The need for the GREAT+ score to predict relapse in Graves' disease: a questionnaire among patients and internal medicine specialists.

PURPOSE: Graves' disease (GD) is an auto-immune cause of hyperthyroidism. First-line treatment often consists of a 12-18 month course of antithyroid drugs (ATD). After discontinuation of ATD, GD relapses in approximately 50% of patients. The 'Graves recurrent event after therapy+ ' (GREAT+) score may predict individual relapse chances after ATD discontinuation more accurately based on clinical and laboratory parameters at diagnosis. We investigated the need for the GREAT+ score through an online questionnaire among GD patients and physicians treating GD. METHODS: An anonymous online questionnaire was distributed to patients and physicians between June 2022 and August 2023. RESULTS: The questionnaire was completed by 532 patients and 44 physicians. Results showed that 94% of patients were interested in knowing their GREAT+ score at the start of treatment. 55% would consider definite treatment (radioiodine/thyroidectomy) as first-line treatment in case of a high relapse chance. 98% of the physicians indicated the GREAT + score would support patient counseling. 84% may change their advice for first-line treatment if a patient has a high relapse chance based on the score. CONCLUSION: Patients and physicians considered the GREAT+ score as a valuable addition to the current available information which could change treatment decisions. Therefore, external validation of the GREAT+ score is justified to implement this score in clinical practice.

Symmetric expression of ohnologs encoding conserved antiviral responses in tetraploid common carp suggest absence of subgenome dominance after whole genome duplication.

Allopolyploids often experience subgenome dominance, with one subgenome showing higher levels of gene expression and greater gene retention. Here, we address the functionality of both subgenomes of allotetraploid common carp (Cyprinus carpio) by analysing a functional network of interferon-stimulated genes (ISGs) crucial in anti-viral immune defence. As an indicator of subgenome dominance we investigated retainment of a core set of ohnologous ISGs. To facilitate our functional genomic analysis a high quality genome was assembled (WagV4.0). Transcriptome data from an in vitro experiment mimicking a viral infection was used to infer ISG expression. Transcriptome analysis confirmed induction of 88 ISG ohnologs on both subgenomes. In both control and infected states, average expression of ISG ohnologs was comparable between the two subgenomes. Also, the highest expressing and most inducible gene copies of an ohnolog pair could be derived from either subgenome. We found no strong evidence of subgenome dominance for common carp.

No more glowing in the dark: how deep learning improves exposure date estimation in thermoluminescence dosimetry.

The time- or temperature-resolved detector signal from a thermoluminescence dosimeter can reveal additional information about circumstances of an exposure to ionising irradiation. We present studies using deep neural networks to estimate the date of a single irradiation with 12 mSv within a monitoring interval of 42 days from glow curves of novel TL-DOS personal dosimeters developed by the Materialprüfungsamt NRW in cooperation with TU Dortmund University. Using a deep convolutional network, the irradiation date can be predicted from raw time-resolved glow curve data with an uncertainty of roughly 1-2 days on a 68% confidence level without the need for a prior transformation into temperature space and a subsequent glow curve deconvolution (GCD). This corresponds to a significant improvement in prediction accuracy compared to a prior publication, which yielded a prediction uncertainty of 2-4 days using features obtained from a GCD as input to a neural network.

A full-body transcriptome and proteome resource for the European common carp.

BACKGROUND: The common carp (Cyprinus carpio) is the oldest, most domesticated and one of the most cultured fish species for food consumption. Besides its economic importance, the common carp is also highly suitable for comparative physiological and disease studies in combination with the animal model zebrafish (Danio rerio). They are genetically closely related but offer complementary benefits for fundamental research, with the large body mass of common carp presenting possibilities for obtaining sufficient cell material for advanced transcriptome and proteome studies. RESULTS: Here we have used 19 different tissues from an F1 hybrid strain of the common carp to perform transcriptome analyses using RNA-Seq. For a subset of the tissues we also have performed deep proteomic studies. As a reference, we updated the European common carp genome assembly using low coverage Pacific Biosciences sequencing to permit high-quality gene annotation. These annotated gene lists were linked to zebrafish homologs, enabling direct comparisons with published datasets. Using clustering, we have identified sets of genes that are potential selective markers for various types of tissues. In addition, we provide a script for a schematic anatomical viewer for visualizing organ-specific expression data. CONCLUSIONS: The identified transcriptome and proteome data for carp tissues represent a useful resource for further translational studies of tissue-specific markers for this economically important fish species that can lead to new markers for organ development. The similarity to zebrafish expression patterns confirms the value of common carp as a resource for studying tissue-specific expression in cyprinid fish. The availability of the annotated gene set of common carp will enable further research with both applied and fundamental purposes.

