Time-dependent lipid profile inversely associates with mortality in hemodialysis patients - independent of inflammation/malnutrition.

BACKGROUND: Patients with end-stage kidney disease have an extremely high cardiovascular mortality rate, but there is a paradoxical relationship between lipid profile and survival in haemodialysis patients. To investigate whether inflammation/malnutrition confounds the associations between lipids and mortality, we studied a full lipid profile comprising of five clinically well-established lipid parameters and its associations with mortality in a large, multinational European cohort with a median follow-up >3 years. METHODS: The association between quartiles of total, high-density lipoprotein (HDL), non-HDL, low-density lipoprotein (LDL) cholesterol, as well as triglyceride, levels and the end-points of all-cause, cardiovascular and non-cardiovascular mortality was assessed in a cohort of 5,382 incident, adult haemodialysis patients from >250 Fresenius Medical Care dialysis centres out of 14 participating countries using baseline and time-dependent Cox models. Analyses were fully adjusted and stratified for inflammation/malnutrition status and other patient-level variables. RESULTS: Time-dependent quartiles of total, HDL, non-HDL and LDL cholesterol were inversely associated with the hazard for all-cause, cardiovascular and non-cardiovascular mortality. Compared with the lowest quartile of the respective lipid parameter, hazard ratios of other quartiles were <0.86. Similar, albeit weaker, associations were found with baseline lipid profile and mortality. Neither time-dependent nor baseline associations between lipid profile and mortality were affected by inflammation/malnutrition, statin use or geography. CONCLUSIONS: Baseline and time-dependent lipid profile are inversely associated with mortality in a large, multicentre cohort of incident haemodialysis patients. Inflammation/malnutrition is not a confounder nor effect modificator of the associations between lipid profile and mortality in European haemodialysis patients.

Circulating Pro-Neurotensin in gestational diabetes mellitus.

BACKGROUND AND AIMS: Pro-Neurotensin (NT), a stable surrogate parameter of NT, has recently been introduced as a peptide predicting the development of obesity, diabetes mellitus, cardiovascular diseases, and cardiovascular mortality. However, regulation of Pro-NT in gestational diabetes mellitus (GDM) remains uninvestigated. METHODS AND RESULTS: Pro-NT was quantified in 74 women with GDM, 74 healthy, gestational age-matched, pregnant controls, as well as in a second cohort comprising of 74 healthy, non-pregnant control women, using a chemiluminometric sandwich immunoassay. Pro-NT was correlated to measures of obesity, hypertension, glucose and lipid metabolism, renal function, and inflammation. Mean ± standard deviation of circulating Pro-NT levels were not significantly different in women with GDM (100.2 ± 75.7 pmol/l) as compared to healthy, pregnant controls (103.2 ± 37.4 pmol/l) and healthy, non-pregnant female controls (105.9 ± 38.9 pmol/l) (p = 0.661). Homeostasis model assessment of insulin resistance (HOMA-IR) and creatinine positively correlated with serum Pro-NT in multivariate regression analysis. In contrast, free fatty acids (FFA) were inversely correlated with circulating Pro-NT. Results sustained adjustment for pregnancy status. CONCLUSIONS: Circulating Pro-NT is not independently associated with GDM, but is with HOMA-IR, creatinine, and FFA even after adjustment for pregnancy status.

Association of metabolic parameters and rs726344 in FNDC5 with serum irisin concentrations.

BACKGROUND/OBJECTIVES: Irisin has been suggested as a novel myokine with beneficial effects in rodents. However, previous data in humans showed conflicting results regarding its association with metabolic phenotypes and regulation of secretion. Furthermore, although an association of rs726344 in FNDC5 (fibronectin type III domain containing 5) coding for irisin with insulin sensitivity was reported, the effects of genetic variation at this locus on irisin serum levels have not been investigated, so far. Therefore, we investigated circulating irisin and the associations with rs726344 in a cohort of >1000 subjects. SUBJECTS/METHODS: Irisin serum concentrations were measured with enzyme-linked immunosorbent assay. Associations with metabolic parameters including renal function, glucose and lipid metabolism, inflammation, as well as adipokine profiles, were assessed in regression models. Dynamic changes of serum irisin were investigated during oral glucose tolerance test (OGTT) in a subset of the cohort (n=136). rs726344 was genotyped in all subjects and analyzed for associations with serum irisin and traits of the metabolic syndrome. RESULTS: Irisin was negatively associated with fat mass, fasting glucose and dyslipidemia but not with other adipokines. Moreover, irisin decreased during an OGTT in a subcohort comprising subjects with normal glucose tolerance, impaired fasting glucose, impaired glucose tolerance and type 2 diabetes mellitus. rs726344 was not associated with serum irisin levels or with other anthropometric and biochemical parameters. CONCLUSIONS: Circulating irisin levels are associated with a beneficial metabolic profile but not with other adipokines and not with rs726344 in our cohort. Our data suggest a potential favorable role of irisin in the regulation of metabolism.

