Trends, Variation, and Factors Influencing Antibiotic Prescribing: A Longitudinal Study in Primary Care Using a Multilevel Modelling Approach

Antimicrobial resistance has become one of the greatest threats to global health. Over 80% of antibiotics are prescribed in primary care, with many prescriptions considered to be issued inappropriately. The aim of this study was to examine the association between prescribing rates and demographic, practice, geographic, and socioeconomic characteristics using a multilevel modelling approach. Antibiotic prescribing data by 320 GP surgeries in Northern Ireland were obtained from Business Services Organisation for the years 2014–2020. A linear mixed-effects model was used to identify factors influencing antibiotic prescribing rates. Overall, the number of antibacterial prescriptions decreased by 26.2%, from 1,564,707 items in 2014 to 1,155,323 items in 2020. Lower levels of antibiotic prescribing were associated with urban practices (p < 0.001) and practices in less deprived areas (p = 0.005). The overall decrease in antibacterial drug prescriptions over time was larger in less deprived areas (p = 0.03). Higher prescribing rates were linked to GP practices located in areas with a higher percentage of the population aged ≥65 (p < 0.001) and <15 years (p < 0.001). There were also significant regional differences in antibiotic prescribing. We advocate that any future antibiotic prescribing targets should account for local factors

Contemporary Management of Stent Failure: Part One

The occurrence of in-stent restenosis (ISR) still remains a daunting challenge in the current era, despite advancements in coronary intervention technology. The authors explore the underlying pathophysiology and mechanisms behind ISR, and describe how the use of different diagnostic tools helps to best elucidate these. They propose a simplistic algorithm to manage ISR, including a focus on how treatment strategies should be selected and a description of the contemporary technologies available. This article aims to provide a comprehensive outline of ISR that can be translated into evidence-based routine clinical practice, with the aim of providing the best outcomes for patients

Long-term anaesthesia of broiler chickens

Objective To provide stable anaesthesia of long duration in broiler chickens in order to perform a terminal caecal ligated loop procedure. Study design Prospective experimental study. Animals Seven clinically healthy broiler chickens (Gallus domesticus) aged 27–36 days, weighing 884–2000 g. Methods Anaesthesia was induced and maintained with isoflurane in oxygen. All birds underwent intermittent positive pressure ventilation for the duration. End-tidal carbon dioxide, peripheral haemoglobin oxygen saturation, heart rate and oesophageal temperature were monitored continuously. All birds received intraosseous fluids. Butorphanol (2 mg kg–1) was administered intramuscularly at 2 hourly intervals. Euthanasia by parenteral pentobarbitone was performed at the end of procedure. Results Stable anaesthesia was maintained in four chickens for durations ranging from 435 to 510 minutes. One bird died and one was euthanized after 130 and 330 minutes, respectively, owing to surgical complications and another died from anaesthetic complication after 285 minutes. Conclusions and clinical relevance Long-term, stable anaesthesia is possible in clinically healthy chickens, provided complications such as hypothermia and hypoventilation are addressed and vital signs are carefully monitored. There are no known previous reports describing monitored, controlled anaesthesia of this duration in chickens

The PRECISE (PREgnancy Care Integrating translational Science, Everywhere) Network’s first protocol: deep phenotyping in three sub-Saharan African countries

Background: The PRECISE (PREgnancy Care Integrating translational Science, Everywhere) Network is a new and broadly-based group of research scientists and health advocates based in the UK, Africa and North America. Methods: This paper describes the protocol that underpins the clinical research activity of the Network, so that the investigators, and broader global health community, can have access to ‘deep phenotyping’ (social determinants of health, demographic and clinical parameters, placental biology and agnostic discovery biology) of women as they advance through pregnancy to the end of the puerperium, whether those pregnancies have normal outcomes or are complicated by one/more of the placental disorders of pregnancy (pregnancy hypertension, fetal growth restriction and stillbirth). Our clinical sites are in The Gambia (Farafenni), Kenya (Kilifi County), and Mozambique (Maputo Province). In each country, 50 non-pregnant women of reproductive age will be recruited each month for 1 year, to provide a final national sample size of 600; these women will provide culturally-, ethnically-, seasonallyand spatially-relevant control data with which to compare women with normal and complicated pregnancies. Between the three countries we will recruit ≈10,000 unselected pregnant women over 2 years. An estimated 1500 women will experience one/more placental complications over the same epoch. Importantly, as we will have accurate gestational age dating using the TraCer device, we will be able to discriminate between fetal growth restriction and preterm birth. Recruitment and follow-up will be primarily facility-based and will include women booking for antenatal care, subsequent visits in the third trimester, at time-of-disease, when relevant, during/ immediately after birth and 6 weeks after birth. Conclusions: To accelerate progress towards the women’s and children’s health-relevant Sustainable Development Goals, we need to understand how a variety of social, chronic disease, biomarker and pregnancy-specific determinants health interact to result in either a resilient or a compromised pregnancy for either mother or fetus/ newborn, or both. This protocol has been designed to create such a depth of understanding. We are seeking funding to maintain the cohort to better understand the implications of pregnancy complications for both maternal and child health

