In this review, we explore the concept of ‘double diabetes’, a combination of type 1 diabetes with features of insulin resistance and type 2 diabetes. After considering whether double diabetes is a ...useful concept, we discuss potential mechanisms of increased insulin resistance in type 1 diabetes before examining the extent to which double diabetes might increase the risk of cardiovascular disease (CVD). We then go on to consider the proposal that weight gain from intensive insulin regimens may be associated with increased CV risk factors in some patients with type 1 diabetes, and explore the complex relationships between weight gain, insulin resistance, glycaemic control and CV outcome. Important comparisons and contrasts between type 1 diabetes and type 2 diabetes are highlighted in terms of hepatic fat, fat partitioning and lipid profile, and how these may differ between type 1 diabetic patients with and without double diabetes. In so doing, we hope this work will stimulate much-needed research in this area and an improvement in clinical practice.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Evidence supporting the notion that clinical research activity in itself is of benefit to organisations as a whole is inconclusive. In the recent past, a positive association between research ...activity and reduced mortality has been shown. This study aimed to ascertain if clinical research activity is associated with established organisational outcome measures.
Retrospective cross-sectional study.
For 129 English National Health Service hospital Trusts, National Institute for Health Research study activity data, Summary Hospital-level Mortality Indicator (SHMI) scores and Care Quality Commission (CQC) ratings were collected. Research activity was controlled for Trust size by dividing it by clinical staffing levels. Multiple linear regression and Spearman correlation analyses were performed.
Although there is a significant association between the number of studies and participants with both SHMI score and CQC rating, one particular variable is correlated more significantly than others: the number of participants recruited into interventional studies. It shows a significant correlation with better CQC ratings (standardised coefficient beta 0.26, P-value 0.003) and lower SHMI scores (standardised coefficient beta −0.50, P-value 0.001).
The mortality-related results corroborate with other published data showing a correlation between increased research and reduced deaths. Furthermore, there is also a statistically significant association between clinical trials activity and improved CQC ratings. However, these tie-ins are predominantly driven by the number of participants in interventional research rather than observational research activity.
•Increased National Institute for Health Research–adopted clinical trial activity is associated with reduced mortality.•Increased National Institute for Health Research–adopted clinical trial activity is associated with better Care Quality Commission outcomes.•Particularly, the number of clinical trial patients correlates with improved hospital performance.•The link between clinical trials activity and quality is not Trust-size dependent.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
On May 21, 2019 at 03:02:29 UTC Advanced LIGO and Advanced Virgo observed a short duration gravitational-wave signal, GW190521, with a three-detector network signal-to-noise ratio of 14.7, and an ...estimated false-alarm rate of 1 in 4900 yr using a search sensitive to generic transients. If GW190521 is from a quasicircular binary inspiral, then the detected signal is consistent with the merger of two black holes with masses of 85_{-14}^{+21} M_{⊙} and 66_{-18}^{+17} M_{⊙} (90% credible intervals). We infer that the primary black hole mass lies within the gap produced by (pulsational) pair-instability supernova processes, with only a 0.32% probability of being below 65 M_{⊙}. We calculate the mass of the remnant to be 142_{-16}^{+28} M_{⊙}, which can be considered an intermediate mass black hole (IMBH). The luminosity distance of the source is 5.3_{-2.6}^{+2.4} Gpc, corresponding to a redshift of 0.82_{-0.34}^{+0.28}. The inferred rate of mergers similar to GW190521 is 0.13_{-0.11}^{+0.30} Gpc^{-3} yr^{-1}.
