Search

To accurately capture the dynamic behavior of small nanoparticles in scanning transmission electron microscopy, high-quality data and advanced data processing is needed. The fast scan rate required to observe structural dynamics inherently leads to very noisy data where machine learning tools are essential for unbiased analysis. In this study, we develop a workflow based on two U-Net architectures to automatically localize and classify atomic columns at particle-support interfaces. The model is trained on non-physical image simulations, achieves sub-pixel localization precision, high classification accuracy, and generalizes well to experimental data. We test our model on both in situ and ex situ experimental time series recorded at 5 frames per second of small Pt nanoparticles supported on CeO2(111). The processed movies show sub-second dynamics of the nanoparticles and reveal site-specific movement patterns of individual atomic columns. [ABSTRACT FROM AUTHOR]

The four cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators, ivacaftor, lumacaftor, tezacaftor, and elexacaftor, have revolutionised the treatment of CF by direct action on the protein target behind the disease's development. The aim was to develop and validate a quantification method for these CFTR modulators in plasma and breast milk to better understand inter-patient variability in pharmacokinetics and treatment outcome, including the risk of adverse drug reactions. The ability to monitor CFTR modulators in breast milk enables the estimation of the exposure of breastfed infant, with a potential concern for CFTR modulator-induced liver injury. The analysis was performed on a Thermo Vanquish Flex Binary UHPLC system coupled to a high-resolution mass spectrometer (HRMS), Thermo Q Exactive. The analytes were detected using positive electrospray ionisation in full scan mode. After sample preparation by protein precipitation, the supernatant was injected onto the LC system and the analytes were separated using a Zorbax SB-C18 Rapid Res HPLC column (3.5 µm, 4.6 × 75 mm). This is the first published method for CFTR modulators in breast milk. The validated quantification range for ivacaftor is 0.0050–10 µg/mL with a coefficient of variation < 6% and a mean accuracy of 97–106%; for lumacaftor, tezacaftor, and elexacaftor, the validated quantification range is 0.050–100 µg/mL with a coefficient of variation < 8% and a mean accuracy 93–106%. A simple and sensitive quantification method for CFTR modulators has been developed and used for routine analysis of human plasma and breast milk samples since 2022. [ABSTRACT FROM AUTHOR]

Inflammation, corticosteroids, and loading all affect tendon healing, with an interaction between them. However, underlying mechanisms behind the effect of corticosteroids and the interaction with loading remain unclear. The aim of this study was to investigate the role of dexamethasone during tendon healing, including specific effects on tendon cells. Rats (n = 36) were randomized to heavy loading or mild loading, the Achilles tendon was transected, and animals were treated with dexamethasone or saline. Gene and protein analyses of the healing tendon were performed for extracellular matrix-, inflammation-, and tendon cell markers. We further tested specific effects of dexamethasone on tendon cells in vitro. Dexamethasone increased mRNA levels of S100A4 and decreased levels of ACTA2/α-SMA, irrespective of load level. Heavy loading + dexamethasone reduced mRNA levels of FN1 and TenC (p < 0.05), while resolution-related genes were unaltered (p > 0.05). In contrast, mild loading + dexamethasone increased mRNA levels of resolution-related genes ANXA1, MRC1, PDPN, and PTGES (p < 0.03). Altered protein levels were confirmed in tendons with mild loading. Dexamethasone treatment in vitro prevented tendon construct formation, increased mRNA levels of S100A4 and decreased levels of SCX and collagens. Dexamethasone during tendon healing appears to act through immunomodulation by promoting resolution, but also through an effect on tendon cells. [ABSTRACT FROM AUTHOR]

