A3907, a systemic ASBT inhibitor, improves cholestasis in mice by multiorgan activity and shows translational relevance to humans.

BACKGROUND AND AIMS: Cholestasis is characterized by intrahepatic accumulation of bile constituents, including bile acids (BAs), which promote liver damage. The apical sodium-dependent BA transporter (ASBT) plays an important role in BA reabsorption and signaling in ileum, bile ducts, and kidneys. Our aim was to investigate the pharmacokinetics and pharmacological activity of A3907, an oral and systemically available ASBT inhibitor in experimental mouse models of cholestasis. In addition, the tolerability, pharmacokinetics, and pharmacodynamics of A3907 were examined in healthy humans. APPROACH AND RESULTS: A3907 was a potent and selective ASBT inhibitor in vitro. In rodents, orally administered A3907 distributed to the ASBT-expressing organs, that is, ileum, liver, and kidneys, and dose dependently increased fecal BA excretion. A3907 improved biochemical, histological, and molecular markers of liver and bile duct injury in Mdr2-/- mice and also had direct protective effects on rat cholangiocytes exposed to cytotoxic BA concentrations in vitro . In bile duct ligated mice, A3907 increased urinary BA elimination, reduced serum BA levels, and prevented body weight loss, while improving markers of liver injury. A3907 was well tolerated and demonstrated target engagement in healthy volunteers. Plasma exposure of A3907 in humans was within the range of systemic concentrations that achieved therapeutic efficacy in mouse. CONCLUSIONS: The systemic ASBT inhibitor A3907 improved experimental cholestatic disease by targeting ASBT function at the intestinal, liver, and kidney levels, resulting in marked clearance of circulating BAs and liver protection. A3907 is well tolerated in humans, supporting further clinical development for the treatment of cholestatic liver diseases.

Dietary intervention reverses molecular markers of hepatocellular senescence in the GAN diet-induced obese and biopsy-confirmed mouse model of NASH.

BACKGROUND: Hepatocellular senescence may be a causal factor in the development and progression of non-alcoholic steatohepatitis (NASH). The most effective currently available treatment for NASH is lifestyle intervention, including dietary modification. This study aimed to evaluate the effects of dietary intervention on hallmarks of NASH and molecular signatures of hepatocellular senescence in the Gubra-Amylin NASH (GAN) diet-induced obese (DIO) and biopsy-confirmed mouse model of NASH. METHODS: GAN DIO-NASH mice with liver biopsy-confirmed NASH and fibrosis received dietary intervention by switching to chow feeding (chow reversal) for 8, 16 or 24 weeks. Untreated GAN DIO-NASH mice and chow-fed C57BL/6J mice served as controls. Pre-to-post liver biopsy histology was performed for within-subject evaluation of NAFLD Activity Score and fibrosis stage. Terminal endpoints included blood/liver biochemistry, quantitative liver histology, mitochondrial respiration and RNA sequencing. RESULTS: Chow-reversal promoted substantial benefits on metabolic outcomes and liver histology, as demonstrated by robust weight loss, complete resolution of hepatomegaly, hypercholesterolemia, elevated transaminase levels and hepatic steatosis in addition to attenuation of inflammatory markers. Notably, all DIO-NASH mice demonstrated ≥ 2 point significant improvement in NAFLD Activity Score following dietary intervention. While not improving fibrosis stage, chow-reversal reduced quantitative fibrosis markers (PSR, collagen 1a1, α-SMA), concurrent with improved liver mitochondrial respiration, complete reversal of p21 overexpression, lowered γ-H2AX levels and widespread suppression of gene expression markers of hepatocellular senescence. CONCLUSIONS: Dietary intervention (chow reversal) substantially improves metabolic, biochemical and histological hallmarks of NASH and fibrosis in GAN DIO-NASH mice. These benefits were reflected by progressive clearance of senescent hepatocellular cells, making the model suitable for profiling potential senotherapeutics in preclinical drug discovery for NASH.

Predictors of reoperation after lung volume reduction surgery.

