Bayesian Emulation and History Matching of JUNE

We analyse JO_SCPLOWUNEC_SCPLOW : a detailed model of Covid-19 transmission with high spatial and demographic resolution, developed as part of the RAMP initiative. JO_SCPLOWUNEC_SCPLOW requires substantial computational resources to evaluate, making model calibration and general uncertainty analysis extremely challenging. We describe and employ the Uncertainty Quantification approaches of Bayes linear emulation and history matching, to mimic the JO_SCPLOWUNEC_SCPLOW model and to perform a global parameter search, hence identifying regions of parameter space that produce acceptable matches to observed data.

A Point-of-Care Algorithm to Guide Proper Device Selection for Ambulatory Electrocardiography.

In the outpatient setting, ambulatory electrocardiography is the most frequently used diagnostic modality for the evaluation of patients in whom cardiac arrhythmias or conduction abnormalities are suspected. Proper selection of the device type and monitoring duration is critical for optimizing diagnostic yield and cost-effective resource utilization. However, despite guidance from major professional societies, the lack of systematic guidance for proper test selection in many institutions results in the need for repeat testing, which leads to not only increased resource utilization and cost of care, but also suboptimal patient care. To address this unmet need at our own institution, we formed a multidisciplinary panel to develop a concise, yet comprehensive algorithm, incorporating the most common indications for ambulatory electrocardiography, to efficiently guide clinicians to the most appropriate test option for a given clinical scenario, with the goal of maximizing diagnostic yield and optimizing resource utilization. The algorithm was designed as a single-page, color-coded flowchart to be utilized both as a rapid reference guide in printed form, and a decision support tool embedded within the electronic medical records system at the point of order entry. We believe that systematic adoption of this algorithm will optimize diagnostic efficiency, resource utilization, and importantly, patient care and satisfaction.

Variation in contrast-associated acute kidney injury prophylaxis for percutaneous coronary intervention: insights from the Veterans Affairs Clinical Assessment, Reporting, and Tracking (CART) program.

BACKGROUND: Contrast-Associated Acute Kidney Injury (CA-AKI) is a serious complication associated with percutaneous coronary intervention (PCI). Patients with chronic kidney disease (CKD) have an elevated risk for developing this complication. Although CA-AKI prophylactic measures are available, the supporting literature is variable and inconsistent for periprocedural hydration and N-acetylcysteine (NAC), but is stronger for contrast minimization. METHODS: We assessed the prevalence and variability of CA-AKI prophylaxis among CKD patients undergoing PCI between October 2007 and September 2015 in any cardiac catheterization laboratory in the VA Healthcare System. Prophylaxis included periprocedural hydration with normal saline or sodium bicarbonate, NAC, and contrast minimization (contrast volume to glomerular filtration rate ratio ≤ 3). Multivariable hierarchical logistic regression models quantified site-specific prophylaxis variability. As secondary analyses, we also assessed CA-AKI prophylaxis measures in all PCI patients regardless of kidney function, periprocedural hydration in patients with comorbid CHF, and temporal trends in CA-AKI prophylaxis. RESULTS: From 2007 to 2015, 15,729 patients with CKD underwent PCI. 6928 (44.0%) received periprocedural hydration (practice-level median rate 45.3%, interquartile range (IQR) 35.5-56.7), 5107 (32.5%) received NAC (practice-level median rate 28.3%, IQR 22.8-36.9), and 4656 (36.0%) received contrast minimization (practice-level median rate 34.5, IQR 22.6-53.9). After adjustment for patient characteristics, there was significant site variability with a median odds ratio (MOR) of 1.80 (CI 1.56-2.08) for periprocedural hydration, 1.95 (CI 1.66-2.29) for periprocedural hydration or NAC, and 2.68 (CI 2.23-3.15) for contrast minimization. These trends were similar among all patients (with and without CKD) undergoing PCI. Among patients with comorbid CHF (n = 5893), 2629 (44.6%) received periprocedural hydration, and overall had less variability in hydration (MOR of 1.56 (CI 1.38-1.76)) compared to patients without comorbid CHF (1.89 (CI 1.65-2.18)). Temporal trend analysis showed a significant and clinically relevant decrease in NAC use (64.1% of cases in 2008 (N = 1059), 6.2% of cases in 2015 (N = 128, p = < 0.0001)) and no significant change in contrast-minimization (p = 0.3907). CONCLUSIONS: Among patients with CKD undergoing PCI, there was low utilization and significant site-level variability for periprocedural hydration and NAC independent of patient-specific risk. This low utilization and high variability, however, was also present for contrast minimization, a well-established measure. These findings suggest that a standardized approach to CA-AKI prophylaxis, along with continued development of the evidence base, is needed.

