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Background In cardiovascular outcome trials, the sodium glucose cotransporter 2 inhibitor empagliflozin and glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide caused similar reductions in major adverse cardiac events (MACE). We compared clinical outcomes in routine clinical care. Methods and Results EMPLACE (Cardiovascular and Renal Outcomes, and Mortality in Danish Patients with Type 2 Diabetes Who Initiate Empagliflozin Versus GLP-1RA: A Danish Nationwide Comparative Effectiveness Study) is an ongoing nationwide population-based comparative effectiveness cohort study in Denmark. For the present study, we included 14 498 new users of empagliflozin and 12 706 new users of liraglutide, 2015 to 2018. Co-primary outcomes were expanded major adverse cardiac events (stroke, myocardial infarction, unstable angina, coronary revascularization, hospitalization for heart failure [HHF], or all-cause death); HHF or all-cause death; and first HHF or first initiation of loop-diuretic therapy. Secondary outcomes included all-cause hospitalization or death. We applied propensity score balancing and Cox regression to compute adjusted hazard ratios (aHRs) in on-treatment (OT) and intention-to-treat (ITT) analyses. Cohorts were well balanced at baseline (median age 61 years, 59% men, diabetes mellitus duration 6.6 years, 30% with preexisting cardiovascular disease). During mean follow-up of 1.1 years in OT and 1.5 years in ITT analyses, empagliflozin versus liraglutide was associated with a similar rate of expanded major adverse cardiac events (OT aHR, 1.02; 95% CI, 0.91-1.14; ITT aHR, 1.06; 95% CI, 0.96-1.17), and HHF or all-cause death (OT aHR, 0.97; 95% CI, 0.85-1.11; ITT aHR, 1.02; 95% CI, 0.91-1.14); and a decreased rate of a first incident HHF or loop-diuretic initiation (OT aHR, 0.80; 95% CI, 0.68-0.94; ITT aHR, 0.87; 95% CI, 0.76-1.00), and of all-cause hospitalization or death (OT aHR, 0.93; 95% CI, 0.89-0.98; ITT aHR, 0.93; 95% CI, 0.90-0.97). Conclusions Empagliflozin and liraglutide initiators had comparable rates of expanded major adverse cardiac events, and HHF or all-cause death, whereas empagliflozin initiators had a lower rate of a first HHF or loop-diuretic initiation.

Background: We investigated changes in clinical characteristics of SGLT2i and GLP-1RA real-world initiators in Denmark before/after landmark cardiovascular outcome trials., Methods: We compared first-time SGLT2i (25,070) and GLP-1RA (14,671) initiators to initiators of DPP-4i (n = 34,079), a class without proven cardiovascular benefits. We used linked population-based healthcare data to examine initiation incidence, medication patterns, and pre-existing atherosclerotic cardiovascular disease (ASCVD) during 2014-2017., Results: Nationwide incidence of SGLT2i initiators increased 3.6-fold (53/100,000 to 172/100,000 per year) vs. a 1.5-fold increase for GLP-1RA. DPP-4i initiation remained stable. From the end of 2015, SGLT2i was increasingly used as 2nd-line therapy, while medication patterns were much more stable for GLP-1RA. Among SGLT2i users, ASCVD increased slightly from 28% to 30%; age- and gender-adj. prevalence ratio (aPR) = 1.03 (95% CI:0.97-1.10). In contrast, among GLP-1RA initiators, baseline ASCVD declined from 29% to 27% (aPR: 0.90 (95% CI:0.84-0.97)), and in DPP-4i initiators from 31% to 29% (aPR: 0.91 (95% CI:0.88-0.96))., Conclusions: Following the EMPA-REG OUTCOME trial in 2015, SGLT2i have become increasingly used as 2nd-line treatment in everyday clinical practice, with only minor increases in patient proportions with ASCVD. For GLP-1RA, we observed more stable therapy lines and slightly decreasing ASCVD in new users despite the LEADER trial., Competing Interests: Conflict of interest disclosures: ML, LN and AU are employees of Boehringer Ingelheim. The other authors have no personal conflicts of interest relevant to this article. The Department of Clinical Epidemiology is involved in studies with funding from various companies as research grants to (and administered by) Aarhus University. The commercial affiliation did not alter our adherence to PLOS ONE policies on sharing data and materials. However, Danish law does not allow researchers to share raw data from the registries with third parties. Data can be accessed by researchers through application to the Danish Data Protection Agency and the Danish Health Data Authority

