How data visualisation using historical medical journals can contribute to current debates around antibiotic use and antimicrobial resistance in primary care

BackgroundThe early years of antibiotic use in primary care (c1950-1969) has received little attention. Medical journals provide a rich source for studying historic healthcare practitioners’ views and interests, with the potential to inform contemporary debate around issues of overuse and antimicrobial resistance. AimsPilot study to test the application of digital methods to interrogate historical medical journal data in relation to antibiotic use.Methods / ApproachMeta-data and scanned articles were extracted from the online British Journal of General Practice (BJGP) archive from inception (1953) to 1969. Searchable text was generated using an application called ABBYY optical character recognition, and Python used to generate data visualisations exploring (1) how BJGP changed during the period, (2) mentions of terms ‘antibiotic(s)’, ‘penicillin’, ‘resistance/resistant’ and mapping when and where they occurred.Results / EvaluationFrom 1953-1969, BJGP expanded in terms of number of annual issues (4 to 17) and annual pages (&lt;25 to &gt;1100). Heatmap visualisations were used to facilitate understanding of the frequency with which use of the term ‘antibiotic(s)’ occurred. By 1969 an article mentioning ‘antibiotic(s)’ was published monthly. Bigram searches found ‘treatment’ and ‘therapy’ to be the two most common terms that appeared with ‘antibiotic(s)’. The fourth and seventh most common terms were ‘resistant’ (first appearing in 1955) and ‘resistance’ (1962).ConclusionsThis pilot work shows that primary care publications increased considerably between 1953-1969. Articles on antibiotics featured frequently in relation to therapeutic intervention, and concerns around resistance occurred at an early stage. This approach provides new insights into how attitudes and behaviours around antibiotic use by primary care have evolved over time. It may also have the potential to inform study of the future use of antibiotics in primary care. <br/

Acyl hydrazides as acyl donors for the synthesis of diaryl and aryl alkyl ketones.

In this communication we describe a novel strategy for the formation of valuable diaryl and aryl alkyl ketones from acyl hydrazides. A wide variety of ketones are prepared and the mild reaction conditions allow for the use of a range of functionalities, especially in the synthesis of diaryl ketones

Inhibition of HIV-1 Replication by Isoxazolidine and Isoxazole Sulfonamides

Targeting host factors is a complementary strategy for the development of new antiviral drugs. We screened a library of isoxazolidine and isoxazole sulfonamides and found four compounds that inhibited HIV-1 infection in human CD4+ lymphocytic T cells with no toxicity at IC90 concentrations. Structure-activity relationship showed that benzyl sulfonamides and a halo-substituted aromatic ring on the heterocycle scaffold were critical for antiretroviral activity. The size and position of the incorporated halogen had a marked effect on the antiretroviral activity. The sulfonamide derivatives had no significant effect on HIV-1 entry, reverse transcription and integration but impaired a step necessary for activation of viral gene expression. This step was Tat-independent, strongly suggesting that the target is a cell factor. A virus partially resistant to the least potent compounds could be selected but could not be propagated in the long term, consistent with the possibility that HIV-1 may be less likely to develop resistance against drugs targeting some host factors. Here, we provide evidence that novel synthetic methods can be applied to develop small molecules with antiretroviral activity that target host factors important for HIV-1 replication

A HER2 selective theranostic agent for surgical resection guidance and photodynamic therapy

In many cancers early intervention involves surgical resection of small localised tumour masses. Inadequate resection leads to recurrence whereas overzealous treatment can lead to organ damage. This work describes production of a HER2 targeting antibody Fab fragment dual conjugated to achieve both real time near-infrared fluorescent imaging and photodynamic therapy. The use of fluorescence emission from a NIR-dye could be used to guide resection of tumour bulk, for example during endoscopic diagnosis for oesophago-gastric adenocarcinoma, this would then be followed by activation of the photodynamic therapeutic agent to destroy untreated localised areas of cancer infiltration and tumour infiltrated lymph nodes. This theranostic agent was prepared from the Fab fragment of trastuzumab initially by functional disulfide re-bridging and site-specific click reaction of a NIR-dye. This was followed by further reaction with a novel pre-activated form of the photosensitiser chlorin e6 with the exposed fragments' lysine residues. Specific binding of the theranostic agent was observed in vitro with a HER2 positive cell line and cellular near-infrared fluorescence was observed with flow cytometry. Specific photo-activity of the conjugates when exposed to laser light was observed with HER2 positive but not HER2 negative cell lines in vitro, this selectivity was not seen with the unconjugated drug. This theranostic agent demonstrates that two different photo-active functions can be coupled to the same antibody fragment with little interference to their independent activities

