There is a paucity of global data on cardiovascular disease (CVD) prevalence in people with type 2 diabetes (T2D). The primary objective of the CAPTURE study was to estimate the prevalence of ...established CVD and its management in adults with T2D across 13 countries from five continents. Additional objectives were to further characterize the study sample regarding demographics, clinical parameters and medication usage, with particular reference to blood glucose-lowering agents (GLAs: glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter-2 inhibitors) with demonstrated cardiovascular benefit in randomized intervention trials.
Data were collected from adults with T2D managed in primary or specialist care in Australia, China, Japan, Czech Republic, France, Hungary, Italy, Argentina, Brazil, Mexico, Israel, Kingdom of Saudi Arabia, and Turkey in 2019, using standardized methodology. CVD prevalence, weighted by diabetes prevalence in each country, was estimated for the overall CAPTURE sample and participating countries. Country-specific odds ratios for CVD prevalence were further adjusted for relevant demographic and clinical parameters.
The overall CAPTURE sample included 9823 adults with T2D (n = 4502 from primary care; n = 5321 from specialist care). The overall CAPTURE sample had median (interquartile range) diabetes duration 10.7 years (5.6-17.9 years) and glycated hemoglobin 7.3% (6.6-8.4%) 56 mmol/mol (49-68 mmol/mol). Overall weighted CVD and atherosclerotic CVD prevalence estimates were 34.8% (95% confidence interval CI 32.7-36.8) and 31.8% (95% CI 29.7-33.8%), respectively. Age, gender, and clinical parameters accounted for some of the between-country variation in CVD prevalence. GLAs with demonstrated cardiovascular benefit were used by 21.9% of participants, which was similar in participants with and without CVD: 21.5% and 22.2%, respectively.
In 2019, approximately one in three adults with T2D in CAPTURE had diagnosed CVD. The low use of GLAs with demonstrated cardiovascular benefit even in participants with established CVD suggested that most were not managed according to contemporary diabetes and cardiology guidelines. Study registration NCT03786406 (registered on December 20, 2018), NCT03811288 (registered on January 18, 2019).
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Within the framework of effective mass theory, we investigate the effects of spin-orbit interaction (SOI) and Zeeman splitting on the electronic properties of an electron confined in GaAs single ...quantum rings. Energies and envelope wavefunctions in the system are determined by solving the Schrödinger equation via the finite element method. First, we consider an inversely quadratic model potential to describe electron confining profiles in a single quantum ring. The study also analyzes the influence of applied electric and magnetic fields. Solutions for eigenstates are then used to evaluate the linear inter-state light absorption coefficient through the corresponding resonant transition energies and electric dipole matrix moment elements, assuming circular polarization for the incident radiation. Results show that both SOI effects and Zeeman splitting reduce the absorption intensity for the considered transitions compared to the case when these interactions are absent. In addition, the magnitude and position of the resonant peaks have non-monotonic behavior with external magnetic fields. Secondly, we investigate the electronic and optical properties of the electron confined in the quantum ring with a topological defect in the structure; the results show that the crossings in the energy curves as a function of the magnetic field are eliminated, and, therefore, an improvement in transition energies occurs. In addition, the dipole matrix moments present a non-oscillatory behavior compared to the case when a topological defect is not considered.
Background Apremilast works intracellularly to regulate inflammatory mediators. Objective ESTEEM 1 evaluated efficacy/safety of apremilast at 30 mg twice a day for moderate to severe plaque ...psoriasis. Methods This phase III, multicenter, double-blind, placebo-controlled study randomized adults (2:1) to apremilast or placebo. At week 16, the placebo group switched to apremilast through week 32, followed by a randomized treatment withdrawal phase to week 52. Binary end points were analyzed using χ2 test; continuous end points used analysis of covariance. Results In all, 844 patients were randomized (n = 282, placebo; n = 562, apremilast). At week 16, significantly more patients taking apremilast achieved 75% or greater reduction from baseline Psoriasis Area and Severity Index score (PASI-75) (33.1%) versus placebo (5.3%, P < .0001; primary end point). Most (61.0%) patients rerandomized to apremilast at week 32 achieved PASI-75 at week 52 versus 11.7% rerandomized to placebo. Of patients rerandomized to apremilast at week 32, mean percentage change from baseline PASI score was −88% to −81% (weeks 32-52). During the placebo-controlled period, 55.7% and 69.3% of patients randomized to placebo and apremilast, respectively, had 1 or more adverse events. Most adverse events were mild/moderate in severity. No new significant adverse events emerged with continued apremilast exposure versus the placebo-controlled period. Limitations Data were limited to 52 weeks and may not generalize to nonplaque psoriasis. Conclusions Apremilast was effective in moderate to severe plaque psoriasis.
