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Lithium users are offered routine renal monitoring but few studies have quantified the risk to renal health. The aim of this study was to assess the association between use of lithium carbonate and incidence of renal failure in patients with bipolar disorder. This was a retrospective cohort study using the General Practice Research Database (GPRD) and a nested validation study of lithium exposure and renal failure. A cohort of 6360 participants aged over 18 years had a first recorded diagnosis of bipolar disorder between January 1, 1990 and December 31, 2007. Data were examined from electronic primary care records from 418 general practices across the UK. The primary outcome was the hazard ratio for renal failure in participants exposed to lithium carbonate as compared with non-users of lithium, adjusting for age, gender, co-morbidities, and poly-pharmacy. Ever use of lithium was associated with a hazard ratio for renal failure of 2.5 (95% confidence interval 1.6 to 4.0) adjusted for known renal risk factors. Absolute risk was age dependent, with patients of 50 years or older at particular risk of renal failure: Number Needed to Harm (NNH) was 44 (21 to 150). Lithium is associated with an increased risk of renal failure, particularly among the older age group. The absolute risk of renal failure associated with lithium use remains small.

Since radiation therapy remains a primary treatment modality for gliomas, the radioresistance of glioma cells and targets to modify their radiation tolerance are of significant interest. Human apurinic endonuclease 1 (Ape1, Ref-1, APEX, HAP1, AP endo) is a multifunctional protein involved in base excision repair of DNA and a redox-dependent transcriptional co-activator. This study investigated whether there is a direct relationship between Ape1 and radioresistance in glioma cells, employing the human U87 and U251 cell lines. U87 is intrinsically more radioresistant than U251, which is partly attributable to more cycling U251 cells found in G2/M, the most radiosensitive cell stage, while more U87 cells are found in S and G1, the more radioresistant cell stages. But observed radioresistance is also related to Ape1 activity. U87 has higher levels of Ape1 than does U251, as assessed by Western blot and enzyme activity assays (～1.5-2 fold higher in cycling cells, and ～10 fold higher at G2/M). A direct relationship was seen in cells transfected with CMV-Ape1 constructs; there was a dose-dependent relationship between increasing Ape1 overexpression and increasing radioresistance. Conversely, knock down by siRNA or by pharmacological down regulation of Ape1 resulted in decreased radioresistance. The inhibitors lucanthone and CRT004876 were employed, the former a thioxanthene previously under clinical evaluation as a radiosensitizer for brain tumors and the latter a more specific Ape1 inhibitor. These data suggest that Ape1 may be a useful target for modifying radiation tolerance.

The contraceptive needs of illicit opioid users differ from non-drug users but are poorly understood. The aim of this study was to describe contraceptive use and pregnancy outcomes in opioid-using women, and to examine their association with a range of risk factors. This retrospective cohort study used UK general practice records, Treatment Outcomes Profile and National Drug Treatment Monitoring System data, and a nested data validation exercise. A cohort of 376 women aged 20-61 years were in active treatment for opioid addiction in October 2010 at two specialised primary care practices in North-East England. Outcomes were age-adjusted prevalence estimates for contraceptive use and pregnancy outcomes in users of illicit opioids. The association between lifestyle-related risk factors and contraception was explored. Drug-using women made lower use of planned (non-condom) contraception (24% vs 50%, p<0.001), had more frequent pregnancy terminations (0.46 vs. 0.025, p = 0.004) and higher annual incidence of chlamydia (1.1% vs. 0.33%, p<0.001), when compared with age-matched population data. Specifically, there was low use of oral contraceptives (4% vs. 25%, p<0.001), IUCD (1% vs. 6%, p<0.001), and sterilisation (7% vs. 6%, p = 0.053), but higher rates of injectable contraceptives (6% vs. 3%, p = 0.003). A total of 64% of children aged <16 years born to this group did not live with their mother. No individual risk factor (such as sex-working) significantly explained the lower use or type of non-condom contraception. This is the first study to describe planned contraceptive use among drug-users, as well as the association with a range of risk factors and pregnancy outcomes. The low uptake of planned contraception, set against high rates of terminations and sexually transmitted disease demonstrates the urgent clinical need to improve contraceptive services, informed by qualitative work to explore the values and beliefs influencing low contraceptive uptake.