Aims/hypothesis: The aim of this study was to examine the effect of Roux-en-Y gastric bypass (RYGB) surgery on diabetes remission, subsequent diabetes relapse and micro- and macrovascular complications in individuals with type 2 diabetes and obesity (BMI >35 kg/m 2 ) in a real-world setting., Methods: This was a population-based cohort study of 1111 individuals with type 2 diabetes treated by RYGB at hospitals in Northern Denmark (2006-2015), and 1074 matched non-operated individuals with type 2 diabetes. Diabetes remission was defined as no glucose-lowering drug use with HbA 1c <48 mmol/mol (<6.5%), or metformin monotherapy with HbA 1c <42 mmol/mol (<6.0%). Data on complications were ascertained from medical registries with complete follow-up., Results: At 1 year of follow-up, 74% of the cohort treated by RYGB experienced diabetes remission, while 27% had relapsed after 5 years. Predictors of non-remission were age >50 years, diabetes duration >5 years, use of glucose-lowering drugs other than metformin, and baseline HbA 1c >53 mmol/mol (>7.0%). Compared with the non-operated cohort using adjusted Cox regression (5.3 years follow-up), the cohort treated by RYGB had 47% lower risk of microvascular complications (HR 0.53 [95% CI 0.38, 0.73]) and a statistically non-significant 24% lower risk of macrovascular complications (HR 0.76 [95% CI 0.49, 1.18]). Diabetes remission vs non-remission at 1 year was associated with reduced HR of 0.43 (95% CI 0.25, 0.72) for microvascular complications and with HR of 0.76 (95% CI 0.40, 1.45) for macrovascular complications., Conclusions/interpretation: In routine clinical care, three out of four individuals with type 2 diabetes and obesity treated by RYGB experienced diabetes remission after 1 year, whereas 27% of these individuals had relapsed at 5 years follow-up. RYGB was associated with substantially decreased risk of microvascular complications and non-significantly fewer macrovascular complications, with early diabetes remission as a clear predictor of reduced microvascular complications.

Background and Purpose: To assess long-term treatment effectiveness of disease-modifying therapy (DMT) initiated early in disease course versus later treatment start., Methods: We included all Danish patients with multiple sclerosis (MS) treated with DMT through two nationwide population-based MS registries. Patients were categorized as early treated if treatment started within 2 years after the first MS symptom (n = 2316) and later treated if treatment started between 2 and 8 years after clinical onset (n = 1479). We compared time from treatment start to progression to an Expanded Disability Status Scale (EDSS) score of 6 and mortality between cohorts as hazard ratio (HR) using a Cox proportional hazards model with adjustment for stabilized inverse probability of treatment weights. Several sensitivity analyses were conducted., Results: The median follow-up time of 3795 patients was 7.0 (range 0.6-19.5) years for the EDSS score of 6 outcome and 10.4 (range 1.2-20.1) years for the mortality outcome. Patients with later treatment start showed a 42% increased hazard rate of reaching an EDSS score of 6 compared with the early-treated patients [HR, 1.42; 95% confidence interval (CI), 1.18-1.70; P < 0.001]. When stratified by sex, the increased hazard among later-treated women persisted (HR, 1.53; 95% CI, 1.22-1.93; P < 0.001), whereas the HR was lower in men (1.25; 95% CI, 0.93-1.69; P = 0.15). Mortality was increased by 38% in later starters (HR, 1.38; 95% CI, 0.96-1.99; P = 0.08)., Conclusions: Patients who started treatment with DMT later reached an EDSS score of 6 more quickly compared with patients who started early and the delay showed a tendency to shorten time to death. Our results support the use of early treatment., (© 2018 EAN.)

