Development and Validation of a Risk Model for Predicting Adverse Drug Reactions in Older People during Hospital Stay: Brighton Adverse Drug Reactions Risk (BADRI) Model

Background

Older patients are at an increased risk of developing adverse drug reactions (ADR). Of particular concern are the oldest old, which constitute an increasingly growing population. Having a validated clinical tool to identify those older patients at risk of developing an ADR during hospital stay would enable healthcare staff to put measures in place to reduce the risk of such an event developing. The current study aimed to (1) develop and (2) validate an ADR risk prediction model.

Methods

We used a combination of univariate analysis and multivariate binary logistic regression to identify clinical risk factors for developing an ADR in a population of older people from a UK teaching hospital. The final ADR risk model was then validated in a European population (European dataset).

Results

Six-hundred-ninety patients (median age 85 years) were enrolled in the development stage of the study. Ninety-five reports of ADR were confirmed by independent review in these patients. Five clinical variables were identified through multivariate analysis and included in our final model; each variable was attributed a score of 1. Internal validation produced an AUROC of 0.74, a sensitivity of 80%, and specificity of 55%. During the external validation stage the AUROC was 0.73, with sensitivity and specificity values of 84% and 43% respectively.

Conclusions

We have developed and successfully validated a simple model to use ADR risk score in a population of patients with a median age of 85, i.e. the oldest old. The model is based on 5 clinical variables (≥8 drugs, hyperlipidaemia, raised white cell count, use of anti-diabetic agents, length of stay ≥12 days), some of which have not been previously reported.     

Factors influencing offspring traits in the oviparous multi-clutched lizard,<Emphasis Type="Italic">Calotes versicolor</Emphasis> (Agamidae)

The determinants of offspring size and number in the tropical oviparous multi-clutched lizard,Calotes versicolor, were examined using both univariate and multivariate (path) analyses. InC. versicolor maternal snout-vent length (SVL) and body condition influence clutch mass and clutch size but have no significant influence on offspring size. The positive effect of maternal SVL and body condition on offspring number is counterbalanced by a negative effect of breeding time on egg mass. In fact, breeding time directly influences the offspring body mass and condition through variation in the egg mass. There is a trade-off between offspring mass and condition with offspring number, and breeding time influences both. Offspring hatched from the eggs of early (May–June) or mid (July–August) breeding periods invariably show lower mass and condition than those hatched from the eggs of late breeding season (September–October). Yet, there is no variation in offspring SVL among early, mid and late clutches. Thus, inC. versicolor offspring SVL is optimized while body mass and condition are not optimized.     

Characterizing the Propagation of Uterine Electrophysiological Signals Recorded with a Multi-Sensor Abdominal Array in Term Pregnancies

The objective of this study was to quantify the number of segments that have contractile activity and determine the propagation speed from uterine electrophysiological signals recorded over the abdomen. The uterine magnetomyographic (MMG) signals were recorded with a 151 channel SARA (SQUID Array for Reproductive Assessment) system from 36 pregnant women between 37 and 40 weeks of gestational age. The MMG signals were scored and segments were classified based on presence of uterine contractile burst activity. The sensor space was then split into four quadrants and in each quadrant signal strength at each sample was calculated using center-of-gravity (COG). To this end, the cross-correlation analysis of the COG was performed to calculate the delay between pairwise combinations of quadrants. The relationship in propagation across the quadrants was quantified and propagation speeds were calculated from the delays. MMG recordings were successfully processed from 25 subjects and the average values of propagation speeds ranged from 1.3–9.5 cm/s, which was within the physiological range. The propagation was observed between both vertical and horizontal quadrants confirming multidirectional propagation. After the multiple pairwise test (99% CI), significant differences in speeds can be observed between certain vertical or horizontal combinations and the crossed pair combinations. The number of segments containing contractile activity in any given quadrant pair with a detectable delay was significantly higher in the lower abdominal pairwise combination as compared to all others. The quadrant-based approach using MMG signals provided us with high spatial-temporal information of the uterine contractile activity and will help us in the future to optimize abdominal electromyographic (EMG) recordings that are practical in a clinical setting.     

