Aims/hypothesis
The aim of this study was to analyse patterns of continuous glucose monitoring (CGM) data for associations with large for gestational age (LGA) infants and an adverse neonatal ...composite outcome (NCO) in pregnancies in women with type 1 diabetes.
Methods
This was an observational cohort study of 186 pregnant women with type 1 diabetes in Sweden. The interstitial glucose readings from 92 real-time (rt) CGM and 94 intermittently viewed (i) CGM devices were used to calculate mean glucose, SD, CV%, time spent in target range (3.5–7.8 mmol/l), mean amplitude of glucose excursions and also high and low blood glucose indices (HBGI and LBGI, respectively). Electronic records provided information on maternal demographics and neonatal outcomes. Associations between CGM indices and neonatal outcomes were analysed by stepwise logistic regression analysis adjusted for confounders.
Results
The number of infants born LGA was similar in rtCGM and iCGM users (52% vs 53%). In the combined group, elevated mean glucose levels in the second and the third trimester were significantly associated with LGA (OR 1.53, 95% CI 1.12, 2.08, and OR 1.57, 95% CI 1.12, 2.19, respectively). Furthermore, a high percentage of time in target in the second and the third trimester was associated with lower risk of LGA (OR 0.96, 95% CI 0.94, 0.99 and OR 0.97, 95% CI 0.95, 1.00, respectively). The same associations were found for mean glucose and for time in target and the risk of NCO in all trimesters. SD was significantly associated with LGA in the second trimester and with NCO in the third trimester. Glucose patterns did not differ between rtCGM and iCGM users except that rtCGM users had lower LBGI and spent less time below target.
Conclusions/interpretation
Higher mean glucose levels, higher SD and less time in target range were associated with increased risk of LGA and NCO. Despite the use of CGM throughout pregnancy, the day-to-day glucose control was not optimal and the incidence of LGA remained high.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Nucleic acids in the form of siRNA, antisense oligonucleotides or mRNA are currently explored as new promising modalities in the pharmaceutical industry. Particularly, the success of mRNA‐vaccines ...against SARS‐CoV‐2, along with the successful development of the first sugar‐modified siRNA therapeutics has inspired the field. The development of nucleic acid therapeutics requires efficient chemistry to link oligonucleotides to chemical structures that can improve stability, boost cellular uptake, or enable specific targeting. For the siRNA therapeutics currently in use, modification of the 3′‐end of the oligonucleotides with triple‐N‐acetylgalactosamine (GalNAc)3 was shown to be of significance. This modification is currently achieved through cumbersome multistep synthesis and subsequent loading onto the solid support material. Herein, we report the development of a bifunctional click‐reactive linker that allows the modification of oligonucleotides in a tandem click reaction with multiple sugars, regardless of the position within the oligonucleotide, with remarkable efficiency and in a one‐pot reaction.
A bifunctional dendrimeric linker was developed that allows the modification of oligonucleotides in a tandem click reaction with multiple sugars in just one step. The method exploits different click reactivities of the linker azides in a copper‐catalyzed reaction with alkynes. The new method is fast, highly selective and allows the modification of the oligonucleotide with multiple sugars at any given position.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Psychological stress (PS) is associated with systemic inflammation and accelerates inflammatory disease progression (e.g., atherosclerosis). The mechanisms underlying stress-mediated inflammation and ...future health risk are poorly understood. Monocytes are key in sustaining systemic inflammation, and recent studies demonstrate that they maintain the memory of inflammatory insults, leading to a heightened inflammatory response upon rechallenge. We show that PS induces remodeling of the chromatin landscape and transcriptomic reprogramming of monocytes, skewing them to a primed hyperinflammatory phenotype. Monocytes from stressed mice and humans exhibit a characteristic inflammatory transcriptomic signature and are hyperresponsive upon stimulation with Toll-like receptor ligands. RNA and ATAC sequencing reveal that monocytes from stressed mice and humans exhibit activation of metabolic pathways (mTOR and PI3K) and reduced chromatin accessibility at mitochondrial respiration-associated loci. Collectively, our findings suggest that PS primes the reprogramming of myeloid cells to a hyperresponsive inflammatory state, which may explain how PS confers inflammatory disease risk.