Species with extensive geographical ranges pose special challenges to assessing drivers of wildlife disease, necessitating collaborative and large-scale analyses. The imperilled foothill ...yellow-legged frog (
) inhabits a wide geographical range and variable conditions in rivers of California and Oregon (USA), and is considered threatened by the pathogen
(Bd). To assess drivers of Bd infections over time and space, we compiled over 2000 datapoints from
museum specimens (collected 1897-2005) and field samples (2005-2021) spanning 9° of latitude. We observed a south-to-north spread of Bd detections beginning in the 1940s and increase in prevalence from the 1940s to 1970s, coinciding with extirpation from southern latitudes. We detected eight high-prevalence geographical clusters through time that span the species' geographical range. Field-sampled male
exhibited the highest prevalence, and juveniles sampled in autumn exhibited the highest loads. Bd infection risk was highest in lower elevation rain-dominated watersheds, and with cool temperatures and low stream-flow conditions at the end of the dry season. Through a holistic assessment of relationships between infection risk, geographical context and time, we identify the locations and time periods where Bd mitigation and monitoring will be critical for conservation of this imperilled species.
Fifteen months of cumulative CoGeNT data are examined for indications of an annual modulation, a predicted signature of weakly interacting massive particle (WIMP) interactions. Presently available ...data support the presence of a modulated component of unknown origin, with parameters prima facie compatible with a galactic halo composed of light-mass WIMPs. Unoptimized estimators yield a statistical significance for a modulation of ∼2.8σ, limited by the short exposure.
Predation is considered to be an important factor structuring natural communities. However, it is often difficult to determine how it may influence long-term, broad-scale, diversity patterns, ...particularly in diverse tropical systems. Biological introductions can provide powerful insight to test the sustained consequences of predation in natural communities, if pre-introduction data are available. Half a century ago, Zaret and Paine demonstrated strong and immediate community-level effects following the introduction of a novel apex predator (peacock bass, Cichla monoculus) into Lake Gatun, Panama. To test for long-term changes associated with this predator introduction, we followed up on their classic study by replicating historical sampling methods and examining changes in the littoral fish community at two sites in Lake Gatun 45 years post-introduction. To broaden our inference, we complemented this temporal comparison with a spatial analysis, wherein we compared the fish communities from two lakes with and one lake without peacock bass. Comparisons with historical data revealed that the peacock bass remains the most abundant predator in Lake Gatun. Furthermore, the collapse of the littoral prey community observed immediately following the invasion has been sustained over the past 45 years. The mean abundance of native littoral fish is now 96% lower than it was prior to the introduction. Diversity (rarefied species richness) declined by 64% post-introduction, and some native species appear to have been locally extirpated. We observed a similar pattern across invaded and uninvaded lakes: the mean abundance of native fishes was 5–40 times lower in lakes with (Gatun, Alajuela) relative to the lake without peacock bass (Bayano). In particular, small-bodied native fishes (Characidae, Peociliidae), which are common prey of the peacock bass, were more than two orders of magnitude (307 times) less abundant in Gatun and one order of magnitude (28 times) less abundant in Alajuela than in Bayano. However, total native fish diversity did not differ significantly across lakes, suggesting that while many native species have declined in abundance, few have been completely extirpated. Introduced predators can have strong effects on community structure and functional diversity, even in highly diverse tropical communities, and these effects can persist over multiple decades.
Abstract
Pain is an individual experience. Previous studies have highlighted changes in brain activation and morphology associated with within- and interindividual pain perception. In this study we ...sought to characterize brain mechanisms associated with between-individual differences in pain in a sample of healthy adolescent and adult participants (N = 101). Here we show that pain ratings varied widely across individuals and that individuals reported changes in pain evoked by small differences in stimulus intensity in a manner congruent with their pain sensitivity, further supporting the utility of subjective reporting as a measure of the true individual experience. Furthermore, brain activation related to interindividual differences in pain was not detected, despite clear sensitivity of the Blood Oxygenation Level-Dependent (BOLD) signal to small differences in noxious stimulus intensities within individuals. These findings suggest fMRI may not be a useful objective measure to infer reported pain intensity.
Background and Aims
Nonanastomotic biliary strictures (NAS) are a major cause of morbidity after orthotopic liver transplantation (OLT). Although ischemic injury of peribiliary glands (PBGs) and ...peribiliary vascular plexus during OLT has been associated with the later development of NAS, the exact underlying mechanisms remain unclear. We hypothesized that bile ducts of patients with NAS suffer from ongoing biliary hypoxia and lack of regeneration from PBG stem/progenitor cells.
