Artificial intelligence and machine learning for clinical pharmacology.

Artificial intelligence (AI) will impact many aspects of clinical pharmacology, including drug discovery and development, clinical trials, personalized medicine, pharmacogenomics, pharmacovigilance and clinical toxicology. The rapid progress of AI in healthcare means clinical pharmacologists should have an understanding of AI and its implementation in clinical practice. As with any new therapy or health technology, it is imperative that AI tools are subject to robust and stringent evaluation to ensure that they enhance clinical practice in a safe and equitable manner.

Management of Heart Failure in Patients with Chronic Kidney Disease.

Chronic kidney disease (CKD) is increasingly prevalent in patients with heart failure (HF) and HF is one of the leading causes of hospitalisation, morbidity and mortality in patients with impaired renal function. Currently, there is strong evidence to support the symptomatic and prognostic benefits of β-blockers, renin-angiotensin-aldosterone inhibitors (RAASis), angiotensin receptor-neprilysin inhibitors (ARNIs) and mineralocorticoid receptor antagonists (MRA) in patients with HF and CKD stages 1-3. However, ARNIs, RAASis and MRAs are often suboptimally prescribed for patients with CKD owing to concerns about hyperkalaemia and worsening renal function.

Elevated Urinary Biomarkers of Oxidative Damage in Photocopier Operators following Acute and Chronic Exposures.

Inhalation exposures to nanoparticles (NPs) from printers and photocopiers have been associated with upper airway and systemic inflammation, increased blood pressure, and cases of autoimmune and respiratory disorders. In this study we investigate oxidative stress induced by exposures to copier-emitted nanoparticles using a panel of urinary oxidative stress (OS) biomarkers representing DNA damage (8-hydroxydeoxyguanosine, 8-OHdG; 8-hydroxyguanosine, 8-OHG; 5-hydroxymethyl uracil 5-OHMeU), lipid peroxidation (8-isoprostane; 4-hydroxynonenal, HNE), and protein oxidation biomarkers (o-tyrosine, 3-chlorotyrosine, and 3-nitrotyrosine) under conditions of acute (single 6 h exposure, 9 volunteers, 110 urine samples) and chronic exposures (6 workers, 11 controls, 81 urine samples). Urinary biomarkers were quantified with liquid chromatography-tandem mass spectrometry after solid phase extraction sample cleanup.

Sleep Disordered Breathing, Obesity and Atrial Fibrillation: A Mendelian Randomisation Study.

It remains unclear whether the association between obstructive sleep apnoea (OSA), a form of sleep-disordered breathing (SDB), and atrial fibrillation (AF) is causal or mediated by shared co-morbidities such as obesity. Existing observational studies are conflicting and limited by confounding and reverse causality. We performed Mendelian randomisation (MR) to investigate the causal relationships between SDB, body mass index (BMI) and AF.

Leveraging genetic data to investigate the effects of interleukin-6 receptor signalling on levels of 40 circulating cytokines.

Interleukin 6 (IL-6) is a circulating cytokine implicated in inflammatory processes. However, the broad effects of IL-6 receptor (IL-6R) signalling on other circulating cytokines is not known. Using summary-level data from genome-wide association studies, we leveraged genetic variants that proxy IL-6R signalling in two-sample Mendelian randomization analyses to investigate effects on levels of 40 circulating cytokines.

Metabolic Traits and Stroke Risk in Individuals of African Ancestry: Mendelian Randomization Analysis.

Background And Purpose: Metabolic traits affect ischemic stroke (IS) risk, but the degree to which this varies across different ethnic ancestries is not known. Our aim was to apply Mendelian randomization to investigate the causal effects of type 2 diabetes (T2D) liability and lipid traits on IS risk in African ancestry individuals, and to compare them to estimates obtained in European ancestry individuals.

Methods: For African ancestry individuals, genetic proxies for T2D liability and circulating lipids were obtained from a meta-analysis of the African Partnership for Chronic Disease Research study, the UK Biobank, and the Million Veteran Program (total N=77 061).