The Master Clinician's Elective: Integrating Evidence-Based Physical Examination and Point of Care Ultrasonography in Modern Clinical Medicine.

Background: Many internal medicine residency programs have incorporated ultrasonography into their curriculum; however, its integration with physical examination skills teaching at a graduate medical level is scarce. The program's aim is to create a reproducible elective that combines physical exam and bedside ultrasound as a method for augmenting residents' knowledge and competence in these techniques with the ultimate goal of improving patient care. Methods: We designed and implemented a two-week elective rotation for senior internal medicine residents, combining evidence-based physical examination with diagnostic bedside ultrasonography. The rotation took place in an inpatient setting at Denver Health Hospital. Program evaluation data was collected data between February 2016 to March 2019. IRB approval was waived. Results: Since its inception in 2016, 19 residents completed the rotation. Residents performed a pre-test and a post-test under direct observation by course faculty. Each resident was measured on the ability to perform pre-determined physical exam and point-of-care ultrasound (POCUS) skills. In the pre-test, participants correctly performed an average of 40% of expected physical exam maneuvers and 32% of expected POCUS skills. At elective conclusion, all participants were effectively able to demonstrate the highest yield physical exam and ultrasound maneuvers. Discussion and Conclusion: An elective designed specifically to integrate POCUS and physical exam modalities improves the ability of resident physicians to utilize both diagnostic modalities.

Predictors of oral anticoagulant non-prescription in patients with atrial fibrillation and elevated stroke risk.

BACKGROUND: Many patients with atrial fibrillation (AF) and elevated stroke risk are not prescribed oral anticoagulation (OAC) despite evidence of benefit. Identification of factors associated with OAC non-prescription could lead to improvements in care. METHODS AND RESULTS: Using NCDR PINNACLE, a United States-based ambulatory cardiology registry, we examined factors associated with OAC non-prescription in patients with non-valvular AF at elevated stroke risk (CHA2DS2-VASc ≥2) between January 5, 2008 and December 31, 2014. Among 674,841 patients, 57% were treated with OAC (67% of whom were treated with warfarin). OAC prescription varied widely (28%-75%) across preselected strata of age, stroke risk (CHA2DS2-VASc), and bleeding risk (HAS-BLED), generally indicating that older patients at high stroke and low bleeding risk are commonly treated with OAC. Other factors associated with OAC non-prescription included reversible AF etiology; female sex; liver, renal, or vascular disease; and physician versus non-physician provider. Antiplatelet use was common (57%) and associated with the greatest risk of OAC non-prescription (odds ratio [OR] 4.44, 95% confidence interval [CI] 4.39-4.49). CONCLUSIONS: In this registry of AF patients, older patients at elevated stroke and low bleeding risk were commonly treated with OAC. However, a variety of factors were associated with OAC non-prescription. Specifically, antiplatelet use was prevalent and associated with the highest likelihood of OAC non-prescription. Future studies are warranted to understand provider and patient rationale that may underlie observed associations with OAC non-prescription.

Genetic analyses of the functions of [NiFe]-hydrogenase maturation endopeptidases in the hyperthermophilic archaeon Thermococcus kodakarensis.

