Mechanisms of checkpoint inhibition-induced adverse events.

Immune checkpoint inhibition has revolutionized the treatment of several solid cancers, most notably melanoma and non-small-cell lung cancer (NSCLC). Drugs targeting cytotoxic T lymphocyte antigen (CTLA)-4 and programmed cell death 1 (PD-1) have made their way into routine clinical use; however, this has not been without difficulties. Stimulation of the immune system to target cancer has been found to result in a reduction of self-tolerance, leading to the development of adverse effects that resemble autoimmunity. These adverse effects are erratic in their onset and severity and can theoretically affect any organ type. Several mechanisms for immune-related toxicity have been investigated over recent years; however, no consensus on the cause or prediction of toxicity has been reached. This review seeks to examine reported evidence for possible mechanisms of toxicity, methods for prediction of those at risk and a discussion of future prospects within the field.

Depressive symptoms in inflammatory bowel disease: an extraintestinal manifestation of inflammation?

Depressive symptoms are reported by more than 20% of people with inflammatory bowel disease (IBD), while sleep difficulties and fatigue are even more common. Co-morbid depressive symptoms predict a poor IBD course, including increased risk of relapse and surgery, which is inconsistently improved by psychological treatments. Rather than being distinct systems, there is compelling evidence for bidirectional communication between gut and brain, driven by neural, metabolic, endocrine and inflammatory mediators. An emerging concept is that depressive symptoms may be mechanistically linked to excess inflammation and dysregulation of the gut-brain axis. Given the close link between the intestinal microbiota and host immune responses, patients prone to shifts in their intestinal microbiome, including smokers, those with poor diet and early life stress, may be exposed to exaggerated immune responses. Excess inflammation is associated with brain changes (depressive symptoms, fatigue, sleep difficulties) and worsening gastrointestinal symptoms, which are exacerbated by psychological distress. Equally, treatments both for depressive symptoms and IBD provide opportunities to break this cycle by reducing the causes and effects of inflammation. As well as addressing potential risk factors such as smoking and diet, treatments to alter the microbiome may reduce depressive symptoms. Observational evidence suggests that anti-inflammatory treatments for IBD may improve co-morbid depressive symptoms correlating with reduction in inflammation. With a growing range of treatments targeting inflammation centrally, peripherally and in the gut, IBD provides a unique model to understand the interplay between brain and gut in the pathogenesis of depressive symptoms, both in IBD and in the whole population.

Recurrence of vulval intraepithelial neoplasia following treatment with cidofovir or imiquimod: results from a multicentre, randomised, phase II trial (RT3VIN).

OBJECTIVE: To compare the recurrence rates after complete response to topical treatment with either cidofovir or imiquimod for vulval intraepithelial neoplasia (VIN) 3. DESIGN: A prospective, open, randomised multicentre trial. SETTING: 32 general hospitals located in Wales and England. POPULATION OR SAMPLE: 180 patients were randomised consecutively between 21 October 2009 and 11 January 2013, 89 to cidofoovir (of whom 41 completely responded to treatment) and 91 to imiquimod (of whom 42 completely responded to treatment). METHODS: After 24 weeks of treatment, complete responders were followed up at 6-monthly intervals for 24 months. At each visit, the Common Terminology Criteria for Adverse Events (CTCAE) v3.0 was assessed and any new lesions were biopsied for histology. MAIN OUTCOME MEASURES: Time to histologically confirmed disease recurrence (any grade of VIN). RESULTS: The median length of follow up was 18.4 months. At 18 months, more participants were VIN-free in the cidofovir arm: 94% (95% CI 78.2-98.5) versus 71.6% (95% CI 52.0-84.3) [univariable hazard ratio (HR) 3.46, 95% CI 0.95-12.60, P = 0.059; multivariable HR 3.53, 95% CI 0.96-12.98, P = 0.057). The number of grade 2+ events was similar between treatment arms (imiquimod: 24/42 (57%) versus cidofovir: 27/41 (66%), χ2 = 0.665, P = 0.415), with no grade 4+. CONCLUSIONS: Long-term data indicates a trend towards response being maintained for longer following treatment with cidofovir than with imiquimod, with similar low rates of adverse events for each drug. Adverse event rates indicated acceptable safety of both drugs TWEETABLE ABSTRACT: Long-term follow up in the RT3VIN trial suggests cidofovir may maintain response for longer than imiquimod.

