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Ensuring the safety of drugs is a critical aspect of healthcare. Accurate interpretation of drug safety evidence is vital to understand the safety profile and to evaluate the benefits and risks of the medicinal product. However, validity of this evidence has numerous challenges that must be carefully considered, highlighting the need for a heightened appreciation of data interpretation pitfalls. This paper aims to delve into the intricacies of analytic considerations in drug safety data interpretation aiming at providing insights into the safety profile of pharmaceutical interventions. The applicability of these analytic considerations extends to controlled and observational data as well as spontaneously reported individual case reports. Increasing the understanding of scientific underpinnings of evidence interpretation empowers Pharmacovigilance professionals to grasp fundamental concepts, use appropriate terminology, engage in meaningful discussions with colleagues conducting analyses, and critically evaluate evidence. These skills and knowledge enable them to make informed decisions and enhance their expertise in drug safety. By correct utilization of analytic approaches while appreciating their strengths and limitations, one can advance drug safety and benefit-risk research using evidence-based decisionmaking and ultimately ensure better healthcare outcomes for patients. [ABSTRACT FROM AUTHOR]

In this work, the magnetothermal characteristics and magnetocaloric effect in YFe3 and HoFe3 compounds are calculated as function of temperature and magnetic field. These properties were investigated using the two-sublattice mean field model and the first-principles DFT calculation using the WIEN2k code. The two-sublattice model of the mean-field theory was used to calculate the temperature and field-dependences of magnetization, magnetic heat capacity, magnetic entropy, and the isothermal change in entropy ∆Sm. We used the WIEN2k code to determine the elastic constants and, subsequently, the bulk and shear moduli, the Debye temperature, and the density-of-states at Ef. According to the Hill prediction, YFe3 has bulk and shear moduli of roughly 99.3 and 101.2 GPa respectively. The Debye temperature is ≈ 500 K, and the average sound speed is ≈ 4167 m/s. In fields up to 60 kOe and at temperatures up to and above the Curie point for both substances, the trapezoidal method was used to determine ∆Sm. For instance, the highest ∆Sm values for YFe3 and HoFe3 in 30 kOe are approximately 0.8 and 0.12 J/mol. K, respectively. For the Y and Ho systems, respectively, the adiabatic temperature change in a 3 T field decreases at a rate of around 1.3 and 0.4 K/T. The ferro (or ferrimagnetic) to paramagnetic phase change in these two compounds, as indicated by the temperature and field dependences of the magnetothermal and magnetocaloric properties, ∆Sm and ∆Tad, is a second-order phase transition. The Arrott plots and the universal curve for YFe3 were also calculated and their features give an additional support to the second order nature of the phase transition. [ABSTRACT FROM AUTHOR]

An exercise ankle–brachial index (ABI) test can provide further insight into the functional significance of peripheral artery disease (PAD). The variability in its use, associated patient factors and its relation to patients' symptoms are unknown. From the international PORTRAIT registry, we identified 1131 patients with PAD. We fit a hierarchical logistic regression model, adjusting for patient factors, country and site, to examine predictors of and variation in ordering exercise ABI testing. We also examined the associations between test components and health status as quantified by the Peripheral Artery Questionnaire (PAQ) using semi-parametric regression methods. Testing was ordered in 22% in the United States versus 80% in the Netherlands and 90% in Australia. Testing was likely to be performed if the patient was male, younger, had typical symptoms and a higher resting ABI, with substantial variability across sites (median odds ratio=5.9, 95% CI: 3.2–19.5). Adjusting for country and site, the resting ABI and all exercise ABI metrics were associated with the PAQ Physical Limitation score. In addition, important components of the test, namely time to onset of claudication, pain-free walking distance (PFWD), and maximum walking distance (MWD), were also associated with PAQ Symptoms and Summary scores. More importantly, even after adjusting for resting ABI, a patient with a post-exercise ABI of 0.29 (25th percentile), compared to 0.61 (75th percentile), achieved 4.4 (95% CI: 0.4–8.4, p=0.031) points less on the PAQ Physical Limitation score. Exercise ABI test use is remarkably variable, and less used in the United States. Its data, specifically PFWD and MWD, might help in objectively assessing the impact of PAD on patients' functioning and quality of life. [ABSTRACT FROM AUTHOR]