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•Psychological stress reprograms monocytes to a hyperinflammatory primed phenotype•Stress-mediated priming activates transcriptomic and metabolic pathways in monocytes•Stress-mediated priming alters inflammatory responses in mice and humans
Barrett et al. investigate the impact of psychological stress on monocytes. They report that psychological stress remodels the chromatin landscape of monocytes and the myeloid transcriptome, with stress-mediated changes skewing monocytes to a primed-hyperinflammatory phenotype. This study provides mechanistic insight into how psychological stress confers risk to inflammation-based disorders.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Activating anaplastic lymphoma kinase (ALK) mutations were recently detected in most familial and 10% of sporadic neuroblastomas. However, the role of mutated ALK in tumorigenesis remains elusive. We ...demonstrate that targeted expression of the most frequent and aggressive variant, ALK(F1174L), is tumorigenic in mice. Tumors resembled human neuroblastomas in morphology, metastasis pattern, gene expression, and the presence of neurosecretory vesicles as well as synaptic structures. This ALK-driven neuroblastoma mouse model precisely recapitulated the genetic spectrum of the disease. Chromosomal aberrations were syntenic to those in human neuroblastoma, including 17q gain and MYCN oncogene amplification. Targeted ALK(F1174L) and MYCN coexpression revealed a strong synergism in inducing neuroblastoma with minimal chromosomal aberrations, suggesting that fewer secondary hits are required for tumor induction if both oncoproteins are targeted. Treatment of ALK(F1174L) transgenic mice with the ALK inhibitor TAE-684 induced complete tumor regression, indicating that tumor cells were addicted to ALK(F1174L) activity. We conclude that an activating mutation within the ALK kinase domain is sufficient to induce neuroblastoma development, and ALK inhibitors show promise for treating human neuroblastomas harboring ALK mutations.
Active surveillance in high-risk sites in Cambodia has identified multiple low-pathogenicity influenza A(H7) viruses, mainly in ducks. None fall within the A/Anhui/1/2013(H7N9) lineage; however, some ...A(H7) viruses from 2018 show temporal and phylogenetic similarity to the H7N4 virus that caused a nonfatal infection in Jiangsu Province, China, in December 2017.
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DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The phosphatidylcholine floppase multidrug resistance protein 3 (MDR3) is an essential hepatobiliary transport protein. MDR3 dysfunction is associated with various liver diseases, ranging from severe ...progressive familial intrahepatic cholestasis to transient forms of intrahepatic cholestasis of pregnancy and familial gallstone disease. Single amino acid substitutions are often found as causative of dysfunction, but identifying the substitution effect in in vitro studies is time and cost intensive. We developed variant assessor of MDR3 (Vasor), a machine learning‐based model to classify novel MDR3 missense variants into the categories benign or pathogenic. Vasor was trained on the largest data set to date that is specific for benign and pathogenic variants of MDR3 and uses general predictors, namely Evolutionary Models of Variant Effects (EVE), EVmutation, PolyPhen‐2, I‐Mutant2.0, MUpro, MAESTRO, and PON‐P2 along with other variant properties, such as half‐sphere exposure and posttranslational modification site, as input. Vasor consistently outperformed the integrated general predictors and the external prediction tool MutPred2, leading to the current best prediction performance for MDR3 single‐site missense variants (on an external test set: F1‐score, 0.90; Matthew's correlation coefficient, 0.80). Furthermore, Vasor predictions cover the entire sequence space of MDR3. Vasor is accessible as a webserver at https://cpclab.uni‐duesseldorf.de/mdr3_predictor/ for users to rapidly obtain prediction results and a visualization of the substitution site within the MDR3 structure. The MDR3‐specific prediction tool Vasor can provide reliable predictions of single‐site amino acid substitutions, giving users a fast way to initially assess whether a variant is benign or pathogenic.
We developed Vasor (Variant assessor of MDR3), a machine learning‐based model to classify novel MDR3 missense variants into the categories of benign or pathogenic. Vasor was trained on the, to date, largest dataset specific for MDR3 of benign and pathogenic variants. Vasor consistently outperformed the integrated general predictors and the external prediction tool MutPred2.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Introduction
Continuous glucose monitoring (CGM) provides detailed information about glucose level fluctuations over time. The method is increasingly being used in pregnant women with type 1 ...diabetes. However, only one previous study compared CGM results related to pregnancy outcomes in women using insulin pumps with those administering multiple daily injections (MDI). We performed a secondary analysis of CGM metrics from an observational cohort of pregnant women with type 1 diabetes and compared insulin pump and MDI therapies in relation to maternal and neonatal outcomes.