Chronic kidney disease is most desirably and cost-effectively treated by renal transplantation, but graft survival is a major challenge. Although irreversible graft damage can be averted by timely treatment, intervention is delayed when early graft dysfunction goes undetected by standard clinical metrics. A more sensitive and specific parameter for delineating graft health could be the viscoelastic properties of the renal parenchyma, which are interrogated non-invasively by Viscoelastic Response (VisR) ultrasound, a new acoustic radiation force (ARF)-based imaging method. Assessing the performance of VisR imaging in delineating histologically confirmed renal transplant pathologies in vivo is the purpose of the study described here. VisR imaging was performed in patients with (n = 19) and without (n = 25) clinical indication for renal allograft biopsy. The median values of VisR outcome metrics (τ, relative elasticity [RE] and relative viscosity [RV]) were calculated in five regions of interest that were manually delineated in the parenchyma (outer, center and inner) and in the pelvis (outer and inner). The ratios of a given VisR metric for all possible region-of-interest combinations were calculated, and the corresponding ratios were statistically compared between biopsied patients subdivided by diagnostic categories versus non-biopsied, control allografts using the two-sample Wilcoxon test (p <0.05). Although τ ratios non-specifically differentiated allografts with vascular disease, tubular/interstitial scarring, chronic allograft nephropathy and glomerulonephritis from non-biopsied control allografts, RE distinguished only allografts with vascular disease and tubular/interstitial scarring, and RV distinguished only vascular disease. These results suggest that allografts with scarring and vascular disease can be identified using non-invasive VisR RE and RV metrics., (Copyright © 2018 World Federation for Ultrasound in Medicine and Biology. Published by Elsevier Inc. All rights reserved.)

Social isolation is associated with increased mortality. Meta-analytic results, however, indicate heterogeneity in effect sizes. We aimed to provide new evidence to the association between social isolation and mortality by conducting a population-based cohort study. We reconstructed the Berkman and Syme's social network index (SNI), which combines four components of social networks (partnership, interaction with family/friends, religious activities, and membership in organizations/clubs) into an index, ranging from 0/1 (most socially isolated) to 4 (least socially isolated). We estimated cumulative mortality and adjusted mortality rate ratios (MRR) associated with SNI. We adjusted for potential important confounders, including psychiatric and somatic status, lifestyle, and socioeconomic status. Cumulative 7-year mortality in men was 11% for SNI 0/1 and 5.4% for SNI 4 and in women 9.6% for SNI 0/1 and 3.9% for SNI 4. Adjusted MRRs comparing SNI 0/1 with SNI 4 were 1.7 (95% CI: 1.1-2.6) among men and 1.6 (95% CI: 0.83-2.9) among women. Having no partner was associated with an adjusted MRR of 1.5 (95% CI: 1.2-2.1) for men and 1.7 (95% CI: 1.2-2.4) for women. In conclusion, social isolation was associated with 60-70% increased mortality. Having no partner was associated with highest MRR.

