Showing papers by "Barts Health NHS Trust published in 2014"

Myocardial Injury after Noncardiac Surgery: A Large, International, Prospective Cohort Study Establishing Diagnostic Criteria, Characteristics, Predictors, and 30-day Outcomes

Abstract: Background Myocardial injury after noncardiac surgery (MINS) was defined as prognostically relevant myocardial injury due to ischemia that occurs during or within 30 days after noncardiac surgery. The study's four objectives were to determine the diagnostic criteria, characteristics, predictors, and 30-day outcomes of MINS. Methods In this international, prospective cohort study of 15,065 patients aged 45 yr or older who underwent in-patient noncardiac surgery, troponin T was measured during the first 3 postoperative days. Patients with a troponin T level of 0.04 ng/ml or greater (elevated "abnormal" laboratory threshold) were assessed for ischemic features (i.e., ischemic symptoms and electrocardiography findings). Patients adjudicated as having a nonischemic troponin elevation (e.g., sepsis) were excluded. To establish diagnostic criteria for MINS, the authors used Cox regression analyses in which the dependent variable was 30-day mortality (260 deaths) and independent variables included preoperative variables, perioperative complications, and potential MINS diagnostic criteria. Results An elevated troponin after noncardiac surgery, irrespective of the presence of an ischemic feature, independently predicted 30-day mortality. Therefore, the authors' diagnostic criterion for MINS was a peak troponin T level of 0.03 ng/ml or greater judged due to myocardial ischemia. MINS was an independent predictor of 30-day mortality (adjusted hazard ratio, 3.87; 95% CI, 2.96-5.08) and had the highest population-attributable risk (34.0%, 95% CI, 26.6-41.5) of the perioperative complications. Twelve hundred patients (8.0%) suffered MINS, and 58.2% of these patients would not have fulfilled the universal definition of myocardial infarction. Only 15.8% of patients with MINS experienced an ischemic symptom. Conclusion Among adults undergoing noncardiac surgery, MINS is common and associated with substantial mortality.

Clinical picture and treatment of 2212 patients with common variable immunodeficiency

Abstract: Background Common variable immunodeficiency (CVID) is an antibody deficiency with an equal sex distribution and a high variability in clinical presentation. The main features include respiratory tract infections and their associated complications, enteropathy, autoimmunity, and lymphoproliferative disorders. Objective This study analyzes the clinical presentation, association between clinical features, and differences and effects of immunoglobulin treatment in Europe. Methods Data on 2212 patients with CVID from 28 medical centers contributing to the European Society for Immunodeficiencies Database were analyzed retrospectively. Results Early disease onset ( Conclusion Patients with CVID are being managed differently throughout Europe, affecting various outcome measures. Clinically, CVID is a truly variable antibody deficiency syndrome.

Controlled trial of transfusions for silent cerebral infarcts in sickle cell anemia

Abstract: Background Silent cerebral infarcts are the most common neurologic injury in children with sickle cell anemia and are associated with the recurrence of an infarct (stroke or silent cerebral infarct). We tested the hypothesis that the incidence of the recurrence of an infarct would be lower among children who underwent regular blood-transfusion therapy than among those who received standard care. Methods In this randomized, single-blind clinical trial, we randomly assigned children with sickle cell anemia to receive regular blood transfusions (transfusion group) or standard care (observation group). Participants were between 5 and 15 years of age, with no history of stroke and with one or more silent cerebral infarcts on magnetic resonance imaging and a neurologic examination showing no abnormalities corresponding to these lesions. The primary end point was the recurrence of an infarct, defined as a stroke or a new or enlarged silent cerebral infarct. Results A total of 196 children (mean age, 10 years) we...

