Excess mortality in Type 1 diabetes diagnosed in childhood and adolescence: a systematic review of population-based cohorts

Aims: Systematic review of mortality in childhood-/adolescent-diagnosed Type 1 diabetes and examination of factors explaining the mortality variation between studies. 
Methods: Relevant studies were identified from systematic searches of MEDLINE and EMBASE. Observed and expected numbers of deaths were extracted, and standardised mortality ratios (SMRs) and 95 % confidence intervals (CIs) were calculated. Negative binomial regression was used to investigate association between mortality and study/country characteristics.
Results: Thirteen relevant publications with mortality data were identified describing 23 independent studies. SMRs varied markedly ranging from 0 to 854 (chi-squared = 70.68,df = 21, p<0.0001). Significant associations were observed between SMR and mid-year of follow-up [incidence rate ratio (IRR) 0.95, 95 % CI 0.91–0.99 equivalent to a 5 % decrease per year], between SMR and infant mortality rate (IRR 1.07, 95 % CI 1.02–1.12, a 7 % increase for each death per 1,000 live births) and, after omitting an outlier, between SMR and health expenditure as a percentage of gross domestic product (GDP) (IRR 0.79, 95 % CI 0.68–0.93, a 21 % decrease for each one percent increase in GDP). No relationship was detected between SMR and a country’s childhood diabetes incidence rate or GDP.
Conclusions: Excess mortality in childhood-/adolescent diagnosed Type 1 diabetes is apparent across countries worldwide. Excesses were less marked in more recent studies and in countries with lower infant mortality and higher health expenditure.

T- and L-type Ca2+ currents in freshly dispersed smooth muscle cells from the human proximal urethra

The purpose of the present study was to characterise Ca2+ currents in smooth muscle cells isolated from biopsy samples taken from the proximal urethra of patients undergoing surgery for bladder or prostate cancer. Cells were studied at 37 degreesC using the amphotericin B perforated-patch configuration of the patch-clamp technique. Currents were recorded using Cs+-rich pipette solutions to block K+ currents. Two components of current, with electrophysiological and pharmacological properties typical of T- and L-type Ca2+ currents, were present in these cells. When steady-state inactivation curves for the L current were fitted with a Boltzmann equation, this yielded a V-1/2 of -45 +/- 5 mV. In contrast, the T current inactivated with a V-1/2 of -80 +/- 3 mV. The L currents were reduced in a concentration-dependent manner by nifedipine (ED50 = 159 +/- 54 nm) and Ni2+ (ED50 = 65 +/- 16 muM) but were enhanced when external Ca2+ was substituted with Ba2+. The T current was little affected by TTX, reduction in external Na+, application of nifedipine at concentrations below 300 nm or substitution of external Ca2+ with Ba2+, but was reduced by Ni2+ with an ED50 of 6 +/- 1 mum. When cells were stepped from -100 to -30 mV in Ca2+-free conditions, small inward currents could be detected. These were enhanced 40-fold in divalent-cation-free solution and blocked in a concentration-dependent manner by Mg2+ with an ED50 of 32 +/- 16 mum. These data support the idea that human urethral myocytes possess currents with electrophysiological and pharmacological properties typical of T- and L-type Ca2+ currents.

The association between glucose lowering drug use and mortality among breast cancer patients with type 2 diabetes.

This study assessed the association between glucose-lowering drug (GLD) use, including metformin, sulphonylurea derivatives and insulin, after breast cancer diagnosis and breast cancer-specific and all-cause mortality. 1763 breast cancer patients, diagnosed between 1998 and 2010, with type 2 diabetes were included. Cancer information was retrieved from English cancer registries, prescription data from the UK Clinical Practice Research Datalink and mortality data from the Office of National Statistics (up to January 2012). Time-varying Cox regression models were used to calculate HRs and 95 % CIs for the association between GLD use and breast cancer-specific and all-cause mortality. In 1057 patients with diabetes before breast cancer, there was some evidence that breast cancer-specific mortality decreased with each year of metformin use (adjusted HR 0.88; 95 % CI 0.75–1.04), with a strong association seen with over 2 years of use (adjusted HR 0.47; 95 % CI 0.26–0.82). Sulphonylurea derivative use for less than 2 years was associated with increased breast cancer-specific mortality (adjusted HR 1.70; 95 % CI 1.18–2.46), but longer use was not (adjusted HR 0.94; 95 % CI 0.54–1.66). In 706 patients who developed diabetes after breast cancer, similar patterns were seen for metformin, but sulphonylurea derivative use was strongly associated with cancer-specific mortality (adjusted HR 3.64; 95 % CI 2.16–6.16), with similar estimates for short- and long-term users. This study provides some support for an inverse association between, mainly long-term, metformin use and (breast cancer-specific) mortality. In addition, sulphonylurea derivative use was associated with increased breast cancer-specific mortality, but this should be interpreted cautiously, as it could reflect selective prescribing in advanced cancer patients.