Introduction: Continuous glucose monitoring (CGM) introduces novel indicators of glycemic control. Methods: This cross-sectional study, based on the Swedish National Diabetes Register, examines 27,980 adults with type 1 diabetes. It explores the relationships between HbA1c (glycated hemoglobin) and various CGM-derived metrics, including TIR (time in range, representing the percentage of time within the range of 4–10 mmol/l for 2 weeks), TAR (time above range), TBR (time below range), mean glucose, standard deviation (SD), and coefficient of variation (CV). Pearson correlation coefficients and linear regression models were utilized for estimation. Results: The analysis included 46% women, 30% on insulin pump, 7% with previous coronary heart disease and 64% with retinopathy. Mean ± SD values were age 48 ± 18 years, diabetes duration 25 ± 16 years, HbA1c 58.8 ± 12.8 mmol/mol, TIR 58.8 ± 19.0%, TAR 36.3 ± 20.0%, TBR 4.7 ± 5.4%, mean sensor glucose 9.2 ± 2.0 mmol/l, SD 3.3 ± 1.0 mmol/l, and CV 36 ± 7%. The overall association between HbA1c and TIR was − 0.71 (Pearson's r), with R2 0.51 in crude linear regression and 0.57 in an adjusted model. R2 values between HbA1c and CGM mean glucose were 0.605 (unadjusted) 0.619 (adjusted) and TAR (unadjusted 0.554 and fully adjusted 0.568, respectively), while fully adjusted R2 values were 0.458, 0.175 and 0.101 between HbA1c and CGM SD, CGM CV and TBR, respectively. Conclusions: This descriptive study demonstrates that the degree of association between HbA1c and new and readily available CGM-derived metrics, i.e., time in range (TIR), time above range (TAR), and CGM mean glucose, is robust in assessing the management of individuals with type 1 diabetes in clinical settings. Metrics from CGM that pertain to variability and hypoglycemia exhibit only weak correlations with HbA1c. [ABSTRACT FROM AUTHOR]

According to guidelines, total ischemic time for homografts at processing must be kept short to avoid degeneration. Many homografts are discarded due to practical inability to finish all steps from procurement to cryopreservation within the time limit. Although, several studies have shown that homografts with prolonged ischemic time show adequate quality and performance. Twenty aortic and 12 pulmonary homografts were collected and biopsies were retrieved at preparation (day 0) and after 1, 2, 3, 4, 7, 14, 21, 28, and 60 days in antibiotic decontamination at 4 °C. Biopsies were prepared for light microscopy (LM) and transmission electron microscopy (TEM). Assessment generated scores for cells, elastin, and collagen. Relative differences between times were compared with Wilcoxon signed rank test. Bonferroni corrected p value of 0.0056 was considered significant. LM could only reveal decrease in cell count at 60 days in aortic homografts, no other differences was detected. TEM showed affected cell appearance in day 3 and day 4 and beyond for aortic and pulmonary homografts respectively. Elastin appearance was affected at day 60 for aortic and day 21 for pulmonary homografts. Collagen appearance was affected at day 28 for aortic homografts, with no significant differences in pulmonary homografts. Cell degeneration starts early after homograft procurement, but elastic and collagen fibers are more resistant to degeneration. Overall structure integrity as seen in LM was not affected at all, while TEM could reveal small degeneration signs in individual elastic fibers and collagen bundles at 21 and 28 days respectively. [ABSTRACT FROM AUTHOR]