Durable efficacy of liraglutide in patients with type 2 diabetes and pronounced insulin-associated weight gain: 52-week results from the Effect of Liraglutide on insulin-associated wEight GAiN in patients with Type 2 diabetes' (ELEGANT) randomized controlled trial.

BACKGROUND: Pronounced weight gain frequently complicates insulin therapy in patients with type 2 diabetes (T2DM). We have previously reported that addition of liraglutide for 26 weeks can reverse insulin-associated weight gain, decrease insulin dose and improve glycaemic control, as compared with continuation of standard insulin treatment. OBJECTIVES: To investigate whether the beneficial effects of liraglutide are sustained up to 52 weeks and whether similar effects could be obtained when liraglutide is added 6 months later. METHODS: Adult T2DM patients with ≥ 4% weight gain within 16 months of insulin therapy completing the first 26-week trial period of open-label addition of liraglutide 1.8 mg day(-1) (n = 26) versus continuation of standard insulin therapy (n = 24) were all treated with liraglutide for another 26 weeks. Results were analysed according to the intention-to-treat principle. RESULTS: Overall, 24 (92%) and 18 (75%) patients originally assigned to liraglutide and standard therapy, respectively, completed the study. Addition of liraglutide decreased body weight to a similar extend when given in the first 26 weeks (liraglutide group) or second 26 weeks (original standard therapy group): -4.4 vs. -4.3 kg (difference -0.32 kg, 95% confidence interval -2.2 to 1.6 kg; P = 0.74). Similar results were also seen in the two groups with regard to decrease in haemoglobin A1c (HbA1c ) (-0.77 vs. -0.66%; P = 0.23) and insulin dose (-28 vs. -26 U day(-1) ; P = 0.32). In both groups, 22% of patients could discontinue insulin. Continuation of liraglutide until 52 weeks led to sustained effects on body weight, HbA1c and insulin-dose requirements. CONCLUSION: In T2DM patients with pronounced insulin-associated weight gain, addition of liraglutide within 2 years leads to sustained reversal of body weight, improved glycaemic control and decrease in insulin dose. Thus, liraglutide offers a valuable therapeutic option.

Hydrodynamic confinement and capillary alignment of gold nanorods.

Controlling the alignment and orientation of nanorods on various surfaces poses major challenges. In this work, we investigate hydrodynamic confinement and capillary alignment of gold nanorod assembly on chemically stripe-patterned substrates. The surface patterns consist of alternating hydrophilic and hydrophobic micrometer wide stripes; a macroscopic wettability gradient enables controlling the dynamics of deposited suspension droplets. We show that drying of residual liquid on the hydrophilic stripes gives rise to spatially localized deposition and alignment of the nanorods. Moreover, a universal relation between the extent of order within the single layers of nanoparticles and the lateral dimension of the deposits is presented and discussed.

Water-induced blister formation in a thin film polymer.

A failure mechanism of thin film polymers immersed in water is presented: the formation of blisters. The growth of blisters is counterintuitive as the substrates were noncorroding and the polymer does not swell in water. We identify osmosis as the driving force behind the blister formation. The dynamics of the blister formation is studied experimentally as well as theoretically, and a quantitative model describing the blister growth is developed, which accurately describes the temporal evolution of the blisters.

A new high-quality set of singly ((2) H) and doubly ((2) H and (18) O) stable isotope labeled reference waters for biomedical and other isotope-labeled research.