Identification of small molecule inhibitors against UBE2C by using docking studies

An increased expression of UBE2C (Ubiquitin-conjugating enzyme E2C) has been associated with high tumor grade and cancer progression. It is an essential indicator of the mitotic destruction events. Our microarray study on cervical cancers showed UBE2C to be over expressed in cervical cancer. Subsequent studies from our laboratory, showed that inhibition of UBE2C can enhance radiation and chemosensitivity. Therefore it can be an appropriate target for drug development to identify potential and specific inhibitor of cancer. To identify small molecule inhibitors, a computational approach was used to model UBE2C and further docking studies were carried out. Different ligand subsets such as ChemBank, PDB, KEGG, Drug-likeness NCI, Not annotated NCI of ligand library ligands were downloaded and docked with UBE2C. Schrodinger tools were used for identifying active sites and docking studies of ligands with UBE2C. Based on glide score, the potential ligands were screened and its interaction with UBE2C was identified. We also analyzed the drug like properties such as absorption, distribution, metabolism, excretion and toxicity (ADME/T) of docked compounds. Our results suggest that 2,4-diimino-1-methyl-1,3,5-triazepan-6-one, sulfuric acid compound with 5,6-diamino-2,4-pyrimidinediol (1:1) and 7-alpha-d-ribofuranosyl-2-aminopurine-5''-phosphate may act as best inhibitors and further in vitro studies, may lead to development of novel and best inhibitor of UBE2C.     

Modeling Magnetomyograms of Uterine Contractions during Pregnancy Using a Multiscale Forward Electromagnetic Approach

Understanding the mechanisms of uterine contractions during pregnancy is especially important in predicting the onset of labor and thus in forecasting preterm deliveries. Preterm birth can cause serious health problems in newborns, as well as large financial burdens to society. Various techniques such as electromyography (EMG) and magnetomyography (MMG) have been developed to quantify uterine contractions. However, no widely accepted method to predict labor based on electromagnetic measurement is available. Therefore, developing a biophysical model of EMG and MMG could help better understand uterine contractions, interpret real measurements, and detect labor. In this work, we propose a multiscale realistic model of uterine contractions during pregnancy. At the cellular level, building on bifurcation theory, we apply generalized FitzHugh-Nagumo (FHN) equations that produces both plateau-type and bursting-type action potentials. At the tissue level, we introduce a random fiber orientation model applicable to an arbitrary uterine shape. We also develop an analytical expression for the propagation speed of transmembrane potential. At the organ level, a realistic volume conductor geometry model is provided based on magnetic resonance images of a pregnant woman. To simulate the measurements from the SQUID Array for Reproductive Assessment (SARA) device, we propose a sensor array model. Our model is able to reproduce the characteristics of action potentials. Additionally, we investigate the sensitivity of MMG to model configuration aspects such as volume geometry, fiber orientation, and pacemaker location. Our numerical results show that fiber orientation and pacemaker location are the key aspects that greatly affect the MMG as measured by the SARA device. We conclude that sphere is appropriate as an approximation of the volume geometry. The initial step towards validating the model against real MMG measurement is also presented. Our results show that the model is flexible to mimic the limited-propagation magnetic signature during the emergence and decay of a uterine contraction.     

Comparative effects of insulin and insulin-like growth factor-1 on follicle-stimulating hormone-induced responses in porcine granulosa cells

The effect of insulin and insulin-like growth factor-1 (IGF-1) on progesterone secretion by porcine granulosa cells and their modulatory effect on follicle-stimulating hormone (FSH)-induced responses were examined. For comparative purposes, growth hormone (GH), previously shown to stimulate IGF-1 secretion, was also included. Granulosa cells from ovarian follicles (3 to 5 mm) were cultured in multiwell plates for the first 48 hours, either in the presence or absence of 1% fetal bovine serum (FBS). Following plating, all cultures were maintained in serum-free media. The addition of only insulin, but not IGF-1 or GH, enhanced progesterone secretion under both culture conditions. When low-density lipoprotein was provided as steroid substrate, a stimulatory effect of insulin on progesterone accumulation was observed with a minimum dose of 10 ng/ml. Granulosa cells cultured in serum-free media from the time of plating secreted less progesterone and were less responsive to FSH compared with cultures plated with 1% FBS. Only insulin, but not IGF-1, enhanced FSH responses to threefold in cells cultured with 1% FBS. However, when cells were cultured in serum-free media from the time of plating, both insulin and IGF-1, but not GH, potentiated the responses to FSH, but insulin was more potent than IGF-1. Insulin-like growth-factor-1 binding studies with granulosa cells indicate the presence of specific high-affinity binding sites (Kd 3.96 nM). A dose of 100 ng/ml of insulin had negligible cross-reactivity with IGF-1 receptors.     