Premature death in diabetes is increasingly caused by cancer. The objectives were to estimate the excess mortality when individuals with type 2 diabetes(T2D) were diagnosed with cancer, and to examine the impact of modifiable diabetes-related risk factors. This longitudinal nationwide cohort study included individuals with T2D registered in the Swedish National Diabetes Register between 1998–2019. Poisson models were used to estimate mortality as a function of time-updated risk-factors, adjusted for sex, age, diabetes duration, marital status, country of birth, BMI, blood pressure, lipids, albuminuria, smoking, and physical activity. We included 690,539 individuals with T2D and during 4,787,326 person-years of follow-up 179,627 individuals died. Overall, the all-cause mortality rate ratio was 3.75 [95%confidence interval(CI):3.69–3.81] for individuals with T2D and cancer compared to those remaining free of cancer. The most marked risk factors associated to mortality among individuals with T2D and cancer were low physical activity, 1.59 (1.57–1.61) and smoking, 2.15 (2.08–2.22), whereas HbA1c, lipids, hypertension, and BMI had no/weak associations with survival. In a future with more patients with comorbid T2D and cancer diagnoses, these results suggest that smoking and physical activity might be the two most salient modifiable risk factors for mortality in people with type 2 diabetes and cancer. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: This register-based study aimed to describe autoimmune comorbidity in children and young adults from type 1 diabetes onset, and to investigate whether such comorbidity was associated with a difference in HbA1c or mortality risk compared with children/young adults with type 1 diabetes without autoimmune comorbidity. Methods: A total of 15,188 individuals from the Swedish National Diabetes Register, registered with type 1 diabetes before 18 years of age between 2000 and 2019, were included. Five randomly selected control individuals from the Swedish population (Statistics Sweden) were matched to each individual with type 1 diabetes (n=74,210 [346 individuals with type 1 diabetes were not found in the Statistics Sweden register at the date of type 1 diabetes diagnosis, so could not be matched to control individuals]). The National Patient Register was used to attain ICD-10 codes on autoimmune diseases and the Cause of Death Register was used to identify deceased individuals. Results: In the total type 1 diabetes cohort, mean±SD age at onset of type 1 diabetes was 9.5±4.4 years and mean disease duration at end of follow-up was 8.8±5.7 years. Of the individuals with type 1 diabetes, 19.2% were diagnosed with at least one autoimmune disease vs 4.0% of the control group. The HRs for comorbidities within 19 years from onset of type 1 diabetes were 11.6 (95% CI 10.6, 12.6) for coeliac disease, 10.6 (95% CI 9.6, 11.8) for thyroid disease, 1.3 (95% CI 1.1, 1.6) for psoriasis, 4.1 (95% CI 3.2, 5.3) for vitiligo, 1.7 (95% CI 1.4, 2.2) for rheumatic joint disease, 1.0 (95% CI 0.8, 1.3) for inflammatory bowel disease, 1.0 (95% CI 0.7, 1.2) for systemic connective tissue disorder, 1.4 (95% CI 1.1, 1.9) for uveitis, 18.3 (95% CI 8.4, 40.0) for Addison's disease, 1.8 (95% CI 0.9, 3.6) for multiple sclerosis, 3.7 (95% CI 1.6, 8.7) for inflammatory liver disease and 19.6 (95% CI 4.2, 92.3) for atrophic gastritis. Autoimmune disease in addition to type 1 diabetes had no statistically significant effect on HbA1c or mortality risk. Conclusions/interpretation: To our knowledge, this is the first comprehensive study where young individuals with type 1 diabetes were followed regarding development of a wide spectrum of autoimmune diseases, from onset of type 1 diabetes. In this nationwide and population-based study, there was already a high prevalence of autoimmune diseases in childhood, especially coeliac and thyroid disease. The presence of autoimmune comorbidity did not have a statistically significant effect on metabolic control or mortality risk. [ABSTRACT FROM AUTHOR]