Tissue magnetic susceptibility mapping as a marker of tau pathology in Alzheimer's disease.

Alzheimer's disease is connected to a number of other neurodegenerative conditions, known collectively as 'tauopathies', by the presence of aggregated tau protein in the brain. Neuroinflammation and oxidative stress in AD are associated with tau pathology and both the breakdown of axonal sheaths in white matter tracts and excess iron accumulation grey matter brain regions. Despite the identification of myelin and iron concentration as major sources of contrast in quantitative susceptibility maps of the brain, the sensitivity of this technique to tau pathology has yet to be explored. In this study, we perform Quantitative Susceptibility Mapping (QSM) and T2* mapping in the rTg4510, a mouse model of tauopathy, both in vivo and ex vivo. Significant correlations were observed between histological measures of myelin content and both mean regional magnetic susceptibility and T2* values. These results suggest that magnetic susceptibility is sensitive to tissue myelin concentrations across different regions of the brain. Differences in magnetic susceptibility were detected in the corpus callosum, striatum, hippocampus and thalamus of the rTg4510 mice relative to wild type controls. The concentration of neurofibrillary tangles was found to be low to intermediate in these brain regions indicating that QSM may be a useful biomarker for early stage detection of tau pathology in neurodegenerative diseases.

Recent advances in gut immunology.

In recent years, there have been significant advances in our understanding of the mucosal immune system. In addition to unravelling some of the complexities of this system, including the discovery of completely new cells types, further insights into the three-way interactions between mucosal immune cells, the intestinal epithelium and the microbial communities colonizing the GI tract promise to redefine our understanding of how intestinal homeostasis is maintained, but also how dysregulation of these highly integrated interactions conspires to cause disease. In this review, we will discuss major recent advances in the role of key immune players in the gut, including innate lymphoid cells (ILCs), mucosa-associated invariant T cells (MAIT cells) and cells of the mononuclear phagocyte system (MPS), including how these cells interact with the intestinal epithelial and their crosstalk with components of the intestinal microbiota, and how these interactions shape host health.

Exploring why a complex intervention piloted in general practices did not result in an increase in chlamydia screening and diagnosis: a qualitative evaluation using the fidelity of implementation model.

BACKGROUND: Chlamydia trachomatis (chlamydia) is the most commonly diagnosed sexually transmitted infection (STI) in England; approximately 70% of diagnoses are in sexually active young adults aged under 25. To facilitate opportunistic chlamydia screening in general practice, a complex intervention, based on a previously successful Chlamydia Intervention Randomised Trial (CIRT), was piloted in England. The modified intervention (3Cs and HIV) aimed to encourage general practice staff to routinely offer chlamydia testing to all 15-24 year olds regardless of the type of consultation. However, when the 3Cs (chlamydia screening, signposting to contraceptive services, free condoms) and HIV was offered to a large number of general practitioner (GP) surgeries across England, chlamydia screening was not significantly increased. This qualitative evaluation addresses the following aims: a) Explore why the modified intervention did not increase screening across all general practices. b) Suggest recommendations for future intervention implementation. METHODS: Phone interviews were carried out with 26 practice staff, at least 5 months after their initial educational workshop, exploring their opinions on the workshop and intervention implementation in the real world setting. Interview transcripts were thematically analysed and further examined using the fidelity of implementation model. RESULTS: Participants who attended had a positive attitude towards the workshops, but attendee numbers were low. Often, the intervention content, as detailed in the educational workshops, was not adhered to: practice staff were unaware of any on-going trainer support; computer prompts were only added to the female contraception template; patients were not encouraged to complete the test immediately; complete chlamydia kits were not always readily available to the clinicians; and videos and posters were not utilised. Staff reported that financial incentives, themselves, were not a motivator; competing priorities and time were identified as major barriers. CONCLUSION: Not adhering to the exact intervention model may explain the lack of significant increases in chlamydia screening. To increase fidelity of implementation outside of Randomised Controlled Trial (RCT) conditions, and consequently, improve likelihood of increased screening, future public health interventions in general practices need to have: more specific action planning within the educational workshop; computer prompts added to systems and used; all staff attending the workshop; and on-going practice staff support with feedback of progress on screening and diagnosis rates fed back to all staff.