The maturation of [NiFe]-hydrogenases requires a number of accessory proteins, which include hydrogenase-specific endopeptidases. The endopeptidases carry out the final cleavage reaction of the C-terminal regions of [NiFe]-hydrogenase large subunit precursors. The hyperthermophilic archaeon Thermococcus kodakarensis harbors two [NiFe]-hydrogenases, a cytoplasmic Hyh and a membrane-bound Mbh, along with two putative hydrogenase-specific endopeptidase genes. In this study, we carried out a genetic examination on the two endopeptidase genes, TK2004 and TK2066. Disruption of TK2004 resulted in a strain that could not grow under conditions requiring hydrogen evolution. The Mbh large subunit precursor (pre-MbhL) in this strain was not processed at all whereas Hyh cleavage was not affected. On the other hand, disruption of TK2066 did not affect the growth of T. kodakarensis under the conditions examined. Cleavage of the Hyh large subunit precursor (pre-HyhL) was impaired, but could be observed to some extent. In a strain lacking both TK2004 and TK2066, cleavage of pre-HyhL could not be observed. Our results indicate that pre-MbhL cleavage is carried out solely by the endopeptidase encoded by TK2004. Pre-HyhL cleavage is mainly carried out by TK2066, but TK2004 can also play a minor role in this cleavage.

Dual Antiplatelet Therapy in Patients with Stable Ischemic Heart Disease.

Dual antiplatelet therapy (DAPT) is the use of a P2Y12 receptor antagonist (clopidogrel, prasugrel, or ticagrelor) in combination with aspirin. Recommendations for its use are primarily in patients who have experienced acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI) in the preceding 12 months. There is a growing body of evidence, however, investigating the use of long-duration DAPT in patients with stable ischemic heart disease (SIHD). SIHD is defined as clinical evidence of ischemic heart disease, without an ACS event in the preceding 12 months, and includes patients with stable angina, elective PCI, and remote history of ACS. The use of DAPT in the SIHD population and the recent advancements in our understanding of its use are the focus of this review.

Early detection of occult atrial fibrillation and stroke prevention.

Atrial fibrillation (AF) is a very common arrhythmia and significantly increases stroke risk. This risk can be mitigated with oral anticoagulation, but AF is often asymptomatic, or occult, preventing timely detection and treatment. Accordingly, occult AF may cause stroke before it is clinically diagnosed. Currently, guidelines for the early detection and treatment of occult AF are limited. This review addresses recent advancements in occult AF detection methods, identification of populations at high risk for occult AF, the treatment of occult AF with oral anticoagulation, as well as ongoing trials that may answer critically important questions regarding occult AF screening.

N-terminal fatty acylated His-dPhe-Arg-Trp-NH(2) tetrapeptides: influence of fatty acid chain length on potency and selectivity at the mouse melanocortin receptors and human melanocytes.

The melanocortin system is involved in the regulation of a diverse number of physiologically important pathways including pigmentation, feeding behavior, weight and energy homeostasis, inflammation, and sexual function. All the endogenous melanocortin agonist ligands possess the conserved His-Phe-Arg-Trp tetrapeptide sequence that is postulated to be important for melanocortin receptor molecular recognition and stimulation. Previous studies by our laboratory resulted in the discovery that increasing alkyl chain length at the N-terminal "capping" region of the His-dPhe-Arg-Trp-NH(2) tetrapeptide resulted in a 100-fold increased melanocortin receptor agonist potency. This study was undertaken to systematically evaluate the pharmacological effects of increasing N-capping alkyl chain length of the CH(3)(CH(2))(n)CO-His-dPhe-Arg-Trp-NH(2) (n = 6-16) tetrapeptide template. Twelve analogues were synthesized and pharmacologically characterized at the mouse melanocortin receptors MC1R and MC3R-MC5R and human melanocytes known to express the MC1R. These peptides demonstrated melanocortin receptor selectivity profiles different from those of previously published tetrapeptides. The most notable results of enhanced ligand potency (20- to 200-fold) and receptor selectivity were observed at the MC1R. Tetrapeptides that possessed greater than nine alkyl groups were superior to alpha-MSH in terms of the stimulation of human melanocyte tyrosinase activity. Additionally, the n-pentadecanoyl derivative had a residual effect on tyrosinase activity that existed for at least 4 days after the peptide was removed from the human melanocyte culture medium. These data demonstrate the utility, potency, and residual effect of melanocortin tetrapeptides by adding N-terminal fatty acid moieties.