Diabetic ketoacidosis and hyperglycemic hyperosmolar state

Abstract: aDivision of Endocrinology, Boston Children’s Hospital, Boston, MA, USA; bBarts Health NHS Trust, Royal London Hospital, London, UK; cInstitute of Endocrinology and Diabetes, The Children’s Hospital at Westmead; School of Women’s and Children’s Health, University of New South Wales, Sydney, Australia; dOxfordshire Children’s Diabetes Service, Oxford Children’s Hospital, Oxford, UK; eSection of Endocrinology, University of California, Davis School of Medicine, Sacramento, CA, USA; fPediatric Endocrinology Division, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India; gEndocrinology Service, Department of Paediatrics, KK Women’s and Children’s Hospital, Singapore; hDepartment of Paediatrics and Child Health, University of Nairobi, Nairobi, Kenya ; iDepartment of Pediatrics, University of Florida College of Medicine, Gainesville, FL, USA; jDivision of Endocrinology, Diabetes and Metabolism, Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA and kDepartment of Pediatrics, NU Hospital Group, Uddevalla and Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden

Classification of HHV-6A and HHV-6B as distinct viruses.

Abstract: Shortly after the discovery of human herpesvirus 6 (HHV-6), two distinct variants, HHV-6A and HHV-6B, were identified. In 2012, the International Committee on Taxonomy of Viruses (ICTV) classified HHV-6A and HHV-6B as separate viruses. This review outlines several of the documented epidemiological, biological, and immunological distinctions between HHV-6A and HHV-6B, which support the ICTV classification. The utilization of virus-specific clinical and laboratory assays for distinguishing HHV-6A and HHV-6B is now required for further classification. For clarity in biological and clinical distinctions between HHV-6A and HHV-6B, scientists and physicians are herein urged, where possible, to differentiate carefully between HHV-6A and HHV-6B in all future publications.

Fluid management for the prevention and attenuation of acute kidney injury

Abstract: In patients with acute kidney injury (AKI), optimization of systemic haemodynamics is central to the clinical management. However, considerable debate exists regarding the efficacy, nature, extent and duration of fluid resuscitation, particularly when the patient has undergone major surgery or is in septic shock. Crucially, volume resuscitation might be required to maintain or restore cardiac output. However, resultant fluid accumulation and tissue oedema can substantially contribute to ongoing organ dysfunction and, particularly in patients developing AKI, serious clinical consequences. In this Review, we discuss the conflict between the desire to achieve adequate resuscitation of shock and the need to mitigate the harmful effects of fluid overload. In patients with AKI, limiting and resolving fluid overload might prompt earlier use of renal replacement therapy. However, rapid or early excessive fluid removal with diuretics or extracorporeal therapy might lead to hypovolaemia and recurrent renal injury. Optimal management might involve a period of guided fluid resuscitation, followed by management of an even fluid balance and, finally, an appropriate rate of fluid removal. To obtain best clinical outcomes, serial fluid status assessment and careful definition of cardiovascular and renal targets will be required during fluid resuscitation and removal.

First-trimester uterine artery Doppler and adverse pregnancy outcome: a meta-analysis involving 55,974 women

Abstract: Objectives To determine the accuracy with which uterine artery Doppler in the first trimester of pregnancy predicts pre-eclampsia and fetal growth restriction, particularly early-onset disease. Methods We searched MEDLINE (1951–2012), EMBASE (1980–2012) and the Cochrane Library (2012) for relevant citations without language restrictions. Two reviewers independently selected studies that evaluated the accuracy of first-trimester uterine artery Doppler to predict adverse pregnancy outcome and performed data extraction to construct 2 × 2 tables. We synthesized sensitivity and specificity for various Doppler indices using a bivariate random-effects model. Results From 1866 citations, we identified 18 studies (55 974 women). The sensitivity and specificity of abnormal uterine artery flow velocity waveform (FVW) in the prediction of early-onset pre-eclampsia were 47.8% (95% CI: 39.0–56.8) and 92.1% (95% CI: 88.6–94.6), and in the prediction of early-onset fetal growth restriction were 39.2% (95% CI: 26.3–53.8) and 93.1% (95% CI: 90.6–95.0), respectively. The sensitivities for predicting any pre-eclampsia and fetal growth restriction were 26.4% (95% CI: 22.5–30.8) and 15.4% (95% CI: 12.4–18.9), respectively, and the specificities were 93.4% (95% CI: 90.4–95.5%) and 93.3% (95% CI: 90.9–95.1), respectively. The number needed to treat (NNT) with aspirin to prevent one case of early-onset pre-eclampsia fell from 1000 to 173 and from 2500 to 421 for background risks varying between 1% and 0.4%, respectively. Conclusions First-trimester uterine artery Doppler is a useful tool for predicting early-onset pre-eclampsia, as well as other adverse pregnancy outcomes. Based on the NNT, abnormal uterine artery Doppler in low-risk women achieves a sufficiently high performance to justify aspirin prophylaxis in those who test positive. Copyright © 2013 ISUOG. Published by John Wiley & Sons Ltd.