This study on technology education in preschool aims to explore how technology activities in preschool are enacted and what knowledge, related to the five dimensions of the nature of technology, is made possible for the children to learn when intersubjectivity is established in the interaction between the participants. The empirical data encompass three video-documented technology activities, involving five children and one preschool teacher. Drawing on the five dimensions of the nature of technology by DiGironimo, the participants' interactions were analysed using interaction analysis. The results showed that the teacher, through well-defined and sensitive orchestration, enacted goal-oriented activities by allowing a play-oriented approach, and that intersubjectivity on technology was established related to four of the five dimensions of technology. The lack of knowledge related to the historical dimension of technology suggests further scrutiny and is discussed as essential in ECE technology education for contemporary children, growing up in high-tech societies. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Roux-en-Y gastric bypass surgery (RYGB) frequently results in remission of type 2 diabetes as well as exaggerated secretion of glucagon-like peptide-1 (GLP-1). Here, we assessed RYGB-induced transcriptomic alterations in the small intestine and investigated how they were related to the regulation of GLP-1 production and secretion in vitro and in vivo. Methods: Human jejunal samples taken perisurgically and 1 year post RYGB (n=13) were analysed by RNA-seq. Guided by bioinformatics analysis we targeted four genes involved in cholesterol biosynthesis, which we confirmed to be expressed in human L cells, for potential involvement in GLP-1 regulation using siRNAs in GLUTag and STC-1 cells. Gene expression analyses, GLP-1 secretion measurements, intracellular calcium imaging and RNA-seq were performed in vitro. OGTTs were performed in C57BL/6j and iScd1−/− mice and immunohistochemistry and gene expression analyses were performed ex vivo. Results: Gene Ontology (GO) analysis identified cholesterol biosynthesis as being most affected by RYGB. Silencing or chemical inhibition of stearoyl-CoA desaturase 1 (SCD1), a key enzyme in the synthesis of monounsaturated fatty acids, was found to reduce Gcg expression and secretion of GLP-1 by GLUTag and STC-1 cells. Scd1 knockdown also reduced intracellular Ca2+ signalling and membrane depolarisation. Furthermore, Scd1 mRNA expression was found to be regulated by NEFAs but not glucose. RNA-seq of SCD1 inhibitor-treated GLUTag cells identified altered expression of genes implicated in ATP generation and glycolysis. Finally, gene expression and immunohistochemical analysis of the jejunum of the intestine-specific Scd1 knockout mouse model, iScd1−/−, revealed a twofold higher L cell density and a twofold increase in Gcg mRNA expression. Conclusions/interpretation: RYGB caused robust alterations in the jejunal transcriptome, with genes involved in cholesterol biosynthesis being most affected. Our data highlight SCD as an RYGB-regulated L cell constituent that regulates the production and secretion of GLP-1. [ABSTRACT FROM AUTHOR]

Sphingosine-1-phosphate (S1P) is a phosphosphingolipid with pleiotropic biological functions. S1P acts as an intracellular second messenger, as well as extracellular ligand to five G-protein coupled receptors (S1PR1-5). In the brain, S1P regulates neuronal proliferation, apoptosis, synaptic activity and neuroglia activation. Moreover, S1P metabolism alterations have been reported in neurodegenerative disorders. We have previously reported that S1PRs are present in nerve terminals, exhibiting distinct sub-synaptic localization and neuromodulation actions. Since type 2 diabetes (T2D) causes synaptic dysfunction, we hypothesized that S1P signaling is modified in nerve terminals. In this study, we determined the density of S1PRs in cortical synaptosomes from insulin-resistant Goto-Kakizaki (GK) rats and Wistar controls, and from mice fed a high-fat diet (HFD) and low-fat-fed controls. Relative to their controls, GK rats showed similar cortical S1P concentration despite higher S1P levels in plasma, yet lower density of S1PR1, S1PR2 and S1PR4 in nerve-terminal-enriched membranes. HFD-fed mice exhibited increased plasma and cortical concentrations of S1P, and decreased density of S1PR1 and S1PR4. These findings point towards altered S1P signaling in synapses of insulin resistance and diet-induced obesity models, suggesting a role of S1P signaling in T2D-associated synaptic dysfunction. [ABSTRACT FROM AUTHOR]

The study aimed to identify the most predictive factors for the development of type 2 diabetes. Using an XGboost classification model, we projected type 2 diabetes incidence over a 10-year horizon. We deliberately minimized the selection of baseline factors to fully exploit the rich dataset from the UK Biobank. The predictive value of features was assessed using shap values, with model performance evaluated via Receiver Operating Characteristic Area Under the Curve, sensitivity, and specificity. Data from the UK Biobank, encompassing a vast population with comprehensive demographic and health data, was employed. The study enrolled 450,000 participants aged 40–69, excluding those with pre-existing diabetes. Among 448,277 participants, 12,148 developed type 2 diabetes within a decade. HbA1c emerged as the foremost predictor, followed by BMI, waist circumference, blood glucose, family history of diabetes, gamma-glutamyl transferase, waist-hip ratio, HDL cholesterol, age, and urate. Our XGboost model achieved a Receiver Operating Characteristic Area Under the Curve of 0.9 for 10-year type 2 diabetes prediction, with a reduced 10-feature model achieving 0.88. Easily measurable biological factors surpassed traditional risk factors like diet, physical activity, and socioeconomic status in predicting type 2 diabetes. Furthermore, high prediction accuracy could be maintained using just the top 10 biological factors, with additional ones offering marginal improvements. These findings underscore the significance of biological markers in type 2 diabetes prediction. [ABSTRACT FROM AUTHOR]