OBJECTIVES: Lung volume reduction surgery (LVRS) has proven an effective treatment for emphysema, by decreasing hyperinflation and improving lung function, activity level and reducing dyspnoea. However, postoperative air leak is an important complication, often leading to reoperation. Our aim was to analyse reoperations after LVRS and identify potential predictors. METHODS: Consecutive single-centre unilateral VATS LVRS performed from 2017 to 2022 were included. Typically, 3-5 minor resections were made using vascular magazines without buttressing. Data were obtained from an institutional database and analysed. Multivariable logistic regression was used to identify predictors of reoperation. Number and location of injuries were registered. RESULTS: In total, 191 patients were included, 25 were reoperated (13%). In 21 patients, the indication for reoperation was substantial air leak, 3 patients bleeding and 1 patient empyema. Length of stay (LOS) was 21 (11-33) vs. 5 days (3-11), respectively. Only 3 injuries were in the stapler line, 13 within < 2cm and 15 injuries were in another site. Multivariable logistic regression analysis showed that decreasing DLCO increased risk of reoperation, OR 1.1 (1.03, 1.18, P = 0.005). Resections in only one lobe, compared to resections in multiple lobes, were also a risk factor OR 3.10 (1.17, 9.32, P = 0.03). Patients undergoing reoperation had significantly increased 30-day mortality, OR 5.52 (1.03, 26.69, P = 0.02). CONCLUSIONS: Our incidence of reoperation after LVRS was 13% leading to prolonged LOS and increased 30-day mortality. Low DLCO and resections in a single lobe were significant predictors of reoperation. The air leak was usually not localized in the stapler line.

National and education-specific trends in life and health expectancies in Denmark 2004-2015.

BACKGROUND: Several studies have revealed widening of inequalities in life expectancy, but little is known about the recent changes in health expectancy nationally and between socioeconomic groups. This study examines dynamics of national and education-specific life expectancy and health expectancies at age 50 years in Denmark from 2004/2007 to 2015. METHODS: Nationwide register data on education and mortality were linked and combined with Danish health data from the Survey of Health, Ageing and Retirement in Europe and changes in life expectancy and three health expectancy indicators were estimated by Sullivan's method. RESULTS: From 2004 to 2015, national life expectancy at age 50 years increased by 2.4 years for men and 2.1 years for women. Simultaneously, after an initial rapid improvement from 2004 to 2007, the pace of progress in health expectancy decreased. From 2007 to 2015, the difference in life expectancy at age 50 years between men with long and short education increased from 4.3 to 5.0 years. For women, the corresponding increase in the life expectancy gap was less pronounced from 3.5 to 3.8 years. The educational gap in lifetime without long-term illness decreased from 4.6 years to 3.1 years for men and from 6.1 years to 4.6 years for women. On the contrary, the educational gap increased for lifetime without activity limitations and in self-rated good health. CONCLUSIONS: Previously observed improvements in health expectancy in Denmark slowed down despite continuing progress in life expectancy. This worrying change coincides with persistent educational inequalities in life expectancy and health expectancy and is a challenge to a sustainable social and health development in the future.

Hepatoprotective effects of the long-acting fibroblast growth factor 21 analog PF-05231023 in the GAN diet-induced obese and biopsy-confirmed mouse model of nonalcoholic steatohepatitis.