Smoking in inflammatory bowel disease: Impact on disease course and insights into the aetiology of its effect

Abstract: The chronic intestinal inflammation that characterises Crohn's disease and ulcerative colitis arises from a complex interplay between host genotype, the immune system, and the intestinal microbiota. In addition, environmental factors such as smoking impact on disease onset and progression. Individuals who smoke are more likely to develop Crohn's disease, and smoking is associated with recurrence after surgery and a poor response to medical therapy. Conversely, smoking appears protective against ulcerative colitis and smokers are less likely to require colectomy. The mechanism by which smoking exerts its impact on disease and the rational for the dichotomous effect in patients with Crohn's disease and ulcerative colitis is not clear. Recent evidence suggests that smoking induces alterations to both the innate and acquired immune system. In addition, smoking is associated with a distinct alteration in the intestinal microbiota both in patients with active Crohn's disease and healthy subjects.

Endothelial C-type natriuretic peptide maintains vascular homeostasis

Abstract: The endothelium plays a fundamental role in maintaining vascular homeostasis by releasing factors that regulate local blood flow, systemic blood pressure, and the reactivity of leukocytes and platelets. Accordingly, endothelial dysfunction underpins many cardiovascular diseases, including hypertension, myocardial infarction, and stroke. Herein, we evaluated mice with endothelial-specific deletion of Nppc, which encodes C-type natriuretic peptide (CNP), and determined that this mediator is essential for multiple aspects of vascular regulation. Specifically, disruption of CNP leads to endothelial dysfunction, hypertension, atherogenesis, and aneurysm. Moreover, we identified natriuretic peptide receptor–C (NPR-C) as the cognate receptor that primarily underlies CNP-dependent vasoprotective functions and developed small-molecule NPR-C agonists to target this pathway. Administration of NPR-C agonists promotes a vasorelaxation of isolated resistance arteries and a reduction in blood pressure in wild-type animals that is diminished in mice lacking NPR-C. This work provides a mechanistic explanation for genome-wide association studies that have linked the NPR-C (Npr3) locus with hypertension by demonstrating the importance of CNP/NPR-C signaling in preserving vascular homoeostasis. Furthermore, these results suggest that the CNP/NPR-C pathway has potential as a disease-modifying therapeutic target for cardiovascular disorders.

Nuclear translocation of FGFR1 and FGF2 in pancreatic stellate cells facilitates pancreatic cancer cell invasion

Abstract: Pancreatic cancer is characterised by desmoplasia, driven by activated pancreatic stellate cells (PSCs). Over-expression of FGFs and their receptors is a feature of pancreatic cancer and correlates with poor prognosis, but whether their expression impacts on PSCs is unclear. At the invasive front of human pancreatic cancer, FGF2 and FGFR1 localise to the nucleus in activated PSCs but not cancer cells. In vitro, inhibiting FGFR1 and FGF2 in PSCs, using RNAi or chemical inhibition, resulted in significantly reduced cell proliferation, which was not seen in cancer cells. In physiomimetic organotypic co-cultures, FGFR inhibition prevented PSC as well as cancer cell invasion. FGFR inhibition resulted in cytoplasmic localisation of FGFR1 and FGF2, in contrast to vehicle-treated conditions where PSCs with nuclear FGFR1 and FGF2 led cancer cells to invade the underlying extra-cellular matrix. Strikingly, abrogation of nuclear FGFR1 and FGF2 in PSCs abolished cancer cell invasion. These findings suggest a novel therapeutic approach, where preventing nuclear FGF/FGFR mediated proliferation and invasion in PSCs leads to disruption of the tumour microenvironment, preventing pancreatic cancer cell invasion.

