Recent literature suggests that catalytic doses (≤10 g/meal or 36 g/day) of D-fructose and D-allulose may reduce postprandial blood glucose responses to carbohydrate loads in people with and without ...type 2 diabetes by inducing glycogen synthesis. To assess the effect of small single doses of fructose and allulose on postprandial blood glucose regulation in response to a 75 g-oral glucose tolerance test (75 g-OGTT) in healthy individuals, we conducted an acute randomized, crossover, equivalence trial in healthy adults. Each participant randomly received six treatments, separated by a minimum one-week washout. Treatments consisted of a 75 g-OGTT with the addition of fructose or allulose at 0 g (control), 5 g or 10 g. A standard 75 g-OGTT protocol was followed with blood samples at −30, 0, 30, 60, 90, 120 min. The primary outcome was the difference in plasma glucose incremental area under the curve (iAUC). A total of 27 participants underwent randomization with data available from 25 participants. Small doses of fructose or allulose did not show a significant effect on plasma glucose iAUC or other secondary markers of postprandial blood glucose regulation in response to a 75 g-OGTT in healthy individuals. These results were limited by the low power to detect a significant difference, owing to greater than expected intra-individual coefficient of variation (CV) in plasma glucose iAUC. Overall, we failed to confirm the catalytic effects of small doses of fructose and allulose in healthy individuals. Future trials may consider recruiting larger sample sizes of healthy individuals.
clinicaltrials.gov identifier, NCT02459834.
The ZFIRE survey has spectroscopically confirmed two proto-clusters using the MOSFIRE instrument on Keck I: one at z = 2.095 in COSMOS and another at z = 1.62 in UKIRT Infrared Deep Sky Survey (UDS). ...Here, we use an updated ZFIRE data set to derive the properties of ionized gas regions of proto-cluster galaxies by extracting fluxes from emission lines Hβ 4861 , O iii 5007 , H 6563 , N ii 6585 , and S ii 6716,6731 . We measure gas-phase metallicity of members in both proto-clusters using two indicators, including a strong-line indicator relatively independent of the ionization parameter and electron density. Proto-cluster and field galaxies in both UDS and COSMOS lie on the same Mass-Metallicity Relation with both metallicity indicators. We compare our results to recent IllustrisTNG results, which report no significant gas-phase metallicity offset between proto-cluster and field galaxies until z = 1.5. This is in agreement with our observed metallicities, where no offset is measured between proto-cluster and field populations. We measure tentative evidence from stacked spectra that indicate UDS high-mass proto-cluster and field galaxies have differing O iii/Hβ ratios; however, these results are dependent on the sample size of the high-mass stacks.
Background The benefit of carotid endarterectomy (CEA) in female patients has been questioned by various randomized, prospective trials, particularly in asymptomatic cases; several have noted an ...increase in perioperative stroke among women after CEA. The outcome of carotid angioplasty and stenting (CAS) has not been extensively examined in women. This study examined the outcome of CEA and CAS in women vs men by using a national database. Methods Outcomes of CEA and CAS were stratified by sex using discharge data from the Nationwide Inpatient Sample (NIS), Healthcare Cost and Utilization Project (HCUP), Agency for Healthcare Research and Quality. The NIS was used to identify patient discharges that occurred during 2004 and 2005. Appropriate International Classification of Diseases, 9th Revision (ICD-9) procedure and diagnosis codes were used to identify CEA and CAS cases. Outcome measures included in-hospital perioperative stroke and death. Comparisons of demographics, procedures, and outcome were performed between men and women. Additional analysis was performed among women alone to attempt to identify whether improved outcome was noted with either procedure. Results Of 54,658 procedures, 94.2% were CEA and 5.8% were CAS. Women comprised 42.3% of the analyzed cases. Women and men were equally likely to be symptomatic (5.3% vs 5.3%, P = .8). Women were significantly less likely to undergo CAS than men (5.4% vs 6.1%, P < .001). Women and men had equivalent rates of perioperative stroke when undergoing CEA (1.0% vs 1.0%, P = .9) and CAS (2.7% vs 2.0%, P = .2). Symptomatic women had a significantly higher rate of perioperative stroke overall than did symptomatic men (3.8% vs 2.3%, P = .03). Asymptomatic women had a significantly lower perioperative stroke rate after CEA than after CAS (0.9% vs 2.1%, P < .001). Rates of perioperative showed a trend favoring CEA vs CAS among symptomatic women (3.4% vs 6.2%, P = .1). Conclusions The concern regarding an increased perioperative stroke rate after CEA among asymptomatic women appears to be unfounded. The perioperative stroke rate among symptomatic women was higher than that of symptomatic men, but still well within the acceptable range for symptomatic patients undergoing a cerebrovascular intervention. Nationally, women underwent CAS significantly less frequently than did men. Outcome among women for perioperative stroke favored CEA over CAS, particularly in asymptomatic patients. CEA may be the preferred treatment in women seeking intervention for cerebrovascular disease, unless compelling reasons exist to perform CAS.