Acid-cleavable thiomaleamic acid linker for homogeneous antibody-drug conjugation

In this communication we describe a novel acid-cleavable linker strategy for antibody-drug conjugation. Functional disulfide bridging of the single interchain disulfide bond of a trastuzumab Fab fragment yields a homogeneous antibody-drug conjugate bearing a thiomaleamic acid linker. This linker is stable at physiological pH and temperature, but quantitatively cleaves at lysosomal pH to release the drug payload

Players, Characters, and the Gamer's Dilemma

Is there any difference between playing video games in which the player's character commits murder and video games in which the player's character commits pedophilic acts? Morgan Luck's “Gamer's Dilemma” has established this question as a puzzle concerning notions of permissibility and harm. We propose that a fruitful alternative way to approach the question is through an account of aesthetic engagement. We develop an alternative to the dominant account of the relationship between players and the actions of their characters, and argue that the ethical difference between so-called “virtual murder” and “virtual pedophilia” is to be understood in terms of the fiction-making resources available to players. We propose that the relevant considerations for potential players to navigate concern (1) attempting to make certain characters intelligible, and (2) using aspects of oneself as resources for homomorphic representation.Peer reviewe

Adjusting to Retirement from Sport: Narratives of Former Competitive Rhythmic Gymnasts

This study used narrative inquiry to understand the retirement experiences of rhythmic gymnasts. Eight female former competitive gymnasts (M age = 24.5, SD = 8.33) each participated in four life-history interviews. Following dialogical narrative analysis, three narrative typologies were outlined: Entangled Narrative, Going Forward Narrative, and Making Sense Narrative. The entangled narrative shows an individual with a monological athletic identity, who is unable to develop a new identity following her retirement to the detriment of her well-being, and wishes to return to being a gymnast. The going-forward narrative describes those former gymnasts who were able to develop multiple identities during their gymnastics career, and are now flourishing in their life post-retirement. The making-sense narrative is an emergent narrative, which transcends the previous two narratives. Findings expand narrative research by providing new narrative resources to understand the experience of retirement from gymnastics. These narrative resources might assist gymnasts to expand their narrative repertoire by raising awareness of different narratives available in their culture

Optimising the spatial planning of prescribed burns to achieve multiple objectives in a fire-dependent ecosystem

1. There is potential for negative consequences for the ecological integrity of fire-dependent ecosystems as a result of inappropriate fire regimes. This can occur when asset (property) protection is prioritised over conservation objectives in burn programs

Enhanced tonic GABAA inhibition in typical absence epilepsy

The cellular mechanisms underlying typical absence seizures, which characterize various idiopathic generalized epilepsies, are not fully understood, but impaired GABAergic inhibition remains an attractive hypothesis. In contrast, we show here that extrasynaptic GABAA receptor–dependent ‘tonic’ inhibition is increased in thalamocortical neurons from diverse genetic and pharmacological models of absence seizures. Increased tonic inhibition is due to compromised GABA uptake by the GABA transporter GAT–1 in the genetic models tested, and GAT–1 is critical in governing seizure genesis. Extrasynaptic GABAA receptors are a requirement for seizures in two of the best characterized models of absence epilepsy, and the selective activation of thalamic extrasynaptic GABAA receptors is sufficient to elicit both electrographic and behavioural correlates of seizures in normal animals. These results identify an apparently common cellular pathology in typical absence seizures that may have epileptogenic significance, and highlight novel therapeutic targets for the treatment of absence epilepsy.peer-reviewe