496 research outputs found
Protocol for an observational cohort study investigating personalised medicine for intensification of treatment in people with type 2 diabetes mellitus: the PERMIT study
INTRODUCTION: For people with type 2 diabetes mellitus (T2DM) who require an antidiabetic drug as an add-on to metformin, there is controversy about whether newer drug classes such as dipeptidyl peptidase-4 inhibitors (DPP4i) or sodium-glucose co-transporter-2 inhibitors (SGLT2i) reduce the risk of long-term complications compared with sulfonylureas (SU). There is widespread variation across National Health Service Clinical Commissioning Groups (CCGs) in drug choice for second-line treatment in part because National Institute for Health and Care Excellence guidelines do not specify a single preferred drug class, either overall or within specific patient subgroups. This study will evaluate the relative effectiveness of the three most common second-line treatments in the UK (SU, DPP4i and SGLT2i as add-ons to metformin) and help target treatments according to individual risk profiles. METHODS AND ANALYSIS: The study includes people with T2DM prescribed one of the second-line treatments-of-interest between 2014 and 2020 within the UK Clinical Practice Research Datalink linked with Hospital Episode Statistics and Office of National Statistics. We will use an instrumental variable (IV) method to estimate short-term and long-term relative effectiveness of second-line treatments according to individuals' risk profiles. This method minimises bias from unmeasured confounders by exploiting the natural variation in second-line prescribing across CCGs as an IV for the choice of prescribed treatment. The primary outcome to assess short-term effectiveness will be change in haemoglobin A1c (%) 12 months after treatment initiation. Outcome measures to assess longer-term effectiveness (maximum ~6 years) will include microvascular and macrovascular complications, all-cause mortality and hospital admissions during follow-up. ETHICS AND DISSEMINATION: This study was approved by the Independent Scientific Advisory Committee (20-064) and the London School of Hygiene & Tropical Medicine Research Ethics Committee (21395). Results, codelists and other analysis code will be made available to patients, clinicians, policy-makers and researchers
Selection of Medical Diagnostic Codes for Analysis of Electronic Patient Records. Application to Stroke in a Primary Care Database
BACKGROUND: Electronic patient records from primary care databases are increasingly used in public health and health services research but methods used to identify cases with disease are not well described. This study aimed to evaluate the relevance of different codes for the identification of acute stroke in a primary care database, and to evaluate trends in the use of different codes over time.METHODS: Data were obtained from the General Practice Research Database from 1997 to 2006. All subjects had a minimum of 24 months of up-to-standard record before the first recorded stroke diagnosis. Initially, we identified stroke cases using a supplemented version of the set of codes for prevalent stroke used by the Office for National Statistics in Key health statistics from general practice 1998 (ONS codes). The ONS codes were then independently reviewed by four raters and a restricted set of 121 codes for 'acute stroke' was identified but the kappa statistic was low at 0.23.RESULTS: Initial extraction of data using the ONS codes gave 48,239 cases of stroke from 1997 to 2006. Application of the restricted set of codes reduced this to 39,424 cases. There were 2,288 cases whose index medical codes were for 'stroke annual review' and 3,112 for 'stroke monitoring'. The frequency of stroke review and monitoring codes as index codes increased from 9 per year in 1997 to 1,612 in 2004, 1,530 in 2005 and 1,424 in 2006. The one year mortality of cases with the restricted set of codes was 29.1% but for 'stroke annual review,' 4.6% and for 'stroke monitoring codes', 5.7%.CONCLUSION: In the analysis of electronic patient records, different medical codes for a single condition may have varying clinical and prognostic significance; utilisation of different medical codes may change over time; researchers with differing clinical or epidemiological experience may have differing interpretations of the relevance of particular codes. There is a need for greater transparency in the selection of sets of codes for different conditions, for the reporting of sensitivity analyses using different sets of codes, as well as sharing of code sets among researchers
Rhesus TRIM5Ī± disrupts the HIV-1 capsid at the inter-hexamer interfaces
