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  • Assessment of Mycobacterium tuberculosis transmission in Oxfordshire, UK, 2007-12, with whole pathogen genome sequences: an observational study.

    15 June 2018

    BACKGROUND: Patients born outside the UK have contributed to a 20% rise in the UK's tuberculosis incidence since 2000, but their effect on domestic transmission is not known. Here we use whole-genome sequencing to investigate the epidemiology of tuberculosis transmission in an unselected population over 6 years. METHODS: We identified all residents with Oxfordshire postcodes with a Mycobacterium tuberculosis culture or a clinical diagnosis of tuberculosis between Jan 1, 2007, and Dec 31, 2012, using local databases and checking against the national Enhanced Tuberculosis Surveillance database. We used Illumina technology to sequence all available M tuberculosis cultures from identified cases. Sequences were clustered by genetic relatedness and compared retrospectively with contact investigations. The first patient diagnosed in each cluster was defined as the index case, with links to subsequent cases assigned first by use of any epidemiological linkage, then by genetic distance, and then by timing of diagnosis. FINDINGS: Although we identified 384 patients with a diagnosis of tuberculosis, country of birth was known for 380 and we sequenced isolates from 247 of 269 cases with culture-confirmed disease. 39 cases were genomically linked within 13 clusters, implying 26 local transmission events. Only 11 of 26 possible transmissions had been previously identified through contact tracing. Of seven genomically confirmed household clusters, five contained additional genomic links to epidemiologically unidentified non-household members. 255 (67%) patients were born in a country with high tuberculosis incidence, conferring a local incidence of 109 cases per 100,000 population per year in Oxfordshire, compared with 3·5 cases per 100,000 per year for those born in low-incidence countries. However, patients born in the low-incidence countries, predominantly UK, were more likely to have pulmonary disease (adjusted odds ratio 1·8 [95% CI 1·2-2·9]; p=0·009), social risk factors (4·4 [2·0-9·4]; p<0·0001), and be part of a local transmission cluster (4·8 [1·6-14·8]; p=0·006). INTERPRETATION: Although inward migration has contributed to the overall tuberculosis incidence, our findings suggest that most patients born in high-incidence countries reactivate latent infection acquired abroad and are not involved in local onward transmission. Systematic screening of new entrants could further improve tuberculosis control, but it is important that health care remains accessible to all individuals, especially high-risk groups, if tuberculosis control is not to be jeopardised. FUNDING: UK Clinical Research Collaboration (Wellcome Trust, Medical Research Council, National Institute for Health Research [NIHR]), and NIHR Oxford Biomedical Research Centre.

  • A Prospective Investigation of Body Size, Body Fat Composition and Colorectal Cancer Risk in the UK Biobank.

    15 June 2018

    Obesity has been consistently associated with a greater colorectal cancer risk, but this relationship is weaker among women. In the UK Biobank, we investigated the associations between body size (body mass index [BMI], height, waist circumference, and waist-to-hip ratio) and body fat composition (total body fat percentage and trunk fat percentage) measurements with colorectal cancer risk among 472,526 men and women followed for 5.6 years on average. Multivariable hazard ratios (HRs) and 95% confidence intervals (95%CI) for developing colorectal cancer (2,636 incident cases) were estimated using Cox proportional hazards models. Among men, when the highest and lowest fifths were compared, BMI (HR = 1.35, 95%CI: 1.13-1.61; Ptrend < 0.0001), waist circumference (HR = 1.66, 95%CI: 1.39-1.99; Ptrend < 0.0001), waist-to-hip ratio (HR = 1.58, 95%CI: 1.31-1.91; Ptrend < 0.0001), total body fat percentage (HR = 1.27, 95%CI: 1.06-1.53; Ptrend = 0.002), and trunk fat percentage (HR = 1.31, 95%CI: 1.09-1.58; Ptrend = 0.002) were associated with greater colorectal cancer risk. For women, only waist-to-hip ratio (HR for highest versus lowest fifth = 1.33, 95%CI: 1.08-1.65; Ptrend = 0.005) was positively associated with colorectal cancer risk. Greater body size (overall and abdominal adiposity) was positively associated with colorectal cancer development in men. For women, abdominal adiposity, rather than overall body size, was associated with a greater colorectal cancer risk.