Patients with inflammatory bowel disease (IBD) demonstrate an inflammatory response which bears some similarities to that seen in ischaemic heart disease (IHD). The nature of the association of IBD with IHD is uncertain. We aimed to define the extent and direction of that association. This retrospective cohort study examined records from patients aged ≥ 15 years with IBD from 1987-2009 (n = 19163) who were age and gender matched with patients without IBD (n = 75735) using the General Practice Research Database. The primary outcome was the hazard ratio for IHD. A higher proportion of IBD patients had a recorded diagnosis of IHD ever, 2220 (11.6%) compared with 6504 (8.6%) of controls. However, the majority (4494, 51.5%) developed IHD prior to IBD diagnosis (1404 (63.2%) of IBD cases and 3090 (47.5%) of controls). There was increased IHD incidence in the first year after IBD diagnosis. Mean age at IHD diagnosis was statistically similar across all IBD groups apart from for those with Ulcerative Colitis (UC) who were slightly younger at diagnosis of angina compared to controls (64.5y vs. 67.0y, p = 0.008) and coronary heart disease (65.7y vs.67.9y, p = 0.015). Of those developing IHD following IBD diagnosis, UC patients were at higher risk of IHD (unadjusted HR 1.3 (95% CI 1.1-1.5), p<0.001) or MI (unadjusted HR 1.4 (95% CI 1.1-1.6), p = 0.004). Although IHD prevalence was higher in IBD patients, most IHD diagnoses predated the diagnosis of IBD. This implies a more complex relationship than previously proposed between the inflammatory responses associated with IHD and IBD, and alternative models should be considered.

Chromatin structure regulates the dynamics of the recognition and repair of DNA double strand breaks; open chromatin enhances the recruitment of DNA damage response factors, while compact chromatin is refractory to the assembly of radiation-induced repair foci. MU2, an orthologue of human MDC1, a scaffold for ionizing radiation-induced repair foci, is a widely distributed chromosomal protein in Drosophila melanogaster that moves to DNA repair foci after irradiation. Here we show using yeast 2 hybrid screens and co-immunoprecipitation that MU2 binds the chromoshadow domain of the heterochromatin protein HP1 in untreated cells. We asked what role HP1 plays in the formation of repair foci and cell cycle control in response to DNA damage. After irradiation repair foci form in heterochromatin but are shunted to the edge of heterochromatic regions an HP1-dependent manner, suggesting compartmentalized repair. Hydroxyurea-induced repair foci that form at collapsed replication forks, however, remain in the heterochromatic compartment. HP1a depletion in irradiated imaginal disc cells increases apoptosis and disrupts G2/M arrest. Further, cells irradiated in mitosis produced more and brighter repair foci than to cells irradiated during interphase. Thus, the interplay between MU2 and HP1a is dynamic and may be different in euchromatin and heterochromatin during DNA break recognition and repair.