Fibroblast growth factor 21 (FGF21) plays a key role in hepatic lipid metabolism and long-acting FGF21 analogs have emerged as promising drug candidates for the treatment of nonalcoholic steatohepatitis (NASH). It remains to characterize this drug class in translational animal models that recapitulate the etiology and hallmarks of human disease. To this end, we evaluated the long-acting FGF21 analog PF-05231023 in the GAN (Gubra Amylin NASH) diet-induced obese (DIO) and biopsy-confirmed mouse model of NASH. Male C57BL/6J mice were fed the GAN diet high in fat, fructose, and cholesterol for 34 wk before the start of the study. GAN DIO-NASH mice with biopsy-confirmed NAFLD Activity Score (NAS ≥5) and fibrosis (stage ≥F1) were biweekly administered with PF-05231023 (10 mg/kg sc) or vehicle (sc) for 12 wk. Vehicle-dosed chow-fed C57BL/6J mice served as healthy controls. Pre-to-post liver biopsy histopathological scoring was performed for within-subject evaluation of NAFLD Activity Score (NAS) and fibrosis stage. Terminal endpoints included quantitative liver histology and transcriptome signatures as well as blood and liver biochemistry. PF-05231023 significantly reduced body weight, hepatomegaly, plasma transaminases, and plasma/liver lipids in GAN DIO-NASH mice. Notably, PF-05231023 reduced both NAS (≥2-point improvement) and fibrosis stage (1-point improvement). Improvements in NASH and fibrosis severity were supported by reduced quantitative histological markers of steatosis, inflammation, and fibrogenesis as well as improvements in disease-associated liver transcriptome signatures. In conclusion, PF-05231023 reduces NASH and fibrosis severity in a translational biopsy-confirmed mouse model of NASH, supporting development of FGF21 analogs for the treatment of NASH.NEW & NOTEWORTHY It is unclear if long-acting FGF21 analogs have antifibrotic efficacy in NASH. We therefore profiled the clinically relevant FGF21 analog PF-05231023 in a translational diet-induced obese and biopsy-confirmed mouse model of NASH. We found PF-05231023 to exert hepatoprotective effects as indicated by notable improvements in plasma markers and histological hallmarks of NASH, including improved fibrosis stage. Collectively, the present study supports the continued exploration of long-acting FGF21 analogs for the treatment of NASH and other fibrotic diseases.

Pulmonary telerehabilitation vs. conventional pulmonary rehabilitation - a secondary responder analysis.

Home-based pulmonary telerehabilitation (PTR) has been proposed to be equivalent to supervised outpatient pulmonary rehabilitation (PR) but available randomised trials have failed to reach the minimal important changes (MIC). The purpose of this study was to analyse the proportion of MIC responders and non-responders on short-term (10 weeks from baseline) and long-term (62 weeks from baseline) in total and between groups in 134 patients with COPD randomised (1:1) to either home-based PTR or traditional hospital-based outpatient PR. Difference between PTR and PR on 6MWD response proportion could not be shown at 10 (OR=0.72, CI=0.34 to 1.51, p=0.381) or 62 weeks (OR=1.12, CI=0.40 to 3.14, p=0.834). While the evidence and knowledge of PTR accumulate, outpatient supervised PR for now remains the standard of care, with home-based PTR as a strong secondary option for those unable to attend out-patient programmes.

Plasma concentration of orally administered amoxicillin and clindamycin in patients receiving haemodialysis.

OBJECTIVES: In the randomized controlled trial PANTHEM, the prophylactic effect of oral amoxicillin or clindamycin is investigated in patients receiving chronic haemodialysis (HD). However, data on plasma concentrations of these antibiotics during HD are sparse. This study aims to determine if the plasma concentration of amoxicillin and clindamycin is sufficient during HD after oral administration of amoxicillin and clindamycin at three different time intervals prior to the HD procedure. METHODS: Adult patients receiving chronic HD were investigated twice with an interval of at least 7 days starting with either a tablet of 500/125 mg amoxicillin/clavulanic acid or a tablet of 600 mg clindamycin. Patients were randomized to take the antibiotics either 30, 60 or 120 min prior to the HD procedure. Plasma antibiotic concentrations were measured at start, midway and at the end of HD. A lower threshold was set at 2.0 mg/L for amoxicillin and at 1.0 mg/L for clindamycin. In addition, a population pharmacokinetic (PK) analysis was performed, assessing PTA. RESULTS: In the amoxicillin cohort (n = 37), 84% of patients and 95% of all plasma amoxicillin concentrations were above or at the threshold throughout the dialysis procedure. In the clindamycin cohort (n = 33), all concentrations were above the threshold throughout the dialysis procedure. Further, in all patients, the mean plasma concentration of both amoxicillin and clindamycin across the HD period was well above the threshold. Finally, the PK model predicted a high PTA in the majority of patients. DISCUSSION: In patients on chronic HD, oral administration of amoxicillin/clavulanic acid (500/125 mg) or clindamycin (600 mg) within 30-120 min prior to HD leads to a sufficient prophylactic plasma concentration across the HD period.