In vivo imaging of tau pathology using multi-parametric quantitative MRI.

As the number of people diagnosed with Alzheimer's disease (AD) reaches epidemic proportions, there is an urgent need to develop effective treatment strategies to tackle the social and economic costs of this fatal condition. Dozens of candidate therapeutics are currently being tested in clinical trials, and compounds targeting the aberrant accumulation of tau proteins into neurofibrillary tangles (NFTs) are the focus of substantial current interest. Reliable, translatable biomarkers sensitive to both tau pathology and its modulation by treatment along with animal models that faithfully reflect aspects of the human disease are urgently required. Magnetic resonance imaging (MRI) is well established as a valuable tool for monitoring the structural brain changes that accompany AD progression. However the descent into dementia is not defined by macroscopic brain matter loss alone: non-invasive imaging measurements sensitive to protein accumulation, white matter integrity and cerebral haemodynamics probe distinct aspects of AD pathophysiology and may serve as superior biomarkers for assessing drug efficacy. Here we employ a multi-parametric array of five translatable MRI techniques to characterise the in vivo pathophysiological phenotype of the rTg4510 mouse model of tauopathy (structural imaging, diffusion tensor imaging (DTI), arterial spin labelling (ASL), chemical exchange saturation transfer (CEST) and glucose CEST). Tau-induced pathological changes included grey matter atrophy, increased radial diffusivity in the white matter, decreased amide proton transfer and hyperperfusion. We demonstrate that the above markers unambiguously discriminate between the transgenic group and age-matched controls and provide a comprehensive profile of the multifaceted neuropathological processes underlying the rTg4510 model. Furthermore, we show that ASL and DTI techniques offer heightened sensitivity to processes believed to precede detectable structural changes and, as such, provides a platform for the study of disease mechanisms and therapeutic intervention.

Can someone call my PA?

The aim of this paper is to outline the background of the Physician Associate (known in the USA as physician assistant¹) role in the USA and follow its recent journey to the UK where it is becoming a rapidly developing new healthcare role. Through the use of two case studies from UK Hospital Trusts who are currently utilising Physician Associates (PAs) in their workforce we describe the implementation and development opportunities for the role, with particular reference to their role in Acute Medicine teams of the future.

Stripe rust resistance genes in the UK winter wheat cultivar Claire.

Stripe rust resistance in the winter wheat cultivar Claire had remained effective in the UK and Europe since its release in 1999 and consequently has been used extensively in wheat breeding programs. However, in 2012, reports indicated that this valuable resistance may now have been compromised. To characterise stripe rust resistance in Claire and determine which genes may still confer effective resistance a cross was made between Claire and the stripe rust susceptible cultivar Lemhi. A genetic linkage map, constructed using SSR, AFLP, DArT and NBS-AFLP markers had a total map length of 1,730 cM. To improve the definition of two quantitative trait loci (QTL) identified on the long arm of chromosome 2D further markers were developed from wheat EST. Stripe rust resistance was evaluated on adult plants under field and glasshouse conditions by measuring the extent of fungal growth and sporulation, percentage infection (Pi) and the necrotic/chlorotic responses of the plant to infection, infection type (IT). Four QTL contributing to stripe rust adult plant resistance (APR) were identified in Claire, QYr.niab-2D.1, QYr.niab-2D.2, QYr.niab-2B and QYr.niab-7B. For Pi QYr.niab-2D.1 explained up to 25.4 % of the phenotypic variation, QYr.niab-2D.2 up to 28.7 %, QYr.niab-2B up to 21.7 % and QYr.niab-7B up to 13.0 %. For IT the percentages of phenotypic variation explained were 23.4, 31.8, 17.2 and 12.6 %, respectively. In addition to the four QTL conferring APR in Claire, a race-specific, seedling expressed resistance gene was identified on chromosome 3B.

