Genetic Drivers of Heterogeneity in Type 2 Diabetes Pathophysiology

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P \u3c 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care

Genetic drivers of heterogeneity in type 2 diabetes pathophysiology

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P &lt; 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.</p

The evaluation of risk for obstructive sleep apnea in patients with type 2 diabetes

Cilj istraživanja je procijeniti rizik za opstrukcijsku apneju tijekom spavanja (engl. Obstructive sleep apnea, OSA) u bolesnika sa šećernom bolešću tipa 2, s pomoću STOP upitnika (engl. Snoring, Tiredness, Observed, Pressure; STOP). S pomoću Epworthove ljestvice pospanosti (ESS) procijenjena je prekomjerna dnevna pospanost i ispitana povezanost pospanosti i rizika za OSA-u u bolesnika sa šećernom bolešću tipa 2. Dosadašnja istraživanja pokazala su da oštećena tolerancije glukoze i šećerna bolest tipa 2 predstavljaju čimbenik rizika za OSA-u, ali i da OSA predstavlja čimbenik rizika za šećernu bolest tipa 2. U našem istraživanju sudjelovala su 252 ispitanika sa šećernom bolešću tipa 2, koji su bili anketirani za vrijeme redovitih pregleda u Kliničkom bolničkom centru Split. Rezultati našeg istraživanja pokazali su da je 156 ispitanika (61,9%) imalo povećan rizik za OSA-u prema rezultatima STOP upitnika. Nadalje, ispitanici koji su imali povećani rizik u odnosu na ispitanike koji nisu imali rizik za OSA-u bili su stariji (65 vs. 61 godina, p < 0,05), imali viši indeks tjelesne mase (28,6 ± 5,1 vs. 26,5 ± 4,1, p < 0,001), veći opseg vrata (41,5 ± 4,7 vs. 39,6 ± 6,2, p < 0,009) i bili pospaniji prema rezultatima ESS (5,3 ± 3,1 vs. 3,9 ± 2,5, p < 0,001). Uz šećernu bolest, većina ispitanika imala je i pridružene bolesti: arterijska hipertenzija (46%), gastroezofagealna refluksna bolest (28%), depresija (10%) i astma (8%). OSA je dio širokoga spektra poremećaja disanja tijekom spavanja koja se dovodi u vezu s metaboličkim poremećajima poput šećerne bolesti tipa 2, a epidemiološki podaci o zastupljenosti OSA u Hrvatskoj su nedostatni. Ovo istraživanje ukazuje na potrebu provođenja probira za OSA u bolesnika sa šećernom bolešću tipa 2, koristeći STOP upitnik.The aim of this study was to evaluate the risk for obstructive sleep apnea (OSA) in patients with type 2 diabetes using the STOP questionnaire (Snoring, Tiredness, Observed, Pressure; STOP). Excessive daytime sleepiness was evaluated with the Epworth sleepiness scale (ESS). Previous studies support the idea that glucose intolerance and type 2 diabetes might represent risk factors for OSA, as well as the idea of OSA being the risk factor for type 2 diabetes. A total of 252 patients with type 2 diabetes were surveyed during the regular follow-up in the Regional Centre for Diabetes, Endocrinology and Metabolic Diseases of Split University Hospital. The results of our study indicate that 156 patients (61.9%) had increased risk for OSA according to STOP questionnaire score. In addition, those at high risk for OSA were older (65 vs. 61 years of age, p < 0.05), had higher body mass index (BMI, 28.6 ± 5.1 vs. 26.5 ± 4.1, p < 0.001), higher neck circumference (41.5 ± 4.7 vs. 39.6 ± 6.2, p < 0.009), and had excessive daytime sleepiness according to the ESS score (5.3 ± 3.1 vs. 3.9 ± 2.5, p < 0.001). Individuals with type 2 diabetes reported to have comorbidities, mainly hypertension (46%), gastroesophageal reflux disease (28%), depression (10%), and asthma (8%). Based on current evidence from literature, OSA could be related to clinical conditions such as diabetes and essential hypertension. More epidemiological data are needed to establish the prevalence of OSA in Croatian patients with type 2 diabetes. Our findings indicate the relevance of STOP questionnaire use as a screening tool for obstructive sleep apnea in patients with type 2 diabetes in Croatia

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Correction to: Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

The original version of this article unfortunately contained a mistake

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Diffusion-Controlled Rotation of Triptycene in a Metal–Organic Framework (MOF) Sheds Light on the Viscosity of MOF-Confined Solvent

[Image: see text] Artificial molecular machines are expected to operate under conditions of very low Reynolds numbers with inertial forces orders of magnitude smaller than viscous forces. While these conditions are relatively well understood in bulk fluids, opportunities to assess the role of viscous forces in confined crystalline media are rare. Here we report one such example of diffusion-controlled rotation in crystals and its application as a probe for viscosity of MOF-confined solvent. We describe the preparation and characterization of three pillared paddlewheel MOFs, with 9,10-bis(4-pyridylethynyl)triptycene 3 as a pillar and molecular rotator, and three axially substituted dicarboxylate linkers with different lengths and steric bulk. The noncatenated structure with a bulky dicarboxylate linker (UCLA-R3) features a cavity filled by 10 molecules of N,N-dimethylformamide (DMF). Solid-state (2)H NMR analysis performed between 293 and 343 K revealed a fast 3-fold rotation of the pillar triptycene group with the temperature dependence consistent with a site exchange process determined by rotator-solvent interactions. The dynamic viscosity of the MOF-confined solvent was estimated to be 13.3 N·s/m(2) (or Pa·s), which is 4 orders of magnitude greater than that of bulk DMF (8.2 × 10(–4) N·s/m(2)), and comparable to that of honey

A Validated RP-HPLC Method for the Determination of Citrinin in Xuezhikang Capsule and other Monascus-Fermented Products

Citrinin is a toxic product usually produced during the Monascus fermentation. The presence of citrinin in xuezhikang capsule has been a concern due to its ingredient which is derived from monascus-fermented rice. A rapid and sensitive RP-HPLC method with fluorescence detection at λex = 331 nm and λem = 500 nm for analysis of citrinin in Monascus-fermented products was developed to analyze citrinin in Monascus-fermented products. The chromatography was performed with mobile phase containing acidified water and acetonitrile. The calibration curve was linear (r = 0.9999) over a range of 0.0107- 0.537 μg/mL. The limit of detection (LOD) and the limit of quantitation (LOQ) were 0.187 ng/mL and 0.6 ng/mL respectively. The analysis of xuezhikang capsules using the developed method suggested that the product does not contain detectable citrinin and the result has been further confirmed using independent LC-MS/MS analysis. The proposed method has also been applied to analyze 11 samples of other Monascus-fermented products. The results suggested that there were no detectable citrinin in 4 of the 11 samples, however citrinin with the levels between 0.10-594 ng/kg has been detected in the other 7 samples. It indicates that the proposed method can also be applied to carry out the quantitative detection of citrinin for other Monascus-fermented products