Knowledge Exchange Trials: Pilot Programme Bridging the Academic-Policy Divide

The ESRC supported Manchester and Cambridge Universities to undertake pilot knowledge exchange projects in 2013-2014 to extend understanding of the issues facing social scientists seeking to interact with non academic communities and to increase knowledge of effective knowledge exchange (that helps non academics apply social science to their work for positive social and economic benefit). This is a brief summary of University of Manchester’s pilot knowledge exchange project

Exploring the Applications of PBPK Modelling to Optimise HIV-1 Treatment

Human immunodeficiency virus (HIV-1) infection continues to be a significant public health concern, with 36.3 million lives being claimed by the infection thus far. Currently there is no cure for HIV. Antiretroviral (ARV) therapy has considerably increased life expectancy in people living with HIV (PLWH), however, several challenges remain. This thesis investigates the various ways in which physiologically based pharmacokinetic (PBPK) modelling can be developed and applied with the aim of optimising treatment for human immunodeficiency virus (HIV-1) infection. Neonatal patients are considered a vulnerable population as limited clinical studies are conducted in this population. Newborns born to mothers with HIV are at risk of receiving HIV. Lack of pharmacokinetic (PK) data means fewer treatment options are available. Chapters 2 & 3 focus on developing and applying a neonatal PBPK model to investigate the PK of integrase inhibitors, dolutegravir and bictegravir in neonates. Chapter 4 goes on to describe how modelling can be used to predict the PK of novel formulations by simulating long-acting, intramuscular, cabotegravir in neonates. Polypharmacy is routinely observed in PLWH, and drug-drug interactions (DDIs) prove an obstacle in HIV treatment, Chapter 5 involved developing an adult PBPK model to evaluate the magnitude of moderate inducers on novel ARVs. Residual levels of viraemia hinder the ability to develop a cure, Chapter 6 investigated the penetration of ARV drugs in lymphoid tissues using a mechanistic lymphatic PBPK model. Understanding the penetration of drugs in target tissues can help optimise ARV therapy. Collectively, this thesis evaluates the possible ways HIV treatment can be improved and optimised by investigating the potential of treatments in special populations, novel formulations of ARV drugs, management of drug-drug interactions and the penetration of therapy in target tissues

Muslims in the UK: Policies for Engaged Citizens

Explores equality and discrimination, education, employment, and criminal justice issues for British Muslims, and the extent to which government policy addresses their needs as a group

Islamophobia and Twitter: A Typology of Online Hate Against Muslims on Social Media

The Woolwich attack in May 2013 has led to a spate of hate crimes committed against Muslim communities in the United Kingdom. These incidents include Muslim women being targeted for wearing the headscarf and mosques being vandalized. While street level Islamophobia remains an important area of investigation, an equally disturbing picture is emerging with the rise in online anti-Muslim abuse. This article argues that online Islamophobia must be given the same level of attention as street level Islamophobia. It examines 500 tweets from 100 different Twitter users to examine how Muslims are being viewed and targeted by perpetrators of online abuse via the Twitter search engine, and offers a typology of offender characteristics

Tuning the binding affinity and selectivity of perfluoroaryl-stapled peptides by cysteine-editing.

A growing number of approaches to 'staple' α-helical peptides into a bioactive conformation using cysteine cross-linking are emerging. Here we explore the replacement of L-cysteine with 'cysteine analogues' in combinations of different stereochemistry, side chain length and beta-carbon substitution, to examine the influence that the thiol-containing residue(s) has on target protein-binding affinity in a well explored model system, p53-MDM2/MDMX. In some cases, replacement of one or more L-cysteine residues afforded significant changes in the measured binding affinity and target selectivity of the peptide. Computationally constructed homology models indicate that some modifications, such as incorporating two D-cysteines favourably alter the positions of key functional amino acid side chains, which is likely to cause changes in binding affinity, in agreement with measured SPR data

Predicting Drug-Drug Interactions between Rifampicin and Ritonavir-Boosted Atazanavir Using PBPK Modelling

ObjectivesThe aim of this study was to simulate the drug-drug interaction (DDI) between ritonavir-boosted atazanavir (ATV/r) and rifampicin (RIF) using physiologically based pharmacokinetic (PBPK) modelling, and to predict suitable dose adjustments for ATV/r for the treatment of people living with HIV (PLWH) co-infected with tuberculosis.MethodsA whole-body DDI PBPK model was designed using Simbiology 9.6.0 (MATLAB R2019a) and verified against reported clinical data for all drugs administered alone and concomitantly. The model contained the induction mechanisms of RIF and ritonavir (RTV), the inhibition effect of RTV for the enzymes involved in the DDI, and the induction and inhibition mechanisms of RIF and RTV on the uptake and efflux hepatic transporters. The model was considered verified if the observed versus predicted pharmacokinetic values were within twofold. Alternative ATV/r dosing regimens were simulated to achieve the trough concentration (Ctrough) clinical cut-off of 150 ng/mL.ResultsThe PBPK model was successfully verified according to the criteria. Simulation of different dose adjustments predicted that a change in regimen to twice-daily ATV/r (300/100 or 300/200 mg) may alleviate the induction effect of RIF on ATV Ctrough, with > 95% of individuals predicted to achieve Ctrough above the clinical cut-off.ConclusionsThe developed PBPK model characterized the induction-mediated DDI between RIF and ATV/r, accurately predicting the reduction of ATV plasma concentrations in line with observed clinical data. A change in the ATV/r dosing regimen from once-daily to twice-daily was predicted to mitigate the effect of the DDI on the Ctrough of ATV, maintaining plasma concentration levels above the therapeutic threshold for most patients

Nurturing a knowledge economy in Qatar

Zamila Bunglawal