Discovering subgroups of patients from DNA copy number data using NMF on compacted matrices

In the study of complex genetic diseases, the identification of subgroups of patients sharing similar genetic characteristics represents a challenging task, for example, to improve treatment decision. One type of genetic lesion, frequently investigated in such disorders, is the change of the DNA copy number (CN) at specific genomic traits. Non-negative Matrix Factorization (NMF) is a standard technique to reduce the dimensionality of a data set and to cluster data samples, while keeping its most relevant information in meaningful components. Thus, it can be used to discover subgroups of patients from CN profiles. It is however computationally impractical for very high dimensional data, such as CN microarray data. Deciding the most suitable number of subgroups is also a challenging problem. The aim of this work is to derive a procedure to compact high dimensional data, in order to improve NMF applicability without compromising the quality of the clustering. This is particularly important for analyzing high-resolution microarray data. Many commonly used quality measures, as well as our own measures, are employed to decide the number of subgroups and to assess the quality of the results. Our measures are based on the idea of identifying robust subgroups, inspired by biologically/clinically relevance instead of simply aiming at well-separated clusters. We evaluate our procedure using four real independent data sets. In these data sets, our method was able to find accurate subgroups with individual molecular and clinical features and outperformed the standard NMF in terms of accuracy in the factorization fitness function. Hence, it can be useful for the discovery of subgroups of patients with similar CN profiles in the study of heterogeneous diseases.

Genetic risk factors affecting mitochondrial function are associated with kidney disease in people with Type 1 diabetes

AIM: To evaluate the association with diabetic kidney disease of single nucleotide polymorphisms (SNPs) that may contribute to mitochondrial dysfunction.

METHODS: The mitochondrial genome and 1039 nuclear genes that are integral to mitochondrial function were investigated using a case (n=823 individuals with diabetic kidney disease) vs. control (n=903 individuals with diabetes and no renal disease) approach. All people included in the analysis were of white European origin and were diagnosed with Type 1 diabetes before the age of 31 years. Replication was conducted in 5093 people with similar phenotypes to those of the discovery collection. Association analyses were performed using the plink genetic analysis toolset, with adjustment for relevant covariates.

RESULTS: A total of 25 SNPs were evaluated in the mitochondrial genome, but none were significantly associated with diabetic kidney disease or end-stage renal disease. A total of 38 SNPs in nuclear genes influencing mitochondrial function were nominally associated with diabetic kidney disease and 16 SNPS were associated with end-stage renal disease, secondary to diabetic kidney disease, with meta-analyses confirming the same direction of effect. Three independent signals (seven SNPs) were common to the replication data for both phenotypes with Type 1 diabetes and persistent proteinuria or end-stage renal disease.

CONCLUSIONS: Our results suggest that SNPs in nuclear genes that influence mitochondrial function are significantly associated with diabetic kidney disease in a white European population

Glycemic targets in the second and third trimester of pregnancy for women with type 1 diabetes

OBJECTIVE: To assess the relationship between second and third trimester glycemic control and adverse outcomes in pregnant women with type 1 diabetes, as uncertainty exists about optimum glycemic targets.

RESEARCH DESIGN AND METHODS: Pregnancy outcomes were assessed prospectively in 725 women with type 1 diabetes from the Diabetes and Pre-eclampsia Intervention Trial. HbA1c (A1C) values at 26 and 34 weeks' gestation were categorized into five groups, the lowest, <6.0% (42 mmol/mol), being the reference. Average pre- and postprandial results from an eight-point capillary glucose profile the previous day were categorized into five groups, the lowest (preprandial <5.0 mmol/L and postprandial <6.0 mmol/L) being the reference.

RESULTS: An A1C of 6.0-6.4% (42-47 mmol/mol) at 26 weeks' gestation was associated with a significantly increased risk of large for gestational age (LGA) (odds ratio 1.7 [95% CI 1.0-3.0]) and an A1C of 6.5-6.9% (48-52 mmol/mol) with a significantly increased risk of preterm delivery (odds ratio 2.5 [95% CI 1.3-4.8]), pre-eclampsia (4.3 [1.7-10.8]), need for a neonatal glucose infusion (2.9 [1.5-5.6]), and a composite adverse outcome (3.2 [1.3-8.0]). These risks increased progressively with increasing A1C. Results were similar at 34 weeks' gestation. Glucose data showed less consistent trends, although the risk of a composite adverse outcome increased with preprandial glucose levels between 6.0 and 6.9 mmol/L at 34 weeks (3.3 [1.3-8.0]).