TRIM proteins play important roles in the innate immune defense against retroviral infection, including human immunodeficiency virus type-1 (HIV-1). Rhesus macaque TRIM5Ī± (TRIM5Ī±rh) targets the HIV-1 capsid and blocks infection at an early post-entry stage, prior to reverse transcription. Studies have shown that binding of TRIM5Ī± to the assembled capsid is essential for restriction and requires the coiled-coil and B30.2/SPRY domains, but the molecular mechanism of restriction is not fully understood. In this study, we investigated, by cryoEM combined with mutagenesis and chemical cross-linking, the direct interactions between HIV-1 capsid protein (CA) assemblies and purified TRIM5Ī±rh containing coiled-coil and SPRY domains (CC-SPRYrh). Concentration-dependent binding of CC-SPRYrh to CA assemblies was observed, while under equivalent conditions the human protein did not bind. Importantly, CC-SPRYrh, but not its human counterpart, disrupted CA tubes in a non-random fashion, releasing fragments of protofilaments consisting of CA hexamers without dissociation into monomers. Furthermore, such structural destruction was prevented by inter-hexamer crosslinking using P207C/T216C mutant CA with disulfide bonds at the CTD-CTD trimer interface of capsid assemblies, but not by intra-hexamer crosslinking via A14C/E45C at the NTD-NTD interface. The same disruption effect by TRIM5Ī±rh on the inter-hexamer interfaces also occurred with purified intact HIV-1 cores. These results provide insights concerning how TRIM5Ī± disrupts the virion core and demonstrate that structural damage of the viral capsid by TRIM5Ī± is likely one of the important components of the mechanism of TRIM5Ī±-mediated HIV-1 restriction. Ā© 2011 Zhao et al
Effect of Contemporary Bariatric Surgical Procedures on Type 2 Diabetes Remission. A Population-Based Matched Cohort Study.
OBJECTIVE: The objective of the study is to evaluate the effect of gastric banding, gastric bypass and sleeve gastrectomy on medium to long-term diabetes control in obese participants with type 2 diabetes mellitus. RESEARCH DESIGN AND METHODS: Matched cohort study using primary care electronic health records from the UK Clinical Practice Research Datalink. Obese participants with type 2 diabetes who received bariatric surgery from 2002 to 2014 were compared with matched control participants who did not receive BS. Remission was defined for each year of follow-up as HbA1c <6.5Ā % and no antidiabetic drugs prescribed. RESULTS: There were 826 obese participants with T2DM who received bariatric surgery including adjustable gastric banding (LAGB) 220; gastric bypass (GBP) 449; or sleeve gastrectomy (SG) 153; with four procedures undefined. Mean HbA1c declined from 8.0Ā % before BS to 6.5Ā % in the second postoperative year; proportion with HbA1c <6.5Ā % (<48Ā mmol/mol) increased from 17 to 47Ā %. The proportion of patients in remission was 30Ā % in the second year, being 20Ā % for LAGB, 34Ā % for GBP and 38Ā % for SG. The adjusted relative rate of remission over the first six postoperative years was 5.97 (4.86 to 7.33, Pā<ā0.001) overall; for LAGB 3.32 (2.27 to 4.86); GBP 7.16 (5.64 to 9.08); and SG 6.82 (5.05 to 9.19). Rates of remission were maintained into the sixth year of follow-up. CONCLUSIONS: Remission of diabetes may continue for up to 6Ā years after bariatric surgical procedures. Diabetes outcomes are generally more favourable after gastric bypass or sleeve gastrectomy than LAGB
Palliative care in urgent need of recognition and development in general practice: the example of Germany
Background: Specialist palliative care is being increasingly recognised and developed to improve end-of-life care in many developed countries. However, only a small proportion of the total number of patients with incurable, progressive diseases actually has direct contact with specialist palliative care practitioners. Using the German situation as an example, the main purpose of this paper is to argue that the emphasis on specialist palliative care services without a similar encouragement of primary palliative care will deliver a constrained service
Measurement of the hadronic photon structure function F_{2}^{Ī³} at LEP2
The hadronic structure function of the photon F_{2}^{Ī³} (x, QĀ²) is measured as a function of Bjorken x and of the photon virtuality QĀ² using deep-inelastic scattering data taken by the OPAL detector at LEP at eāŗeā» centre-of-mass energies from 183 to 209 GeV. Previous OPAL measurements of the x dependence of F_{2}^{Ī³} are extended to an average QĀ² of ćQĀ²ć=780 GeVĀ² using data in the kinematic range 0.15<x<0.98. The QĀ² evolution of F_{2}^{Ī³} is studied for 12.1<ćQĀ²ć<780 GeVĀ² using three ranges of x. As predicted by QCD, the data show positive scaling violations in F_{2}^{Ī³} with F_{2}^{Ī³} (QĀ²)/Ī± = (0.08Ā±0.02āŗā°Ā·ā°āµ_ā.āā) + (0.13Ā±0.01āŗā°Ā·ā°Ā¹_ā.āā) lnQĀ², where QĀ² is in GeVĀ², for the central x region 0.10ā0.60. Several parameterisations of F_{2}^{Ī³} are in qualitative agreement with the measurements whereas the quark-parton model prediction fails to describe the data
