulatory authorities, especially in LMICs.

Comparative analysis of calcification parameters with Agatston Score approximations for ex vivo atherosclerotic lesions.

BACKGROUND: The Agatston Calcium Score is a predictor of major adverse cardiovascular events but it is unable to identify high-risk lesions. Recent research suggests that examining calcification phenotype could be more indicative of plaque stability. OBJECTIVE: To examine the Agatston score's ability to determine atherosclerotic calcification phenotype. METHODS: Micro-Computed Tomography was performed on 20 carotid and 20 peripheral lower limb lesions. ImageJ pixel histogram analysis quantified the non-calcified (≥30HU, <130HU) and calcified (≥130HU) tissue volumes. ImageJ '3D Objects Counter' plugin determined the calcified particle count, volumes and maximum attenuation density of each particle. Image stacks were subsequently downsampled to a resolution of 0.7 × 0.7 × 3 mm and an approximation for the Extra-Coronary Calcium Scores (ECCS) were calculated. Spearman's correlation examined the relationships between ECCS approximations and calcification parameters. RESULTS: ECCS has a strong positive correlation with the Calcified Volume Fraction (CVF) (rs = 0.865, p < 0.0005), weak positive correlations with Calcified Particle Fraction (CPF) (rs = 0.422, p = 0.007) and Microcalcification Fraction (micro-CF) (rs = 0.361, p = 0.022). There is no correlation evident between ECCS and Calcified Particle Index (CPI) (rs = -0.162, p = 0.318). It is apparent that there is a high prevalence of microcalcifications in both carotid and peripheral lower limb lesions. Additionally, an inverse relationship exists between calcified particle volume and maximum-recorded attenuation density. CONCLUSION: The density-weighted Agatston calcium scoring methodology needs to be reviewed. Calcium scoring which differentiates between critical calcification morphologies, rather than presenting a density-weighted score, is required to direct high-risk plaques towards tailored treatment.

Discovery, Optimization, and Biological Characterization of 2,3,6-Trisubstituted Pyridine-Containing M4 Positive Allosteric Modulators.

Herein we describe the discovery and optimization of a new series of 2,3-disubstituted and 2,3,6-trisubstituted muscarinic acetylcholine receptor 4 (M4 ) positive allosteric modulators (PAMs). Iterative libraries enabled rapid exploration of one-dimensional structure-activity relationships (SAR) and identification of potency-enhancing heterocycle and N-alkyl pyrazole substituents. Further optimization led to identification of the potent, receptor-subtype-selective, brain-penetrant tool compound 24 (7-[3-[1-[(1-fluorocyclopentyl)methyl]pyrazol-4-yl]-6-methyl-2-pyridyl]-3-methoxycinnoline). It is efficacious in preclinical assays that are predictive of antipsychotic effects, producing dose-dependent reversal of amphetamine-induced hyperlocomotion in rats and mice, but not in M4 knockout mice. Cholinergic-related adverse effects observed in rats treated with 24 at unbound plasma concentrations more than 3-fold higher than an efficacious dose in the hyperlocomotion assay were fewer and less severe than those observed in rats treated with the nonselective M4 agonist xanomeline, suggesting a receptor-subtype-selective PAM has the potential for an improved safety profile.

Experience with uncrossmatched blood refrigerator in emergency department.

BACKGROUND: Uncrossmatched packed red blood cell (PRBC) transfusion is fundamental in resuscitation of hemorrhagic shock. Ready availability of uncrossmatched blood can be achieved by storing uncrossmatched blood in a blood bank refrigerator in the emergency department (ED), but could theoretically lead to inappropriate uncrossmatched use. METHODS: This retrospective study was performed at a level I trauma center from January 2013 to March 2014. Possibly inappropriate transfusion was defined as patients who received at least one unit of blood from the ED refrigerator and no more than two units of PRBC in the first 24 hours. Deaths within the first 24 hours were excluded. Patients who received blood from the ED refrigerator who received ≤2 units total in 24 hours were compared with those who received >2 units. RESULTS: 158 adults received blood from the ED refrigerator. 140 (88.6%) were trauma patients. 37 (23.4%) received massive transfusion (MT). 42 (26.6%) deaths were excluded. 29 patients received ≤2 units and 87 received >2 units in the first 24 hours. The ≤2 units group had a higher systolic blood pressure (116 mm Hg vs. 102 mm Hg, p=0.042), lower base deficit (6.4 mEq/L vs. 9.4 mEq/L, p=0.032), higher hematocrit (34% vs. 30%, p=0.024), lower rate of MT protocol activation (27.6% vs. 58.6%, p=0.005), and lower rates of transfusion of fresh frozen plasma (17.2% vs. 54.0%, p=0.001) and platelets (13.8% vs. 39.1%, p=0.012). Appropriately transfused patients were more likely to have evidence of shock with active, non-compressible hemorrhage. Potentially inappropriate uses were more likely in patients either without evidence of hemorrhage or without signs of shock. DISCUSSION: Storing uncrossmatched blood in the ED is an effective way to get PRBCs transfused quickly in hemorrhaging patients and is associated with a low rate of unnecessary uncrossmatched transfusion. Provider education and good clinical judgment are imperative to prevent unnecessary use. LEVEL OF EVIDENCE: Level III, therapeutic.

Relating the mechanical properties of atherosclerotic calcification to radiographic density: A nanoindentation approach.

Calcification morphology can determine atherosclerotic plaque stability and is associated with increased failures rates for endovascular interventions. Computational efforts have sought to elucidate the relationship between calcification and plaque rupture in addition to predicting tissue response during aggressive revascularisation techniques. However, calcified material properties are currently estimated and may not reflect real tissue conditions. The objective of this study is to correlate calcification mechanical properties with three radiographic density groups obtained from corresponding Computed Tomography (CT) images. Seventeen human plaques extracted from carotid (n = 10) and peripheral lower limb (n = 7) arteries were examined using micro-computed tomography (µCT), simultaneously locating the calcified deposits within their internal structure and quantifying their densities. Three radiographic density groups were defined based on the sample density distribution: (A) 130-299.99 Hounsfield Units (HU), (B) 300-449.99 HU and (C) >450 HU. Nanoindentation was employed to determine the Elastic Modulus (E) and Hardness (H) values within the three density groups. Results reveal a clear distinction between mechanical properties with respect to radiographic density groups (p < 0.0005). No significant differences exist in the density-specific behaviours observed between carotid and peripheral samples. Previously defined calcification classifications indicate an association with specific radiographic density patterns. Scanning Electron Microscopy (SEM) examination revealed that density group A regions consist of both calcified and non-calcified tissues. Further research is required to define the radiographic thresholds which identify varying degrees of tissue calcification. This study demonstrates that the mechanical properties of fully mineralised atherosclerotic calcification emulate that of bone tissues (17-25 GPa), affording computational models with accurate material parameters. STATEMENT OF SIGNIFICANCE: Global mechanical characterisation techniques disregard the heterogeneous nature of atherosclerotic lesions. Previous nanoindentation results for carotid calcifications have displayed a wide range. This study evaluates calcification properties with respect to radiographic density obtained from Micro-CT images. This is the first work to characterise calcifications from peripheral lower limb arteries using nanoindentation. Results demonstrate a strong positive correlation between radiographic density and calcification mechanical properties. Characterising calcifications using their density values provides clarity on the variation in published properties for calcified tissues. Furthermore, this study confirms the hypothesis that fully calcified plaque tissue behaviour similar to that of bone. Appropriate material parameters for calcified tissues can now be employed in computational simulations.