Switching from imatinib to nilotinib plus pegylated interferon-α2b in chronic phase CML failing to achieve deep molecular response: clinical and immunological effects.

In order to improve molecular response for a discontinuation attempt in chronic myeloid leukemia (CML) patients in chronic phase, who had not achieved at least a molecular response <0.01% BCR-ABL1IS (MR4.0) after at least 2 years of imatinib therapy, we prospectively evaluated whether they could attain MR4.0 after a switch to a combination of nilotinib and 9 months of pegylated interferon-α2b (PegIFN). The primary endpoint of confirmed MR4.0 at month 12 (a BCR-ABL1IS level ≤ 0.01% both at 12 and 15 months) was reached by 44% (7/16 patients, 95% confidence interval (CI): 23- 67%) of patients, with 81% (13/16 patients, 95% CI: 57-93%) of patients achieving an unconfirmed MR4.0. The scheduled combination was completed by 56% of the patients, with premature discontinuations, mainly due to mood disturbances after the introduction of PegIFN, questioning the feasibility of the combination of nilotinib and PegIFN for this patient population and treatment goal. A comprehensive clinical substudy program was implemented to characterize the impact of the treatment changes on the immunological profile. This trial was registered at www.clinicaltrials.gov as #NCT01866553.

Impact of acute coronary syndrome on clinical outcomes after revascularization with the dual-therapy CD34 antibody-covered sirolimus-eluting Combo stent and the sirolimus-eluting Orsiro stent.

OBJECTIVES: To compare the efficacy and safety of the dual-therapy CD34 antibody-covered sirolimus-eluting Combo stent (DTS) and the sirolimus-eluting Orsiro stent (O-SES) in patients with and without acute coronary syndrome (ACS) included in the SORT OUT X study. BACKGROUND: The incidence of target lesion failure (TLF) after treatment with modern drug-eluting stents has been reported to be significantly higher in patients with ACS when compared to patients without ACS. Whether the results from the SORT OUT X study apply to patients with and without ACS remains unknown. METHODS: In total, 3146 patients were randomized to stent implantation with DTS (n = 1578; ACS: n = 856) or O-SES (n = 1568; ACS: n = 854). The primary end point, TLF, was a composite of cardiac death, target-lesion myocardial infarction (MI), or target lesion revascularization (TLR) within 1 year. RESULTS: At 1 year, the rate of TLF was higher in the DTS group compared to the O-SES group, both among patients with ACS (6.7% vs. 4.1%; incidence rate ratio: 1.65 [95% confidence interval, CI: 1.08-2.52]) and without ACS (6.0% vs. 3.2%; incidence rate ratio: 1.88 [95% CI: 1.13-3.14]). The differences were mainly explained by higher rates of TLR, whereas rates of cardiac death and target lesion MI did not differ significantly between the two stent groups in patients with or without ACS CONCLUSION: Compared to the O-SES, the DTS was associated with a higher risk of TLF at 12 months in patients with and without ACS. The differences were mainly explained by higher rates of TLR.

Far infrared treatment on the arteriovenous fistula induces changes in sVCAM and sICAM in patients on hemodialysis.