Psychosocial stress and inflammation in cancer.

Stress-induced immune dysregulation results in significant health consequences for immune related disorders including viral infections, chronic autoimmune disease, and tumor growth and metastasis. In this mini-review we discuss the sympathetic, neuroendocrine and immunologic mechanisms by which psychosocial stress can impact cancer biology. Both human and animal studies have shown the sympathetic and neuroendocrine responses to psychosocial stress significantly impacts cancer, in part, through regulation of inflammatory mediators. Psychosocial stressors stimulate neuroendocrine, sympathetic, and immune responses that result in the activation of the hypothalamic-pituitary-adrenal (HPA)-axis, sympathetic nervous system (SNS), and the subsequent regulation of inflammatory responses by immune cells. Social disruption (SDR) stress, a murine model of psychosocial stress and repeated social defeat, provides a novel and powerful tool to probe the mechanisms leading to stress-induced alterations in inflammation, tumor growth, progression, and metastasis. In this review, we will focus on SDR as an important model of psychosocial stress in understanding neural-immune mechanisms in cancer.

Effect of whey storage on biogas produced by co-digestion of sewage sludge and whey.

Biogas production from municipal anaerobic digesters could potentially be boosted via co-digestion with organic wastes such as whey. The challenge is that whey production is seasonal. This research examined the effect of storing whey at ambient temperature on: (1) whey composition; (2) biogas production from co-digestion of the stored whey with municipal primary sludge. Whey storage resulted in acidification with formation of acetate, propionate and butyrate and a 9% reduction in total chemical oxygen demand (COD) over the 9-month trial. A control digester fed with primary sludge produced 0.18-0.23 m3 CH4/kgCOD(added). Co-digestion of fresh whey and sludge increased biogas production and the methane contribution from the whey was 0.29 m3CH4/kgCOD(added). When the fresh whey was substituted with stored whey, methane production by the whey remained at 0.29 m3CH4/kgCOD(added). The ability to store whey at ambient temperature and allow co-digestion year round will significantly improve the economics of biogas production from whey.

Enhanced biogas production using cow manure to stabilize co-digestion of whey and primary sludge.

Increasing biogas production from municipal anaerobic digesters via additional loading with industrial/agricultural wastes offers a low-cost, sustainable energy generation option of significant untapped potential. In this work, bench-top reactors were used to mimic a full-scale primary sludge digester operating at an organic loading rate (OLR) of 2.4 kg COD/m3 d and a 20 d hydraulic retention time (HRT). Co-digestion of whey with primary sludge was sustained at a loading rate of 3.2 kg COD/m3 d (17 d HRT) and boosted gas production to 151% compared to primary sludge digestion alone. Addition of chemical alkalinity enabled co-digestion of whey with primary sludge to be maintained at an elevated OLR of 6.4 kg COD/m3 d (11 d HRT) with gas production increased to 208%. However, when the chemical addition was simply replaced by cow manure, stable operation was maintained at OLRs of 5.2-6.9 kg COD/m3 d (11-14 d HRT) with gas production boosted up to 268%.

Effect of diindolylmethane supplementation on low-grade cervical cytological abnormalities: double-blind, randomised, controlled trial.

