Monogenic diabetes, a young-onset form of diabetes, is often misdiagnosed as type 1 diabetes, resulting in unnecessary treatment with insulin. A screening approach for monogenic diabetes is needed to ...accurately select suitable patients for expensive diagnostic genetic testing. We used C-peptide and islet autoantibodies, highly sensitive and specific biomarkers for discriminating type 1 from non-type 1 diabetes, in a biomarker screening pathway for monogenic diabetes.
We studied patients diagnosed at age 30 years or younger, currently younger than 50 years, in two U.K. regions with existing high detection of monogenic diabetes. The biomarker screening pathway comprised three stages:
) assessment of endogenous insulin secretion using urinary C-peptide/creatinine ratio (UCPCR);
) if UCPCR was ≥0.2 nmol/mmol, measurement of GAD and IA2 islet autoantibodies; and
) if negative for both autoantibodies, molecular genetic diagnostic testing for 35 monogenic diabetes subtypes.
A total of 1,407 patients participated (1,365 with no known genetic cause, 34 with monogenic diabetes, and 8 with cystic fibrosis-related diabetes). A total of 386 out of 1,365 (28%) patients had a UCPCR ≥0.2 nmol/mmol, and 216 out of 386 (56%) were negative for GAD and IA2 and underwent molecular genetic testing. Seventeen new cases of monogenic diabetes were diagnosed (8 common Maturity Onset Diabetes of the Young Sanger sequencing and 9 rarer causes next-generation sequencing) in addition to the 34 known cases (estimated prevalence of 3.6% 51/1,407 95% CI 2.7-4.7%). The positive predictive value was 20%, suggesting a 1-in-5 detection rate for the pathway. The negative predictive value was 99.9%.
The biomarker screening pathway for monogenic diabetes is an effective, cheap, and easily implemented approach to systematically screening all young-onset patients. The minimum prevalence of monogenic diabetes is 3.6% of patients diagnosed at age 30 years or younger.
Effects of hydrologic variability on reservoir biogeochemistry are relatively unknown, particularly for less studied metals like vanadium (V). Further, few studies have investigated the fate and ...effects of sediment-associated V to aquatic organisms in hydrologically variable systems. Our primary objective was to assess effects of hydrologic manipulation on speciation and toxicity of V (range: 635 to 1620mgkg−1) and other metals to Hyalella azteca and Daphnia magna. Sediments were collected from a reservoir located in a former mining area and microcosm experiments were conducted to emulate 7-day drying and inundation periods. Despite high sediment concentrations, V bioavailability remained low with no significant effects to organism survival, growth, or reproduction. The lack of V toxicity was attributed to reduced speciation (III, IV), non-labile complexation, and sorption to Al/Fe/Mn-oxyhydroxides. Zinc (Zn) increased in surface and porewater with inundation, for some sediments exceeding the U.S. EPA threshold for chronic toxicity. While no effects of Zn to organism survival or growth were observed, Zn body concentrations were negatively correlated with H. azteca growth. Results from this study indicate that V bioavailability and environmental risk is dependent on V-speciation, and V is less influenced by hydrologic variability than more labile metals such as Zn.
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•Fate and effects of vanadium in hydrodynamic aquatic ecosystems are assessed.•Sediment speciation led to low bioavailability of sediment V and thus no effects to organisms.•Water level fluctuation and sediment oxidation led to Zn-release, affecting H. azteca growth.•It is important to consider V sediment speciation when assessing environmental risk.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The decline in C-peptide in the 5 years after diagnosis of type 1 diabetes has been well studied, but little is known about the longer-term trajectory. We aimed to examine the association between ...log-transformed C-peptide levels and the duration of diabetes up to 40 years after diagnosis.
We assessed the pattern of association between urinary C-peptide/creatinine ratio (UCPCR) and duration of diabetes in cross-sectional data from 1,549 individuals with type 1 diabetes using nonlinear regression approaches. Findings were replicated in longitudinal follow-up data for both UCPCR (
= 161 individuals, 326 observations) and plasma C-peptide (
= 93 individuals, 473 observations).