INTRODUCTION: There is a substantial risk of developing stenosis and dysfunction in the arteriovenous fistula (AVF) in patients on hemodialysis (HD). Far infrared radiation (FIR) is a non-invasive local intervention with a potentially beneficial effect on AVF patency. The underlying mechanism is not clear. It was hypothesized that a single FIR treatment reduces factors of inflammation and promotes endothelial vasodilators in the AVF. METHODS: Forty HD patients with an AVF were included in an open-label intervention study. Patients were randomized to receive either FIR (FIR group) or no FIR (control group). Blood samples were drawn directly from the AVF and from a peripheral vein in the non-AVF arm before (T0) and 40 min after (T40) treatment during a HD session. The changes [median (interquartile range)] in circulating factors of inflammation, endothelial function and vasoreactivity during FIR were measured. RESULTS: In the AVF a single FIR treatment during dialysis resulted in a significantly diminished decrease in soluble vascular cell adhesion molecule, sVCAM [-31.6 (-54.3; 22.1) vs -89.9 (-121.6; -29.3), P = .005] and soluble intercellular adhesion molecule, sICAM [-24.2 (-43.5; 25.3) vs -49 (-79.9; -11.6), P = .02] compared with the control group. Other factors, such as interleukins, nitrite, nitrate and tumor necrosis factor 1, also declined during dialysis, but with no significant differences related to FIR in either the AVF or the non-AVF arm. CONCLUSION: A single FIR treatment attenuated the decrease in sVCAM and sICAM in the AVF compared with a control group during HD. Findings do not support the hypothesis of a vaso-protective effect of FIR. The long-term effects of FIR on the AVF are unknown.

Impact of the association between education and obesity on diabetes-free life expectancy.

BACKGROUND: The purpose of the study was to quantify the association between body weight and health by estimating the expected lifetime with and without diabetes (diabetes-free life expectancy) at age 30 and 65. In addition, the diabetes-free life expectancy was stratified by educational level. METHODS: Life tables by sex, level of education and obese/not obese were constructed using nationwide register data and self-reported data on body weight and height and diabetes from the Danish National Health Survey in 2021. Diabetes-free life expectancies were estimated by Sullivan's method. RESULTS: The difference in life expectancy between not obese 30-year-old men with a long and a short education was 5.7 years. For not obese women, the difference was 4.1 years. For obese men and women, the difference in life expectancy at age 30 was 7.0 and 5.2 years. Women could expect more years without and fewer years with diabetes than men regardless of body weight and educational level. Diabetes-free life expectancy differed by 6.9 years between not obese 30-year-old men with a short and a long education and by 7.7 years for obese men with a short and a long education. For women, the differences were 5.9 and 6.6 years. CONCLUSION: The results demonstrate an association of obesity and educational level with life expectancy and diabetes-free life expectancy. There is a need for preventive efforts to reduce educational inequality in life expectancy and diabetes-free life expectancy. Structural intervention will particularly benefit overweight people with short education.

The COVID-19 pandemic in Greenland, epidemic features and impact of early strict measures, March 2020 to June 2022.

BackgroundThe COVID-19 pandemic was of major concern in Greenland. There was a high possibility of rapid transmission in settlements, and an increased risk of morbidity and mortality because of comorbidities in the population and limited access to specialised healthcare in remote areas.AimTo describe the epidemiology of the COVID-19 pandemic in Greenland and evaluate the effects of a strict COVID-19 strategy until risk groups were immunised.MethodsWe studied the epidemiology during March 2020 to June 2022. We describe the non-pharmaceutical interventions (NPIs), PCR-confirmed COVID-19 cases and vaccination coverage with data from the registries of the Greenlandic health authority.ResultsWe found 21,419 confirmed cases per 100,000 inhabitants (54% female, 46% male), 342 per 100,000 were hospitalised and 16 per 100,000 were admitted to the intensive care unit. The COVID-19 mortality rate was 39 per 100,000, all those affected were aged above 65 years. No excess overall mortality was observed. The vaccination coverage by June 2022 was 71.67 and 41% for one, two and three doses, respectively.ConclusionSARS-CoV-2 circulation in Greenland was low, given strict restrictions until all eligible inhabitants had been offered immunisation. The main impact of the pandemic was from May 2021 onwards with increasing numbers of confirmed cases. This occurred after introduction of the vaccine programme, which may have had an influence on the severity of the associated morbidity and mortality experienced. Halting community transmission of SARS-CoV-2 with NPIs until the majority of the population had been immunised was a successful strategy in Greenland.