Epigenetic dysregulation may influence disease progression. Here we explore whether epigenetic alterations in human pancreatic islets impact insulin secretion and type 2 diabetes (T2D). In islets, 5,584 DNA methylation sites exhibit alterations in T2D cases versus controls and are associated with HbA1c in individuals not diagnosed with T2D. T2D-associated methylation changes are found in enhancers and regions bound by β-cell-specific transcription factors and associated with reduced expression of e.g. CABLES1, FOXP1, GABRA2, GLR1A, RHOT1, and TBC1D4. We find RHOT1 (MIRO1) to be a key regulator of insulin secretion in human islets. Rhot1-deficiency in β-cells leads to reduced insulin secretion, ATP/ADP ratio, mitochondrial mass, Ca2+, and respiration. Regulators of mitochondrial dynamics and metabolites, including L-proline, glycine, GABA, and carnitines, are altered in Rhot1-deficient β-cells. Islets from diabetic GK rats present Rhot1-deficiency. Finally, RHOT1methylation in blood is associated with future T2D. Together, individuals with T2D exhibit epigenetic alterations linked to mitochondrial dysfunction in pancreatic islets. Type 2 diabetes (T2D) is characterized by hyperglycemia caused by insufficient insulin release from pancreatic islets, often in combination with insulin resistance. Here the authors present an epigenetic case-control study in human pancreatic islets revealing changes that contribute to type 2 diabetes development, e.g., epigenetic downregulation of RHOT1. [ABSTRACT FROM AUTHOR]

Introduction: A post hoc analysis of the PIONEER 1–5 and 8 trials assessed the clinically relevant composite endpoints of HbA1c (glycated haemoglobin) reduction ≥ 1% and body weight loss of ≥ 5% or ≥ 10% with orally administered semaglutide versus comparators. Methods: In the PIONEER trials, people with type 2 diabetes were randomised to orally administered semaglutide versus placebo (PIONEER 1, 4, 5 and 8), empagliflozin (PIONEER 2), sitagliptin (PIONEER 3) and liraglutide (PIONEER 4) for 26–78 weeks. This analysis assessed the proportion of people achieving an HbA1c reduction of ≥ 1% and body weight loss of ≥ 5% at week 26 and at end of treatment, and the proportion of people achieving an HbA1c reduction of ≥ 1% and body weight loss of ≥ 10% at end of treatment. Results: Overall, 3506 people in PIONEER 1–5 and 8 were included. At week 26 and at end of treatment, odds of achieving the composite endpoint of an HbA1c reduction of ≥ 1% and body weight loss of ≥ 5% were significantly greater with orally administered semaglutide 14 mg than with placebo (PIONEER 1, 4, 5 and 8; all p < 0.0001), empagliflozin 25 mg (PIONEER 2, p < 0.0001), sitagliptin 100 mg (PIONEER 3, p < 0.0001) and liraglutide 1.8 mg (PIONEER 4, p < 0.0001). Odds of achieving the composite endpoint of HbA1c reduction of ≥ 1% and body weight loss of ≥ 10% at end of treatment were also significantly greater with orally administered semaglutide versus comparators. Conclusion: In PIONEER 1–5 and 8, odds of achieving clinically relevant reductions in both HbA1c and body weight were significantly greater with orally administered semaglutide versus comparators. [ABSTRACT FROM AUTHOR]