RATIONALE: Research using water with enriched levels of the rare stable isotopes of hydrogen and/or oxygen requires well-characterized enriched reference waters. The International Atomic Energy Agency (IAEA) did have such reference waters available, but these are now exhausted. New reference waters thus had to be produced in sufficient quantity, and higher characterization quality was desired. METHODS: The reference waters have been prepared gravimetrically from three parent waters: natural water, pure (2) H water and highly (18) O-enriched water. These parent waters have been thoroughly assessed for their full isotopic compositions. To ensure the integrity and correctness of the gravimetric procedure, validation measurements have been carried out on the isotopic composition of the produced reference waters by two of our laboratories. These measurements corroborate the values obtained on the basis of gravimetric data. RESULTS: Two new sets of three reference waters enriched in the stable isotopes have been produced and certified: one set of singly labeled waters, only enriched in (2) H, and another set of Doubly Labeled Waters, enriched in both (2) H and (18) O. They cover δ(2) H and δ(18) O values in the range of 800-16000 ‰ and 100-2000 ‰, respectively. The process has led to highly accurate isotopic values for these waters. CONCLUSIONS: These reference waters are now available (called IAEA-604 to IAEA-609). They will be valuable as reference materials for all fields using isotope labeling of water, most prominently, but not exclusively, biomedical research (body composition analyses, metabolic rate measurements). The two waters with the lowest enrichments will also be useful as anchor values for isotope measurements around the natural range.

[Combination of Excessive Weight Gain and Interleukin-8: A Possible Predictor of Necrotising Enterocolitis in Neonates?]. / Kann ein Gewichtssprung in Kombination mit einem Anstieg des Interleukin-8 eine nekrotisierende Enterokolitis bei Neonaten vorhersagen?

BACKGROUND: Weight gain before the clinical diagnosis of necrotising enterocolitis (NEC) is described as a predictive factor. HYPOTHESIS: Weight gain of more than 5% one day prior to clinical suspicion plus increase of plasma Iinterleukin-8 (IL-8) are predictive for NEC. METHODS: 48 infants with diagnosis of NEC stage II and III were enrolled in a case-control study. Oral and parenteral nutrition, diuresis and kinetics of weight and of IL-8 were documented. RESULTS: 31 infants with NEC-II and 17 infants with NEC-III were enrolled. Weight gain>5% occurred in 35.3% of NEC-III, in 0% of NEC-II and in 4.2% of the control group. IL-8 increased significantly [NEC-III (6 561.4 pg/mL) vs. NEC-II: (326.7 pg/mL) vs. control group (38.9 pg/mL); p<0.05]. Sensitivity of IL-8 in NEC-II was 87.10% (70.15-96.25) and in NEC-III 100.00% (80.33-100.00). Sensitivity of weight gain was 0.00% (0.00-11.32) in NEC-II and 35.29% (14.30-61.65) in NEC-III. CONCLUSION: Weight gain>5% was found in only 35.3% of the cases with NEC-III. Combination of weight gain and IL-8 did not improve the diagnosis of NEC.

Shape of picoliter droplets on chemically striped patterned substrates.

We studied the shape of water droplets deposited using an inkjet nozzle on a chemically striped patterned substrate consisting of alternating hydrophobic and hydrophilic stripes. The droplet dimensions are comparable to the period of the stripes, typically covering up to 13 stripes. As such, our present results bridge the gap linking two regimes previously considered: (i) droplets on single stripes and (ii) droplets covering more than 50 stripes. In line with previous work on markedly smaller water droplets, the exact deposition position is important for the final shape of the droplets. A droplet with its center deposited on a hydrophobic stripe reaches a shape that is different than when it is deposited on a hydrophilic stripe. Experimental results of different droplet configurations on the same surface are in agreement with simulations using the lattice Boltzmann model. In addition, the simulations enable a detailed analysis of droplet free energies and the volume dependence. The latter reveals scaling properties of shape parameters in terms of droplet radius scaled to the period of the stripe pattern, which have remained unexplored until now.

Universal spreading of water drops on complex surfaces.