Inhibition of interleukin 6 signalling and renal function: A Mendelian randomization study.

Inhibition of interleukin 6 (IL-6) signalling has been proposed as a potential cardioprotective strategy for patients with chronic kidney disease (CKD), but the direct effects of IL-6 inhibition on renal function are not known. A Mendelian randomization (MR) study was performed to investigate the association of genetically proxied inhibition of IL-6 signalling with estimated glomerular filtration rate (eGFR), CKD and blood urea nitrogen (BUN). Inverse-variance weighted MR was used as the main analysis, with sensitivity analyses performed using simple median, weighted median and MR-Egger methods.

Comprehensive Assessment of Short-Lived ROS and HO in Laser Printer Emissions: Assessing the Relative Contribution of Metal Oxides and Organic Constituents.

Inhalation exposure to nanoparticles from toner-based laser printer and photocopier emissions (LPEs) induces airway inflammation and systemic oxidative stress, cytotoxicity, and genotoxicity (such as DNA damage). Recent evidence from human and in vitro studies suggests a strong role for oxidative stress caused by free radicals, such as reactive oxygen species (ROS), in the toxicity of laser printer emissions. However, the amount of ROS generated from laser printer nanoparticle emissions and the relative contribution of various fractions (vapors, organics, metals, and metal oxides) have not been investigated to-date.

Early screening and treatment of gestational diabetes in high-risk women improves maternal and neonatal outcomes: A retrospective clinical audit.

Aims: Evidence suggests that screening for gestational diabetes (GDM) occurs too late in pregnancy, when changes in glucose metabolism and fetal growth rates can already be detected. In August 2016 NHS Lothian began screening women with risk factors for GDM during early pregnancy (11-13 weeks). We hypothesised that an earlier identification and treatment of dysglycaemia would improve pregnancy outcomes compared to previous standard care.

Characterizing the interaction between uranyl ion and fulvic acid using regional integration analysis (RIA) and fluorescence quenching.

The development of chemometric methods has substantially improved the quantitative usefulness of the fluorescence excitation-emission matrix (EEM) in the analysis of dissolved organic matter (DOM). In this study, Regional Integration Analysis (RIA) was used to quantitatively interpret EEMs and assess fluorescence quenching behavior in order to study the binding between uranyl ion and fulvic acid. Three fulvic acids including soil fulvic acid (SFA), Oyster River fulvic acid (ORFA) and Suwannee River fulvic acid (SRFA) were used and investigated by the spectroscopic techniques.

Toxicity of the 13 priority pollutant metals to Vibrio fisheri in the Microtox chronic toxicity test.

The Microtox Acute Toxicity Test has been successfully used to measure the toxicity of metals and other pollutants at high concentrations (ppm) in selected environmental samples. However, metals and other toxicants are often found in much lower concentrations (ppb) in many municipal wastewaters and receiving waters. In order to assess the toxicity of these pollutants in these samples, a more sensitive toxicity assay is needed.

A modified multisite Stern-Volmer equation for the determination of conditional stability constants and ligand concentrations of soil fulvic acid with metal ions.

In this work, we modify the multisite Stern-Volmer (MSV) equation for fitting fluorescence titration curves. Under the condition of a static quenching mechanism, the MSV postulates an underlying 1:1 fulvic acid (FA)/copper coordination ratio at multisites. Approximates of six fitting parameters characterize the stability constants (K1 and K2) of FA ligands with Cu2+, micromolar ligand site concentrations (CL1 and CL2), the unquenched, steady-state fractional fluorescence contributions (fx), and the residual fluorescence intensity (IRES).

Multi-wavelength fluorescence-quenching model for determination of Cu2+ conditional stability constants and ligand concentrations of fulvic acid.

In this work, a multi-wavelength model (MWM) is developed. It uses fluorescence bands in the fulvic acid (FA) spectrum that quench upon binding of inorganic Cu2+ to FA. Quenching data at pH values of 5, 6, and 7 are placed in sets, containing fluorescence measures at select wavelengths versus added copper (CM).