We identified two clear phases of C-peptide decline: an initial exponential fall over 7 years (47% decrease/year 95% CI -51, -43) followed by a stable period thereafter (+0.07%/year -1.3, +1.5). The two phases had similar durations and slopes in patients above and below the median age at diagnosis (10.8 years), although levels were lower in the younger patients irrespective of duration. Patterns were consistent in both longitudinal UCPCR (
= 162; ≤7 years duration: -48%/year -55, -38; >7 years duration -0.1% -4.1, +3.9) and plasma C-peptide (
= 93; >7 years duration only: -2.6% -6.7, +1.5).
These data support two clear phases of C-peptide decline: an initial exponential fall over a 7-year period, followed by a prolonged stabilization where C-peptide levels no longer decline. Understanding the pathophysiological and immunological differences between these two phases will give crucial insights into understanding β-cell survival.
Small studies using ultrasensitive C-peptide assays suggest endogenous insulin secretion is frequently detectable in patients with long-standing type 1 diabetes (T1D), but these studies do not use ...representative samples. We aimed to use the stimulated urine C-peptide-to-creatinine ratio (UCPCR) to assess C-peptide levels in a large cross-sectional, population-based study of patients with T1D.
We recruited 924 patients from primary and secondary care in two U.K. centers who had a clinical diagnosis of T1D, were under 30 years of age when they received a diagnosis, and had a diabetes duration of >5 years. The median age at diagnosis was 11 years (interquartile range 6-17 years), and the duration of diabetes was 19 years (11-27 years). All provided a home postmeal UCPCR, which was measured using a Roche electrochemiluminescence assay.
Eighty percent of patients (740 of 924 patients) had detectable endogenous C-peptide levels (UCPCR >0.001 nmol/mmol). Most patients (52%, 483 of 924 patients) had historically very low undetectable levels (UCPCR 0.0013-0.03 nmol/mmol); 8% of patients (70 of 924 patients) had a UCPCR ≥0.2 nmol/mmol, equivalent to serum levels associated with reduced complications and hypoglycemia. Absolute UCPCR levels fell with duration of disease. Age at diagnosis and duration of disease were independent predictors of C-peptide level in multivariate modeling.
This population-based study shows that the majority of long-duration T1D patients have detectable urine C-peptide levels. While the majority of patients are insulin microsecretors, some maintain clinically relevant endogenous insulin secretion for many years after the diagnosis of diabetes. Understanding this may lead to a better understanding of pathogenesis in T1D and open new possibilities for treatment.
Researchers have developed numerous per- and polyfluoroalkyl substances (PFAS)-free aqueous film-forming foam (AFFF) formulations to replace PFAS-containing AFFF used for fire suppression. As part of ...the Department of Defense’s Strategic Environmental Research and Development Program (SERDP), we examined the direct lethal effects of seven PFAS-free AFFF and a PFAS-containing AFFF on 14 aquatic species using a series of lethal concentration (LC50) tests. We assessed the LC10, LC50, and LC90 values using log–logistic and logit analyses. Across all aquatic species tested, we discovered that exposure to at least one PFAS-free AFFF was more or as toxic as exposure to the PFAS-containing AFFF. For most cases, National Foam Avio F3 Green KHC 3% and Buckeye Platinum Plus C6MILSPEC 3% were the most and least toxic formulations, respectively. Moreover, we found consistency among results from multiple experiments using the same minnow species (Pimephales promelas) and among closely related taxa (e.g., daphnids, amphibians). Lastly, the LC50 values for AFFF formulations trended lower for tested marine species as compared to those of freshwater species. These results dramatically increase the current knowledge on the potentially toxic effects of AFFF but also highlight the need for additional research and the development of new PFAS-free AFFF that are more “ecologically friendly” than those containing persistent PFAS.