Randomized Clinical Comparison of the Dual-Therapy CD34 Antibody-Covered Sirolimus-Eluting Combo Stent With the Sirolimus-Eluting Orsiro Stent in Patients Treated With Percutaneous Coronary Intervention: The SORT OUT X Trial.

BACKGROUND: Target lesion failure remains an issue with contemporary drug-eluting stents. Thus, the dual-therapy sirolimus-eluting and CD34+ antibody-coated Combo stent (DTS) was designed to further improve early healing. This study aimed to investigate whether the DTS is noninferior to the sirolimus-eluting Orsiro stent (SES) in an all-comers patient population. METHODS: The SORT OUT X (Combo Stent Versus Orsiro Stent) trial, was a large-scale, randomized, multicenter, single-blind, 2-arm, noninferiority trial with registry-based follow-up. The primary end point target lesion failure was a composite of cardiac death, myocardial infarction, or target lesion revascularization within 12 months, analyzed using intention-to-treat. The trial was powered for assessing target lesion failure noninferiority of the DTS compared with the SES with a predetermined noninferiority margin of 0.021. RESULTS: A total of 3146 patients were randomized to treatment with the DTS (1578 patients; 2008 lesions) or SES (1568 patients; 1982 lesions). At 12 months, intention-to-treat analysis showed that 100 patients (6.3%) assigned the DTS and 58 patients (3.7%) assigned the SES met the primary end point (absolute risk difference, 2.6% [upper limit of 1-sided 95% CI, 4.1%]; P (noninferiority)=0.76). The SES was superior to the DTS (incidence rate ratios for target lesion failure, 1.74 [95% CI, 1.26-2.41]; P=0.00086). The difference was explained mainly by a higher incidence of target lesion revascularization in the DTS group compared with the SES group (53 [3.4%] vs. 24 [1.5%]; incidence rate ratio, 2.22 [95% CI, 1.37-3.61]; P=0.0012). CONCLUSIONS: The DTS did not confirm noninferiority to the SES for target lesion failure at 12 months in an all-comer population. The SES was superior to the DTS mainly because the DTS was associated with an increased risk of target lesion revascularization. However, rates of death, cardiac death, and myocardial infarction at 12 months did not differ significantly between the 2 stent groups. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03216733.

Cold agglutinin disease revisited: a multinational, observational study of 232 patients.

We retrospectively studied 232 patients with cold agglutinin disease (CAD) at 24 centers in 5 countries. In Norway and a northern region of Italy, the study was close to being population-based. For the first time, we demonstrate fourfold differences between cold and warmer climates regarding prevalence (20 vs 5 cases/million) and incidence (1.9 vs 0.48 cases/million per year). Mean baseline hemoglobin level was 9.3 g/dL, but 27% had hemoglobin <8 g/dL. Identification of typical features of CAD-associated lymphoproliferative disorder in the bone marrow was greatly increased by centralized biopsy assessment. CAD seems to be associated with a slightly increased risk of venous thrombosis. This work includes a follow-up study of therapies, focusing on the long-term outcomes of the rituximab plus bendamustine and rituximab plus fludarabine regimens. Rituximab plus bendamustine therapy resulted in responses in 35 (78%) of 45 patients; 24 (53%) achieved complete response. Interestingly, these rates were still higher than observed in the original (2017) prospective trial, and we also found a shift toward deeper responses with time. This is explained by the prolonged time to response seen in many patients, probably related to long-lived plasma cells. In patients responding to rituximab-bendamustine, median response duration was not reached after 88 months, and estimated 5-year sustained remission was 77%. The regimen appeared safe regarding late-occurring malignancies. Rituximab plus fludarabine therapy seems to carry a higher risk of long-term adverse effects.

Adamantyl Side Chains as Anti-Aggregating Moieties in Dyes for Dye-Sensitized Solar Cells.