  • Factors affecting delay in initiation of treatment of tuberculosis in the Thames Valley, UK

    30 April 2018

    Objective: To quantify and determine factors associated with delay in initiation of tuberculosis (TB) treatment in the Thames Valley area, South East England, and the proportion of this delay that could be attributed to patient care-seeking or to delay within the National Health Service (NHS). Study design: Retrospective analysis study reviewing medical notes and enhanced TB surveillance data. Methods: Demographic and clinical information was collected from medical notes and the Enhanced TB Surveillance database for patients who were diagnosed with TB and resident in the Thames Valley. Treatment delay was defined as the period between the onset of symptoms and the start of treatment. Patient delay was defined as the period between the onset of symptoms and the first presentation to the NHS. Health service delay was defined as the period between the first contact with the NHS and the start of treatment. Univariate and multivariate linear regression analyses were used to assess the association between delays and explanatory variables (age, gender, place of birth, ethnicity, disease site, sputum smear, culture, primary care trust of residence). Results: The study included 273 patients with TB. The median time between symptom onset and initiation of treatment was 73 days [95% confidence interval (CI) 65-89], of which the contributions of health service, patient and referral delays were 39 (95% CI 34-55), 29 (95% CI 22-36) and 16 (95% CI 12-24) days, respectively. On multivariate analysis, extrapulmonary TB (. P = 0.010), female (. P = 0.003) and UK-born (. P = 0.008) patients were associated with longer health service delay. Age (. P = 0.001) and extrapulmonary TB (. P = 0.010) were associated with longer overall treatment delay. Conclusion: Treatment delay for TB, especially delay after first presentation to the NHS, remains a public health concern. Differences in health service delay, for example by gender and country of birth, highlight that some of this should be open to health service intervention. © 2012 The Royal Society for Public Health.

  • Thalamic Deep Brain Stimulation for Neuropathic Pain: Efficacy at Three Years' Follow-Up.

    14 June 2018

    OBJECT: Chronic neuropathic pain is estimated to affect 3-4.5% of the worldwide population, posing a serious burden to society. Deep Brain Stimulation (DBS) is already established for movement disorders and also used to treat some "off-label" conditions. However, DBS for the treatment of chronic, drug refractory, neuropathic pain, has shown variable outcomes with few studies performed in the last decade. Thus, this procedure has consensus approval in parts of Europe but not the USA. This study prospectively evaluated the efficacy at three years of DBS for neuropathic pain. METHODS: Sixteen consecutive patients received 36 months post-surgical follow-up in a single-center. Six had phantom limb pain after amputation and ten deafferentation pain after brachial plexus injury, all due to traumas. To evaluate the efficacy of DBS, patient-reported outcome measures were collated before and after surgery, using a visual analog scale (VAS) score, University of Washington Neuropathic Pain Score (UWNPS), Brief Pain Inventory (BPI), and 36-Item Short-Form Health Survey (SF-36). RESULTS: Contralateral, ventroposterolateral sensory thalamic DBS was performed in sixteen patients with chronic neuropathic pain over 29 months. A postoperative trial of externalized DBS failed in one patient with brachial plexus injury. Fifteen patients proceeded to implantation but one patient with phantom limb pain after amputation was lost for follow-up after 12 months. No surgical complications or stimulation side effects were noted. After 36 months, mean pain relief was sustained, and the median (and interquartile range) of the improvement of VAS score was 52.8% (45.4%) (p = 0.00021), UWNPS was 30.7% (49.2%) (p = 0.0590), BPI was 55.0% (32.0%) (p = 0.00737), and SF-36 was 16.3% (30.3%) (p = 0.4754). CONCLUSIONS: DBS demonstrated efficacy at three years for chronic neuropathic pain after traumatic amputation and brachial plexus injury, with benefits sustained across all pain outcomes measures and slightly greater improvement in phantom limb pain.

  • Methylphenidate enhances implicit learning in healthy adults.