We investigated the forces that connect the genetic program of development to morphogenesis in Drosophila. We focused on dorsal closure, a powerful model system for development and wound healing. We ...found that the bulk of progress toward closure is driven by contractility in supracellular "purse strings" and in the amnioserosa, whereas adhesion-mediated zipping coordinates the forces produced by the purse strings and is essential only for the end stages. We applied quantitative modeling to show that these forces, generated in distinct cells, are coordinated in space and synchronized in time. Modeling of wild-type and mutant phenotypes is predictive; although closure in myospheroid mutants ultimately fails when the cell sheets rip themselves apart, our analysis indicates that $\beta_{PS}$ integrin has an earlier, important role in zipping.
The prognosis of recurrent malignant peripheral nerve sheath tumors (MPNST) is dismal, with surgical resection being the only definitive salvage therapy. Treatment with chemoradiation approaches has ...not significantly improved patient outcomes. Similarly, trials of therapies targeting MPNST genomic drivers have thus far been unsuccessful. Improved understanding of the molecular pathogenesis of MPNST indicates frequent activation of the mitogen-activated protein kinase (MAPK) cell signaling pathway. MEK inhibitors have shown activity in preclinical studies; however, their clinical efficacy has not been reported to date. We describe here a case of sustained complete response to MEK inhibition in an adolescent patient with a recurrent metastatic MPNST with multiple alterations in the MAPK pathway, guided by a precision oncology approach.
The COVID-19 pandemic response has shown how vaccine platform technologies can be used to rapidly and effectively counteract a novel emerging infectious disease. The speed of development for mRNA and ...vector-based vaccines outpaced those of subunit vaccines, however, subunit vaccines can offer advantages in terms of safety and stability. Here we describe a subunit vaccine platform technology, the molecular clamp, in application to four viruses from divergent taxonomic families: Middle Eastern respiratory syndrome coronavirus (MERS-CoV), Ebola virus (EBOV), Lassa virus (LASV) and Nipah virus (NiV). The clamp streamlines subunit antigen production by both stabilising the immunologically important prefusion epitopes of trimeric viral fusion proteins while enabling purification without target-specific reagents by acting as an affinity tag. Conformations for each viral antigen were confirmed by monoclonal antibody binding, size exclusion chromatography and electron microscopy. Notably, all four antigens tested remained stable over four weeks of incubation at 40°C. Of the four vaccines tested, a neutralising immune response was stimulated by clamp stabilised MERS-CoV spike, EBOV glycoprotein and NiV fusion protein. Only the clamp stabilised LASV glycoprotein precursor failed to elicit virus neutralising antibodies. MERS-CoV and EBOV vaccine candidates were both tested in animal models and found to provide protection against viral challenge.
Summary Background Intermediate or surrogate endpoints for survival can shorten time lines for drug approval. We aimed to assess circulating tumour cell (CTC) count as a prognostic factor for ...survival in patients with progressive, metastatic, castration-resistant prostate cancer receiving first-line chemotherapy. Methods We identified patients with progressive metastatic castration-resistant prostate cancer starting first-line chemotherapy in the IMMC38 trial. CTCs were isolated by immunomagnetic capture from blood samples at baseline and after treatment. Baseline variables, including CTC count, titre of prostate-specific antigen (PSA), and concentration of lactate dehydrogenase (LDH), and post-treatment variables (change in CTCs and PSA) were tested for association with survival with Cox proportional hazards models. Concordance probability estimates were used to gauge discriminatory strength of the informative factors in identifying patients at low-risk and high-risk of survival. Findings Variables associated with high risk of death were high LDH concentration (hazard ratio 6·44, 95% CI 4·24–9·79), high CTC count (1·58, 1·41–1·77), and high PSA titre (1·26, 1·10–1·45), low albumin (0·10, 0·03–0·39), and low haemoglobin (0·72, 0·64–0·81) at baseline. At 4 weeks, 8 weeks, and 12 weeks after treatment, changes in CTC number were strongly associated with risk, whereas changes in PSA titre were weakly or not associated (p>0·04). The most predictive factors for survival were LDH concentration and CTC counts (concordance probability estimate 0·72–0·75). Interpretation CTC number, analysed as a continuous variable, can be used to monitor disease status and might be useful as an intermediate endpoint of survival in clinical trials. Prospective recording of CTC number as an intermediate endpoint of survival in randomised clinical trials is warranted. Funding The Prostate Cancer Foundation, Immunicon Corporation, Memorial Sloan-Kettering Cancer Center.