Prior studies have assessed the prognostic value of a decrease, not an increase, of the post-exercise ankle-brachial index (ABI) among patients with normal resting results. Thus, we sought to evaluate the prognostic significance of an increase in post-exercise ABI among these patients. From a single center vascular laboratory database between September 2005 and January 2010, we retrospectively identified 1437 consecutive patients with a normal resting ABI (1.00-1.40) and available post-exercise results. We classified them into group 1 (normal subjects; post-exercise ABI drop > 20%, 58%) and group 2 (post-exercise ABI increase, 42%) after excluding those with an ABI drop > 20% (peripheral artery disease) as they had known disease (n=192). The primary outcome was to assess the risk of ischemic events, defined as a composite of unadjudicated death, stroke, or myocardial infraction (MACE). Associations between groups and outcomes were examined using multivariable Cox proportional hazard and propensity analyses. Both groups had similar prevalence of cardiovascular comorbidities. In unadjusted analysis, group 2 was more likely to have MACE (p = 0.001). After adjusting for all baseline characteristics, an increase in post-exercise ABI compared to normal subjects was associated with a higher MACE (adjusted HR: 1.70, 95% CI: 1.14-2.53; p=0.009). This association stayed statistically significant after propensity matching (adjusted HR: 1.80, 95% CI: 1.17-2.76; p=0.007). This hypothesis-generating analysis showed that an increase in post-exercise ABI appears to identify a population with a higher risk for MACE. A prospective study of this association and mechanisms of risk should be conducted. [ABSTRACT FROM AUTHOR]

Peripheral artery disease (PAD) is associated with increased mortality and concomitant coronary artery disease (CAD). However, it is unclear whether uncovering the presence of functional coronary ischemia by single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) would further help stratifying that excess risk. From January 2000 to 2009, 4294 individuals underwent cardiac stress testing within 180 days of ankle–brachial index (ABI) measurements. Of these, 645 had PAD and SPECT MPI stress testing. Abnormal ABI was defined as ⩽0.9 or prior lower extremity arterial revascularization. Myocardial ischemic burden and total jeopardized myocardium were represented by the summed difference score (SDS) and summed stress score (SSS), respectively. Univariate and multivariable Cox proportional hazard analyses were used to study the impact of SDS and SSS on all-cause mortality. Additionally, using a hierarchical approach, we examined the step-wise addition of post-stress test coronary and lower extremity arterial revascularizations as time-varying covariates on outcomes. We found no significant difference in all-cause mortality between patients with ischemic myocardium (SDS>0) and those without (SDS=0) (adjusted HR: 0.94, 95% CI: 0.53–1.69; p=0.84). Similarly, the presence of jeopardized myocardium (SSS>0) did not have a significant impact on mortality (adjusted HR: 1.16, 95% CI: 0.67–2.00; p=0.59). Moreover, adjustment for post-testing coronary and lower extremity arterial revascularizations did not affect our results. In conclusion, ischemic and jeopardized myocardia are not predictors of all-cause mortality in PAD; thus, SPECT MPI does not appear to be a useful risk stratification tool in these patients. [ABSTRACT FROM AUTHOR]

Background: Inflammation and immune dysregulation have been associated with adverse outcomes in cardiovascular disease. There is limited understanding of the association of different profiles of white blood cell (WBC) subsets and red cell distribution width (RDW) in patients with chronic limb-threatening ischemia (CLTI). Methods: Patients with CLTI undergoing endovascular revascularization in our single-center, tertiary care hospital from 2017 to 2019, who had a preceding complete blood count (CBC) with WBC differentials (n =213), were included in the analysis. Patient characteristics, laboratory values, and clinical outcomes were collected. Cox proportional hazards regression models were used to assess for associations between all-cause mortality and leukocyte subset; multivariate analysis was used to account for confounders. Kaplan–Meier curves were generated to depict survival censored at 1 year postrevascularization using baseline CBC indices. Results: Adjusting for confounders, elevated RDW was associated with increased mortality (continuous per % increase, adjusted hazard ratio [HR] 1.33, p < 0.001). Baseline lymphopenia was associated with mortality in univariate analysis. Other leukocyte subtypes were not associated with mortality outcomes in our population. Exploratory analysis showed negative deflections in ∆WBC from pre- to postprocedure day 1 were affiliated with increased mortality when adjusted for age, sex, race, chronic kidney disease, and baseline hemoglobin (∆WBC HR 1.16, p = 0.004). Further exploratory analysis showed an association between RDW and all-comers readmission. Conclusions: The utilization of a periprocedural WBC subset differential can be a useful adjunct to risk-stratify patients with CLTI undergoing endovascular revascularization. Further studies are needed to understand potential ways to modulate immune dysregulation so as to improve mortality outcomes. [ABSTRACT FROM AUTHOR]

Objectives: Evaluation of the safety and efficacy of the Penumbra device as an adjunct to percutaneous coronary intervention (PCI) in patients with myocardial infarction (MI) and a large thrombus burden that requires thrombectomy.Background: For patients with acute MI, PCI is the primary reperfusion method. Large thrombus burden has always been a limitation of successful reperfusion. However, the use of current aspiration devices has been associated with an increased incidence of stroke.Methods: We performed a retrospective chart review at the University Hospitals Medical Center in Cleveland. Our study included data from patients who underwent PCI for ST segment elevation myocardial infarction (STEMI) and non-ST segment elevation myocardial infarction (NSTEMI) assisted by the Penumbra Cat RX device (a wide-lumen thrombus aspiration catheter) between May 2019 and February 2021. The primary outcome was the final thrombolysis in myocardial infarction (TIMI) flow. The secondary endpoints were a composite of adverse cardiac events at 6 months. About 50% of the patients did undergo transfemoral PCI as per preference of individual operators. The Penumbra thrombectomy device can be used both by radial and femoral approach and does not need any different guide catheter use.Results: TIMI flow 3 was achieved in 111 patients (90.2%). The secondary endpoint occurred in 11 patients (8.9%, 3 MI, 8 heart failure hospitalizations). There were no stroke events or device-related complications. The door-to-balloon time was not affected by usage of the Penumbra device. Failure in the restoration of TIMI 3 flow was associated with the use of balloon angioplasty prior to the application of the Penumbra device, leading to distal embolization.Conclusions: The Penumbra Cat RX provides safe and effective thrombus removal with better clinical outcomes, even in high-risk patients with acute coronary syndrome. [ABSTRACT FROM AUTHOR]