Measurement of the charm structure function F_{2,c)^{Ī³} of the photon at LEP
The production of charm quarks is studied in deep-inelastic electronāphoton scattering using data recorded by the OPAL detector at LEP at nominal eāŗeā» centre-of-mass energies from 183 to 209 GeV. The charm quarks have been identified by full reconstruction of charged D* mesons using their decays into Dā°Ļ with the Dā° observed in two decay modes with charged particle final states, KĻ and KĻĻĻ. The cross-section Ļ^{D*} for production of charged D* in the reaction eāŗeā»āeāŗeā»D*Ī§ is measured in a restricted kinematical region using two bins in Bjorken x, 0.00140.1 the perturbative QCD calculation at next-to-leading order agrees perfectly with the measured cross-section. For x<0.1 the measured cross-section is 43.8Ā±14.3Ā±6.3Ā±2.8 pb with a next-to-leading order prediction of 17.0āŗĀ²Ā·ā¹_ā.ā pb
Brain white matter structure and information processing speed in healthy older age
Cognitive decline, especially the slowing of information processing speed, is associated with normal ageing. This decline may be due to brain cortico-cortical disconnection caused by age-related white matter deterioration. We present results from a large, narrow age range cohort of generally healthy, community-dwelling subjects in their seventies who also had their cognitive ability tested in youth (age 11Ā years). We investigate associations between older age brain white matter structure, several measures of information processing speed and childhood cognitive ability in 581 subjects. Analysis of diffusion tensor MRI data using Tract-based Spatial Statistics (TBSS) showed that all measures of information processing speed, as well as a general speed factor composed from these tests (g(speed)), were significantly associated with fractional anisotropy (FA) across the white matter skeleton rather than in specific tracts. Cognitive ability measured at age 11Ā years was not associated with older age white matter FA, except for the g(speed)-independent components of several individual processing speed tests. These results indicate that quicker and more efficient information processing requires global connectivity in older age, and that associations between white matter FA and information processing speed (both individual test scores and g(speed)), unlike some other aspects of later life brain structure, are generally not accounted for by cognitive ability measured in youth
Measurement of triple gauge boson couplings from WāŗWā» production at LEP energies up to 189 GeV
A measurement of triple gauge boson couplings is presented, based on W-pair data recorded by the OPAL detector at LEP during 1998 at a centre-of-mass energy of 189 GeV with an integrated luminosity of 183 pbā»Ā¹. After combining with our previous measurements at centre-of-mass energies of 161ā183 GeV we obtain Īŗ = 0.97_{-0.16}^{+0.20}, g_{1}^{z} = 0.991_{-0.057}^{+0.060} and Ī» = -0.110_{-0.055}^{+0.058}, where the errors include both statistical and systematic uncertainties and each coupling is determined by setting the other two couplings to their Standard Model values. These results are consistent with the Standard Model expectations
Patterns of care and survival for adolescents and young adults with acute leukaemia ā a population-based study
We report a population-based study of patterns of care and survival for people with acute leukaemia diagnosed at age 15ā29 years during 1984ā94 in regions of England and Wales covered by specialist leukaemia registries. There were 879 patients: 417 with acute lymphoblastic leukaemia (ALL) and 462 with acute myeloid leukaemia (AML). For ALL, actuarial survival rates were 43% at 5 years after diagnosis and 37% at 10 years. Survival improved significantly between 1984ā88 and 1989ā94 for those aged 15ā19 at diagnosis. Patients entered in national clinical trials and those not entered had similar survival rates. Survival rates were similar at teaching and non-teaching hospitals and at hospitals treating different numbers of study patients per year. For AML, survival rates were 42% at 5 years after diagnosis and 39% at 10 years. Survival improved significantly between 1984ā88 and 1989ā94. Patients entered in the Medical Research Council AML10 trial had a higher survival rate than those who were in the earlier AML9 trial. Survival did not vary with category of hospital. We conclude that survival has improved for adolescents and young adults with acute leukaemia but that there is at present no evidence that centralized treatment results in a survival benefit for patients in this age group. Ā© 1999 Cancer Research Campaig
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