Background: Herpes zoster (HZ) is a vaccine-preventable disease caused by reactivation of the varicella-zoster virus. Unfortunately, formulation of recommendations on routine immunization is hampered by a lack of data on disease burden, since most countries do not record cases of HZ in the general population. We developed and validated an algorithm to identify HZ based on routinely collected registry data and used it to quantify HZ occurrence and risk factors in Denmark prior to marketing of the HZ vaccine., Methods: We included patients aged ≥40years with a first-time systemic Acyclovir, Valacyclovir, or Famciclovir prescription or a hospital-based HZ diagnosis in the Danish nationwide health registries during 1997-2013. In a validation substudy (n=176), we computed the proportion of persons with HZ among patients who redeemed antiviral prescriptions. In a cohort study, we computed age-specific rates of HZ (45,297,258 person-years). In a case-control study, we then computed odds ratios (ORs) for common chronic diseases and immunosuppressive factors among HZ cases (n=189,025) vs. matched population controls (n=945,111)., Results: Medical record review confirmed HZ in 87% (95% confidence interval: 79-93%) of persons ≥40years who dispensed antivirals at doses recommended for HZ. HZ rates increased from 2.15/1000 person-years in 40-year-olds to 9.45/1000 person-years in 95-year-olds. Rates were highest in women. HZ was diagnosed during hospitalization among 3.5%. As expected, persons with severe immunosuppressive conditions had the highest ORs of HZ (between 1.82 and 4.12), but various autoimmune diseases, asthma, chronic kidney disease, and inhaled glucocorticoids were also associated with increased ORs (between 1.06 and 1.64)., Conclusion: This algorithm is a valid tool for identifying HZ in routine healthcare data. It shows that HZ is common in Denmark, especially in patients with certain chronic conditions. Prioritized vaccination of such high-risk patients might be an option in countries considering alternatives to universal vaccination., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: We investigated the association of early achieved HbA 1c level and magnitude of HbA 1c reduction with subsequent risk of cardiovascular events or death in patients with type 2 diabetes who initiate metformin., Research Design and Methods: This was a population-based cohort study including all metformin initiators with HbA 1c tests in Northern Denmark, 2000-2012. Six months after metformin initiation, we classified patients by HbA 1c achieved (<6.5% or higher) and by magnitude of HbA 1c change from the pretreatment baseline. We used Cox regression to examine subsequent rates of acute myocardial infarction, stroke, or death, controlling for baseline HbA 1c and other confounding factors., Results: We included 24,752 metformin initiators (median age 62.5 years, 55% males) with a median follow-up of 2.6 years. The risk of a combined outcome event gradually increased with rising levels of HbA 1c achieved compared with a target HbA 1c of <6.5%: adjusted hazard ratio (HR) 1.18 (95% CI 1.07-1.30) for 6.5-6.99%, HR 1.23 (1.09-1.40) for 7.0-7.49%, HR 1.34 (1.14-1.57) for 7.5-7.99%, and HR 1.59 (1.37-1.84) for ≥8%. Results were consistent for individual outcome events and robust by age-group and other patient characteristics. A large absolute HbA 1c reduction from baseline also predicted outcome: adjusted HR 0.80 (0.65-0.97) for Δ = -4, HR 0.98 (0.80-1.20) for Δ = -3, HR 0.92 (0.78-1.08) for Δ = -2, and HR 0.99 (0.89-1.10) for Δ = -1 compared with no HbA 1c change (Δ = 0)., Conclusions: A large initial HbA 1c reduction and achievement of low HbA 1c levels within 6 months after metformin initiation are associated with a lower risk of cardiovascular events and death in patients with type 2 diabetes., (© 2017 by the American Diabetes Association.)

Background: Observational studies on effectiveness of influenza vaccination in the elderly are thought to be biased by healthier lifestyles and higher socioeconomic status among vaccinated vs. unvaccinated persons. We examined this hypothesis in a uniform tax-supported health care system with free-of-charge influenza vaccination to the elderly., Methods: We conducted a cross-sectional study among Danes aged 65-79years participating in a survey. We compared elderly persons with and without a recent (within six months) influenza vaccination in terms of (i) lifestyle and socioeconomic characteristics obtained from the survey and (ii) health factors including medical history provided by Danish registries. We compared the prevalence of study variables among vaccinated and unvaccinated persons using age- and sex-adjusted prevalence ratios (aPRs) with 95% confidence intervals (CIs)., Results: Among the 4237 elderly persons completing the survey, 1718 (41%) had received an influenza vaccination. Vaccinated persons had more comorbidity than unvaccinated persons (aPR for high comorbidity level: 1.51 95% CI 1.24-1.84), were less likely to never have smoked (aPR: 0.88, 95% CI 0.80-0.97), and had a higher prevalence of physical inactivity (aPR: 1.08, 95% CI 1.03-1.13). Levels of education and income were similar in the two groups. Vaccinated persons had a higher prevalence of major physical limitations (aPR: 1.40, 95% CI 1.17-1.66) and need for assistance with activities of daily living (aPR: 1.29, 95% CI 1.13-1.47)., Conclusion: Elderly influenza vaccinated persons were not healthier in terms of lifestyle and burden of disease, did not have a higher socioeconomic status, and were more frail than unvaccinated persons., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Aims: To examine the usage and real-life effectiveness of intensification therapies in people with Type 2 diabetes treated with basal insulin., Methods: We used population-based healthcare databases in Denmark during 2000-2012 to identify all individuals with a first basal insulin prescription (with or without oral drugs), and evaluated subsequent intensification therapy with bolus insulin, premixed insulin or glucagon-like peptide-1 (GLP-1) receptor agonists. Poisson regression was used to compute the adjusted relative risks of reaching glycaemic control targets., Results: We included 7034 initiators of basal insulin (median age 64 years, diabetes duration 5.3 years, 84% with oral co-medication and median (interquartile range) pre-insulin HbA 1c level 77 (65-92) mmol/mol [9.2% (8.1-10.6%)]. Of these, 3076 (43.7%) received intensification therapy after a median of 11 months: 58.5% with premixed insulin, 29.0% with bolus insulin, 10.6% with GLP-1 receptor agonists, and 1.9% with more than one add-on. Overall, 22% had attained an HbA 1c level of < 53 mmol/mol (< 7%) by 3-6 months after intensification, while 38% attained an HbA 1c < 58 mmol/mol (< 7.5%). Compared with premixed insulin intensification, attainment of HbA 1c < 53 and < 58 mmol/mol was similar with bolus insulin add-on [adjusted relative risk 1.03 (95% CI 0.86-1.24) and 1.02 (95% CI 0.91-1.15), and higher for GLP-1 receptor agonist add-on [adjusted relative risk 1.56 (95% CI 1.27-1.92) and 1.27 (1.10-1.47)]., Conclusions: Among people with Type 2 diabetes, 22 and 38% reached a target HbA 1c < 53 mmol/mol (< 7%) or < 58 mmol/mol (< 7.5%), respectively, after intensification of their basal insulin therapy. Compared with premixed insulin, target attainment was similar with bolus insulin and higher with GLP-1 receptor agonists., (© 2016 Diabetes UK.)