German MedicalTeachingNetwork (MDN) implementing national standards for teacher training.

BACKGROUND: An increasing demand for proof of professionalism in higher education strives for quality assurance (QA) and improvement in medical education. A wide range of teacher trainings is available to medical staff in Germany. Cross-institutional approval of individual certificates is usually a difficult and time consuming task for institutions. In case of non-acceptance it may hinder medical teachers in their professional mobility. AIM: The faculties of medicine aimed to develop a comprehensive national framework, to promote standards for formal faculty development programmes across institutions and to foster professionalization of medical teaching. METHODS AND RESULTS: Addressing the above challenges in a joint approach, the faculties set up the national MedicalTeacherNetwork (MDN). Great importance is attributed to work out nationally concerted standards for faculty development and an agreed-upon quality control process across Germany. Medical teachers benefit from these advantages due to portability of faculty development credentials from one faculty of medicine to another within the MDN system. CONCLUSION: The report outlines the process of setting up the MDN and the national faculty development programme in Germany. Success factors, strengths and limitations are discussed from an institutional, individual and general perspective. Faculties engaged in similar developments might be encouraged to transfer the MDN concept to their countries.

Adipocyte fatty acid-binding protein is released from adipocytes by a non-conventional mechanism.

Adipocyte fatty acid-binding protein (AFABP) is an adipokine, which induces insulin resistance. However, AFABP does not possess any secretion-directed signals and the mechanisms for AFABP release have not been thoroughly assessed so far. In the current study, mechanisms for AFABP secretion were elucidated in 3T3-L1 adipocytes in vitro in the presence or absence of hormonal stimulation, calcium ionophore and secretion inhibitors by cell fractionation experiments, immunoblotting and ELISAs. We demonstrate that AFABP secretion is upregulated during adipocyte differentiation. AFABP secretion is not influenced by treatment with protein secretion inhibitors that block vesicular traffic at the endoplasmic reticulum and the Golgi apparatus. AFABP is secreted partially by adipocyte-derived microvesicles (ADMs), an established mechanism for unconventional secretion from adipocytes. Both total and ADM-secreted AFABP are downregulated by insulin and upregulated by the calcium ionophore ionomycin. Furthermore, murine RAW 264.7 macrophages secrete AFABP and AFABP release from these cells is upregulated by lipopolysaccharide treatment. Taken together, these results suggest that AFABP is actively released by unconventional mechanisms and by ADMs from 3T3-L1 adipocytes. Furthermore, AFABP secretion from fat cells is regulated by insulin and intracellular calcium.

Serum levels of fractalkine are associated with markers of insulin resistance in gestational diabetes.

AIMS: Fractalkine has recently been introduced as an adipokine that improves glucose tolerance. Regulation of fractalkine in gestational diabetes, as well as its association with markers of obesity, glucose and lipid metabolism, inflammation and renal function, has not been elucidated. METHODS: Circulating fractalkine was quantified by enzyme-linked immunosorbent assay in 74 women with gestational diabetes and 74 healthy, pregnant control subjects matched for age, BMI, and gestational age. RESULTS: Median (interquartile range) levels of fractalkine were not significantly different between the two groups [gestational diabetes: 2.24 (2.16) µg/l; control: 2.45 (1.38) µg/l] (P = 0.461). In multivariate linear regression analysis, fractalkine remained independently associated with homeostasis model assessment of insulin resistance (ß = -0.253, P = 0.002) and the proinflammatory adipokine progranulin (ß = 0.218, P = 0.007). CONCLUSIONS: Circulating fractalkine is not different between women with gestational diabetes and control subjects, but the adipokine is independently associated with markers of insulin resistance and proinflammatory progranulin in pregnancy.

Relationship between serum levels of angiopoietin-related growth factor and metabolic risk factors.