BACKGROUND: Cervical screening identifies many women with low-grade abnormalities. In vitro and in vivo studies have shown that diindolylmethane (DIM) could potentially halt (cervical) carcinogenesis. We report on a randomised controlled trial of the effect of DIM in women with low-grade cervical cytological abnormalities. METHODS: We conducted a pragmatic double-blind, randomised controlled trial of 150 mg DIM (from BioResponse DIM) or placebo daily for 6 months in women with newly diagnosed, low-grade cytological abnormalities. Randomisation was in the ratio 2 (DIM) to 1 (placebo). All women were invited for colposcopy at 6 months with biopsy of any abnormality. RESULTS: Of the 551 randomised women available for analysis, 9% on DIM and 12% on placebo had cervical intraepithelial neoplasia-2 (CIN2) or worse after 6-month supplementation (risk ratio (RR) 0.7 (95% confidence interval (CI): 0.4-1.2)), whereas 4.6% and 5.1%, respectively, had CIN3 or worse (RR 0.9 (95% CI: 0.4-2.0)). A total of 27.3% of women on DIM and 34.3% on placebo had no sign of disease (negative cytology, colposcopy and human papilloma virus (HPV) tests) at 6 months (RR 0.8 (95% CI: 0.6-1.0)). Of those HPV-positive at baseline, 69% (114 out of 166) of the DIM group were positive at 6 months compared with 61% (43 out of 71) of the placebo group: RR 1.1 (95% CI: 0.9-1.4). Diindolylmethane supplementation was well tolerated. CONCLUSION: The results suggest that short-term DIM supplementation (150 mg day(-1)) is well tolerated, but is unlikely to have an effect on cytology or HPV infection. Uncertainty remains regarding its effect on CIN2+.

Helicobacter pylori induces in-vivo expansion of human regulatory T cells through stimulating interleukin-1ß production by dendritic cells.

Helicobacter pylori is one of the most common infections in the world. Despite inciting inflammation, immunological clearance of the pathogen is often incomplete. CD4(+) CD25(hi) forkhead box protein 3 (FoxP3(+)) regulatory T cells (T(regs)) are potent suppressors of different types of immune responses and have been implicated in limiting inflammatory responses to H. pylori. Investigating the influence of H. pylori on T(reg) function and proliferation, we found that H. pylori-stimulated dendritic cells (DCs) induced proliferation in T(regs) and impaired their suppressive capability. This effect was mediated by interleukin (IL)-1ß produced by H. pylori-stimulated DCs. These data correlated with in-vivo observations in which H. pylori(+) gastric mucosa contained more T(regs) in active cell division than uninfected stomachs. Inciting local proliferation of T(regs) and inhibiting their suppressive function may represent a mechanism for the chronic gastritis and carcinogenesis attributable to H. pylori.

Beta adrenergic blockade decreases the immunomodulatory effects of social disruption stress.

During physiological or psychological stress, catecholamines produced by the sympathetic nervous system (SNS) regulate the immune system. Previous studies report that the activation of ß-adrenergic receptors (ßARs) mediates the actions of catecholamines and increases pro-inflammatory cytokine production in a number of different cell types. The impact of the SNS on the immune modulation of social defeat has not been examined. The following studies were designed to determine whether SNS activation during social disruption stress (SDR) influences anxiety-like behavior as well as the activation, priming, and glucocorticoid resistance of splenocytes after social stress. CD-1 mice were exposed to one, three, or six cycles of SDR and HPLC analysis of the plasma and spleen revealed an increase in catecholamines. After six cycles of SDR the open field test was used to measure behaviors characteristic of anxiety and indicated that the social defeat induced increase in anxiety-like behavior was blocked by pre-treatment with the ß-adrenergic antagonist propranolol. Pre-treatment with the ß-adrenergic antagonist propranolol did not significantly alter corticosterone levels indicating no difference in activation of the hypothalamic-pituitary-adrenal axis. In addition to anxiety-like behavior the SDR induced splenomegaly and increase in plasma IL-6, TNFα, and MCP-1 were each reversed by pre-treatment with propranolol. Furthermore, flow cytometric analysis of cells from propranolol pretreated mice reduced the SDR-induced increase in the percentage of CD11b(+) splenic macrophages and significantly decreased the expression of TLR2, TLR4, and CD86 on the surface of these cells. In addition, supernatants from 18h LPS-stimulated ex vivo cultures of splenocytes from propranolol-treated SDR mice contained less IL-6. Likewise propranolol pre-treatment abrogated the glucocorticoid insensitivity of CD11b(+) cells ex vivo when compared to splenocytes from SDR vehicle-treated mice. Together, this study demonstrates that the immune activation and priming effects of SDR result, in part, as a consequence of SNS activation.