A drop of water spreads very rapidly just after it is gently deposited on a solid surface. Here we experimentally investigate how these early stages of spreading are influenced by different types of surface complexity. In particular, we consider micro-textured substrates, chemically striped substrates and soft substrates. For all these complex substrates, it is found that there always exists an inertial regime where the radius r of the wetted area grows as r ∼ t(1/2). For perfectly wetting substrates, this regime extends over several decades in time, whereas we observe a deviation from a pure power-law for partially wetting substrates. Our experiments reveal that even the cross-over from the 1/2 power law to the final equilibrium radius displays a universal dynamics. This cross-over is governed only by the final contact angle, regardless of the details of the substrate.

[Trauma centre admission of severely injured or critically ill patients: comparison of estimated and real arrival times]. / Schockraumaufnahme schwerverletzter oder kritisch kranker Patienten: Geschätzte und tatsächliche Eintreffzeiten im Vergleich.

BACKGROUND: During early in-hospital management of the arriving trauma patient the timing of the trauma team alert is an important organisational step. To evaluate the accordance of the estimated and the real arriving time we performed a retrospective data analysis at a level I German trauma centre. METHODS: Retrospective data analysis. Trauma team alerts from September 2010 until March 2011 were analysed. According to the hospitals pre-alert algorithm, trauma team alert took place 10 min before the estimated time of arrival. RESULTS: There were 165 trauma team alerts included in the analysis. The estimated arrival time coincided with the real arrival time in less than 10 % of cases. In 76 % of the cases, the patient arrived in an acceptable time frame with the trauma team waiting less than 14 min. In 3 % of the cases, the patient arrived prior to the trauma team. CONCLUSION: An exact estimation of the arrival time is rare. With a trauma team alert 10 min prior to the estimated time of arrival, an acceptable waiting time can be achieved. Arrival of the patient prior to the trauma team can be avoided.

Start of insulin therapy in patients with type 2 diabetes mellitus promotes the influx of macrophages into subcutaneous adipose tissue.

AIMS/HYPOTHESIS: Insulin therapy in patients with type 2 diabetes mellitus is accompanied by weight gain characterised by an increase in abdominal fat mass. The expansion of adipose tissue mass is generally paralleled by profound morphological and inflammatory changes. We hypothesised that the insulin-associated increase in fat mass would also result in changes in the morphology of human subcutaneous adipose tissue and in increased inflammation, especially when weight gain was excessive. METHODS: We investigated the effects of weight gain on adipocyte size, macrophage influx, and mRNA expression and protein levels of key inflammatory markers within the adipose tissue in patients with type 2 diabetes mellitus before and 6 months after starting insulin therapy. RESULTS: As expected, insulin therapy significantly increased body weight. At the level of the subcutaneous adipose tissue, insulin treatment led to an influx of macrophages. When comparing patients gaining no or little weight with patients gaining >4% body weight after 6 months of insulin therapy, both subgroups displayed an increase in macrophage influx. However, individuals who had gained weight had higher protein levels of monocyte chemoattractant protein-1, TNF-α and IL-1ß after 6 months of insulin therapy compared with those who had not gained weight. CONCLUSIONS/INTERPRETATION: We conclude that insulin therapy in patients with type 2 diabetes mellitus improved glycaemic control but also induced body weight gain and an influx of macrophages into the subcutaneous adipose tissue. In patients characterised by a pronounced insulin-associated weight gain, the influx of macrophages into the adipose tissue was accompanied by a more pronounced inflammatory status. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00781495. FUNDING: The study was funded by European Foundation for the Study of Diabetes and the Dutch Diabetes Research Foundation.

Determinants of HbA1c in nondiabetic Dutch adults: genetic loci and clinical and lifestyle parameters, and their interactions in the Lifelines Cohort Study.