Angiopoietin-related growth factor (AGF, also known as angiopoietin-like protein 6) has been introduced as a novel hepatocyte-derived factor, which antagonizes obesity and insulin resistance in mice. However, human studies show conflicting results and are limited to a small cohort of patients. In the current study, we therefore sought to investigate AGF serum levels in a large metabolically well-characterized cohort. AGF serum concentrations were determined by commercial enzyme-linked immunosorbent assay in 697 patients of a cohort from Eastern Germany (Sorbs). Correlations of AGF serum levels with clinical and biochemical measures of glucose and lipid metabolism, as well as markers of renal function, were investigated. In nondiabetic subjects (n=627), AGF was positively correlated with markers of insulin resistance and negatively correlated with high-density lipoprotein cholesterol in univariate analyses (p<0.05). After adjustment for age, gender, and body mass index, none of these factors remained independently associated with AGF, neither in nondiabetic subjects nor in patients with type 2 diabetes mellitus (T2DM) (n=70). However, we confirmed existing data of significantly higher AGF concentrations in patients with T2DM as compared to controls in this large cohort. Circulating AGF is elevated in subjects with T2DM and related to the type of antidiabetic treatment, but is not independently associated with anthropometric parameters, indices of insulin sensitivity and secretion, or a number of other adipokines.

Different associations of adipokines in lean and healthy adults.

Regulation of adipokines in lean adults without metabolic disease and without eating disorders has not been comprehensively elucidated. We hypothesized that some of the established associations of these adipocyte-secreted proteins with anthropometric and biochemical measures of glucose homeostasis, lipid metabolism, renal function, as well as inflammation, differ in healthy and low weight adults as compared to overweight/obese patients. Eighty-one subjects with a body mass-index below 22.0 kg/m2 and without malnutrition or eating disorders, as well as fifty overweight/obese patients, were recruited for the study. Serum concentrations of seven adipokines (adiponectin, leptin, adipocyte fatty acid-binding protein [AFABP], chemerin, fibroblast growth factor [FGF]-21, resistin, retinol-binding protein [RBP]-4) were measured by enzyme-linked immunosorbent assays. Lean probands had significantly higher levels of adiponectin and resistin, as well as lower levels of leptin, AFABP, and RBP-4, as compared to overweight/obese subjects. Serum concentrations of adiponectin, leptin, AFABP, chemerin, and resistin were significantly higher in lean women as compared to men (p<0.05). In lean subjects, fasting insulin independently predicted leptin and resistin concentrations. Furthermore, C-reactive protein was independently associated with circulating AFABP and chemerin. Moreover, lean body mass was an independent predictor of leptin, fat mass predicted AFABP levels, whereas RBP-4 was independently correlated to age and triglycerides. In addition, high density lipoprotein cholesterol predicted AFABP. Our results support the notion that several of these adipokines are regulated in a different manner in lean adults as compared to overweight/obese subjects and patients with eating disorders.

Circulating adipocyte fatty acid binding protein is increased in chronic and acute renal dysfunction.

BACKGROUND AND AIMS: The adipokine adipocyte fatty acid binding protein (AFABP) is positively associated with the development of the metabolic syndrome, diabetes mellitus, and cardiovascular disease. We hypothesized that AFABP also increases with deteriorating renal function. METHODS AND RESULTS: Serum AFABP levels were quantified by enzyme linked immunosorbent assay in 532 patients with chronic kidney disease (CKD) covering the whole spectrum of estimated glomerular filtration rate (eGFR) categories from G1 to G5 (study population 1). Furthermore, AFABP was measured in 32 patients before and within 30 h after elective unilateral nephrectomy, a model of acute kidney dysfunction (AKD) (study population 2). Moreover, circulating AFABP was investigated in rats undergoing bilateral nephrectomy (BNE) as compared to sham-operated animals. Median serum AFABP levels adjusted for age, gender, and body mass index significantly increased with increasing eGFR category (G1: 22.0 µg/l; G2: 34.6 µg/l; G3: 56.7 µg/l; G4: 95.2 µg/l; and G5: 173.9 µg/l). Furthermore, renal dysfunction remained positively associated with AFABP in multivariate analysis in this cohort. In patients undergoing unilateral nephrectomy, AFABP increased significantly after surgery (42.1 µg/l) as compared to pre-surgical values (29.3 µg/l). Furthermore, relative changes of post-to-pre-surgical AFABP levels were independently associated with relative changes of post-to-pre-surgical creatinine concentrations. After BNE in rats, AFABP increased significantly as compared to sham-operated animals. CONCLUSIONS: We show that AFABP is significantly elevated in CKD and AKD patients. Furthermore, measures of renal function are associated with circulating AFABP. Moreover, animal experiments indicate that AFABP levels strongly depend on renal function.