Harnessing the PRECISE network as a platform to strengthen global capacity for maternal and child health research in sub-Saharan Africa

It is widely acknowledged across the global health sector that research programmes need to be designed and implemented in a way that maximise opportunities for strengthening local capacity. This paper examines how the United Kingdom Research and Innovation (UKRI) Grand Challenges Research Fund (GCRF) funded PRECISE (PREgnancy Care Integrating translational Science, Everywhere) Network has been established as a platform to strengthen global capacity for research focused on the improvement of maternal, fetal and newborn health in subSaharan Africa. Best practice principles outlined in an ESSENCE on Health Research report have been considered in relation to the PRECISE Network capacity-building activities described in this paper. These activities are described at the individual, programmatic and institutional levels, and successes, challenges and recommendations for future work are outlined. The paper concludes that the PRECISE leadership have an opportunity to review and refresh activity plans for capacity building at this stage in the project to build on achievements to date

Prebiotic Driven Increases in IL-17A Do Not Prevent Campylobacter jejuni Colonization of Chickens

© Copyright © 2020 Flaujac Lafontaine, Richards, Connerton, O’Kane, Ghaffar, Cummings, Fish and Connerton. Worldwide Campylobacter jejuni is a leading cause of foodborne disease. Contamination of chicken meat with digesta from C. jejuni-positive birds during slaughter and processing is a key route of transmission to humans through the food chain. Colonization of chickens with C. jejuni elicits host innate immune responses that may be modulated by dietary additives to provide a reduction in the number of campylobacters colonizing the gastrointestinal tract and thereby reduce the likelihood of human exposure to an infectious dose. Here we report the effects of prebiotic galacto-oligosaccharide (GOS) on broiler chickens colonized with C. jejuni when challenged at either an early stage in development at 6 days of age or 20 days old when campylobacters are frequently detected in commercial flocks. GOS-fed birds had increased growth performance, but the levels of C. jejuni colonizing the cecal pouches were unchanged irrespective of the age of challenge. Dietary GOS modulated the immune response to C. jejuni by increasing cytokine IL-17A expression at colonization. Correspondingly, reduced diversity of the cecal microbiota was associated with Campylobacter colonization in GOS-fed birds. In birds challenged at 6 days-old the reduction in microbial diversity was accompanied by an increase in the relative abundance of Escherichia spp. Whilst immuno-modulation of the Th17 pro-inflammatory response did not prevent C. jejuni colonization of the intestinal tract of broiler chickens, the study highlights the potential for combinations of prebiotics, and specific competitors (synbiotics) to engage with the host innate immunity to reduce pathogen burdens

Co-designing opportunities for human-centred machine learning in supporting type 1 diabetes decision-making

Type 1 Diabetes (T1D) self-management requires hundreds of daily decisions. Diabetes technologies that use machine learning have significant potential to simplify this process and provide better decision support, but often rely on cumbersome data logging and cognitively demanding reflection on collected data. We set out to use co-design to identify opportunities for machine learning to support diabetes self-management in everyday settings. However, over nine months of interviews and design workshops with 15 people with T1D, we had to re-assess our assumptions about user needs. Our participants reported confidence in their personal knowledge and rejected machine learning based decision support when coping with routine situations, but highlighted the need for technological support in the context of unfamiliar or unexpected situations (holidays, illness, etc.). However, these are the situations where prior data are often lacking and drawing data-driven conclusions is challenging. Reflecting this challenge, we provide suggestions on how machine learning and other artificial intelligence approaches, e.g., expert systems, could enable decision-making support in both routine and unexpected situations