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IJS, KILJ, NUK, PNG, UL, UM
This study mined student interactions with visual representations as a means to automate assessment of learning in a complex, inquiry-based learning environment. Log trace data of 143 middle school ...students' interactions with an interactive map in Research Quest (an inquiry-based, online learning environment) were analyzed. Students used the interactive map to make scientific observations for an evidence-based hypothesis. The examination of classification error using an artificial neural network, compared against the majority class for prediction, suggests that student performance on several metrics of critical thinking can be classified based on different patterns in interactions with visual representations. Two alternative methods are compared in this study for training and evaluating data-mined models of student performance. In accordance with the general consensus in the literature, the error estimates for models' predictions were less variable using a student-level cross-validation. Implications of these findings for open-ended inquiry-based learning environments are discussed.
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BFBNIB, NUK, PILJ, SAZU, UL, UM, UPUK
In aquatic ecosystems, the cycling and toxicity of nickel (Ni) are coupled to other elemental cycles that can limit its bioavailability. Current sediment risk assessment approaches consider ...acid-volatile sulfide (AVS) as the major binding phase for Ni, but have not yet incorporated ligands that are present in oxic sediments. Our study aimed to assess how metal oxides play a role in Ni bioavailability in surficial sediments exposed to effluent from two mine sites. We coupled spatially explicit sediment geochemistry (i.e., separate oxic and suboxic) to the indigenous macroinvertebrate community structure. Effluent-exposed sites contained high concentrations of sediment Ni and AVS, though roughly 80% less AVS was observed in surface sediments. Iron (Fe) oxide mineral concentrations were elevated in surface sediments and bound a substantial proportion of Ni. Redundancy analysis of the invertebrate community showed surface sediment geochemistry significantly explained shifts in community abundances. Relative abundance of the dominant mayfly (Ephemeridae) was reduced in sites with greater bioavailable Ni, but accounting for Fe oxide-bound Ni greatly decreased variation in effect thresholds between the two mine sites. Our results provide field-based evidence that solid-phase ligands in oxic sediment, most notably Fe oxides, may have a critical role in controlling nickel bioavailability.
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IJS, KILJ, NUK, PNG, UL, UM
Genetic studies have recently highlighted the importance of fat distribution, as well as overall adiposity, in the pathogenesis of obesity-associated diseases. Using a large study (n = 1,288) from 4 ...independent cohorts, we aimed to investigate the relationship between mean adipocyte area and obesity-related traits, and identify genetic factors associated with adipocyte cell size. To perform the first large-scale study of automatic adipocyte phenotyping using both histological and genetic data, we developed a deep learning-based method, the Adipocyte U-Net, to rapidly derive mean adipocyte area estimates from histology images. We validate our method using three state-of-the-art approaches; CellProfiler, Adiposoft and floating adipocytes fractions, all run blindly on two external cohorts. We observe high concordance between our method and the state-of-the-art approaches (Adipocyte U-net vs. CellProfiler: R2visceral = 0.94, P < 2.2 × 10-16, R2subcutaneous = 0.91, P < 2.2 × 10-16), and faster run times (10,000 images: 6mins vs 3.5hrs). We applied the Adipocyte U-Net to 4 cohorts with histology, genetic, and phenotypic data (total N = 820). After meta-analysis, we found that mean adipocyte area positively correlated with body mass index (BMI) (Psubq = 8.13 × 10-69, βsubq = 0.45; Pvisc = 2.5 × 10-55, βvisc = 0.49; average R2 across cohorts = 0.49) and that adipocytes in subcutaneous depots are larger than their visceral counterparts (Pmeta = 9.8 × 10-7). Lastly, we performed the largest GWAS and subsequent meta-analysis of mean adipocyte area and intra-individual adipocyte variation (N = 820). Despite having twice the number of samples than any similar study, we found no genome-wide significant associations, suggesting that larger sample sizes and a homogenous collection of adipose tissue are likely needed to identify robust genetic associations.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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