Spatially resolved online particle detector using scintillators for laser-driven particle sources.

Laser-based particle accelerators have been an active field of research for over two decades moving from laser systems capable of one shot every hour to systems able to deliver repetition rates in the Hz regime. Based on the advancements in laser technology, the corresponding detection methods need to develop from single to multiple use with high readout speed. Here, we present an online compact tracker of particles using scintillators with nine resolvable energy levels and a spatial resolution of 3.6 × 3.6 mm2 over the whole active area. This paper describes the design and construction of the detector, which is based on pixellated scintillators embedded inside an absorber matrix. The scintillator pixels are fiberoptically coupled to a camera system for online readout and analysis. Calibration with a radioactive source and first experimental data measuring laser accelerated ions at the PHELIX laser at GSI, Darmstadt, Germany, are presented and discussed.

Microstructured layered targets for improved laser-induced x-ray backlighters.

We present the usage of two-layer targets with laser-illuminated front-side microstructures for x-ray backlighter applications. The targets consisted of a silicon front layer and copper back side layer. The structured layer was irradiated by the 500-fs PHELIX laser with an intensity above 10^{20}Wcm^{-2}. The total emission and one-dimensional extent of the copper Kα x-ray emission as well as a wide spectral range between 7.9 and 9.0 keV were recorded with an array of crystal spectrometers. The measurements show that the front-side modifications of the silicon in the form of conical microstructures maintain the same peak brightness of the Kα emission as flat copper foils while suppressing the thermal emission background significantly. The observed Kα source sizes can be influenced by tilting the conical microstructures with respect to the laser axis. Overall, the recorded copper Kα photon yields were in the range of 10^{11}sr^{-1}, demonstrating the suitability of these targets for probing applications without subjecting the probed material to additional heating from thermal line emission.

Analysis of laser-proton acceleration experiments for development of empirical scaling laws.

Numerous experiments on laser-driven proton acceleration in the MeV range have been performed with a large variety of laser parameters since its discovery around the year 2000. Both experiments and simulations have revealed that protons are accelerated up to a maximum cut-off energy during this process. Several attempts have been made to find a universal model for laser proton acceleration in the target normal sheath acceleration regime. While these models can qualitatively explain most experimental findings, they can hardly be used as predictive models, for example, for the energy cut-off of accelerated protons, as many of the underlying parameters are often unknown. Here we analyze experiments on laser proton acceleration in which scans of laser and target parameters were performed. We derive empirical scaling laws from these parameter scans and combine them in a scaling law for the proton energy cut-off that incorporates the laser pulse energy, the laser pulse duration, the focal spot radius, and the target thickness. Using these scaling laws, we give examples for predicting the proton energy cut-off and conversion efficiency for state-of-the-art laser systems.

Heterogeneity of neurons reprogrammed from spinal cord astrocytes by the proneural factors Ascl1 and Neurogenin2.

Astrocytes are a viable source for generating new neurons via direct conversion. However, little is known about the neurogenic cascades triggered in astrocytes from different regions of the CNS. Here, we examine the transcriptome induced by the proneural factors Ascl1 and Neurog2 in spinal cord-derived astrocytes in vitro. Each factor initially elicits different neurogenic programs that later converge to a V2 interneuron-like state. Intriguingly, patch sequencing (patch-seq) shows no overall correlation between functional properties and the transcriptome of the heterogenous induced neurons, except for K-channels. For example, some neurons with fully mature electrophysiological properties still express astrocyte genes, thus calling for careful molecular and functional analysis. Comparing the transcriptomes of spinal cord- and cerebral-cortex-derived astrocytes reveals profound differences, including developmental patterning cues maintained in vitro. These relate to the distinct neuronal identity elicited by Ascl1 and Neurog2 reflecting their developmental functions in subtype specification of the respective CNS region.

Transmission parameters for Candidatus liberibacter asiaticus by Asian citrus psyllid (Hemiptera: Psyllidae).