CONCLUSIONS: LGA increased significantly with an A1C ≥6.0 (42 mmol/mol) at 26 and 34 weeks' gestation and with other adverse outcomes with an A1C ≥6.5% (48 mmol/mol). The data suggest that there is clinical utility in regular measurement of A1C during pregnancy.

Seasonal variation in month of diagnosis in children with type 1 diabetes registered in 23 European centers during 1989-2008: little short-term influence of sunshine hours or average temperature

BACKGROUND: The month of diagnosis in childhood type 1 diabetes shows seasonal variation.

OBJECTIVE: We describe the pattern and investigate if year-to-year irregularities are associated with meteorological factors using data from 50 000 children diagnosed under the age of 15 yr in 23 population-based European registries during 1989-2008.

METHODS: Tests for seasonal variation in monthly counts aggregated over the 20 yr period were performed. Time series regression was used to investigate if sunshine hour and average temperature data were predictive of the 240 monthly diagnosis counts after taking account of seasonality and long term trends.

RESULTS: Significant sinusoidal pattern was evident in all but two small centers with peaks in November to February and relative amplitudes ranging from ±11 to ±38% (median ±17%). However, most centers showed significant departures from a sinusoidal pattern. Pooling results over centers, there was significant seasonal variation in each age-group at diagnosis, with least seasonal variation in those under 5 yr. Boys showed greater seasonal variation than girls, particularly those aged 10-14 yr. There were no differences in seasonal pattern between four 5-yr sub-periods. Departures from the sinusoidal trend in monthly diagnoses in the period were significantly associated with deviations from the norm in average temperature (0.8% reduction in diagnoses per 1 °C excess) but not with sunshine hours.

CONCLUSIONS: Seasonality was consistently apparent throughout the period in all age-groups and both sexes, but girls and the under 5 s showed less marked variation. Neither sunshine hour nor average temperature data contributed in any substantial way to explaining departures from the sinusoidal pattern.

Efficiency assessment of electricity power generation on Ireland’s Single Electricity Market by Data Envelopment Analysis

The efficiency of generation plants is an important measure for evaluating the operating performance. The objective of this paper is to evaluate electricity power generation by conducting an All-Island-Generator-Efficiency-Study (AIGES) for the Republic of Ireland and Northern Ireland by utilising a Data Envelopment Analysis (DEA) approach. An operational performance efficiency index is defined and pursued for the year 2008. The economic activities of electricity generation units/plants examined in this paper are characterized by numerous input and output indicators. Constant returns to scale (CRS) and variable returns to scale (VRS) type DEA models are employed in the analysis. Also a slacks based analysis indicates the level of inefficiency for each variable examined. The findings from this study provide a general ranking and evaluation but also facilitate various interesting efficiency comparisons between generators by fuel type.

Time and Cell Type Dependency of Survival Responses in Co-cultured Tumor and Fibroblast Cells after Exposure to Modulated Radiation Fields

Advanced radiotherapy techniques such as intensity-modulated radiation therapy (IMRT) achieve high levels of conformity to the target volume through the sequential delivery of highly spatially and temporally modulated radiation fields, which have been shown to impact radiobiological response. This study aimed to characterize the time and cell type dependency of survival responses to modulated fields using single cell type (SCT) and mixed cell type (MCT) co-culture models of transformed fibroblast (AG0-1522b) cells, and prostate (DU-145) and lung (H460) cancer cells. In SCT cultures, in-field responses showed no significant time dependency while out-of-field responses occurred early, and plateaued 6 h after irradiation in both DU-145 and H460 cells. Under modulated beam configurations MCT co-cultures showed cell-specific, differential out-of-field responses depending on the irradiated in-field and responding out-of-field cell type. The observed differential out-of-field responses may be due to the genetic background of the cells, in particular p53 status, which has been shown to mediate radiation-induced bystander effects (RIBEs). These data provide further insight into the radiobiological parameters that influence out-of-field responses, which have potential implications for advanced radiotherapy modalities and may provide opportunities for biophysical optimization in radiotherapy treatment planning.