Material and methods
The study included 185 pregnant Swedish women with type 1 diabetes undergoing CGM throughout pregnancy. Women were divided according to insulin administration mode, ie MDI (n = 131) or pump (n = 54). A total of 91 women used real‐time CGM and 94 women used intermittently viewed CGM. Maternal demographics and maternal and neonatal outcome data were collected from medical records. CGM data were analyzed according to predefined glycemic indices: mean glucose; standard deviation; percentage of time within, below and above glucose target range; mean amplitude of glycemic excursion; high and low glucose indices; and coefficient variation in percent. Associations between insulin administration mode and CGM data, on the one hand, and maternal and neonatal outcomes, on the other, were analyzed with analysis of covariance and logistic regression, respectively, adjusted for confounders.
Results
There were no differences in maternal characteristics or glycemic indices between the MDI and pump groups, except for a longer duration of type 1 diabetes and higher frequencies of microangiopathy and real‐time CGM among pump users. Despite improvement with each trimester, glucose levels remained suboptimal throughout pregnancy in both groups. There were no differences between the MDI and pump groups concerning the respective associations with any of the outcomes. The frequency of large for gestational age was high in both groups (MDI 49% vs pump 63%) and did not differ significantly.
Conclusions
Pregnant women with type 1 diabetes did not differ in glycemic control or pregnancy outcome, related to MDI or pump administration of insulin. Glycemic control remained suboptimal throughout pregnancy, regardless of insulin administration mode.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Personnel selection research has recognized the importance of providing applicants with both standardized (i.e., “consistent”) and individualized (i.e., “personable”) treatment during interviews. ...However, research has yet to examine the mechanisms underlying the effects of perceived consistency and personableness in the interview on applicants’ attraction to organizations. Drawing from signaling theory, we investigate how interview consistency and personableness impact organizational attractiveness. To this end, we developed a conceptual model that proposes that applicants interpret perceived interview consistency and personableness as signals about what the organization is like in terms of symbolic organizational attributes (organizational competence and benevolence, Lievens and Highhouse 2003), which in turn influence perceptions of organizational attractiveness. A longitudinal three-wave field study with 129 applicants showed that applicants’ perceptions of both consistency and personableness positively impacted organizational attractiveness. Additionally, these effects were mediated by organizational competence perceptions, but not by organizational benevolence perceptions. Furthermore, consistency and personableness perceptions differed in their relative influence on organizational competence, benevolence, and attractiveness, with personableness perceptions being a more influential predictor. This study contributes to a nuanced theoretical understanding of how applicants interpret interviews as signals about how organizations treat their members.
Cardiac tumors are rare, with a low incidence of between 0.0017 and 0.19%. The majority of cardiac tumors are benign and predominantly occur in females. The aim of our study was to examine how ...outcomes differ between men and women.
From 2015 to 2022, 80 patients diagnosed with suspected myxoma were operated on. In all patients, preoperative, perioperative, and postoperative data were recorded. Such patients were identified and included in a retrospective analysis focused on gender-related differences.
Patients were predominantly female (
= 64; 80%). The mean age was 62.76 ± 13.42 years in female patients and 59.65 ± 15.84 years in male patients (
= 0.438). The body mass index (BMI) was comparable in both groups: between 27.36 ± 6.16 in male and 27.09 ± 5.75 (
= 0.945) in female patients. Logistic EuroSCORE (LogES) (female: 5.89 ± 4.6; male: 3.95 ± 3.06;
= 0.017) and EuroSCORE II (ES II) (female: 2.07 ± 2.1; male: 0.94 ± 0.45;
= 0.043), both scores to predict the mortality in cardiac surgery, were significantly higher in female patients. Two patients died early, within 30 days after surgery: one male and one female patient. Late mortality was defined as the 5-year survival rate, which was 94.8%, and 15-year survival rate, which was 85.3% in our cohort. Causes of death were not related to the primary tumor operation. The follow up showed that satisfaction with surgery and long-term outcome was high.
Predominately female patients presented with left atrial tumors over a 17-year period. Relevant gender differences aside from that were not evident. Surgery could be performed with excellent early (within 30 days after surgery) and late results (follow up after discharge).
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