Characteristics of drugs safety signals that predict safety related product information update

Purpose

Investigation of drug safety signals is one of the major tasks in pharmacovigilance. Among many potential signals identified, only a few reflect adverse drug reactions requiring regulatory actions, such as product information (PI) update. Limited information is available regarding the signal characteristics that might predict PI update following signal evaluation. The objective of this study was to identify signal characteristics associated with PI updates following signal evaluation by the European Medicines Agency Pharmacovigilance Risk Assessment Committee during 2012 to 2016.

Methods

A comparative study was performed based on data from 172 safety signals. Characteristics of signals were extracted from the European Pharmacovigilance Issues Tracking Tool database. Multivariable logistic regression analysis was used to assess the relationship between signal characteristics and the decision to update the PI.

Results

Multivariable logistic regression analysis showed that the presence of evidence in multiple types of data sources (adjusted odds ratio [OR] 7.8 95% CI [1.5, 40.1]); mechanistic plausibility of the drug‐event association (adjusted OR 3.9 95% CI [1.9, 8.0]); seriousness of the event (adjusted OR 4.2 95% CI [1.3, 13.9]); and age of drugs ≤5 years (adjusted OR 3.9 95% CI [1.2, 12.7]) were associated with the decision to change the PI (P < 0.05).

Conclusions

This study identified 4 characteristics of drug safety signals that have shown to be associated with PI changes as outcome of signal evaluation. These characteristics may be used as criteria for selection and prioritization of potential signals that are more likely to necessitate product information updates.     

Clinicopathological Features and Prognosis of Indonesian Patients with Gliomas with IDH Mutation: Insights into Its Significance in a Southeast Asian Population

Background: Gliomas remain one of the most common primary brain tumors. Mutations in the isocitrate dehydrogenase (IDH) gene are associated with a distinct set of clinicopathological profiles. However, the distribution and significance of these mutations have never been studied in the Indonesian population. This study aimed to elucidate the association between IDH mutations and clinicopathological as well as prognostic profiles of Indonesian patients with gliomas. Methods: In total, 106 patients with gliomas were recruited from a tertiary academic medical center in Yogyakarta, Indonesia. Formalin-fixed paraffin-embedded and fresh tissue specimens were obtained and sectioned for hematoxylin-eosin staining and immunohistochemical examinations. Genomic DNA was isolated and analyzed for the presence of IDH mutations using standard polymerase chain reaction and nucleotide sequencing methods. Clinicopathological data were collected from medical records. Results: Although no IDH2 mutation was identified, IDH1 mutations were found in 23 (21.7%) of the patients. Patients with IDH1 mutations tended to have a history of smoking and a shorter interval between onset of symptoms and initial surgical interventions. Frontal lobe involvement, oligodendroglial histology, lower Ki67 expression, WHO grades II and III gliomas, and methylated O6-methylguanine-DNA methyltransferase (MGMT) promoters were significantly associated with the presence of IDH1 mutations. Compared with patients with IDH1-wild-type, patients with IDH1 mutation were observed to have a longer overall survival. Conclusions: IDH1 mutations are associated with certain clinicopathological and prognostic profiles in Indonesian patients with gliomas. This finding demonstrates the importance of identifying IDH mutations as part of the management of patients with glioma in Indonesia.     

Randomized control trial outcomes of tranexamic acid combination serum as a depigmenting agent for the use in healthy individuals

To compare the effectiveness of tranexamic acid (TA) combination serum with hydroquinone, the gold standard in whitening agents for healthy populations. This was a three‐arm randomized controlled trial. The subjects were divided into three groups: the first group received 3% TA combination serum (3% TA, 4% galactomyces ferment filtrate, 2% niacinamide, and 4% alpha arbutin), the second group received 2% TA combination serum, and the third group received 4% hydroquinone. One milliliter of each serum was applied on three holes: Hole A, which was located 4 cm from the left cubital fossa, Hole B, which was located 4 cm from the first hole, and Hole C, which was located 4 cm from the right cubital fossa. The skin brightness and pigmentation intensity were evaluated each week for 4 weeks using a chromameter. A total of 44 subjects were recruited for this study. All groups showed a significant improvement in skin brightness and pigmentation intensity after 4 weeks (p < .001). There were no differences between the treatment groups and hydroquinone (p > .05). TA serum (2 and 3%) combined with 4% galactomyces ferment filtrate, niacinamide, and alpha arbutin is an effective depigmenting agent.     