OBJECTIVES: Glycated haemoglobin (HbA1c) is associated with cardiovascular disease risk in individuals without diabetes, and its use has been recommended for diagnosing diabetes. Therefore, it is important to gain further understanding of the determinants of HbA1c. The aim of this study was to investigate the effects of genetic loci and clinical and lifestyle parameters, and their interactions, on HbA1c in nondiabetic adults. DESIGN: Population-based cohort study. SETTING: Three northern provinces of the Netherlands. SUBJECTS: A total of 2921 nondiabetic adults participating in the population-based LifeLines Cohort Study. MEASUREMENTS: Body mass index (BMI), waist circumference, HbA1c, fasting plasma glucose (FPG) and erythrocyte indices were measured. Data on current smoking and alcohol consumption were collected through questionnaires. Genome-wide genotyping was performed, and 12 previously identified single-nucleotide polymorphisms (SNPs) were selected for replication and categorized as 'glycaemic' and 'nonglycaemic' SNPs according to their presumed mechanism(s) of action on HbA1c. Genetic risk scores (GRSs) were calculated as the sum of the weighted effect of HbA1c-increasing alleles. RESULTS: Age, gender, BMI, FPG, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, current smoking and alcohol consumption were independent predictors of HbA1c, together explaining 26.2% of the variance in HbA1c, with FPG contributing 10.9%. We replicated three of the previously identified SNPs and the GRSs were also found to be independently associated with HbA1c. We found a smaller effect of the 'nonglycaemic GRS' in females compared with males and an attenuation of the effect of the GRS of all 12 SNPs with increasing BMI. CONCLUSIONS: Our results suggest that a substantial portion of HbA1c is determined by nonglycaemic factors. This should be taken into account when considering the use of HbA1c as a diagnostic test for diabetes.

Combined analysis of pharmacokinetic and efficacy data of preclinical studies with statins markedly improves translation of drug efficacy to human trials.

Correct prediction of human pharmacokinetics (PK) and the safety and efficacy of novel compounds based on preclinical data, is essential but often fails. In the current study, we aimed to improve the predictive value of ApoE*3Leiden (E3L) transgenic mice regarding the cholesterol-lowering efficacy of various statins in humans by combining pharmacokinetic with efficacy data. The efficacy of five currently marketed statins (atorvastatin, simvastatin, lovastatin, pravastatin, and rosuvastatin) in hypercholesterolemic patients (low-density lipoprotein ≥ 160 mg/dl) was ranked based on meta-analysis of published human trials. Additionally, a preclinical combined PK efficacy data set for these five statins was established in E3L mice that were fed a high-cholesterol diet for 4 weeks, followed by 6 weeks of drug intervention in which statins were supplemented to the diet. Plasma and tissue levels of the statins were determined on administration of (radiolabeled) drugs (10 mg/kg p.o.). As expected, all statins reduced plasma cholesterol in the preclinical model, but a direct correlation between cholesterol lowering efficacy of the different statins in mice and in humans did not reach statistical significance (R(2) = 0.11, P < 0.57). It is noteworthy that, when murine data were corrected for effective liver uptake of the different statins, the correlation markedly increased (R(2) = 0.89, P < 0.05). Here we show for the first time that hepatic uptake of statins is related to their cholesterol-lowering efficacy and provide evidence that combined PK and efficacy studies can substantially improve the translational value of the E3L mouse model in the case of statin treatment. This strategy may also be applicable for other classes of drugs and other preclinical models.

Doubly Labelled Water analysis: preparation, memory correction, calibration and quality assurance for δ2H and δ18O measurements over four orders of magnitudes.

RATIONALE: The Doubly Labelled Water (DLW) method is an established way of determining the metabolic rate in humans and animals, with the advantage that the subjects need not be confined. The method, however, needs accurate determination of both the δ(2)H and the δ(18)O isotope values over a wide range of enrichments. METHODS: In this paper we describe a number of crucial steps in the process of isotope determination in body fluids. These steps include micro-distillation, correction of the measurements for sample-to-sample memory and calibration of the isotope scales over many orders of magnitudes. In contrast to several published protocols and guidelines, we also take highly enriched samples into account, as they are required for studying the metabolic rate of birds and small mammals. For our isotope scale calibration, we made a set of gravimetrically prepared, double labelled waters with known isotope values. Our quality assurance includes a scheme for easy calculation of the error propagation, leading to a reliable estimate of the analytical error in the metabolic rate. RESULTS: Our memory correction algorithm assumes the existence of three water "pools" that have different sizes and exchange rates with the injected samples. We show that the method can correct even huge memory signals, without the need for "true" values. CONCLUSIONS: With the presented building blocks, we show how to assure a reliable and accurate isotope analysis for the DLW method, both for human and for animal applications. Although our measurements have been performed using isotope ratio mass spectrometry, most of the procedures are also useful for laser spectrometry.