IL4Rα signaling abrogates hypoxic neutrophil survival and limits acute lung injury responses <i>in vivo</i>

Rationale: Acute respiratory distress syndrome is defined by the presence of systemic hypoxia and consequent on disordered neutrophilic inflammation. Local mechanisms limiting the duration and magnitude of this neutrophilic response remain poorly understood.  Objectives: To test the hypothesis that during acute lung inflammation tissue production of proresolution type 2 cytokines (IL-4 and IL-13) dampens the proinflammatory effects of hypoxia through suppression of HIF-1a (hypoxia-inducible factor-1a)mediated neutrophil adaptation, resulting in resolution of lung injury.  Methods: Neutrophil activation of IL4Ra (IL-4 receptor a) signaling pathways was explored ex vivo in human acute respiratory distress syndrome patient samples, in vitro after the culture of human peripheral blood neutrophils with recombinant IL-4 under conditions of hypoxia, and in vivo through the study of IL4Ra-deficient neutrophils in competitive chimera models and wild-type mice treated with IL-4.  Measurements and Main Results: IL-4 was elevated in human BAL from patients with acute respiratory distress syndrome, and its receptor was identified on patient blood neutrophils. Treatment of human neutrophils with IL-4 suppressed HIF-1a-dependent hypoxic survival and limited proinflammatory transcriptional responses. Increased neutrophil apoptosis in hypoxia, also observed with IL-13, required active STAT signaling, and was dependent on expression of the oxygen-sensing prolyl hydroxylase PHD2. In vivo, IL-4Ra-deficient neutrophils had a survival advantage within a hypoxic inflamed niche; in contrast, inflamed lung treatment with IL-4 accelerated resolution through increased neutrophil apoptosis.  Conclusions: We describe an important interaction whereby IL4Ra-dependent type 2 cytokine signaling can directly inhibit hypoxic neutrophil survival in tissues and promote resolution of neutrophil-mediated acute lung injury

Consequences Matter : Compassion in Conservation Means Caring for Individuals, Populations and Species

Funding This research received no external funding. Acknowledgments The manuscript benefitted from significant input from Dan Brockington, J.B. Callicott, Peter Coals, Tim Hodgetts, David Macdonald and Jeremy Wilson. Conflicts of Interest The authors declare no conflict of interest.Peer reviewedPublisher PD

Achieving Optimal Medical Therapy: Insights From the ORBITA Trial

Background: In stable coronary artery disease, medications are used for 2 purposes: cardiovascular risk reduction and symptom improvement. In clinical trials and clinical practice, medication use is often not optimal. The ORBITA (Objective Randomised Blinded Investigation With Optimal Medical Therapy of Angioplasty in Stable Angina) trial was the first placebo-controlled trial of percutaneous coronary intervention. A key component of the ORBITA trial design was the inclusion of a medical optimization phase, aimed at ensuring that all patients were treated with guideline-directed truly optimal medical therapy. In this study, we report the medical therapy that was achieved. Methods and Results: After enrollment into the ORBITA trial, all 200 patients entered a 6-week period of intensive medical therapy optimization, with initiation and uptitration of risk reduction and antianginal therapy. At the prerandomization stage, the median number of antianginals established was 3 (interquartile range, 2-4). A total of 195 patients (97.5%) reached the prespecified target of ≥2 antianginals; 136 (68.0%) did not stop any antianginals because of adverse effects, and the median number of antianginals stopped for adverse effects per patient was 0 (interquartile range, 0-1). Amlodipine and bisoprolol were well tolerated (stopped for adverse effects in 4/175 [2.3%] and 9/167 [5.4%], respectively). Ranolazine and ivabradine were also well tolerated (stopped for adverse effects in 1/20 [5.0%] and 1/18 [5.6%], respectively). Isosorbide mononitrate and nicorandil were stopped for adverse effects in 36 of 172 (20.9%) and 32 of 141 (22.7%) of patients, respectively. Statins were well tolerated and taken by 191 of 200 (95.5%) patients. Conclusions: In the 12-week ORBITA trial period, medical therapy was successfully optimized and well tolerated, with few drug adverse effects leading to therapy cessation. Truly optimal medical therapy can be achieved in clinical trials, and translating this into longer-term clinical practice should be a focus of future study. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02062593