Images of the terminal ileum are more convincing than cecal images for verifying the extent of colonoscopy.

BACKGROUND AND STUDY AIMS: Independent verification of colonoscopy completion is important for quality assurance. Cecal photographs aimed at showing key landmarks, including the ileocecal valve (ICV) and appendiceal orifice are the currently recommended standard, but are often perceived as unreliable. Images of the terminal ileum demonstrating villi may provide more robust evidence of completion. We sought to prospectively evaluate the ease of routine intubation of the terminal ileum and to compare the effectiveness of terminal ileum and cecal photographs in convincing independent reviewers that total colonoscopy had been accomplished. PATIENTS AND METHODS: A prospective, observational study evaluated 216 consecutively completed colonoscopies performed in routine clinical practice. Cecal and terminal ileum photographs were evaluated and scored by independent reviewers. Frequency of terminal ileum intubation, time required, and safety parameters were recorded. RESULTS: The terminal ileum was intubated and photographed in 188/216 (87%) of cases. Median time taken to intubate, or attempt to intubate the terminal ileum was 1 min 24 s, and was achieved without complications or requirement for additional sedation. Terminal ileum images were significantly more likely to be considered convincing than cecal images ( P<0.0001 for all reviewers). There was excellent interobserver agreement amongst the opinion of reviewers regarding terminal ileum photographs (kappa=0.91). CONCLUSION: Terminal ileum intubation is achievable rapidly and safely in the majority of patients undergoing colonoscopy. Terminal ileum images provide more convincing evidence of complete examination of the colon than cecal images, even when attempts to capture images specifically of the ICV and appendiceal orifice are made.

Luxury uptake of phosphorus by microalgae in full-scale waste stabilisation ponds.

Biological phosphorus removal was studied in two full-scale waste stabilisation ponds (WSP). Luxury uptake by microalgae was confirmed to occur and in one pond the biomass contained almost four times the phosphorus required by microalgae for normal metabolism. However, the phosphorus content within the biomass was variable. This finding means that assumptions made in prior publications on modelling of phosphorus removal in WSP are questionable. While fluctuations in microalgal growth causes variation in many water quality parameters, this further variation in luxury uptake explains the high degree of variability in phosphorus removal commonly reported in the literature. To achieve effective biological phosphorus removal high levels of both luxury uptake and microalgal concentration are needed. The findings of this work show that while high levels of these parameters did occur at times in the WSP monitored, they did not occur simultaneously. This is explained because accumulated phosphorus is subsequently consumed during rapid growth of biomass resulting in a high biomass concentration with a low phosphorus content. Previous laboratory research has allowed a number of key considerations to be proposed to optimise both luxury uptake and biomass concentration. Now that is has been shown that high levels of biomass concentration and luxury uptake can occur in the field it may be possible to redesign WSP to optimise these parameters.

Phosphate release from waste stabilisation pond sludge: significance and fate of polyphosphate.

Net phosphorus removal from waste stabilisation pond (WSP) systems is governed by the rate of phosphorus incorporation into the sludge layer and the rate of phosphorus release from this sludge back to the overlying wastewater. Luxury uptake of phosphorus by microalgae has been shown to occur under WSP conditions in the laboratory; however, the significance of this mechanism and the fate of polyphosphate contained in the settled solids have not previously been investigated. In this work the analysis of sludge samples from three WSP showed that up to 71% of the total phosphorus in the sludge was in the form of polyphosphate. This indicates that polyphosphate accumulation could potentially be an important mechanism for phosphorus sequestration in WSP and challenges the common view that chemical precipitation is the predominant phosphorus removal mechanism in these systems. The release of phosphate from WSP sludge samples was monitored in the laboratory. The samples from two different pond systems had release rates in the order of 4.3 microgP/gTSS.d. However, the third sample which was collected during an algal bloom had a release rate of 12.4 microgP/gTSS.d. Phosphate release from fresh microalgal sludge grown under laboratory conditions was also studied and was shown to have a release rate of 160 microgP/gTSS.d. Analysis of polyphosphate during the experiments on laboratory grown microalgal sludge showed that polyphosphate was indeed degraded resulting in phosphate release. Interestingly, after the initial release phase phosphorus was assimilated by the biomass and some polyphosphate was reformed. It is likely that this is due to bacterial growth in the sludge.