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CMK, CTK, FMFMET, IJS, NUK, PNG, UL, UM
Studies have identified significant linkages between depression and diabetes, with depression associated with poor self‐management behaviour, poor clinical outcomes and high rates of mortality. ...However, findings are not consistent across studies, yielding confusing and contradictory results about these relationships. We suggest that there has been a failure to define and measure ‘depression’ in a consistent manner. Because the diagnosis of depression is symptom‐based only, without reference to source or content, the context of diabetes is not considered when addressing the emotional distress experienced by individuals struggling with diabetes. To reduce this confusion, we suggest that an underlying construct of ‘emotional distress’ be considered as a core construct to link diabetes‐related distress, subclinical depression, elevated depression symptoms and major depressive disorder (MDD). We view emotional distress as a single, continuous dimension that has two primary characteristics: content and severity; that the primary content of emotional distress among these individuals include diabetes and its management, other life stresses and other contributors; and that both the content and severity of distress be addressed directly in clinical care. We suggest further that all patients, even those whose emotional distress rises to the level of MDD or anxiety disorders, can benefit from consideration of the content of distress to direct care effectively, and we suggest strategies for integrating the emotional side of diabetes into regular diabetes care. This approach can reduce confusion between depression and distress so that appropriate and targeted patient‐centred interventions can occur.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
1 Diabetes and Metabolism Research Laboratories, Clinical Sciences Research Institute, Warwick Medical School; 2 University Hospital of Coventry and Warwickshire, Coventry, England; and 3 Heart ...Research Institute, Cardiff University, Wales, United Kingdom
Submitted 23 June 2006
; accepted in final form 5 November 2006
Type 2 diabetes (T2DM) is associated with chronic low-grade inflammation. Adipose tissue (AT) may represent an important site of inflammation. 3T3-L1 studies have demonstrated that lipopolysaccharide (LPS) activates toll-like receptors (TLRs) to cause inflammation. For this study, we 1 ) examined activation of TLRs and adipocytokines by LPS in human abdominal subcutaneous (AbdSc) adipocytes, 2 ) examined blockade of NF- B in human AbdSc adipocytes, 3 ) examined the innate immune pathway in AbdSc AT from lean, obese, and T2DM subjects, and 4 ) examined the association of circulating LPS in T2DM subjects. The findings showed that LPS increased TLR-2 protein expression twofold ( P < 0.05). Treatment of AbdSc adipocytes with LPS caused a significant increase in TNF- and IL-6 secretion (IL-6, Control: 2.7 ± 0.5 vs. LPS: 4.8 ± 0.3 ng/ml; P < 0.001; TNF- , Control: 1.0 ± 0.83 vs. LPS: 32.8 ± 6.23 pg/ml; P < 0.001). NF- B inhibitor reduced IL-6 in AbdSc adipocytes (Control: 2.7 ± 0.5 vs. NF- B inhibitor: 2.1 ± 0.4 ng/ml; P < 0.001). AbdSc AT protein expression for TLR-2, MyD88, TRAF6, and NF- B was increased in T2DM patients ( P < 0.05), and TLR-2, TRAF-6, and NF- B were increased in LPS-treated adipocytes ( P < 0.05). Circulating LPS was 76% higher in T2DM subjects compared with matched controls. LPS correlated with insulin in controls ( r = 0.678, P < 0.0001). Rosiglitazone (RSG) significantly reduced both fasting serum insulin levels (reduced by 51%, P = 0.0395) and serum LPS (reduced by 35%, P = 0.0139) in a subgroup of previously untreated T2DM patients. In summary, our results suggest that T2DM is associated with increased endotoxemia, with AT able to initiate an innate immune response. Thus, increased adiposity may increase proinflammatory cytokines and therefore contribute to the pathogenic risk of T2DM.
toll-like receptors; adipocytes; nuclear factor- B; inflammation; insulin
Address for reprint requests and other correspondence: S. Kumar, Clinical Sciences Research Institute, Clinical Sciences Bldg., University Hospital Coventry and Warwickshire, Clifford Bridge Road, Coventry CV2 2DX, West Midlands, UK (e-mail Sudhesh.Kumar{at}warwick.ac.uk )
We use a global chemical transport model (GEOS-Chem CTM) to interpret observations of black carbon (BC) and organic aerosol (OA) from the NASA ARCTAS aircraft campaign over the North American Arctic ...in April 2008, as well as longer-term records in surface air and in snow (2007-2009). BC emission inventories for North America, Europe, and Asia in the model are tested by comparison with surface air observations over these source regions. Russian open fires were the dominant source of OA in the Arctic troposphere during ARCTAS but we find that BC was of prevailingly anthropogenic (fossil fuel and biofuel) origin, particularly in surface air. This source attribution is confirmed by correlation of BC and OA with acetonitrile and sulfate in the model and in the observations. Asian emissions are the main anthropogenic source of BC in the free troposphere but European, Russian and North American sources are also important in surface air. Russian anthropogenic emissions appear to dominate the source of BC in Arctic surface air in winter. Model simulations for 2007-2009 (to account for interannual variability of fires) show much higher BC snow content in the Eurasian than the North American Arctic, consistent with the limited observations. We find that anthropogenic sources contribute 90% of BC deposited to Arctic snow in January-March and 60% in April-May 2007-2009. The mean decrease in Arctic snow albedo from BC deposition is estimated to be 0.6% in spring, resulting in a regional surface radiative forcing consistent with previous estimates.
