Perspectives of attenders and non-attenders to SARS-CoV-2 asymptomatic community testing in England: a qualitative interview study.

OBJECTIVES: In December 2020, Derbyshire County Council in England introduced 'walk-in' asymptomatic community COVID-19 testing sites. Our study aimed to explore people's views of the newly established COVID-19 community testing (CT) sites among those who attended and those who did not attend them, alongside gathering individuals' experiences of attending a CT site to complete a lateral flow test. SETTING: This qualitative research study comprised of one-to-one interviews with those attending a COVID-19 CT sites in Derbyshire and those from the surrounding area who did not attend. PARTICIPANTS: A combination of purposive and convenience sampling was used to recruit those who had (n=18) and those who had not attended (n=15) a walk-in asymptomatic CT site. RESULTS: Employers played a key role in raising awareness of the testing sites, with most attending CT at the request of their workplace. The experience of attending a CT site was overwhelmingly positive and those who got tested spoke about the reassurance a negative result offered, knowing they were not passing on the virus when going about their daily lives. However, there was a perception that awareness of CT sites was low across the county and some confusion about who was eligible to attend and under what circumstances. Individuals linked this to low level of advertising they had seen, in addition to a lack of clarity in the information provided. CONCLUSIONS: People's experience of attending a 'walk-in' asymptomatic CT site in Derbyshire was generally very positive; however, ensuring clear communication for future testing programmes is essential to maximise their uptake.

Market segmentation tools provide insights into demographic variations in bowel cancer screening uptake.

BACKGROUND: The National Health Service Bowel Cancer Screening Programme (NHS BCSP) aims to detect individuals who have precancerous polyps or early stage cancer, when it is easier to treat. To be effective, a screening uptake of at least 52% is required. Variations in uptake by demographic characteristic are reported and the aim of this study was to better understand who participates in the NHS BCSP, to inform action to address inequalities in screening uptake. METHODS: Invitation-level data for the Derbyshire population were supplied by the NHS BCSP Eastern Hub for the period 1 April 2014 to 31 March 2016. Data were linked by postal code to the Mosaic Public Sector Segmentation tool. Descriptive analysis using 14 groups and 61 types within Mosaic was undertaken to offer insight into the demographic, lifestyle and behavioural traits of people living in small geographies against their screening uptake, with a particular focus on identifying population groups with an uptake below 52% and so at risk of health inequalities. RESULTS: 180 176 screening invitations were dispatched with an overall uptake of 60.55%. Six Mosaic groups have an uptake below the 52% acceptable level: urban cohesion, rental hubs, transient renters, family basics, vintage value and municipal tenants. These groups are characterised by high levels of social-rented accommodation, multicultural urban communities and transient populations. CONCLUSION: Segmentation tools offer an effective way to generate novel insights into bowel cancer screening uptake and develop tailored strategies for working with identified communities to increase participation.

Validity of ligand efficiency metrics.

A recent viewpoint article (Improving the plausibility of success with inefficient metrics. ACS Med. Chem. Lett. 2014, 5, 2-5) argued that the standard definition of ligand efficiency (LE) is mathematically invalid. In this viewpoint, we address this criticism and show categorically that the definition of LE is mathematically valid. LE and other metrics such as lipophilic ligand efficiency (LLE) can be useful during the multiparameter optimization challenge faced by medicinal chemists.

Over expression of wild type or a catalytically dead mutant of Sirtuin 6 does not influence NFκB responses.

SIRT6 is involved in inflammation, aging and metabolism potentially by modulating the functions of both NFκB and HIF1α. Since it is possible to make small molecule activators and inhibitors of Sirtuins we wished to establish biochemical and cellular assays both to assist in drug discovery efforts and to validate whether SIRT6 represents a valid drug target for these indications. We confirmed in cellular assays that SIRT6 can deacetylate acetylated-histone H3 lysine 9 (H3K9Ac), however this deacetylase activity is unusually low in biochemical assays. In an effort to develop alternative assay formats we observed that SIRT6 overexpression had no influence on TNFα induced nuclear translocation of NFκB, nor did it have an effect on nuclear mobility of RelA/p65. In an effort to identify a gene expression profile that could be used to identify a SIRT6 readout we conducted genome-wide expression studies. We observed that overexpression of SIRT6 had little influence on NFκB-dependent genes, but overexpression of the catalytically inactive mutant affected gene expression in developmental pathways.