Approach and Results
Forty‐two patients, requiring retransplantation for either NAS (n = 18), hepatic artery thrombosis (HAT; n = 13), or nonbiliary graft failure (controls; n = 11), were included in this study. Histomorphological analysis of perihilar bile ducts was performed to assess differences in markers of cell proliferation and differentiation in PBGs, microvascular density (MVD), and hypoxia. In addition, isolated human biliary tree stem cells (hBTSCs) were used to examine exo‐metabolomics during in vitro differentiation toward mature cholangiocytes.
Bile ducts of patients with NAS or HAT had significantly reduced indices of PBG mass, cellular proliferation and differentiation (mucus production, secretin receptor expression, and primary cilia), reduced MVD, and increased PBG apoptosis and hypoxia marker expression, compared to controls. Metabolomics of hBTSCs during in vitro differentiation toward cholangiocytes revealed a switch from a glycolytic to oxidative metabolism, indicating the need for oxygen.
Conclusions
NAS are characterized by a microscopic phenotype of chronic biliary hypoxia attributed to loss of microvasculature, resulting in reduced proliferation and differentiation of PBG stem/progenitor cells into mature cholangiocytes. These findings suggest that persistent biliary hypoxia is a key mechanism underlying the development of NAS after OLT.
Non‐digestible oligosaccharides and Bifidobacterium breve enhance galectin‐9 and suppress murine ovalbumin allergy, while reducing intestinal DC and Th2 activation, and increasing regulatory T cell ...frequency.
Dietary intervention with short‐chain galacto‐oligosaccharides (scGOS), long‐chain fructo‐oligosaccharides (lcFOS) and Bifidobacterium breve M‐16V (Bb) (GF/Bb) suppresses food allergic symptoms in mice, potentially via intestinal epithelial cell (IEC)–derived galectin‐9. Furthermore, in vitro studies showed galacto‐ and fructo‐oligosaccharides (GF) to enhance the immunomodulatory capacity of a TLR9 ligand representing bacterial CpG DNA when exposed to IEC. In this study, we investigated whether GF/Bb modulates dendritic cells (DCs) and subsequent Th2 and regulatory T cell (Treg) frequency in the small intestinal lamina propria (SI‐LP). BALB/c mice were fed GF/Bb during oral OVA sensitization. DC and T cell phenotype were determined in SI‐LP mononuclear cells using flow cytometry. Murine bone marrow‐derived DCs (BMDCs) were exposed to recombinant galectin‐9 or human monocyte‐derived DCs (moDCs) and were cultured in IEC‐conditioned medium from GF and TLR9 ligand‐exposed HT‐29 cells. GF/Bb reduced allergic symptoms and enhanced serum galectin‐9 levels, while suppressing activation, restoring phagocytic capacity, and normalizing CD103 expression of SI‐LP DCs of OVA‐allergic mice. In vitro, galectin‐9 suppressed LPS‐induced activation markers and cytokine secretion by BMDCs, and IEC‐conditioned medium suppressed moDC activation in a galectin‐9–dependent manner. Besides suppression of SI‐LP DC activation, dietary GF/Bb also lowered the frequency of activated Th2 cells, while enhancing Treg in the SI‐LP of OVA‐allergic mice compared to the control diet. Dietary intervention with GF/Bb enhances galectin‐9 and suppresses allergic symptoms of OVA‐allergic mice in association with reduced intestinal DC and Th2 activation and increased Treg frequency in these mice.
The spinophilin (Spn, PPP1R9B) gene is located at 17q21.33, a region frequently associated with microsatellite instability and loss of heterozygosity, especially in breast tumors. Spn is a regulatory ...subunit of phosphatase1a (PP1), which targets the catalytic subunit to distinct subcellular locations. Spn downregulation reduces PPP1CA activity against the retinoblastoma protein, pRb, thereby maintaining higher levels of phosphorylated pRb. This effect contributes to an increase in the tumorigenic properties of cells in certain contexts. Here, we explored the mechanism of how Spn downregulation contributes to the malignant phenotype and poor prognosis in breast tumors and found an increase in the stemness phenotype. Analysis of human breast tumors showed that Spn mRNA and protein are reduced or lost in 15% of carcinomas, correlating with a worse prognosis, a more aggressive tumor phenotype and triple-negative tumors, whereas luminal tumors showed high Spn levels. Downregulation of Spn by shRNA increased the stemness properties along with the expression of stem-related genes (Sox2, KLF4, Nanog and OCT4), whereas ectopic overexpression of Spn cDNA reduced these properties. Breast tumor stem cells appeared to have low levels of Spn mRNA, and Spn loss correlated with increased stem-like cell appearance in breast tumors as indicated by an increase in CD44+/CD24- cells. A reduction of the levels of PPP1CA mimicked the cancer stem-like cell phenotype of Spn downregulation, suggesting that the mechanism of Spn involves PP1a. These increased cancer stem cell-like properties with reduced Spn might account for the malignant phenotype observed in Spn-loss tumors and may contribute to a worse patient prognosis.
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