Serum Creatinine Changes Associated with Critical Illness and Detection of Persistent Renal Dysfunction after AKI

Abstract: Background and objectives AKI is a risk factor for development or worsening of CKD. However, diagnosis of renal dysfunction by serum creatinine could be confounded by loss of muscle mass and creatinine generation after critical illness. Design, setting, participants, & measurements A retrospective, single center analysis of serum in patients surviving to hospital discharge with an intensive care unit admission of 5 or more days between 2009 and 2011 was performed. Results In total, 700 cases were identified, with a 66% incidence of AKI. In 241 patients without AKI, creatinine was significantly lower (P,0.001) at hospital discharge than admission (median, 0.61 versus 0.88 mg/dl; median decrease, 33%). In 160 patients with known baseline, discharge creatinine was significantly lower than baseline in all patients except those patients with severe AKI (Kidney Disease Improving Global Outcomes category 3), who had no significant difference. In a multivariable regression model, median duration of hospitalization was associated with a predicted 30% decrease (95% confidence interval, 8% to 45%) in creatinine from baseline in the absence of AKI; after allowing for this effect, AKI was associated with a 29% (95% confidence interval, 10% to 51%) increase in predicted hospital discharge creatinine. Using a similar model to exclude the confounding effect of prolonged major illness on creatinine, 148 of 700 patients (95% confidence interval, 143 to 161) would have eGFR,60 ml/min per 1.73 m 2 at hospital discharge compared with only 63 of 700 patients using eGFR based on unadjusted hospital creatinine (a 135% increase in potential CKD diagnoses; P,0.001). ConclusionCriticalillnessisassociatedwithsignificantfallsinserumcreatininethatpersisttohospitaldischarge, potentially causing inaccurate assessment of renal function at discharge, particularly in survivors of AKI. Prospective measurements of GFR and creatinine generation are required to confirm the significance of these findings.

Hypogammaglobulinaemia after rituximab treatment-incidence and outcomes.

Abstract: Background: Rituximab, a chimeric monoclonal antibody against CD20, is increasingly used in the treatment of B-cell lymphomas and autoimmune conditions. Transient peripheral B-cell depletion is expected following rituximab therapy. Although initial clinical trials did not show significant hypogammaglobulinaemia, reports of this are now appearing in the literature. Methods: We performed a retrospective review of patients previously treated with rituximab that were referred to Clinical Immunology with symptomatic or severe hypogammaglobulinaemia. Patient clinical histories, immunological markers, length of rituximab treatment and need for intravenous immunoglobulin replacement therapy (IVIG) were evaluated. An audit of patients receiving rituximab for any condition in a 12-month period and frequency of hypogammaglobulinaemia was also carried out. Results: We identified 19 post-rituximab patients with persistent, symptomatic panhypogammaglobulinaemia. Mean IgG level was 3.42 ± 0.4 g/l (normal range 5.8–16.3 g/l). All patients had reduced or absent B-cells. Haemophilus Influenzae B, tetanus and Pneumococcal serotype-specific antibody levels were all reduced and patients failed to mount an immune response post-vaccination. Nearly all of them ultimately required IVIG. The mean interval from the last rituximab dose and need for IVIG was 36 months (range 7 months–7 years). Of note, 23.7% of 114 patients included in the audit had hypogammaglobulinaemia. Conclusion: With the increasing use of rituximab, it is important for clinicians treating these patients to be aware of hypogammaglobulinaemia and serious infections occurring even years after completion of treatment and should be actively looked for during follow-up. Referral to clinical immunology services and, if indicated, initiation of IVIG should be considered.