Heart disease continues to affect health outcomes globally, accounting for a quarter of all deaths in the United States. Despite the improvement in the development and implementation of guideline-directed medical therapy, the risk of adverse cardiac events remains substantially high. Historically, it has been debated whether omega-3 polyunsaturated fatty acids provide clinical benefit in cardiac disease. The recently published REDUCE-IT trial demonstrated a statistically significant absolute risk reduction of 4.8% in its primary endpoint (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina) with the use of icosapent ethyl, which is a highly purified eicosapentaenoic acid (EPA) ethyl ester. However, the mechanism of action of omega-3 fatty acids is not commonly discussed. Moreover, the use of EPA was not without risk, as the incidence of atrial fibrillation was increased along with a trend towards increased bleeding risk. Thus, our aim is to help explain the function of purified EPA ethyl ester, especially at the molecular level, which will ultimately lead to a better understanding of their clinically observable effects. [ABSTRACT FROM AUTHOR]

The efficacy of biologic therapies in critical limb ischemia (CLI) remains elusive, in part, due to limitations in trial design and patient selection. Using a novel design, we examined the impact of complementing revascularization therapy with intramuscular JVS-100 – a non-viral gene therapy that activates endogenous regenerative repair pathways. In this double-blind, placebo-controlled, Phase 2B trial, we randomized 109 patients with CLI (Rutherford class V or VI) to 8 mg or 16 mg intramuscular injections of placebo versus JVS-100. Patients were eligible if they persistently had reduced forefoot perfusion, by toe–brachial index (TBI) or skin perfusion pressure (SPP), following successful revascularization with angiographic demonstration of tibial arterial flow to the ankle. The primary efficacy end point was a 3-month wound healing score assessed by an independent wound core laboratory. The primary safety end point was major adverse limb events (MALE). Patients' mean age was 71 years, 33% were women, 79% had diabetes, and 8% had end-stage renal disease. TBI after revascularization was 0.26, 0.27, and 0.26 among the three groups (placebo, 8 mg, and 16 mg injections, respectively). Only 26% of wounds completely healed at 3 months, without any differences between the three groups (26.5%, 26.5%, and 25%, respectively). Similarly, there were no significant changes in TBI at 3 months. Three (2.8%) patients died and two (1.8%) had major amputations. Rates of MALE at 3 months were 8.8%, 20%, and 8.3%, respectively. While safe, JVS-100 failed to improve wound healing or hemodynamic measures at 3 months. Only one-quarter of CLI wounds healed at 3 months despite successful revascularization, highlighting the need for additional research in therapies that can improve microcirculation in these patients. ClinicalTrials.gov Identifier: NCT02544204 [ABSTRACT FROM AUTHOR]

Abstract: Background: Overproduction of pro-inflammatory cytokines may play a role in increased morbidity and mortality from neonatal sepsis. Objective of this study was to compare secretion of pro-inflammatory cytokines by the cord blood cells of healthy term neonates to the venous blood cells of healthy adults in vitro after stimulation with common neonatal pathogens. Method: Blood samples were cultured in the presence of heat-killed group B β-hemolytic streptococci (GBS), Escherichia coli (E. coli) and Staphylococcus epidermidis (S. epi). Concentrations of secreted cytokines (interleukine-6, IL-6, tumor necrosis factor-α, TNF-α, interleukine-1 β, IL-1β and interleukine-8, IL-8) were measured after 0, 1, 2 and 4 h of incubation using chemiluminescent immunometric automated assay. Results: Blood samples from 22 neonates and 16 adults were compared. After stimulation by GBS and E. coli, cord blood cells secreted significantly higher levels of IL-6 and IL-8 than blood cells of healthy adults. In cord blood, E. coli induced secretion of higher concentration of IL-6, TNF-α, IL-1β and IL-8 than S. epi, and more IL-6 than GBS; GBS induced more IL-1β than S.epi. Conclusions: Response of cord blood to microbial activators is different from that of adult controls. Each isolate of heat-killed bacteria induced different amount of pro-inflammatory cytokines in vitro. This may represent a useful in vitro virulence test. [Copyright &y& Elsevier]