Aims: To identify individual predictors of early glycaemic control in people with Type 2 diabetes mellitus after initiation of first glucose-lowering drug treatment in everyday clinical practice., Methods: Using medical registries, we identified a population-based cohort of people with a first-time glucose-lowering drug prescription in Northern Denmark in the period 2000-2012. We used Poisson regression analysis to examine patient-level predictors of success in reaching early glycaemic control [HbA 1c target of < 53 mmol/mol (7%)] < 6 months after treatment start., Results: Among the 38 418 people (median age 63 years), 27 545 (72%) achieved early glycaemic control. The strongest predictor of achieving early control was pre-treatment HbA 1c level; compared with a pre-treatment HbA 1c level of ≤ 58 mmol/mol (7.5%), the adjusted relative risks of attaining early control were 0.63 (95% CI 0.61-0.64) for baseline HbA 1c levels of > 58 and ≤ 75 mmol/mol (> 7.5 and ≤ 9%), and 0.58 (95% CI 0.57-0.59) for a baseline HbA 1c level of > 9% (> 75 mmol/mol). All other examined predictors were only weakly associated with the chance of achieving early control. After adjustment, the only characteristics that remained independently associated with early control (in addition to high baseline HbA 1c ) were being widowed (adjusted relative risk 0.95; 95% CI 0.93-0.97) and having a high Charlson comorbidity index score (score ≥ 3; adjusted relative risk 0.94; 95% CI 0.90-0.97)., Conclusions: In a real-world clinical setting, people with Type 2 diabetes mellitus initiating glucose-lowering medication had a similar likelihood of achieving glycaemic control, regardless of sex, age, comorbidities and other individual factors; the only strong and potentially modifiable predictor was HbA 1c before therapy start., (© 2016 Diabetes UK.)

Unlabelled: Perceived stress is associated with several adverse health outcomes; however, little is known about the impact of stress on fracture risk. In this population-based cohort study, persons with high perceived stress have an increased 5-year risk of any osteoporotic fracture, in particular hip fracture., Introduction: We conducted a population-based cohort study in Denmark to examine the association between perceived stress and risk of subsequent osteoporotic fracture., Methods: A 2006 population-based health survey in the Central Danish Region (with 1.25 million inhabitants) was used to identify 7943 persons who were 55 years or older on the survey date and completed the Perceived Stress Scale. Individuals were categorized into two groups: high level of stress and low level of stress (including no stress). We obtained information on all osteoporotic fractures through linkage to the Danish National Registry of Patients. We used Cox regression to compute hazard ratios (HRs) with 95 % confidence interval (CI) adjusted for a number of lifestyle factors, socioeconomic data, perceived general health, and prescription history, comparing high- and low-stress persons., Results: A total of 1799 persons (22.6 %) reported high level of perceived stress, whereas 6144 (77.4 %) reported low level or no stress. The 5-year risk of any osteoporotic fracture was 7.4 and 5.4 % in persons with high and low perceived stress, respectively, corresponding to adjusted HR of 1.37 (CI 1.00-1.89). The adjusted HR for hip fracture within 5 years associated with high perceived stress was 1.68 (CI 1.04-2.72). The associations weakened with increasing follow-up time., Conclusions: Persons with high perceived stress have an increased risk of any osteoporotic fracture, in particular risk of hip fracture within 5 years of stress assessment even after adjusting for differences in lifestyle, comorbidities, osteoporosis presence, medication use, and socioeconomic status at the time of stress level evaluation. The association attenuated after longer follow-up time.