Technology education in early childhood education (ECE) has only recently been established internationally as a curriculum content area. The interdisciplinary character of technology education and its status as a field under development occasion a need to distinguish and define technology in the merging of disciplines. This literature review presents an overview of technology education in ECE in recent empirical studies. The literature review was carried out systematically, resulting in 23 studies that were scrutinised to present an overall picture regarding study design, findings and how technology is characterised. The analysis of the nature of technology in the reviewed studies builds on DiGironimo's (Int J Sci Education, 33(10):1337–1352. https://doi.org/10.1080/09500693.2010.495400, 2011) conceptual framework, representing five distinct but merging dimensions of an ever-changing human technological creation process. In the synthesised findings, four subthemes derived from the studies' overall themes were identified: two focusing on preschool teachers and pre-service teachers, and two focusing on technology activities with children. The aligned outcomes are discussed concerning the conceptual dimensions of technology, along with possibilities, challenges and implications for the current field of research on technology education in ECE. [ABSTRACT FROM AUTHOR]

The aim of this study was to measure and model the fuel consumption of cut-to-length (CTL) logging machinery in cutting and forwarding under Nordic harvesting conditions, and to clarify which factors had the greatest effect on the fuel consumption. In addition, the total annual fuel consumption and CO2eq emissions were calculated for CTL logging operations in Finland in 2020. The data were collected during a long-term follow-up study on the fuel consumption of harvesters and forwarders conducted between March 2018 and April 2019. The fuel consumption data were obtained from a total of 16 harvesters and 13 forwarders equipped with digital flow metres featuring an accuracy of ± 1% of the fuel volume measured. The engine power of the forest machines explained most of the hour-based fuel consumption. Correspondingly, the harvesting conditions of the forest stand best explained the cubic-metre-based fuel consumption. The fuel consumption of CTL logging operations (cutting and forwarding) averaged 1.4 L m−3 in final felling, and 3.1 and 2.2 L m−3 in first and later thinning, respectively. There was a large variation in the cubic-metre-based fuel consumption between individual machines, both for harvesters and forwarders. The total calculated fuel consumption in Finnish CTL operations in 2020 was 126.6 million L, with the calculated CO2eq emissions totalling 334,209 t (i.e. 5.7 kg m−3). Several measures to accelerate fuel and energy efficiency and reduce CO2eq emissions in CTL logging operations are discussed in the paper. [ABSTRACT FROM AUTHOR]

Purpose: Suboptimal adherence to adjuvant endocrine treatment (AET) is an important clinical concern. A correlation between CYP2D6 activity and tamoxifen discontinuation has been described. The main aim of this study was to investigate the consistency between pharmacy dispensation data and medical records on adherence to AET. Methods: Adherence was calculated for patients with at least 4.5 years of follow up and was defined as Medical Possession Rate ≥ 80%. Subgroup analyses were performed based on menopausal status, recurrence risk and CYP2D6 activity. Results: In 86% of the 1235 included patients the consistency between the two sources of information was within 80–125%. Poor consistency, < 80%, was most frequent in the premenopausal/ high-risk group and CYP2D6 Poor Metabolizers (PMs). Among 899 patients with at least 4.5 years follow up, 72% were adherent to tamoxifen based on pharmacy dispensation data, compared with 77% as reported by medical records. When including patients who switched to aromatase inhibitors after tamoxifen, adherence increased to 82% and 88%, respectively. Adherence did not differ by menopausal status or risk for recurrence. CYP2D6 PMs had poorer adherence (54%) to tamoxifen compared to patients with the highest CYP2D6 activity (83%). Conclusions: There was a good consistency between medical records and pharmacy dispensing data on the use of AET. Adherence to AET was adequate, especially when including switch to aromatase inhibitors. Surprisingly, CYP2D6 PMs had low adherence to tamoxifen, despite a likely reduced risk of side effects according to previous data. [ABSTRACT FROM AUTHOR]