Cellulitis (erysipelas) is a recurring and debilitating bacterial infection of the skin and underlying tissue. We assessed the cost-effectiveness of prophylactic antibiotic treatment to prevent the recurrence of cellulitis using low dose penicillin V in patients following a first episode (6 months prophylaxis) and more recurrent cellulitis (12 months prophylaxis, or 6 months in those declining 12 months). Within-trial cost-effectiveness analysis was conducted using the findings of two randomised placebo-controlled multicentre trials (PATCH I and PATCH II), in which patients recruited in the UK and Ireland were followed-up for up to 3 years. Incremental cost, reduction in recurrence, cost per recurrence prevented and cost/QALY were estimated. National unit and reference costs for England in 2010 were applied to resource use, exploring NHS and societal perspectives. A total of 397 patients from the two trials contributed to the analysis. There was a 29% reduction in the number of recurrences occurring within the trial (IRR: 0.71 95%CI: 0.53 to 0.90, p = 0.02), corresponding to an absolute reduction of recurrence of 0.31 recurrences/patient (95%CI: 0.05 to 0.59, p = 0.02). Incremental costs of prophylaxis suggested a small cost saving but were not statistically significant, comparing the two groups. If a decision-maker is willing to pay up to £25,000/QALY then there is a 66% probability of antibiotic prophylaxis being cost-effective from an NHS perspective, rising to 76% probability from a secondary, societal perspective. Following first episode or recurrent cellulitis of the leg, prophylactic low dose penicillin is a very low cost intervention which, on balance, is effective and cost-effective at preventing subsequent attacks. Antibiotic prophylaxis reduces cellulitis recurrence by nearly a third but is not associated with a significant increase in costs.

ObjectivesTo assess the impact of both the Committee on Safety of Medicines (CSM) warning (December 2003) and the National Institute for Health and Care Excellence (NICE) guidance (September 2005) on antidepressant prescription rates in children and adolescents within the UK primary care service.SettingPopulation based study of primary care antidepressant prescribing using the Clinical Practice Research Datalink (CPRD).ParticipantsUnder-18s presenting to primary care with a depressive disorder or related diagnostic code recorded in the CPRD.Primary outcome measureAntidepressant prescription rates per month per 100 000 depressed 4–17 year olds.ResultsFollowing the CSM warning, the prior trend towards increased prescribing rates for selective serotonin reuptake inhibitors (SSRIs) in children was significantly reversed (β for change in trend −12.34 (95% CI −18.67 to −6.00, p<0.001)). However, after the publication of the NICE guidelines the prior trend towards increased prescribing resumed for those SSRIs mentioned as potential treatments in the guidance (fluoxetine, citalopram and sertraline) (β for change in trend 11.52 (95% CI 5.32 to 17.73, p<0.001)). Prescribing of other SSRIs and tricyclics remained low.ConclusionsDespite a strong emphasis on psychosocial interventions for child and adolescent depression, it may be that the NICE guidelines inadvertently encouraged further antidepressant prescribing, at least for those SSRIs cited. Although the guidelines gave cautions and caveats for the use of antidepressants, practitioners may have interpreted these recommendations as endorsing their use in young people with depression and related conditions. However, more accurate prevalence trend estimates for depression in this age group, and information on the use of psychosocial interventions would be needed to rule out other reasons underlying this increase in prescribing.

Telomere capture, a rare event that stabilizes chromosome breaks, is associated with certain genetic abnormalities in humans. Studies pertaining to the generation, maintenance, and biological effects of telomere formation are limited in metazoans. A mutation, mu2(a), in Drosophila melanogaster decreases the rate of repair of double strand DNA breaks in oocytes, thus leading to chromosomes that have lost a natural telomere and gained a new telomere. Amino acid sequence, domain architecture, and protein interactions suggest that MU2 is an ortholog of human MDC1. The MU2 protein is a component of meiotic recombination foci and localizes to repair foci in S2 cells after irradiation in a manner similar to that of phosphorylated histone variant H2Av. Domain searches indicated that the protein contains an N-terminal FHA domain and a C-terminal tandem BRCT domain. Peptide pull-down studies showed that the BRCT domain interacts with phosphorylated H2Av, while the FHA domain interacts with the complex of MRE11, RAD50, and NBS. A frameshift mutation that eliminates the MU2 BRCT domain decreases the number and size of meiotic phospho-H2Av foci. MU2 is also required for the intra-S checkpoint in eye-antennal imaginal discs. MU2 participates at an early stage in the recognition of DNA damage at a step that is prerequisite for both DNA repair and cell cycle checkpoint control. We propose a model suggesting that neotelomeres may arise when radiation-induced chromosome breaks fail to be repaired, fail to arrest progression through meiosis, and are deposited in the zygote, where cell cycle control is absent and rapid rounds of replication and telomere formation ensue.