Designing and evaluating novel dye concepts is crucial for the development of the field of dye-sensitized solar cells (DSSCs). In our recent report, the novel concept of tethering the anti-aggregation additive chenodeoxycholic acid (CDCA) to dyes for DSSC was introduced. Based on the performance improvements seen for this modification, the aim of this study is to see if a simplified anti-aggregation unit could achieve similar results. The following study reports the synthesis and photovoltaic characterization of two novel dyes decorated with the steric ethyladamantyl moiety on the π-spacer, and on the triarylamine donor. This modification is demonstrated to be successful in increasing the photovoltages in devices employing copper-based electrolytes compared to the non-modified reference dye. The best photovoltaic performance is achieved by a device prepared with the adamantyl decorated donor dye and CDCA, this device achieves a power conversion efficiency of 6.1 % (Short-circuit current=8.3 mA cm-2 , Open-circuit voltage=1054 mV, Fill factor=0.69). The improved photovoltaic performance seen for the adamantyl decorated donor demonstrate the potential of ethyladamantyl side chains as a tool to ensure surface protection of TiO2 .

Impact of diabetes on clinical outcomes after revascularization with the dual therapy CD34 antibody-covered sirolimus-eluting Combo stent and the sirolimus-eluting Orsiro stent.

OBJECTIVES: To compare the efficacy and safety of the dual therapy CD34 antibody-covered sirolimus-eluting Combo stent (DTS) and the sirolimus-eluting Orsiro stent (SES) in patients with and without diabetes mellitus (DM) included in the Scandinavian Organization for Randomized Trials with Clinical Outcome (SORT OUT) X study. BACKGROUND: The incidence of target lesion failure (TLF) after treatment with modern drug-eluting stents has been reported to be significantly higher in patients with DM when compared to patients without DM. Thus, whether the results from the SORT OUT X study apply to patients with and without DM remains unknown. METHODS: In total 3146 patients were randomized to stent implantation with DTS (n = 1578; DM: n = 279) or SES (n = 1568; DM: n = 271). The primary end point, TLF, was a composite of cardiac death, target-lesion myocardial infarction (MI), or target lesion revascularization (TLR) within 1 year. RESULTS: At 1 year, the rate of TLF was increased in the DTS group compared to the SES group, both among patients with DM (9.3% vs. 4.8%; risk difference: 4.5%; incidence rate ratio: 1.99, 95% confidence interval [CI]: 1.02-3.90) and without DM (5.7% vs. 3.5%; incidence rate ratio: 1.67, 95% CI: 1.15-2.42). The differences were mainly explained by higher rates of TLR. CONCLUSION: Compared to the SES, the DTS was associated with an increased risk of TLF at 12 months in patients with and without DM. The differences were mainly explained by higher rates of TLR, whereas rates of cardiac death and target lesion MI did not differ significantly between the two stent groups in patients with or without DM.

Simulation-based VATS resection of the five lung lobes: a technical skills test.

BACKGROUND: Video-Assisted Thoracoscopic Surgery (VATS) lobectomy is an advanced procedure and to maximize patient safety it is important to ensure the competency of thoracic surgeons before performing the procedure. The objective of this study was to investigate validity evidence for a virtual reality simulator-based test including multiple lobes of the lungs. METHOD: VATS experts from the department of Cardiothoracic Surgery at Rigshospitalet, Copenhagen, Denmark, worked with Surgical Science (Gothenburg, Sweden) to develop VATS lobectomy modules for the LapSim® virtual reality simulator covering all five lobes of the lungs. Participants with varying experience in VATS were recruited and classified as either novice, intermediate, or experienced surgeons. Each participant performed VATS lobectomy on the simulator for three different randomly chosen lobes. Nine predefined simulator metrics were automatically recorded on the simulator. RESULTS: Twenty-two novice, ten intermediate, and nine experienced surgeons performed the test resulting in a total of 123 lobectomies. Analysis of Variances (ANOVA) found significant differences between the three groups for parameters: blood loss (p < 0.001), procedure time (p < 0.001), and total instrument path length (p = 0.03). These three metrics demonstrated high internal consistency and significant test-retest reliability was found between each of them. Relevant pass/fail levels were established for each of the three metrics, 541 ml, 30 min, and 71 m, respectively. CONCLUSION: This study provides validity evidence for a simulator-based test of VATS lobectomy competence including multiple lobes of the lungs. The test can be used to ensure basic competence at the end of a simulation-based training program for thoracic surgery trainees.