The United Kingdom Primary Immune Deficiency (UKPID) Registry: report of the first 4 years' activity 2008-2012

Abstract: This report summarizes the establishment of the first national online registry of primary immune deficency in the United Kingdom, the United Kingdom Primary Immunodeficiency (UKPID Registry). This UKPID Registry is based on the European Society for Immune Deficiency (ESID) registry platform, hosted on servers at the Royal Free site of University College, London. It is accessible to users through the website of the United Kingdom Primary Immunodeficiency Network (www.ukpin.org.uk). Twenty-seven centres in the United Kingdom are actively contributing data, with an additional nine centres completing their ethical and governance approvals to participate. This indicates that 36 of 38 (95%) of recognized centres in the United Kingdom have engaged with this project. To date, 2229 patients have been enrolled, with a notable increasing rate of recruitment in the past 12 months. Data are presented on the range of diagnoses recorded, estimated minimum disease prevalence, geographical distribution of patients across the United Kingdom, age at presentation, diagnostic delay, treatment modalities used and evidence of their monitoring and effectiveness.

Correlates of satisfaction with pain treatment in the acute postoperative period : Results from the international PAIN OUT registry

Abstract: Patient ratings of satisfaction with their postoperative pain treatment tend to be high even in those with substantial pain Determinants are poorly understood and have not previously been studied in large-scale, international datasets PAIN OUT, a European Union-funded acute pain registry and research project, collects patient-reported outcome data on postoperative day 1 using the self-reported International Pain Outcome Questionnaire (IPO), and patient, clinical, and treatment characteristics We investigated correlates of satisfaction and consistency of effects across centres and countries using multilevel regression modelling Our sample comprised 16,868 patients (median age 55 years; 55% female) from 42 centres in 11 European countries plus Israel, USA, and Malaysia, who underwent a wide range of surgical procedures, for example, joint, limb, and digestive tract surgeries Median satisfaction was 9 (interquartile range 7-10) on a 0-10 scale Three IPO items showed strong associations and explained 35% of the variability present in the satisfaction variable: more pain relief received, higher allowed participation in pain treatment decisions, and no desire to have received more pain treatment Patient factors and additional IPO items reflecting pain experience (eg, worst pain intensity), pain-related impairment, and information on pain treatment added little explanatory value, partially due to covariate correlations Effects were highly consistent across centres and countries We conclude that satisfaction with postoperative pain treatment is associated with the patients' actual pain experience, but more strongly with impressions of improvement and appropriateness of care To the degree they desire, patients should be provided with information and involved in pain treatment decisions

British Ocular Syphilis Study (BOSS): 2-year national surveillance study of intraocular inflammation secondary to ocular syphilis.

Abstract: PURPOSE The British Ocular Syphilis Study (BOSS) is the first national prospective epidemiological study of intraocular syphilis (IOS) in light of the global increase in early syphilis (ES). The aims were to ascertain the UK incidence, demographics, clinical features, laboratory data, and posttreatment visual outcomes of patients with IOS. METHODS Prospective study of IOS, reported through the national reporting system (British Ocular Surveillance Unit) from 2009 to 2011. Case definition was any adult presenting with intraocular inflammation in ES. RESULTS A total of 41 new cases (63 eyes) of IOS were reported, giving an annual incidence of 0.3 per million UK adult population. Mean age was 48.7 years (range, 20.6-75.1); 90.2% were male. All had RPR/VDRL titers of ≥1:16. Bilateral ocular involvement occurred in 56%; in unilateral cases, the left eye was more commonly affected (P = 0.009). Mean presenting logMAR visual acuity was 0.52 (20/63 Snellen; range, -0.2 to 2.30 logMAR). Panuveitis was the commonest diagnosis, seen in 41.3%, and isolated anterior uveitis was uncommon (9.5%). Subgroup analysis between HIV-positive and -negative patients found no significant differences in terms of proportion of bilateral disease, presenting or post treatment acuity. HIV-positive patients had higher rates of panuveitis. At final follow-up, 92.1% had visual acuity ≥ 0.3 logMAR (20/40 Snellen) after antibiotic therapy. CONCLUSIONS This study is the largest prospective series of ocular syphilis in the post-penicillin era. It confirms good visual outcomes for treated IOS, irrespective of HIV status or time to presentation. The study identified an unexpected preponderance for left eye involvement in uniocular cases; which is unexplained.