The impact of penicillin allergy de-labelling on the WHO AWaRe antibiotic categories: a retrospective cohort study.

BACKGROUND: The WHO's AWaRe classification categorizes antibiotics into three stewardship groups: Access, Watch and Reserve. The Access group includes antibiotics with lower resistance potential than antibiotics in the other two groups. The UK five-year AMR strategy has set targets for reducing non-Access antibiotic use. The majority of penicillins are in the Access group and therefore patients with a penicillin allergy record are likely to receive more non-Access antibiotics. This study aimed to quantify the impact of penicillin allergy records on non-Access antibiotic prescribing and to estimate potential reductions in non-Access antibiotic use through penicillin allergy de-labelling. METHODS: Inpatients of a 750-patient-bed UK district general hospital in England prescribed antibiotics between 1st April 2018 and 31st March 2019 were included. Variables included: age, sex, co-morbidity, infection treated, antibiotic usage, hospital length of stay, penicillin allergy status. Multivariable logistic regression was used to explore the association between patient characteristics and their receipt of antibiotics in the Access and non-Access groups. RESULTS: A total of 67,059 antibiotic prescriptions for 23,356 inpatients were analysed. Penicillin allergy records were present in 14.3% of hospital admissions. Patients with a penicillin allergy record were around four times more likely (odds ratio = 4.7) to receive an antibiotic from the non-Access groups (i.e. Reserve and Watch groups). We estimate de-labelling 50% of hospital inpatients with a penicillin allergy record could reduce non-Access antibiotic use by 5.8% and total antibiotic use by 0.86%. CONCLUSION: Penicillin allergy records are associated with non-Access antibiotic prescribing. Penicillin allergy de-labelling has potential to reduce non-Access antibiotic use.

Repeated social stress enhances the innate immune response to a primary HSV-1 infection in the cornea and trigeminal ganglia of Balb/c mice.

Three to 5 days after a primary HSV-1 infection, macrophages infiltrate into the trigeminal ganglia (TG) and produce anti-viral cytokines to reduce viral replication. Previous research demonstrated that social disruption stress (SDR) enhances the trafficking of monocytes/macrophages from the bone marrow to the spleen and increases pro-inflammatory cytokine production in vitro and in vivo. The impact of SDR on the trafficking of these cells to loci of herpes simplex virus type 1 (HSV-1) infection and subsequent function has not been examined. The following studies were designed to determine whether SDR would enhance the innate immune response during a primary HSV-1 infection by increasing the number of macrophages in the cornea and TG, thus increasing anti-viral cytokine production and reducing viral replication. BALB/c mice were exposed to six cycles of SDR prior to ocular infection with HSV-1 McKrae virus. Flow cytometric analysis of cells from the TG revealed an increase in the percentage of CD11b+ macrophages in SDR mice compared to controls. Immune cell infiltration into the cornea, however, could not be determined due to low cell numbers. Although gene expression of IFN-beta was decreased, SDR increased gene expression of IFN-alpha, and TNF-alpha, in the cornea and TG. Examination of viral proteins showed decreased expression of infected cell protein 0 (ICP0), glycoprotein B (gB), glycoprotein H (gH) and latency-associated transcript (LAT) in the TG, however, expression of ICP0 and gB were elevated in the cornea of SDR mice. These results indicate that the innate immune response to HSV-1 was altered and enhanced by the experience of repeated social defeat.