Lead optimization using matched molecular pairs: inclusion of contextual information for enhanced prediction of HERG inhibition, solubility, and lipophilicity.

Previous studies of the analysis of molecular matched pairs (MMPs) have often assumed that the effect of a substructural transformation on a molecular property is independent of the context (i.e., the local structural environment in which that transformation occurs). Experiments with large sets of hERG, solubility, and lipophilicity data demonstrate that the inclusion of contextual information can enhance the predictive power of MMP analyses, with significant trends (both positive and negative) being identified that are not apparent when using conventional, context-independent approaches.

Influences on patient satisfaction survey results: is there a need for a rethink?

BACKGROUND: Patient experience is a key principle of the NHS and is increasingly linked to payment of providers. AIM: To establish if any correlation exists between patient satisfaction scores (as measured in the MORI survey) and practice list size or deprivation score. METHOD: This was a retrospective correlation review using data for general practices in Derbyshire County Primary Care Trust extracted from existing publicly available sources. Correlation between satisfaction score and both deprivation index and practice list size was examined. RESULTS: Data from all 96 practices were reviewed. Overall satisfaction showed a statistically significant negative correlation with deprivation (r=-0.28, P=0.006). Neither question pertaining to QOF payment showed a correlation with deprivation, however, there was a statistically significant negative correlation with list size (Q5a r=-0.52, P <0.01. Q7 r=-0.43, P <0.01). Questions regarding satisfaction with the doctor showed weak but statistically significant negative correlations with deprivation, (r varying from -0.21 to -0.39, P <0.05). Satisfaction with nurses showed positive correlations with deprivation, with satisfaction increasing in line with deprivation (r varying from 0.24 to 0.36, P <0.05). Regarding list size, for nurse care the reverse was seen, with increased list size being linked to decreased satisfaction (r varying from -0.21 to -0.45, P <0.05). CONCLUSION: Although variables showed weak correlations, there were correlations between list size and deprivation in the results of the patient experience questionnaire. Linking this to payment has implications for primary care contracting.

Process validation and screen reproducibility in high-throughput screening.

The use of large-scale compound screening has become a key component of drug discovery projects in both the pharmaceutical and the biotechnological industries. More recently, these activities have also been embraced by the academic community as a major tool for chemical genomic activities. High-throughput screening (HTS) activities constitute a major step in the initial drug discovery efforts and involve the use of large quantities of biological reagents, hundreds of thousands to millions of compounds, and the utilization of expensive equipment. All these factors make it very important to evaluate in advance of the HTS campaign any potential issues related to reproducibility of the experimentation and the quality of the results obtained at the end of these very costly activities. In this article, the authors describe how GlaxoSmithKline (GSK) has addressed the need of a true validation of the HTS process before embarking in full HTS campaigns. They present 2 different aspects of the so-called validation process: (1) optimization of the HTS workflow and its validation as a quality process and (2) the statistical evaluation of the HTS, focusing on the reproducibility of results and the ability to distinguish active from nonactive compounds in a vast collection of samples. The authors describe a variety of reproducibility indexes that are either innovative or have been adapted from generic medical diagnostic screening strategies. In addition, they exemplify how these validation tools have been implemented in a number of case studies at GSK.

GALAHAD: 1. pharmacophore identification by hypermolecular alignment of ligands in 3D.