Clinical significance of multi-frequency bioimpedance spectroscopy in peritoneal dialysis patients: independent predictor of patient survival

Abstract: Background. It is becoming increasingly evident that the accurate assessment of hydration status is critical to care of a dialysis patient. Using the Body Composition Monitor, different parameters (overhydration (OH), extra-cellular water/total body water (ECW/TBW) or OH/ECW) have been proposed to indicate hydration status. We wished to determine which parameter (if any) was most predictive of all-cause mortality, and if this was independent of nutritional indices. Methods. We performed a single-centre retrospective analysis of prospectively collected data of all peritoneal dialysis (PD) patients between 1 January 2008 and 30 March 2012. Record review was undertaken to establish patient survival, clinical and demographic data. Follow-up was continued even after PD technique failure (transfer to haemodialysis) and transplantation. Results. The study included 529 patients. OH index (OH and OH/ECW) was the independent predictor of mortality in multi-variate analysis. ECW/TBW as a continuous variable was not associated with increased risk of death. In contrast, patients that were severely overhydrated (highest 33%) had hazard ratios (HRs) that were statistically significant irrespective of the parameter used to define hydration. Using OH, severely overhydrated patients had an HR of 1.83 [95% confidence interval (CI) 1.19–2.82, P < 0.01], OH/ECW: 2.09 (95% CI 1.36–3.20, P< 0.001) and ECW/TBW: 2.05 (95% CI 1.31–3.22, P< 0.005). Conclusions. Our results also indicated that there was no influence of body mass index (BMI) on the hydration parameter OH/ECW. OH/ECW remained an independent predictor of mortality when the BMI and lean tissue index were included in multivariate model. However, it remains to be determined if correcting the OH status of a patient will lead to improvement in mortality.

Ulcerative colitis or Crohn's disease? Pitfalls and problems.

Abstract: The interpretation of colorectal biopsies taken for the initial diagnosis of chronic idiopathic inflammatory bowel disease (IBD) is challenging. Subclassification of IBD as ulcerative colitis (UC) or Crohn's disease, which may be particularly difficult, is the subject of this review. Biopsies taken at first presentation are emphasised, partly because their features have not been modified by time or treatment. Aspects of longstanding disease and of resections are also mentioned. The first part of the review comprises background considerations and a summary of histological features that are discriminant, according to published evidence, between UC and Crohn's disease in initial biopsies. Pitfalls and problems associated with making the distinction between UC and Crohn's disease are then discussed. These include: mimics of IBD; inadequate clinical details; unreliable microscopic features; absence of histological changes in early IBD; discontinuity in UC; cryptolytic granulomas; differences between paediatric and adult UC; reliance on ileal and oesophagogastroduodenal histology; and atypical features in IBD resections. Avoidance by pathologists of known pitfalls should increase the likelihood of accurate and confident subclassification of IBD, which is important for optimum medical and surgical management.

The Day-to-Day Co-Production of Ageing in Place

Abstract: We report findings from a study that set out to explore the experience of older people living with assisted living technologies and care services. We find that successful `ageing in place' is socially and collaboratively accomplished --- `co-produced' --- day-to-day by the efforts of older people, and their formal and informal networks of carers (e.g. family, friends, neighbours). First, we reveal how `bricolage' allows care recipients and family members to customise assisted living technologies to individual needs. We argue that making customisation easier through better design must be part of making assisted living technologies `work'. Second, we draw attention to the importance of formal and informal carers establishing and maintaining mutual awareness of the older person's circumstances day-to-day so they can act in a concerted and coordinated way when problems arise. Unfortunately, neither the design of most current assisted living technologies, nor the ways care services are typically configured, acknowledges these realities of ageing in place. We conclude that rather than more `advanced' technologies, the success of ageing in place programmes will depend on effortful alignments in the technical, organisational and social configuration of support.