Ganglion cells apoptosis in diabetic rats as early prediction of glaucoma: a study of Brn3b gene expression and association with change of quantity of NO, caspase-3, NF-κB, and TNF-α

AIM: To find a new concept to show whether or not apoptosis of retinal ganglion cells (RGCs) can be determined in the histology of acute hyperglycemia in the role of expressed Brn3b gene related to nitric oxide (NO), caspase-3, nuclear factor kappa-B (NF-κB), and tumor necrosis factor-α (TNF-α) as an early predictor of primary open angle glaucoma (POAG) eyes and their associations. METHODS: Experimental in vivo study was carried out using adult male, white Sprague-Dawley rats aged ≥2mo, weighing 150-200 g. The animals were divided into two groups, one group receiving intraperitoneal injection of streptozotociz 50 mg/kg in 0.01 mol/L citric buffer and pH 4.5 and a comparison made with the control group. Retinal tissue was divided into two parts (both experimental and control groups respectively): a) right retina for immunohistochemistry (IHC; caspase-3 and TNF-α); b) left retina was divided into two parts for the purpose of real-time polymerase chain reaction (PCR) test (RNA extraction for Brn3b gene expression analysis) and ELISA test (NO and NF-κB). RESULTS: The experimental group showed a decrease in Brn3b gene expression compared to the control group (1.3-fold lower in 2nd month; 1.1-fold lower in 4th month and 2.5-fold lower in 6th month). However, there was a decrease of NO, caspase-3, and an increase of NF-κB and TNF-α quantity. CONCLUSION: The expression of mRNA Brn3b gene is inversely proportional to apoptosis in RGCs. The quantity of NO, caspase-3, NF-κB and TNF-α is influential in expression of Brn3b in RGCs caused by hyperglycemia in diabetic rats.     

Novel role for CRK adaptor proteins as essential components of SRC/FAK signaling for epithelial–mesenchymal transition and colorectal cancer aggressiveness

Epithelial–mesenchymal transition (EMT) is a cell plasticity process required for metastasis and chemoresistance of carcinoma cells. We report a crucial role of the signal adaptor proteins CRK and CRKL in promoting EMT and tumor aggressiveness, as well as resistance against chemotherapy in colorectal and pancreatic carcinoma. Genetic loss of either CRKL or CRK partially counteracted EMT in three independent cancer cell lines. Strikingly, complete loss of the CRK family shifted cells strongly toward the epithelial phenotype. Cells exhibited greatly increased E-cadherin and grew as large, densely packed clusters, completely lacked invasiveness and the ability to undergo EMT induced by cytokines or genetic activation of SRC. Furthermore, CRK family-deficiency significantly reduced cell survival, proliferation and chemoresistance, as well as ERK1/2 phosphorylation and c-MYC protein levels. In accordance, MYC-target gene expression was identified as novel hallmark process positively regulated by CRK family proteins. Mechanistically, CRK proteins were identified as pivotal amplifiers of SRC/FAK signaling at focal adhesions, mediated through a novel positive feedback loop depending on RAP1. Expression of the CRK family and the EMT regulator ZEB1 was significantly correlated in samples from colorectal cancer patients, especially in invasive regions. Further, high expression of CRK family genes was significantly associated with reduced survival in locally advanced colorectal cancer, as well as in pan-cancer datasets from the TCGA project. Thus, CRK family adaptor proteins are promising therapeutic targets to counteract EMT, chemoresistance, metastasis formation and minimal residual disease. As proof of concept, CRK family-mediated oncogenic signaling was successfully inhibited by a peptide-based inhibitor.     

Correlation between academic motivation and professional identity in medical students in the Faculty of Medicine of the Universitas Gadjah Mada Indonesia

Background

Professionalism is a skills area that should be mastered by medical graduates. The period of formal education is essential for the formation of professionalism. The involvement of internal factors, such as academic motivation, and external factors, such as the learning environment, might play a role in the development and learning of professional identity.

Regulatory elements of stx2 gene and the expression level of Shiga-like toxin 2 in Escherichia coli O157:H7

Background/Purpose

Shiga-like toxin (Stx) is an important factor in the pathogenesis of Escherichia coli O157:H7 infection and is responsible for some severe complications. Stx2 is usually associated with hemolytic uremic syndrome in humans. Its expression is regulated by elements located upstream of the stx2 gene, including stx2-promoter sequence, ribosome binding site, and the antiterminator q gene. The present study aimed to find the correlation between regulatory elements and the expression level of Stx2 in two local isolates of E. coli O157:H7.

Estimated pulse wave velocity (ePWV) as a potential gatekeeper for MRI-assessed PWV: a linear and deep neural network based approach in 2254 participants of the Netherlands Epidemiology of Obesity study

The International Journal of Cardiovascular Imaging - Pulse wave velocity (PWV) assessed by magnetic resonance imaging (MRI) is a prognostic marker for cardiovascular events. Prediction modelling...     