The association between type 2 diabetes (T2D) and the development of cardiac arrhythmias and conduction disturbances has not been extensively studied. Arrhythmia was defined as atrial fibrillation and flutter (AF/AFl), ventricular tachycardia (VT) and ventricular fibrillation (VF), and conduction abnormality as sinus node disease (SND), atrioventricular (AV) block or pacemaker implantation, and intraventricular conduction blocks (IVCB). Incidence rates and Cox regression were used to compare outcomes, and to assess optimal levels for cardiometabolic risk factors and risk associated with multifactorial risk factor control (i.e., HbA1c, LDL-C, systolic blood pressure (SBP), BMI and eGFR), between patients with versus without T2D. The analyses included data from 617,000 patients with T2D and 2,303,391 matched controls. Patients with diabetes and the general population demonstrated a gradual increase in rates for cardiac conduction abnormalities and virtually all age-groups for AF/AFI showed increased incidence during follow-up. For patients with versus without T2D, risks for cardiac arrhythmias were higher, including for AF/AFl (HR 1.17, 95% CI 1.16–1.18), the composite of SND, AV-block or pacemaker implantation (HR 1.40, 95% CI 1.37–1.43), IVCB (HR 1.23, 95% CI 1.18–1.28) and VT/VF (HR 1.08, 95% CI 1.04–1.13). For patients with T2D who had selected cardiometabolic risk factors within target ranges, compared with controls, risk of arrythmia and conduction abnormalities for T2D vs not were: AF/AFl (HR 1.09, 95% CI 1.05–1.14), the composite of SND, AV-block or pacemaker implantation (HR 1.06, 95% CI 0.94–1.18), IVCB (HR 0.80, 95% CI 0.60–0.98), and for VT/VF (HR 0.97, 95% CI 0.80–1.17). Cox models showed a linear risk increase for SBP and BMI, while eGFR showed a U-shaped association. Individuals with T2D had a higher risk of arrhythmias and conduction abnormalities than controls, but excess risk associated with T2D was virtually not evident among patients with T2D with all risk factors within target range. BMI, SBP and eGFR displayed significant associations with outcomes among patients with T2D. [ABSTRACT FROM AUTHOR]

High power lasers have become useful scientific tools, but their large size is determined by their low damage-threshold optical media. A more robust and compact medium for amplifying and manipulating intense laser pulses is plasma. Here we demonstrate, experimentally and through simulations, that few-millijoule, ultra-short seed pulses interacting with 3.5-J counter-propagating pump pulses in plasma, stimulate back-scattering of nearly 100 mJ pump energy with high intrinsic efficiency, when detuned from Raman resonance. This is due to scattering off a plasma Bragg grating formed by ballistically evolving ions. Electrons are bunched by the ponderomotive force of the beat-wave, which produces space-charge fields that impart phase correlated momenta to ions. They inertially evolve into a volume Bragg grating that backscatters a segment of the pump pulse. This, ultra-compact, two-step, inertial bunching mechanism can be used to manipulate and compress intense laser pulses. We also observe stimulated Compton (kinetic) and Raman backscattering. High power short pulse lasers are technologically reaching a limit in term of amplification due to the material damage threshold of amplifying media. The authors conduct experiments and numerical simulations to show the possibility of benefiting from transient plasma structures generated from counter propagating pump and seed pulses to amplify high power lasers. [ABSTRACT FROM AUTHOR]

Severe infections are life-threatening conditions commonly seen in the intensive care units (ICUs). Antibiotic treatment with adequate concentrations is of great importance during the first days when the bacterial load is the highest. Therapeutic drug monitoring (TDM) of β-lactam antibiotics has been suggested to monitor target attainment and to improve the outcome. This prospective multi-center study in seven ICUs in Sweden investigated pharmacokinetic/pharmacodynamic-target (PK/PD-target) attainment for cefotaxime, piperacillin-tazobactam and meropenem, commonly used β-lactams in Sweden. A mid-dose and trough antibiotic concentration blood sample were taken from patients with severe infection daily during the first 72 h of treatment. Antibiotic plasma concentrations were analysed by liquid chromatography-mass spectrometry (LC–MS). Antibiotic concentrations 100% time above MIC (minimal inhibitory concentration), (100% T > MIC) and four times above MIC 50% of the time (50% T > 4xMIC) were used as PK/PD-targets. We included 138 patients with the median age of 67 years and the median Simplified Acute Physiology Score 3 (SAPS3) of 59. Forty-five percent of the study-population failed to reach 100% T > MIC during the first day of treatment. The results were similar the following two days. There was a three-fold risk of not meeting the PK/PD target if the patient was treated with cefotaxime. For the cefotaxime treated patients 8 out of 55 (15%) had at least one end-dose concentrations below the level of detection during the study. Low age, low illness severity, low plasma creatinine, lower respiratory tract infection and cefotaxime treatment were risk factors for not reaching 100% T > MIC. In Swedish ICU-patients treated with β-lactam antibiotics, a high proportion of patients did not reach the PK/PD target. TDM could identify patients that need individual higher dosing regimens already on the first day of treatment. Further studies on optimal empirical start dosing of β-lactams, especially for cefotaxime, in the ICU are needed. Trial registration: The protocol was retrospectively registered 100216 (ACTRN12616000167460). [ABSTRACT FROM AUTHOR]