The performance of biomarkers for heart failure (HF) in older residents in long-term care is poorly understood and has not differentiated between left ventricular systolic dysfunction (LVSD) and HF with preserved ejection fraction (HFpEF). This is the first diagnostic accuracy study in this population to assess the differential diagnostic performance and acceptability of a range of biomarkers against a clinical diagnosis using portable echocardiography. A total of 405 residents, aged 65-100 years (mean 84.2), in 33 UK long-term care facilities were enrolled between April 2009 and June 2010. For undifferentiated HF, BNP or NT-proBNP were adequate rule-out tests but would miss one in three cases (BNP: sensitivity 67%, NPV 86%, cut-off 115 pg/ml; NT-proBNP: sensitivity 62%, NPV 87%, cut-off 760 pg/ml). Using higher test cut-offs, both biomarkers were more adequate tests of LVSD, but would still miss one in four cases (BNP: sensitivity 76%, NPV 97%, cut-off 145 pg/ml; NT-proBNP: sensitivity 73%, NPV 97%, cut-off 1000 pg/ml). At these thresholds one third of subjects would test positive and require an echocardiogram. Applying a stricter 'rule out' threshold (sensitivity 90%), only one in 10 cases would be missed, but two thirds of subjects would require further investigation. Biomarkers were less useful for HFpEF (BNP: sensitivity 63%, specificity 61%, cut-off 110 pg/ml; NT-proBNP: sensitivity 68%, specificity 56%, cut-off 477 pg/ml). Novel biomarkers (Copeptin, MR-proADM, and MR-proANP) and common signs and symptoms had little diagnostic utility. No test, individually or in combination, adequately balanced case finding and rule-out for heart failure in this population; currently, in-situ echocardiography provides the only adequate diagnostic assessment. Controlled-Trials.com ISRCTN19781227.

BackgroundAccurate optical characterisation and removal of small adenomas (<10 mm) at colonoscopy would allow hyperplastic polyps to be left in situ and surveillance intervals to be determined without the need for histopathology. Although accurate in specialist practice the performance of narrow band imaging (NBI), colonoscopy in routine clinical practice is poorly understood.MethodsNBI-assisted optical diagnosis was compared with reference standard histopathological findings in a prospective, blinded study, which recruited adults undergoing routine colonoscopy in six general hospitals in the UK. Participating colonoscopists (N=28) were trained using the NBI International Colorectal Endoscopic (NICE) classification (relating to colour, vessel structure and surface pattern). By comparing the optical and histological findings in patients with only small polyps, test sensitivity was determined at the patient level using two thresholds: presence of adenoma and need for surveillance. Accuracy of identifying adenomatous polyps <10 mm was compared at the polyp level using hierarchical models, allowing determinants of accuracy to be explored.FindingsOf 1688 patients recruited, 722 (42.8%) had polyps <10 mm with 567 (78.5%) having only polyps <10 mm. Test sensitivity (presence of adenoma, N=499 patients) by NBI optical diagnosis was 83.4% (95% CI 79.6% to 86.9%), significantly less than the 95% sensitivity (p<0.001) this study was powered to detect. Test sensitivity (need for surveillance) was 73.0% (95% CI 66.5% to 79.9%). Analysed at the polyp level, test sensitivity (presence of adenoma, N=1620 polyps) was 76.1% (95% CI 72.8% to 79.1%). In fully adjusted analyses, test sensitivity was 99.4% (95% CI 98.2% to 99.8%) if two or more NICE adenoma characteristics were identified. Neither colonoscopist expertise, confidence in diagnosis nor use of high definition colonoscopy independently improved test accuracy.InterpretationThis large multicentre study demonstrates that NBI optical diagnosis cannot currently be recommended for application in routine clinical practice. Further work is required to evaluate whether variation in test accuracy is related to polyp characteristics or colonoscopist training.Trial registration numberThe study was registered with clinicaltrials.gov (NCT01603927).