On entering an era of global warming, the stability of the Greenland ice sheet (GIS) is an important concern, especially in the light of new evidence of rapidly changing flow and melt conditions at ...the GIS margins. Studying the response of the GIS to past climatic change may help to advance our understanding of GIS dynamics. The previous interpretation of evidence from stable isotopes ( 18O) in water from GIS ice cores was that Holocene climate variability on the GIS differed spatially and that a consistent Holocene climate optimum-the unusually warm period from about 9,000 to 6,000 years ago found in many northern-latitude palaeoclimate records-did not exist. Here we extract both the Greenland Holocene temperature history and the evolution of GIS surface elevation at four GIS locations. We achieve this by comparing 18O from GIS ice cores with 18O from ice cores from small marginal icecaps. Contrary to the earlier interpretation of 18O evidence from ice cores, our new temperature history reveals a pronounced Holocene climatic optimum in Greenland coinciding with maximum thinning near the GIS margins. Our 18O-based results are corroborated by the air content of ice cores, a proxy for surface elevation. State-of-the-art ice sheet models are generally found to be underestimating the extent and changes in GIS elevation and area; our findings may help to improve the ability of models to reproduce the GIS response to Holocene climate.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
New predictive markers for managing prostate cancer are urgently required because of the highly variable natural history of this disease. At the time of diagnosis, Gleason score provides the gold ...standard for assessing the aggressiveness of prostate cancer. However, the recent discovery of TMPRSS2 fusions to the ERG gene in prostate cancer raises the possibility of using alterations at the ERG locus as additional mechanism-based prognostic indicators. Fluorescence in situ hybridization (FISH) assays were used to assess ERG gene status in a cohort of 445 prostate cancers from patients who had been conservatively managed. The FISH assays detected separation of 5' (labelled green) and 3' (labelled red) ERG sequences, which is a consequence of the TMPRSS2-ERG fusion, and additionally identify interstitial deletion of genomic sequences between the tandemly located TMPRSS2 and ERG gene sequences on chromosome 21. Cancers lacking ERG alterations exhibited favourable cause-specific survival (90% survival at 8 years). We identify a novel category of prostate cancers, characterized by duplication of the fusion of TMPRSS2 to ERG sequences together with interstitial deletion of sequences 5' to ERG (called '2+Edel'), which by comparison exhibited extremely poor cause-specific survival (hazard ratio=6.10, 95% confidence ratio=3.33-11.15, P<0.001, 25% survival at 8 years). In multivariate analysis, '2+Edel' provided significant prognostic information (P=0.003) in addition to that provided by Gleason score and prostate-specific antigen level at diagnosis. Other individual categories of ERG alteration were associated with intermediate or good prognosis. We conclude that determination of ERG gene status, including duplication of the fusion of TMPRSS2 to ERG sequences in 2+Edel, allows stratification of prostate cancer into distinct survival categories.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Gliomas are the most common primary intracranial tumor, representing 81% of malignant brain tumors. Although relatively rare, they cause significant mortality and morbidity. Glioblastoma, the most ...common glioma histology (∼45% of all gliomas), has a 5-year relative survival of ∼5%. A small portion of these tumors are caused by Mendelian disorders, including neurofibromatosis, tuberous sclerosis, and Li-Fraumeni syndrome. Genomic analyses of glioma have also produced new evidence about risk and prognosis. Recently discovered biomarkers that indicate improved survival include O⁶-methylguanine-DNA methyltransferase methylation, isocitrate dehydrogenase mutation, and a glioma cytosine-phosphate-guanine island methylator phenotype. Genome-wide association studies have identified heritable risk alleles within 7 genes that are associated with increased risk of glioma. Many risk factors have been examined as potential contributors to glioma risk. Most significantly, these include an increase in risk by exposure to ionizing radiation and a decrease in risk by history of allergies or atopic disease(s). The potential influence of occupational exposures and cellular phones has also been examined, with inconclusive results. We provide a “state of the science” review of current research into causes and risk factors for gliomas in adults.
The natural history of prostate cancer is highly variable and it is difficult to predict. We showed previously that a cell cycle progression (CCP) score was a robust predictor of outcome in a ...conservatively managed cohort diagnosed by transurethral resection of the prostate. A greater need is to predict outcome in patients diagnosed by needle biopsy.
Total RNA was extracted from paraffin specimens. A CCP score was calculated from expression levels of 31 genes. Clinical variables consisted of centrally re-reviewed Gleason score, baseline prostate-specific antigen level, age, clinical stage, and extent of disease. The primary endpoint was death from prostate cancer.
In univariate analysis (n=349), the hazard ratio (HR) for death from prostate cancer was 2.02 (95% CI (1.62, 2.53), P<10(-9)) for a one-unit increase in CCP score. The CCP score was only weakly correlated with standard prognostic factors and in a multivariate analysis, CCP score dominated (HR for one-unit increase=1.65, 95% CI (1.31, 2.09), P=3 × 10(-5)), with Gleason score (P=5 × 10(-4)) and prostate-specific antigen (PSA) (P=0.017) providing significant additional contributions.
For conservatively managed patients, the CCP score is the strongest independent predictor of cancer death outcome yet described and may prove valuable in managing clinically localised prostate cancer.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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