Early-type stars observed in the ESO UVES Paranal observatory project - IV. studies of CN, CH+ and CH in the interstellar medium

High spectral resolution (~80 000) and signal-to-noise observations from the Ultraviolet and Visual Echelle Spectrograph Paranal Observatory Project (UVES-POP) are used to study the interstellarmolecular lines CN (3874 Å), CH⁺ (3957, 4232 Å) and CH (3886, 4300 Å) towards 74 O- and B-type stellar sightlines. Additionally, archive data are presented for 140 ELODIE early-type stellar sightlines at R = 42 000, plus 25 FEROS at R = 48 000 and 3 UVES at R > 50 000, mainly in the CH⁺ (4232 Å) and CH (3886, 4300 Å) transitions. Detection rates are ~45 per cent for CN and ~67 per cent for the other lines in the POP sample, and ~10-15 per cent for CH⁺ and CH lines in the additional sample. CH and CH⁺ are well correlated between log[N(CH) cm^-2]~12-14, implying that these clouds are CH⁺-like CH and not CN-like CH. CH is also very well correlated with Na I D in the range log[N(Na I cm^-2]) ~12.2-14.2. A few sightlines show tentative velocity shifts of ~2 km s^-1 between CH and CH⁺, which appear to be caused by differences in component strength in blends, and hence do not provide firm evidence for shocks. Finally, we describe a search for ¹³CH⁺ in a sightline towards HD 76341. No ¹³CH⁺ is detected, placing a limit on the ¹³CH⁺ to ¹²CH⁺ ratio of ~0.01. If a formal fit is attempted, the equivalent width ratio in the two isotopes is a factor ~90 but with large errors. 

Early-type stars observed in the ESO UVES Paranal Observatory Project - V. Time-variable interstellar absorption

The structure and properties of the diffuse interstellar medium (ISM) on small scales, sub-au to 1 pc, are poorly understood. We compare interstellar absorption-lines, observed towards a selection of O- and B-type stars at two or more epochs, to search for variations over time caused by the transverse motion of each star combined with changes in the structure in the foreground ISM. Two sets of data were used: 83 VLT- UVES spectra with approximately 6 yr between epochs and 21 McDonald observatory 2.7m telescope echelle spectra with 6 - 20 yr between epochs, over a range of scales from 0 - 360 au. The interstellar absorption-lines observed at the two epochs were subtracted and searched for any residuals due to changes in the foreground ISM. Of the 104 sightlines investigated with typically five or more components in Na I D, possible temporal variation was identified in five UVES spectra (six components), in Ca II, Ca I and/or Na I absorption-lines. The variations detected range from 7\% to a factor of 3.6 in column density. No variation was found in any other interstellar species. Most sightlines show no variation, with 3{\sigma} upper limits to changes of the order 0.1 - 0.3 dex in Ca II and Na I. These variations observed imply that fine-scale structure is present in the ISM, but at the resolution available in this study, is not very common at visible wavelengths. A determination of the electron densities and lower limits to the total number density of a sample of the sightlines implies that there is no striking difference between these parameters in sightlines with, and sightlines without, varying components.

Massive stars exploding in a He-rich circumstellar medium - IV. Transitional Type Ibn supernovae

We present ultraviolet, optical and near-infrared data of the Type Ibn supernovae (SNe) 2010al and 2011hw. SN 2010al reaches an absolute magnitude at peak of M-R = -18.86 +/- 0.21. Its early light curve shows similarities with normal SNe Ib, with a rise to maximum slower than most SNe Ibn. The spectra are dominated by a blue continuum at early stages, with narrow P-Cygni He I lines indicating the presence of a slow-moving, He-rich circumstellar medium. At later epochs, the spectra well match those of the prototypical SN Ibn 2006jc, although the broader lines suggest that a significant amount of He was still present in the stellar envelope at the time of the explosion. SN 2011hw is somewhat different. It was discovered after the first maximum, but the light curve shows a double peak. The absolute magnitude at discovery is similar to that of the second peak (M-R = -18.59 +/- 0.25), and slightly fainter than the average of SNe Ibn. Though the spectra of SN 2011hw are similar to those of SN 2006jc, coronal lines and narrow Balmer lines are clearly detected. This indicates substantial interaction of the SN ejecta with He-rich, but not H-free, circumstellar material. The spectra of SN 2011hw suggest that it is a transitional SN Ibn/IIn event similar to SN 2005la. While for SN 2010al the spectrophotometric evolution favours a H-deprived Wolf-Rayet progenitor (of WN-type), we agree with the conclusion of Smith et al. that the precursor of SN 2011hw was likely in transition from a luminous blue variable to an early Wolf-Rayet (Ofpe/WN9) stage.