The purpose of this investigation was to evaluate acquisition and inoculation (together, transmission) efficiency of Candidatus Liberibacter asiaticus (Las), the pathogen associated with citrus huanglongbing (HLB) by the Asian citrus psyllid, Diaphorina citri (Kuwayama) (Hemiptera: Psyllidae). In laboratory studies, nymphs reared on Las infected plants were more likely to acquire the bacterium than adults. Acquisition by nymphs ranged from 60 to 100%, whereas acquisition by adults only reached 40% after 5 wk of feeding on Las-infected plants. Similar rates of pathogen acquisition by psyllids after nymphal and adult feeding were observed in the field. Transmission of Las from parent to offspring (transovarial) occurred at a rate of 2-6%. One year after psyllid inoculations, successful transmission by individual D. citri ranged from 4 to 10%, whereas groups of 100 or more D. citri transmitted the pathogen at a rate of approximately 88%. In addition, the proportion of Las-positive adult psyllids, determined using quantitative real-time polymerase chain reaction, decreased over time when held on healthy plants. Due to the low rate of pathogen acquisition and long time period required for successful inoculation by adult D. citri, experiments designed to determine the latent period required for replication and successful inoculation of Las by D. citri did not result in Las-infected plants after >1 yr of incubation after inoculation. Collectively, these results indicate that adult D. citri which acquire the HLB pathogen as adults are poor vectors of the pathogen compared with adults that acquired the pathogen as nymphs.

[Treatment mapping of lower urinary tract symptoms due to benign prostatic hyperplasia-an analysis of the Governing Body of German Prostate Centers]. / Versorgungsabbild des benignen Prostatasyndroms ­ eine Analyse des Dachverbandes der Prostatazentren Deutschlands (DVPZ) e. V.

BACKGROUND: Due to the high incidence and demographic development, there is an urgent need for healthcare research data on lower urinary tract symptoms due to benign prostatic hyperplasia (LTUS/BPH). Since 2005 the Governing Body of German Prostate Centers (DVPZ) has been collecting data from 22 prostate centers in order to determine the quality and type of cross-sectoral care in particular for LUTS/BPH patients. OBJECTIVES: Presentation of the DVPZ database in general, as well as an investigation of treatment patterns for medical and instrumental therapies. MATERIALS AND METHODS: The analysis is based on UroCloud data sets from 30 November 2017. In the UroCloud data on diagnostics, therapy and course of disease are recorded in a web-based manner. RESULTS: A total of 29,555 therapies were documented for 18,299 patients (1.6/patient), divided into 48.5% instrumental, 29.2% medical treatment, and 18.0% "wait and see" (in 4.3% no assignment was possible). Patients treated with an instrumental therapy were oldest (median: 72 years, interquartile range: 66-77), had the largest prostate volumes (50 ml, 35-75 ml), and were mostly bothered by symptoms (International Prostate Symptom Score = 19/4). The majority of patients under medical treatment received alphablockers (56%); phytotherapeutics were used least frequently (3%). Instrumental therapies are dominated by transurethral resection (TUR) of the prostate (60.0%), open prostatectomy (9.4%) and laser therapy (5.0%), with laser therapy having the shortest hospital stay (5 days) and the lowest transfusion and re-intervention rates (1.0% and 4.6%, respectively). CONCLUSIONS: The DVPZ certificate covers the complete spectrum of cross-sectoral care for LUTS/BPH patients and documents the use of the various therapies as well as their application and effectiveness in the daily routine setting.

Negative Growth and Longevity in the Purple Sea Urchin Strongylocentrotus purpuratus (Stimpson).

Purple sea urchins were tagged, measured, and placed in a tidepool at Sunset Bay, Oregon. After 1 year, many animals had decreased in size. Accordingly, size is not necessarily a reliable index of age in Strongylocentrotus purpuratus; however, it is possible to conclude that these animals are relatively long-lived.

Aggregation-based crystal growth and microstructure development in natural iron oxyhydroxide biomineralization products.

Crystals are generally considered to grow by attachment of ions to inorganic surfaces or organic templates. High-resolution transmission electron microscopy of biomineralization products of iron-oxidizing bacteria revealed an alternative coarsening mechanism in which adjacent 2- to 3-nanometer particles aggregate and rotate so their structures adopt parallel orientations in three dimensions. Crystal growth is accomplished by eliminating water molecules at interfaces and forming iron-oxygen bonds. Self-assembly occurs at multiple sites, leading to a coarser, polycrystalline material. Point defects (from surface-adsorbed impurities), dislocations, and slabs of structurally distinct material are created as a consequence of this growth mechanism and can dramatically impact subsequent reactivity.