A lipoprotein lipase mutation (Asn291Ser) is associated with reduced HDL cholesterol levels in premature atherosclerosis.

A reduction of high density lipoprotein cholesterol (HDC) is recognized as an important risk factor for coronary artery disease (CAD). We now show in approximately 1 in 20 males with proven atherosclerosis that an Asn291Ser mutation in the human lipoprotein lipase (LPL) gene is associated with significantly reduced HDL levels (P = 0.001) and results in a significant decrease in LPL catalytic activity (P < 0.0009). The relative frequency of this mutation increases in those patients with lower HDL cholesterol levels. In vitro mutagenesis and expression studies confirm that this change is associated with a significant reduction in LPL activity. Our data support the relationship between LPL activity and HDL-C levels, and suggest that a specific LPL mutation may be a factor in the development of atherosclerosis.

Simulating anisotropic droplet shapes on chemically striped patterned surfaces.

The equilibrium shape of droplets on surfaces, functionalized with stripes of alternating wettability, have been investigated using simulations employing a finite element method. Experiments show that a droplet deposited on a surface with relatively narrow hydrophobic stripes compared to the hydrophilic stripes adopts a strongly elongated shape. The aspect ratio, the length of the droplet divided by the width, decreases toward unity when a droplet is deposited on a surface with relatively narrow hydrophilic stripes. The aspect ratio and the contact angle parallel to the stripes show unique scaling behavior as a function of the ratio between the widths of the hydrophobic and hydrophilic stripes. For a small ratio, the contact angle parallel to the stripes is low and the aspect ratio high, while for a large ratio, the contact angle parallel is high and the aspect ratio low. The simulations exhibit similar scaling behavior, both for the aspect ratio of the droplets and for the contact angles in the direction parallel to the stripes. Two liquids with different surface tensions have been investigated both experimentally and in simulations; similarities and differences between the findings are discussed. Generally, three parameters are needed to describe the droplet geometry: (i) the equilibrium contact angles on the hydrophilic and (ii) hydrophobic areas and (iii) the ratio of the widths of these chemically defined stripes. Furthermore, we derive a simple analytical expression that proves to be a good approximation in the quantitative description of the droplet aspect ratio.

Tuning kinetics to control droplet shapes on chemically striped patterned surfaces.

The typically elongated shape of droplets on chemically microstriped surfaces has been suggested to depend strongly on the kinetics during deposition. Here, we unequivocally establish the importance of impact kinetics by comparing the geometry of pico- to microliter droplets deposited from an inkjet nozzle with those obtained by conventional deposition from a syringe. For large Weber numbers, the strongly enhanced spreading during the impact in combination with direction-dependent pinning of the contact line gives rise to more spherical droplets with a low aspect ratio. The impact energy can be minimized by the prolonged firing of small picoliter droplets to form larger droplets or, as shown in the past, by using high-viscosity liquids. In the first case, the impact energy is absorbed by the liquid already present, therewith reducing the impact diameter and consequently forming markedly more elongated droplets.

Tuning a racetrack ring resonator by an integrated dielectric MEMS cantilever.

The principle, fabrication and characterization of a dielectric MEMS cantilever located a few 100 nm above a racetrack ring resonator are presented. After fabrication of the resonators on silicon-on-insulator (SOI) wafers in a foundry process, the cantilevers were integrated by surface micromachining techniques. Off-state deflections of the cantilevers have been optimized to appropriately position them near the evanescent field of the resonator. Using electrostatic actuation, moving the cantilevers into this evanescent field, the propagation properties of the ring waveguide are modulated. We demonstrate 122 pm tuning of the resonance wavelength of the optical ring resonator (in the optical C-band) without change of the optical quality factor, on application of 9 V to a 40 µm long cantilever. This compact integrated device can be used for tuning/switching a specific wavelength, with very little energy for operation and negligible cross talk with surrounding devices.