    15 June 2018

    BACKGROUND AND PURPOSE: One limiting factor in the development of pharmacological interventions to enhance cognition is the absence of biomarkers that can be used in healthy volunteers to screen novel compounds. Drug discovery has tended to rely heavily on explicit measures of cognition, but these are typically insensitive to cognition-enhancing effects in healthy volunteers. This study investigated whether a novel battery of implicit cognition measures is sensitive to the effects of methylphenidate (Ritalin) in healthy volunteers. EXPERIMENTAL APPROACH: Eighty healthy volunteers were randomised to receive either a single (10 mg) dose of methylphenidate or matched placebo. Participants completed a battery of tasks measuring implicit cognition (location priming, contextual cueing, implicit task switching). The effect of methylphenidate on standard, explicit measures of cognition was also assessed. KEY RESULTS: Methylphenidate enhanced implicit learning on the location priming task and the implicit task-switching task. In line with previous work, we found that these effects were greater in male volunteers. There was no evidence for improved learning in any of the explicit measures. CONCLUSION AND IMPLICATIONS: These results demonstrate that implicit measures of cognition are sensitive to pharmacological interventions in healthy volunteers. As such, implicit cognition measures may be a useful way of screening and tracking cognitive effects of novel agents in experimental medicine studies.

  • Exome-Wide Meta-Analysis Identifies Rare 3'-UTR Variant in ERCC1/CD3EAP Associated with Symptoms of Sleep Apnea.

    18 June 2018

    Obstructive sleep apnea (OSA) is a common sleep breathing disorder associated with an increased risk of cardiovascular and cerebrovascular diseases and mortality. Although OSA is fairly heritable (~40%), there have been only few studies looking into the genetics of OSA. In the present study, we aimed to identify genetic variants associated with symptoms of sleep apnea by performing a whole-exome sequence meta-analysis of symptoms of sleep apnea in 1,475 individuals of European descent. We identified 17 rare genetic variants with at least suggestive evidence of significance. Replication in an independent dataset confirmed the association of a rare genetic variant (rs2229918; minor allele frequency = 0.3%) with symptoms of sleep apnea (p-valuemeta = 6.98 × 10-9, βmeta = 0.99). Rs2229918 overlaps with the 3' untranslated regions of ERCC1 and CD3EAP genes on chromosome 19q13. Both genes are expressed in tissues in the neck area, such as the tongue, muscles, cartilage and the trachea. Further, CD3EAP is localized in the nucleus and mitochondria and involved in the tumor necrosis factor-alpha/nuclear factor kappa B signaling pathway. Our results and biological functions of CD3EAP/ERCC1 genes suggest that the 19q13 locus is interesting for further OSA research.

  • Genome-wide linkage and haplotype sharing analysis implicates the MCDR3 locus as a candidate region for a developmental macular disorder in association with digit abnormalities.

    29 March 2018

    BACKGROUND: Developmental macular disorders are a heterogeneous group of rare retinal conditions that can cause significant visual impairment from childhood. Among these disorders, autosomal dominant North Carolina macular dystrophy (NCMD) has been mapped to 6q16 (MCDR1) with recent support for a non-coding disease mechanism of PRDM13. A second locus on 5p15-5p13 (MCDR3) has been implicated in a similar phenotype, but the disease-causing mechanism still remains unknown. METHODS: Two families affected by a dominant developmental macular disorder that closely resembles NCMD in association with digit abnormalities were included in the study. Family members with available DNA were genotyped using the Affymetrix GeneChip Human Mapping 250K Sty array. A parametric multipoint linkage analysis assuming a fully penetrant dominant model was performed using MERLIN. Haplotype sharing analysis was carried out using the non-parametric Homozygosity Haplotype method. Whole-exome sequencing was conducted on selected affected individuals. RESULTS: Linkage analysis excluded MCDR1 from the candidate regions (LOD < -2). There was suggestive linkage (LOD = 2.7) at two loci, including 9p24.1 and 5p15.32 that overlapped with MCDR3. The haplotype sharing analysis in one of the families revealed a 5 cM shared IBD segment at 5p15.32 (p value = 0.004). Whole-exome sequencing did not provide conclusive evidence for disease-causing alleles. CONCLUSIONS: These findings do not exclude that this phenotype may be allelic with NCMD MCDR3 at 5p15 and leave the possibility of a non-coding disease mechanism, in keeping with recent findings on 6q16. Further studies, including whole-genome sequencing, may help elucidate the underlying genetic cause of this phenotype and shed light on macular development and function.