Formation of sphalerite (ZnS) deposits in natural biofilms of sulfate-reducing bacteria.

Abundant, micrometer-scale, spherical aggregates of 2- to 5-nanometer-diameter sphalerite (ZnS) particles formed within natural biofilms dominated by relatively aerotolerant sulfate-reducing bacteria of the family Desulfobacteriaceae. The biofilm zinc concentration is about 10(6) times that of associated groundwater (0.09 to 1.1 parts per million zinc). Sphalerite also concentrates arsenic (0.01 weight %) and selenium (0.004 weight %). The almost monomineralic product results from buffering of sulfide concentrations at low values by sphalerite precipitation. These results show how microbes control metal concentrations in groundwater- and wetland-based remediation systems and suggest biological routes for formation of some low-temperature ZnS deposits.

Evaluating the Effect of Imidacloprid Administered in Artificial Diet on Feeding Behavior of Diaphorina citri (Hemiptera: Liviidae) Using Electropenetrography.

The Asian citrus psyllid, Diaphorina citri Kuwayama (Hemiptera: Liviidae) is the vector of Candidatus Liberibacter asiaticus (CLas), the presumed cause of Huanglongbing (HLB) in citrus. Management strategies were developed in Florida that used soil-applied neonicotinoids to protect young trees. Despite the implementation of intense management programs, infection spread among the most intensively managed groves. We used electopenetrography to test five imidacloprid doses (0.55, 5.5, 55, 550, and 5,500 ppm) administered in artificial diet to approximate the dosage required to reduce feeding activity and prevent salivation/ingestion activity. We failed to detect a significant effect of 0.55 ppm imidacloprid on probing behavior, pathway, or salivation/ingestion activity when compared with the untreated control. We observed a significant reduction in the number of probes and the number of pathway with both 5.5 and 55 ppm imidacloprid. We detected a significant reduction in the number of salivation/ingestion events at both 5.5 ppm and 55 ppm imidacloprid (57 and 54 percent, respectively) compared with the untreated control, and a reduction in number of sustained (>600 s) salivation/ingestion at 55 ppm. While reductions in feeding activity were apparent at dosages of at least 5.5 ppm, we were unable to prevent salivation/ingestion with dosages as high as 5,500 ppm, which is greater than what is known to occur following application in the field. While soil-applied imidacloprid may slow the spread of CLas, our findings suggest that prevention of CLas inoculation in the field is unlikely. Management strategies must be refined to prevent the spread of HLB in Florida.

The brown-fat-secreted adipokine neuregulin 4 is decreased in gestational diabetes mellitus.

AIMS: Neuregulin 4 has recently been recognized as a novel adipokine secreted by brown adipose tissue (BAT), with beneficial effects on murine insulin resistance and hepatic steatosis. Yet, thus far, neither regulation of neuregulin 4 in gestational diabetes mellitus (GDM) nor its longitudinal changes in the peripartum period have been elucidated. METHODS: Circulating neuregulin 4 levels were measured by ELISA in 74 women with GDM and 74 healthy, gestational-age-matched controls. Also, neuregulin 4 was quantified during pregnancy and compared with postpartum levels in a follow-up study of 25 women with previous GDM and 25 healthy control women. RESULTS: Women with GDM had lower median serum levels of the novel BAT-secreted adipokine neuregulin 4 (3.0µg/L) compared with healthy (non-GDM) pregnant controls (3.5µg/L; P=0.020), and the area under the glucose curve (AUCGlucose) was an independent and negative predictor of circulating neuregulin 4 (P=0.033). Also, median postpartum serum concentrations of neuregulin 4 (3.2µg/L) were not significantly different from prepartum levels (2.8µg/L; P=0.328). In addition, neuregulin 4 was positively and independently associated with irisin (P=0.009), but not other BAT-secreted adipokines. CONCLUSION/INTERPRETATION: Women with GDM have significantly lower circulating neuregulin 4 levels compared with healthy pregnant controls, and the AUCGlucose is negatively and independently associated with neuregulin 4 during pregnancy. Neuregulin 4 is positively correlated with irisin during pregnancy, as well as in a longitudinal fashion. Future studies are now needed to better elucidate the precise pathomechanisms of the regulation of BAT-secreted adipokines during pregnancy.