Alignment of multiple ligands based on shared pharmacophoric and pharmacosteric features is a long-recognized challenge in drug discovery and development. This is particularly true when the spatial overlap between structures is incomplete, in which case no good template molecule is likely to exist. Pair-wise rigid ligand alignment based on linear assignment (the LAMDA algorithm) has the potential to address this problem (Richmond et al. in J Mol Graph Model 23:199-209, 2004). Here we present the version of LAMDA embodied in the GALAHAD program, which carries out multi-way alignments by iterative construction of hypermolecules that retain the aggregate as well as the individual attributes of the ligands. We have also generalized the cost function from being purely atom-based to being one that operates on ionic, hydrogen bonding, hydrophobic and steric features. Finally, we have added the ability to generate useful partial-match 3D search queries from the hypermolecules obtained. By running frozen conformations through the GALAHAD program, one can utilize the extended version of LAMDA to generate pharmacophores and pharmacosteres that agree well with crystal structure alignments for a range of literature datasets, with minor adjustments of the default parameters generating even better models. Allowing for inclusion of partial match constraints in the queries yields pharmacophores that are consistently a superset of full-match pharmacophores identified in previous analyses, with the additional features representing points of potentially beneficial interaction with the target.

Unsupervised 3D ring template searching as an ideas generator for scaffold hopping: use of the LAMDA, RigFit, and field-based similarity search (FBSS) methods.

Crystal structures taken from the Cambridge Structural Database were used to build a ring scaffold database containing 19 050 3D structures, with each such scaffold then being used to generate a centroid connecting path (CCP) representation. The CCP is a novel object that connects ring centroids, ring linker atoms, and other important points on the connection path between ring centroids. Unsupervised searching in the scaffold and CCP data sets was carried out using the atom-based LAMDA and RigFit search methods and the field-based similarity search method. The performance of these methods was tested with three different ring scaffold queries. These searches demonstrated that unsupervised 3D scaffold searching methods can find not only the types of ring systems that might be retrieved in carefully defined pharmacophore searches (supervised approach) but also additional, structurally diverse ring systems that could form the starting point for lead discovery programs or other scaffold-hopping applications. Not only are the methods effective but some are sufficiently rapid to permit scaffold searching in large chemical databases on a routine basis.

Lack of effects of guanfacine on executive and memory functions in healthy male volunteers.

RATIONALE: Guanfacine is an alpha2-adrenergic receptor agonist that has been shown to have beneficial effects on working memory and attentional functions in monkeys and in patients with attention deficit hyperactivity disorder. OBJECTIVES: The aim of this study was to further investigate the cognitive-enhancing properties of guanfacine using an established battery of tasks measuring executive and memory functions. METHODS: Sixty healthy male volunteers were randomised into three groups. Cognitive testing was performed from +2 to +4 h after double-blind administration of a single oral dose of 1 or 2 mg of guanfacine or placebo. RESULTS: Systolic blood pressure was significantly reduced by both doses of guanfacine at the end of the testing session. There were no statistically significant effects on any of the cognitive measures. Two trend effects were observed with poorer performance on digit span backward and slower 'Go' reaction times after guanfacine. CONCLUSION: This study found no improvement of prefrontal memory or executive functions after guanfacine. Negative effects on blood pressure and trend effects on digit span backward and go reaction time indicate a mild sedative effect of guanfacine at these doses, possibly via mechanisms of autoreceptor down-regulation.

Alignment of three-dimensional molecules using an image recognition algorithm.

This paper describes a novel approach, based on image recognition in two dimensions, for the atom-based alignment of two rigid molecules in three dimensions. The atoms are characterised by their partial charges and their positions relative to the remaining atoms in the molecule. Based on this information, a cost of matching a pair of atoms, one from each molecule, is assigned to all possible pairs. A preliminary set of intermolecular atom equivalences that minimises the total atom matching cost is then determined using an algorithm for solving the linear assignment problem. Several geometric heuristics are described that aim to reduce the number of atom equivalences that are inconsistent with the 3D structures. Those that remain are used to calculate an alignment transformation that achieves an optimal superposition of atoms that have a similar local geometry and partial charge. This alignment is then refined by calculating a new set of equivalences consisting of atom pairs that are approximately overlaid, irrespective of partial charge. A range of examples is provided to demonstrate the efficiency and effectiveness of the method.