Late-time spectral line formation in Type IIb supernovae, with application to SN 1993J, SN 2008ax, and SN 2011dh

We investigate line formation processes in Type IIb supernovae (SNe) from 100 to 500 days post-explosion using spectral synthesis calculations. The modelling identifies the nuclear burning layers and physical mechanisms that produce the major emission lines, and the diagnostic potential of these. We compare the model calculations with data on the three best observed Type IIb SNe to-date - SN 1993J, SN 2008ax, and SN 2011dh. Oxygen nucleosynthesis depends sensitively on the main-sequence mass of the star and modelling of the [O I] lambda lambda 6300, 6364 lines constrains the progenitors of these three SNe to the M-ZAMS = 12-16 M-circle dot range (ejected oxygen masses 0.3-0.9 M-circle dot), with SN 2011dh towards the lower end and SN 1993J towards the upper end of the range. The high ejecta masses from M-ZAMS greater than or similar to 17 M-circle dot progenitors give rise to brighter nebular phase emission lines than observed. Nucleosynthesis analysis thus supports a scenario of low-to-moderate mass progenitors for Type IIb SNe, and by implication an origin in binary systems. We demonstrate how oxygen and magnesium recombination lines may be combined to diagnose the magnesium mass in the SN ejecta. For SN 2011dh, a magnesium mass of 0.02-0.14 M-circle dot is derived, which gives a Mg/O production ratio consistent with the solar value. Nitrogen left in the He envelope from CNO burning gives strong [N II] lambda lambda 6548, 6583 emission lines that dominate over Ha emission in our models. The hydrogen envelopes of Type IIb SNe are too small and dilute to produce any noticeable H alpha emission or absorption after similar to 150 days, and nebular phase emission seen around 6550 angstrom is in many cases likely caused by [N II] lambda lambda 6548, 6583. Finally, the influence of radiative transport on the emergent line profiles is investigated. Significant line blocking in the metal core remains for several hundred days, which affects the emergent spectrum. These radiative transfer effects lead to early-time blueshifts of the emission line peaks, which gradually disappear as the optical depths decrease with time. The modelled evolution of this effect matches the observed evolution in SN 2011dh.

Developmentally regulated IL6-type cytokines signal to germ cells in the human fetal ovary

Fetal ovarian development and primordial follicle formation are imperative for adult fertility in the female. Data suggest the interleukin (IL)6-type cytokines, leukaemia inhibitory factor (LIF), IL6, oncostatin M (OSM) and ciliary neurotrophic factor (CNTF), are able to regulate the survival, proliferation and differentiation of fetal murine germ cells (GCs) in vivo and in vitro. We postulated that these factors may play a similar role during early human GC development and primordial follicle formation. To test this hypothesis, we have investigated the expression and regulation of IL6-type cytokines, using quantitative reverse transcription polymerase chain reaction and immunohistochemistry. Expression of transcripts encoding OSM increased significantly across the gestational range examined (8-20 weeks), while expression of IL6 increased specifically between the first (8-11 weeks) and early second (12-16 weeks) trimesters, co-incident with the initiation of meiosis. LIF and CNTF expression remained unchanged. Expression of the genes encoding the LIF and IL6 receptors, and their common signalling subunit gp130, was also found to be developmentally regulated, with expression increasing significantly with increasing gestation. LIF receptor and gp130 proteins localized exclusively to GCs, including oocytes in primordial follicles, indicating this cell type to be the sole target of IL6-type cytokine signalling in the human fetal ovary. These data establish that IL6-type cytokines and their receptors are expressed in the human fetal ovary and may directly influence GC development at multiple stages of maturation.

LSQ14bdq: a type Ic Super-luminous Supernova with a double-peaked light curve

We present data for LSQ14bdq, a hydrogen-poor super-luminous supernova (SLSN) discovered by the La Silla QUEST survey and classified by the Public ESO Spectroscopic Survey of Transient Objects. The spectrum and light curve are very similar to slow-declining SLSNe such as PTF12dam. However, detections within ∼1 day after explosion show a bright and relatively fast initial peak, lasting for ∼15 days, prior to the usual slow rise to maximum light. The broader, main peak can be fit with either central engine or circumstellar interaction models. We discuss the implications of the precursor peak in the context of these models. It is too bright and narrow to be explained as a normal ⁵⁶Ni-powered SN, and we suggest that interaction models may struggle to fit the two peaks simultaneously. We propose that the initial peak may arise from the post-shock cooling of extended stellar material, and reheating by a central engine drives the second peak. In this picture, we show that an explosion energy of ∼2 × 10⁵² erg and a progenitor radius of a few hundred solar radii would be required to power the early emission. The competing engine models involve rapidly spinning magnetars (neutron stars) or fallback onto a central black hole. The prompt energy required may favor the black hole scenario. The bright initial peak may be difficult to reconcile with a compact Wolf-Rayet star as a progenitor since the inferred energies and ejected masses become unphysical.