Background Esophageal eosinophilia can be proton pump inhibitor (PPI) resistant or responsive, representing 2 entities known as eosinophilic esophagitis (EoE) and PPI-responsive esophageal ...eosinophilia (PPI-REE), respectively. Although they present with similar clinical features, EoE is accepted to be an antigen-driven, TH 2-associated allergic disorder, whereas the cause of PPI-REE remains a mystery. Objective In this study, our aim was to investigate the pathogenesis of PPI-REE by using a recently described EoE diagnostic panel (EDP) composed of a set of 94 esophageal transcripts and to determine whether PPI therapy reverses any esophageal transcriptional abnormalities. Methods We evaluated the EDP signature in biopsy samples obtained from adult and pediatric patients with PPI-REE from 4 institutions and compared the pre- and post-PPI therapy expression profiles of these subjects with those of patients with active EoE. Results The EDP differentiated patients with EoE from control subjects with 100% accuracy among the 4 clinical sites. Bioinformatics analysis revealed largely overlapping transcriptomes between patients with PPI-REE and those with EoE, including the genes for eosinophil chemotaxis ( eotaxin 3, CCL26) , barrier molecules ( desmoglein 1, DSG1) , tissue remodeling ( periostin, POSTN) , and mast cells ( carboxypeptidase A, CPA3) . PPI monotherapy alone almost completely reversed the allergic inflammatory transcriptome of patients with PPI-REE. Furthermore, we identified a set of candidate genes to differentiate patients with EoE from those with PPI-REE before treatment. Conclusion These findings provide definitive evidence that PPI-REE is a disease entity with significant molecular overlap with EoE, suggesting that many patients with PPI-REE represent a continuum of the same pathogenic allergic mechanisms that underlie EoE and thus might constitute a subphenotype of patients with EoE. The ability of PPI therapy to nearly entirely reverse gene expression associated with PPI-REE, particularly that associated with classic features of allergic inflammation, provides new insight into potential disease etiology and management strategies for patients with significant esophageal eosinophilia.
There is ongoing debate regarding the extent that environment affects galaxy size growth beyond z > or =, slanted 1. To investigate the differences in star-forming and quiescent galaxy properties as ...a function of environment at z = 2.1, we create a mass-complete sample of 59 cluster galaxies and 478 field galaxies with log(Mlow */M sub(middot in circle)) > or =, slanted 9 using photometric redshifts from the ZFOURGE survey. We compare the mass-size relation of field and cluster galaxies using measured galaxy semi-major axis half-light radii (r sub(1/2,maj)) from CANDELS Hubble Space Telescope (HST)/F160W imaging. We find consistent mass-normalized (log(Mlow */M sub(middot in circle)) = 10.7) sizes for quiescent field galaxies (r sub(1/2,maj) = 1.81 + or - 0.29 kpc) and quiescent cluster galaxies (r sub(1/2,maj) = 2.17 + or - 0.63 kpc). The mass-normalized size of star-forming cluster galaxies (r sub(1/2,maj) = 4.00 + or - 0.26 kpc) is 12% larger (Kolmogorov-Smirnov (KS) test 2.1sigma) than star-forming field galaxies (r sub(1/2,maj) = 3.57 + or - 0.10 kpc). From the mass-color relation we find that quiescent field galaxies with 9.7 < log(Mlow */M sub(middot in circle)) < or =, slant 10.4 are slightly redder (KS test 3.6sigma) than quiescent cluster galaxies, while cluster and field quiescent galaxies with log(Mlow */M sub(middot in circle)) > 10.4 have consistent colors. We find that star-forming cluster galaxies are on average 20% redder than star-forming field galaxies at all masses. Furthermore, we stack galaxy images to measure average radial color profiles as a function of mass. Negative color gradients are only present for massive star-forming field and cluster galaxies with log(Mlow */M sub(middot in circle)) > 10.4; the remaining galaxy masses and types have flat profiles. Our results suggest, given the observed differences in size and color of star-forming field and cluster galaxies, that the environment has begun to influence/accelerate their evolution. However, the lack of differences between field and cluster quiescent galaxies indicates that the environment has not begun to significantly influence their evolution at z ~ 2.
Increasingly, attachment representations are being assessed via secure base script knowledge - the degree to which individuals show awareness of the temporal-causal schema that summarizes the basic ...features of seeking and receiving effective support from caregivers during times of need. Limited research has assessed the links between secure base script knowledge and aspects of adult functioning and the role that secure base script knowledge may play in accounting for associations between early caregiving quality and adulthood functioning. We used follow-up assessments of the NICHD Study of Early Child Care and Youth Development cohort (N = 585) to examine whether secure base script knowledge at age 18 years: (a) is associated with later romantic relationship quality, depressive symptoms, and body mass index (BMI) at age 26 years, and (b) mediates expected associations between the quality of maternal and paternal sensitivity across the first 15 years of life and age-26 outcomes. More access to, and elaborated knowledge of the secure base script predicted less extreme hostility with romantic partners, and better emotional and physical health. Moreover, secure base script knowledge mediated the links between early maternal and paternal sensitivity and both later romantic partner hostility and depressive symptoms, but not BMI.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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