Assessing VATS competence based on simulated lobectomies of all five lung lobes.

OBJECTIVES: To determine the number of procedures and expert raters necessary to provide a reliable assessment of competence in Video-Assisted Thoracoscopic Surgery (VATS) lobectomy. METHODS: Three randomly selected VATS lobectomies were performed on a virtual reality simulator by participants with varying experience in VATS. Video recordings of the procedures were independently rated by three blinded VATS experts using a modified VATS lobectomy assessment tool (VATSAT). The unitary framework of validity was used to describe validity evidence, and generalizability theory was used to explore the reliability of different assessment options. RESULTS: Forty-one participants (22 novices, 10 intermediates, and 9 experienced) performed a total of 123 lobectomies. Internal consistency reliability, inter-rater reliability, and test-retest reliability were 0.94, 0.85, and 0.90, respectively. Generalizability theory found that a minimum of two procedures and four raters or three procedures and three raters were needed to ensure the overall reliability of 0.8. ANOVA showed significant differences in test scores between the three groups (P < 0.001). A pass/fail level of 19 out of 25 points was established using the contrasting groups' standard setting method, leaving one false positive (one novice passed) and zero false negatives (all experienced passed). CONCLUSION: We demonstrated validity evidence for a VR simulator test with different lung lobes, and a credible pass/fail level was identified. Our results can be used to implement a standardized mastery learning training program for trainees in VATS lobectomies that ensures that everyone reaches basic competency before performing supervised operations on patients.

Implementation facilitation of the "11 for Health in Denmark": A case study in a Danish 5th grade class.

The "11 for Health in Denmark" concept aims to enhance 10-12-year-old schoolchildren's physical activity levels and health knowledge through an 11-week football intervention and has been shown to induce positive effects in numerous areas. However, little is known about the implementation facilitation of this concept in schools. This case study therefore aims to gain a deeper understanding of the implementation facilitation of "11 for Health" in a Danish 5th grade class comprising 22 schoolchildren (12 boys and 10 girls, Mage 11.86±) and one teacher. Data were derived from multiple school situations using photographs and videos, observations, and informal interviews. Five themes were identified: (1) environmental and organizational factors impacting on the implementation; (2) familiarization with the concept for the teacher and schoolchildren; (3) previous clique formation; (4) the central role of the teacher; and (5) the importance of how praise partners are allocated. We found high adherence to the "11 for Health" concept, in which the teacher played a key role by applying an autonomy-supportive style of teaching and using the praise partner concept in a suitable manner. A clique of football-playing boys was a resource, as their praising of classmates encouraged adherence. However, familiarization with the "11 for Health" concept was a challenge and the clique's competitive nature occasionally built barriers to other schoolchildren without football experience, potentially leading to a more controlled form of motivation. Based on the results, we encourage teachers to apply autonomy-supportive teaching when applying the "11 for Health" concept.

In vitro and in vivo properties of therapeutic oligonucleotides containing non-chiral 3' and 5' thiophosphate linkages.

The introduction of non-bridging phosphorothioate (PS) linkages in oligonucleotides has been instrumental for the development of RNA therapeutics and antisense oligonucleotides. This modification offers significantly increased metabolic stability as well as improved pharmacokinetic properties. However, due to the chiral nature of the phosphorothioate, every PS group doubles the amount of possible stereoisomers. Thus PS oligonucleotides are generally obtained as an inseparable mixture of a multitude of diastereoisomeric compounds. Herein, we describe the introduction of non-chiral 3' thiophosphate linkages into antisense oligonucleotides and report their in vitro as well as in vivo activity. The obtained results are carefully investigated for the individual parameters contributing to antisense activity of 3' and 5' thiophosphate modified oligonucleotides (target binding, RNase H recruitment, nuclease stability). We conclude that nuclease stability is the major challenge for this approach. These results highlight the importance of selecting meaningful in vitro experiments particularly when examining hitherto unexplored chemical modifications.