Aims/hypothesis: The aims of this work were to assess glycaemic control in metformin users receiving their first add-on glucose-lowering therapy and to examine the real-life effectiveness of different add-on drugs., Methods: We carried out a population-based cohort study using healthcare databases in northern Denmark during 2000-2012. We included 4,734 persons who initiated metformin monotherapy and added another glucose-lowering drug within 3 years. Attainment of recommended HbA1c goals within 6 months of add-on was investigated, using Poisson regression analysis adjusted for age, sex, baseline HbA(1c), diabetes duration, complications and Charlson Comorbidity Index., Results: Median metformin treatment duration at intensification was 12 months (interquartile range [IQR] 4-23 months) and pre-intensification HbA(1c) was 8.0% (IQR 7.2-9.2%) (64 [IQR 55-77] mmol/mol). Median HbA(1c) dropped 1.2% (13 mmol/mol) with a sulfonylurea (SU) add-on, 0.8% (9 mmol/mol) with a dipeptidyl peptidase-4 (DPP-4) inhibitor, 1.3% (14 mmol/mol) with a glucagon-like peptide-1 (GLP-1) receptor agonist, 0.9% (10 mmol/mol) with other non-insulin drugs and 2.4% (26 mmol/mol) with insulin. Compared with SU add-on, attainment of HbA(1c) <7% (<53 mmol/mol) was higher with GLP-1 receptor agonists (adjusted RR [aRR] 1.10; 95% CI 1.01, 1.19) and lower with DPP-4 inhibitors (aRR 0.94; 95% CI 0.89, 0.99), other drugs (aRR 0.86; 95% CI 0.77, 0.96) and insulin (aRR 0.88; 95% CI 0.77, 0.99). The proportion of metformin add-on users who attained HbA(1c) <7% (<53 mmol/mol) increased from 46% in 2000-2003 to 59% in 2010-2012, whereas attainment of HbA(1c) <6.5% (<48 mmol/mol) remained 30% among patients aged <65 years without comorbidities., Conclusions/interpretation: Among early type 2 diabetes patients receiving their first metformin add-on treatment, HbA(1c) reduction with different non-insulin drugs is similar to, and comparable with, that observed in randomised trials, yet 41% do not achieve HbA(1c) <7% (<53 mmol/mol) within 6 months.

Aim: To examine real-life time trends in early glycaemic control in patients with type 2 diabetes between 2000 and 2012., Methods: We used population-based medical databases to ascertain the association between achievement of glycaemic control with initial glucose-lowering treatment in patients with incident type 2 diabetes in Northern Denmark. Success in reaching glycated haemoglobin (HbA1c) goals within 3-6 months was examined using regression analysis., Results: Of 38 418 patients, 91% started with oral glucose-lowering drugs in monotherapy. Metformin initiation increased from 32% in 2000-2003 to 90% of all patients in 2010-2012. Pretreatment (interquartile range) HbA1c levels decreased from 8.9 (7.6-10.7)% in 2000-2003 to 7.0 (6.5-8.1)% in 2010-2012. More patients achieved an HbA1c target of <7% (<53 mmol/mol) in 2010-2012 than in 2000-2003 [80 vs 60%, adjusted relative risk (aRR) 1.10, 95% confidence interval (CI) 1.08-1.13], and more achieved an HbA1c target of <6.5% [(<48 mmol/mol) 53 vs 37%, aRR 1.07 95% CI 1.03-1.11)], with similar success rates observed among patients aged <65 years without comorbidities. Achieved HbA1c levels were similar for different initiation therapies, with reductions of 0.8% (from 7.3 to 6.5%) on metformin, 1.5% (from 8.1 to 6.6%) on sulphonylurea, 4.0% (from 10.4 to 6.4%) on non-insulin combination therapies, and 3.8% (from 10.3 to 6.5%) on insulin monotherapy., Conclusions: Pretreatment HbA1c levels in patients with incident type 2 diabetes have decreased substantially, which is probably related to earlier detection and treatment in accordance with changing guidelines. Achievement of glycaemic control has improved, but 20% of patients still do not attain an HbA1c level of <7% within the first 6 months of initial treatment., (© 2015 John Wiley & Sons Ltd.)