Right Ventricular Involvement in Diabetic Cardiomyopathy

OBJECTIVE

To compare magnetic resonance imaging-derived right ventricular (RV) dimensions and function between men with type 2 diabetes and healthy subjects, and to relate these parameters to left ventricular (LV) dimensions and function.

RESEARCH DESIGN AND METHODS

RV and LV volumes and functions were assessed in 78 men with uncomplicated type 2 diabetes and 28 healthy men within the same range of age using magnetic resonance imaging. Steady-state free precession sequences were used to assess ventricular dimensions. Flow velocity mapping across the pulmonary valve and tricuspid valve was used to assess RV outflow and diastolic filling patterns, respectively. Univariate general linear models were used for statistical analyses.

RESULTS

RV end-diastolic volume was significantly decreased in patients compared with healthy subjects after adjustment for BMI and pulse pressure (177 ± 28 mL vs. 197 ± 47 mL, P < 0.01). RV systolic function was impaired: peak ejection rate across the pulmonary valve was decreased (433 ± 54 mL/s vs. 463 ± 71 mL/s, P < 0.01) and pulmonary flow acceleration time was longer (124 ± 17 ms vs. 115 ± 25 ms, P < 0.05). Indexes of RV diastolic function were impaired: peak filling rate and peak deceleration gradient of the early filling phase were 315 ± 63 mL/s vs. 356 ± 90 mL/s (P < 0.01) and 2.3 ± 0.8 mL/s² × 10⁻³ vs. 2.8 ± 0.8 mL/s² × 10⁻³ (P < 0.01), respectively. All RV parameters were strongly associated with its corresponding LV parameter (P < 0.001).

CONCLUSIONS

Diabetic cardiomyopathy affects the right ventricle, as demonstrated by RV remodeling and impaired systolic and diastolic functions in men with type 2 diabetes, in a similar manner as changes in LV dimensions and functions. These observations suggest that RV impairment might be a component of the diabetic cardiomyopathy phenotype.Cardiovascular disease is one of the major adverse consequences of type 2 diabetes. Patients with type 2 diabetes have an increased cardiovascular mortality rate (1). Even in the absence of significant coronary artery disease and hypertension, subclinical left ventricular (LV) dysfunction presents in type 2 diabetes (2). This so-called diabetic cardiomyopathy has a complex and multifactorial pathogenesis. Atherosclerosis, subclinical microinfarctions, mitochondrial dysfunction, and lipotoxicity all have been proposed as contributors to diabetic cardiomyopathy. Furthermore, it has been recognized that deposition of advanced glycation end products, caused by long-standing hyperglycemia, affects ventricular stiffness (3). The formation of advanced glycation end products yields fibrosis by cross-linking collagen (4), thus increasing myocardial stiffness. This may lead to a decreased LV end-diastolic volume and impaired subclinical LV function (5–7).All proposed mechanisms leading to LV impairment in type 2 diabetes are systemic changes and therefore also might hamper right ventricular (RV) function. RV involvement in diabetic cardiomyopathy might be of importance because the right ventricle has a substantial contribution to overall myocardial contractility. RV function has proven to be of importance for patient risk stratification in heart failure (8) and for prediction of development of atrial fibrillation (9). In general, RV dysfunction and fibrosis are associated with lethal ventricular arrhythmias, sudden death, exercise limitation, and impaired RV cardiac output (10). In addition, the prevalence of cardiac conduction abnormalities is increased in diabetic patients (11).However, only limited data exist on RV involvement in type 2 diabetes. Whereas animal studies have shown that dysfunction of the right ventricle might play a role in diabetic cardiomyopathy (12), the right ventricle is largely overlooked in human studies. Only a few echocardiographic studies discuss the right ventricle in diabetes (13–17). These studies were limited by inclusion of patients with cardiovascular diabetes-related complications (13–15,17), and study populations consisted partially (13,14) or entirely of type 1 diabetic patients (16). Moreover, none of these studies reported RV volumes.The right ventricle is a difficult structure from which to obtain reproducible echocardiographic signals because of the irregular geometrical shape and the anterior position within the thorax. Without mathematical modeling, conventional two-dimensional echo techniques commonly underestimate or overestimate the true size of the adult right ventricle (18). Cardiovascular magnetic resonance imaging (MRI) has become the reference standard for the assessment of RV function and volumes because good reproducibility has been shown (19,20).To our knowledge, no studies to date have evaluated volumetric as well as systolic and diastolic functional involvement of the right ventricle in uncomplicated type 2 diabetes compared with healthy subjects assessed by MRI. Accordingly, the purpose of the current study was to compare MRI-derived RV dimensions and systolic and diastolic function between well-controlled uncomplicated type 2 diabetic patients and healthy subjects, in relation to LV dimensions and function.