Misuse of the γ-aminobutyric acid analogues baclofen, gabapentin and pregabalin in the UK.

Abstract: γ-Aminobutyric acid (GABA)-analogue medications, including gabapentin and pregabalin, are recommended first-line treatments for neuropathic pain in the UK [1], and pregabalin has been used in the treatment of various psychiatric conditions, including generalized and social anxiety disorders [2]. Consequently, there has been a large increase in prescription of these drugs over the last decade [3]. The European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) recently highlighted early reports from pharmacovigilance data from four countries, including the UK, regarding the potential for misuse of these medications and indications from toxicological analyses of the involvement of these medications in deaths of users [4]. There is also concern regarding their access from online pharmacies and misuse of legitimately prescribed medication [5]. Furthermore, dependent users of recreational drugs may seek access to these medications in an attempt to prevent or treat withdrawal symptoms [3,6,7]. However, to date there have been no data reported on the prevalence of the misuse of these medications in any country. The aim of this study was to determine the prevalence, frequency and sources of misuse of the GABA analogues (baclofen, gabapentin and pregabalin) in the UK. We partnered with a global market research company, GMI (http://www.gmi-mr.com/global-panel), which has an established global consumer panel of millions of persons. We devised a question-based survey that was formulated by the company into an Internet-based survey (see Appendix S1). Invitations were sent by GMI to existing market research panel members in the UK only, between the ages of 16 and 59 years, and respondents were capped at a maximum of 1500. The raw data of the responses to the questions were given to us, linked to a fully anonymized unique personal identifier. Basic demographics were collected together with data on lifetime prevalence and frequency of misuse of baclofen, gabapentin and pregabalin; where individuals had misused one of these drugs, they were asked to indicate the source(s) of supply for misuse. We included questions based on lifetime prevalence of use of recreational drugs [cocaine, cannabis and 3,4-methylenedioxy-N-methylamphetamine (MDMA, ‘ecstasy’)] so that we could benchmark against existing national data provided by the 2011/2012 Crime Survey for England and Wales [8]. In this way, we could confirm that our survey population provided a reasonable sample of the national population in the UK with respect to recreational drug use and therefore medications misuse. The online survey was completed by 1500 individuals [male, 49.1% (n = 737) and female, 50.9% (n = 763)]; 9.1, 40.5, 21.1 and 29.3% were aged 16–20, 21–39, 40–49 and 50–59 years old, respectively. Lifetime prevalence of use of recreational drugs was comparable to national data from the 2011/2012 Crime Survey for England and Wales. Within the survey cohort, self-reported lifetime prevalence of use of cocaine was 8.1%, cannabis 28.1% and MDMA 8.2%; compared with 9.5, 31.0 and 8.6%, respectively, for the three recreational drugs in the 2011/2012 Crime Survey for England and Wales [7]. The lifetime prevalence of misuse of any of the three surveyed GABA-analogue medications was 2.5% (n = 38); for each drug, this was 1.3% (n = 19) for baclofen, 1.1% (n = 17) for gabapentin, and 0.5% (n = 8) for pregabalin. The frequency of misuse was less than once monthly in 36.8% (n = 14), between once monthly and once weekly in 50% (n = 19), and more than once weekly in 13.1% (n = 5). Of the people misusing these medications, 36.8% (n = 14) obtained their supply from multiple sources, with similar rates of sourcing overall from health services (63.1%, n = 24), from family or acquaintances (57.8%, n = 22) and from the Internet (47.3%, n = 18), with only 7.8% (n = 3) obtaining the medication from abroad. Misuse of medication that had been legitimately prescribed to the individual was the sole source for only 13.1% (n = 5). This study, to our knowledge, is the first report to estimate the prevalence of misuse of GABA-analogue medications conducted in a cohort with similar lifetime prevalence of use of recreational drugs to the UK population. Whilst we did not confirm substance misuse by structured interview or specific analysis, our results suggest that there is appreciable misuse of baclofen, gabapentin and pregabalin in the UK, with approximately one in 40 of survey respondents self-reporting misuse of any of the GABA-analogue medications. The provenance of the majority of misuse appears to be from sources other than legitimately prescribed medication, which has important implications for future strategies to reduce access to these medications. Similar surveys can be used to determine the robustness of early pharmacovigilance data, such as that provided by the EMCDDA, to help regulatory and law-enforcement agencies understand the epidemiology of substance misuse and decide whether further control and/ or monitoring on supply and use is required. In addition, further work is needed to understand the reasons for misuse, to enable appropriately targeted harm-reduction activities through multi-agency responses.