Binding of high-density lipoproteins to luteal membranes: the role of prolactin, luteinizing hormone, and circulating lipoproteins

Ovarian and adrenal membranes from immature gonadotropin-primed rats, treated with 4-amino-pyrazolopyrimidine (4APP) to reduce endogenous lipoprotein levels, displayed higher binding of porcine high-density lipoprotein (HDL) when compared to control rats. Immature, hypophysectomized (HYPOX) rats bearing corpora lutea (CL) on Day 5 after ovulation had lower levels of serum progesterone and reduced capacity for HDL and human chorionic gonadotropin (hCG) binding to ovarian membranes when compared with intact animals. Hypophysectomy also reduced the number of HDL binding sites in adrenal membranes. Treatment of HYPOX animals with luteinizing hormone (LH) and prolactin (Prl) alone or in combination increased the HDL binding sites in the ovary relative to HYPOX-untreated rats. Neither hormone affected binding to adrenals, where only adrenocorticotropic hormone (ACTH) enhanced HDL binding. LH treatment reduced the serum progesterone levels and hCG binding to the ovaries, whereas Prl administration increased progesterone levels with no effect on hCG binding. We conclude from this study that HDL binding in the luteinized ovary is regulated by Prl and LH and circulating lipoproteins, whereas in adrenals it is regulated by ACTH and circulating levels of lipoproteins.     

Effect of melatonin on pulsatile release of luteinizing hormone in female lambs.

This study investigated the effect of melatonin treatment of ewe lambs on LH pulsatility in an attempt to examine the mechanism whereby melatonin advances the onset of puberty. Six ewe lambs were given intravaginal melatonin implants at 12.8 weeks of age. Another six lambs received empty implants. All lambs were serially blood sampled every 15 minutes for six hours on several occasions prior to the onset of puberty. One week after implantation LH pulse frequency and mean LH levels were higher in treated lambs than the control lambs (pulse frequency 0.13/h vs 0.03/h; mean LH levels 2.0 +/- 0.2 ng/ml vs 1.3 +/- 0.1 ng/ml; p less than 0.05). Melatonin treatment failed to alter pulse frequency after the initial increase. Puberty was advanced by 3 weeks in the treated group. In the second experiment six lambs received melatonin implants at 13 weeks of age and another six lambs served as control. In this experiment blood samples were taken intensively during the first few weeks after treatment. Results of this study show that mean plasma LH levels and LH pulse frequency were again higher during the first week after implantation. This transient increase in LH release may be part of the mechanism initiating the eventual advancement of puberty although the significance of this increase is questionable. In both experiments the LH response to estradiol injection was monitored at various times after treatment, but no effects of melatonin were found, although the magnitude of the response increased with age.     

Evaluation of DNA methylation and mRNA expression of heat shock proteins in thermal manipulated chicken

Thermal manipulation during embryogenesis has been demonstrated to enhance the thermotolerance capacity of broilers through epigenetic modifications. Heat shock proteins (HSPs) are induced in response to stress for guarding cells against damage. The present study investigates the effect of thermal conditioning during embryogenesis and thermal challenge at 42 days of age on HSP gene and protein expression, DNA methylation and in vitro luciferase assay in brain tissue of Naked Neck (NN) and Punjab Broiler-2 (PB-2) chicken. On the 15th day of incubation, fertile eggs from two breeds, NN and PB-2, were randomly divided in to two groups: control (C)—eggs were incubated under standard incubation conditions, and thermal conditioning (TC)—eggs were exposed to higher incubation temperature (40.5°C) for 3 h on the 15th, 16th, and 17th days of incubation. The chicks obtained from each group were further subdivided and reared under different environmental conditions from the 15th to the 42nd day as normal [N; 25 ± 1 °C, 70% relative humidity (RH)] and heat exposed (HE; 35 ± 1 °C, 50% RH) resulting in four treatment groups (CN, CHE, TCN, and TCHE). The results revealed that HSP promoter activity was stronger in CHE, which had lesser methylation and higher gene expression. The activity of promoter region was lesser in TCHE birds that were thermally manipulated at the embryonic stage, thus reflecting their stress-free condition. This was confirmed by the lower level of mRNA expression of all the HSP genes. In conclusion, thermal conditioning during embryogenesis has a positive impact and improves chicken thermotolerance capacity in postnatal life.     

Effect of Supplemental Trace Minerals on Hsp-70 mRNA Expression in Commercial Broiler Chicken

The effects of supplementing the organic forms of selenium (Se), chromium (Cr), and zinc (Zn) on Hsp-70 mRNA expression and body weight in broiler chickens were evaluated. 200 chicks were equally distributed into stainless steel battery brooders at the rate of 5 birds per pen and reared under heat stress condition up to 42^nd day. The chicks were fed with three experimental diets supplemented with organic forms of Se (0.30?mg/kg), Cr (2?mg/kg), and Zn (40?mg/kg) during the starter and finisher phases and a control diet without any supplementation. On the 21st and 42nd day, 20 birds from each period were sacrificed and samples were collected for analysis. Organic Se, Cr, and Zn supplementation significantly (P?Hsp-70 mRNA levels. The Hsp-70 mRNA expression levels were significantly (P?Hsp-70 mRNA expression level was not affected by age of the birds. The study concluded that organic trace mineral (oTM) supplementation resulted in low Hsp-70 mRNA expression, indicating reduced heat stress in broilers.