Solar light leads to thymine dimers that are mutagenic and primary cause of skin cancer. Here, we report absorption and synchrotron radiation circular dichroism (CD) spectra of Tn single strands with different number n of bases (n = 2-7, 10, 11) recorded after various 254 nm irradiation times. From a principal component analysis of the CD spectra, we extract fingerprint spectra of both the cyclobutane pyrimidine dimer (CPD) and the pyrimidine (6-4) pyrimidone photoadduct (64PP). Extending the CD measurements to the vacuum ultraviolet region in combination with systematic examinations of size effects is a new approach to gain insight on the dimeric photoproducts. We find a simple linear correlation between n and average number of dimers formed after 1 h of irradiation. The probability for a thymine to engage in a dimer increases from 32% for n = 2 to 41% for n = 11, which implies limited effects of terminal thymines, i.e., the reaction does not occur preferentially at the extremities of the single strands as previously stated. It is even possible to form two dimers with only two bridging thymines. Finally, experiments conducted on calf thymus DNA provided a similar signature of the photodimer, but differences are also evident., (© 2013 The American Society of Photobiology.)

Microsolvation of chromophore ions commonly has large effects on their electronic structure and as a result on their optical absorption spectra. Here spectroscopy of protonated adenine (AdeH(+)) and its complex with one water molecule isolated in vacuo was done using a home-built mass spectrometer in combination with a tuneable pulsed laser system. Experiments also included the protonated adenosine 5'-monophosphate nucleotide (AMPH(+)). In the case of bare AdeH(+) ions, one-photon absorption leads to four dominant fragment ions corresponding to ammonium and ions formed after loss of either NH3, HCN, or NH2CN. The yields of these were measured as a function of the wavelength of the light from 210 nm to 300 nm, and they were combined to obtain the total photoinduced dissociation at each wavelength (i.e., action spectrum). A broad band between 230 nm and 290 nm and the tail of a band with maximum below 210 nm (high-energy band) are seen. In the case of AdeH(+)(H2O), the dominant dissociation channel after photoexcitation in the low-energy band was simply loss of H2O while photodissociation of protonated AMP revealed two dominant dissociation channels associated with the formation of either AdeH(+) or loss of H3PO4. The action spectra of AdeH(+), AdeH(+)(H2O), and AMPH(+) are almost identical in the 230-290 nm region, and they resemble the absorption spectrum of protonated adenine in aqueous solution recorded at low pH. Hence from our work it is firmly established that the lowest-energy transitions are independent of the surroundings.

A validated method for assessing hemostasis in vivo is critical for testing the hemostatic efficacy of therapeutic agents in preclinical animal models and in patients with inherited bleeding disorders, such as von Willebrand disease (VWD) and hemophilia A, or with acquired bleeding disorders such as those resulting from medications or disease processes. In this review, we discuss current methods for assessing hemostasis in vivo and the associated challenges. We also present ARFI-Monitored Hemostatic Challenge; a new, potentially alternate method for in vivo hemostasis monitoring that is in development by our group., (Copyright © 2012. Published by Elsevier Ltd.)

Acoustic radiation force (ARF) ultrasound is a method of elastographic imaging in which micron-scale tissue displacements, induced and tracked by ultrasound, reflect clinically relevant tissue mechanical properties. Our laboratory has recently shown that tissue viscoelasticity is assessed using the novel Multi-Push (MP) ARF method. MP ARF applies the Voigt model for viscoelastic materials and compares the displacements achieved by successive ARF excitations to qualitatively or quantitatively represent the relaxation time for constant stress, which is a direct descriptor of the viscoelastic response of the tissue. We have demonstrated MP ARF in custom viscoelastic tissue mimicking materials and implemented the method in vivo in canine muscle and human renal allografts, with strong spatial correlation between MP ARF findings and histochemical features and previously reported mechanical changes with renal disease. These data support that noninvasive MP ARF is capable of clinically relevant assessment of tissue viscoelastic properties.