In vitro activity of curcumin in combination with epigallocatechin gallate (EGCG) versus multidrug-resistant Acinetobacter baumannii

Abstract: Acinetobacter baumannii is an opportunistic human pathogen often associated with life-threatening infections in the immunocompromised and the critically ill. Strains are often multidrug-resistant (MDR) and due to the lack of new synthetic antimicrobials in development for treatment, attention is increasingly focused on natural compounds either as stand-alone or adjunctive agents. Curcumin (CCM) is a natural polyphenol found in turmeric and isolated from the plant, Curcuma longa. Curcumin has been found to possess many biological properties, including antibacterial activity. In this study the antimicrobial activity of CCM and synergistic effects with epigallocatechin gallate (EGCG) against multidrug-resistant strains of A. baumannii were investigated and assessed via checkerboard and time-kill assays. The MIC of CCM was >256 μg/mL against all strains of A. baumannii whilst those for EGCG ranged from 128-1024 μg/mL. In checkerboard studies synergy was observed against 5/9 isolates, with an additive effect noted in the remaining 4. The addition of EGCG reduced the MIC of CCM by 3- to 7-fold, with the greatest interaction resulting in a CCM MIC of 4 μg/mL. Time-kill curves indicated that a CCM-EGCG (1:8 and 1:4) combination was bactericidal with a 4 to 5-log reduction in viable counts after 24 h compared to the most effective polyphenol alone. This study demonstrates that despite little antibacterial activity alone, CCM activity is greatly enhanced in the presence of EGCG resulting in antibacterial activity against MDR A. baumannii. The combination may have a potential use in medicine as a topical agent to prevent or treat A. baumannii infections.

Whole-genome enrichment and sequencing of Chlamydia trachomatis directly from clinical samples

Abstract: Chlamydia trachomatis is a pathogen of worldwide importance, causing more than 100 million cases of sexually transmitted infections annually. Whole-genome sequencing is a powerful high resolution tool that can be used to generate accurate data on bacterial population structure, phylogeography and mutations associated with antimicrobial resistance. The objective of this study was to perform whole-genome enrichment and sequencing of C. trachomatis directly from clinical samples. C. trachomatis positive samples comprising seven vaginal swabs and three urine samples were sequenced without prior in vitro culture in addition to nine cultured C. trachomatis samples, representing different serovars. A custom capture RNA bait set, that captures all known diversity amongst C. trachomatis genomes, was used in a whole-genome enrichment step during library preparation to enrich for C. trachomatis DNA. All samples were sequenced on the MiSeq platform. Full length C. trachomatis genomes (>95-100% coverage of a reference genome) were successfully generated for eight of ten clinical samples and for all cultured samples. The proportion of reads mapping to C. trachomatis and the mean read depth across each genome were strongly linked to the number of bacterial copies within the original sample. Phylogenetic analysis confirmed the known population structure and the data showed potential for identification of minority variants and mutations associated with antimicrobial resistance. The sensitivity of the method was >10-fold higher than other reported methodologies. The combination of whole-genome enrichment and deep sequencing has proven to be a non-mutagenic approach, capturing all known variation found within C. trachomatis genomes. The method is a consistent and sensitive tool that enables rapid whole-genome sequencing of C. trachomatis directly from clinical samples and has the potential to be adapted to other pathogens with a similar clonal nature.