This study explores features of food system transformations towards sustainability in the Farm to Fork Strategy in relation to perspectives of Swedish food system practitioners. Transformations towards sustainable food systems are essential to achieve the United Nations' 2030 Agenda and the need for more sustainable food systems has been recognised in the European Green Deal and its Farm to Fork Strategy. The Swedish ambition to act as a global leader in achieving the 2030 Agenda and the European Commission's aspiration for Europe to lead global food system transformations offer a critical opportunity to study transformational processes and agents of change in a high-income region with externalised environmental and sustainability impacts. Drawing on theories of complex systems transformations, this study identifies features of food system transformations, exploring places to intervene and examines the roles, responsibilities, and agency related to these changes. The results of this study provide three main conclusions highlighting (i) alignment of high-level policy and the perspectives of national practitioners at the paradigm level, especially concerning how food is valued, which is a crucial first step for transformational processes to come about (ii) a lack of clarity as well as diversity of pathways to transform food systems although common objectives are expressed, and (iii) governance mechanisms as enablers for a diversity of transformations. Moreover, these processes must acknowledge the contextual and complex nature of food systems and the level of agency and power of actors. [ABSTRACT FROM AUTHOR]

Type 1 diabetes is a chronic autoimmune disease requiring insulin treatment for survival. Prolonged duration of type 1 diabetes is associated with increased risk of microvascular complications. Although chronic hyperglycemia and diabetes duration have been considered as the major risk factors for vascular complications, this is not universally seen among all patients. Persons with long-term type 1 diabetes who have remained largely free from vascular complications constitute an ideal group for investigation of natural defense mechanisms against prolonged exposure of diabetes. Transcriptomic signatures obtained from RNA sequencing of the peripheral blood cells were analyzed in non-progressors with more than 30 years of diabetes duration and compared to the patients who progressed to microvascular complications within a shorter duration of diabetes. Analyses revealed that non-progressors demonstrated a reduction in expression of the oxidative phosphorylation (OXPHOS) genes, which were positively correlated with the expression of DNA repair enzymes, namely genes involved in base excision repair (BER) machinery. Reduced expression of OXPHOS and BER genes was linked to decrease in expression of inflammation-related genes, higher glucose disposal rate and reduced measures of hepatic fatty liver. Results from the present study indicate that at transcriptomic level reduction in OXPHOS, DNA repair and inflammation-related genes is linked to better insulin sensitivity and protection against microvascular complications in persons with long-term type 1 diabetes. [ABSTRACT FROM AUTHOR]

G protein-coupled receptors (GPCRs) enable cells to sense environmental cues and are indispensable for coordinating vital processes including quorum sensing, proliferation, and sexual reproduction. GPCRs comprise the largest class of cell surface receptors in eukaryotes, and for more than three decades the pheromone-induced mating pathway in baker's yeast Saccharomyces cerevisiae has served as a model for studying heterologous GPCRs (hGPCRs). Here we report transcriptome profiles following mating pathway activation in native and hGPCR-signaling yeast and use a model-guided approach to correlate gene expression to morphological changes. From this we demonstrate mating between haploid cells armed with hGPCRs and endogenous biosynthesis of their cognate ligands. Furthermore, we devise a ligand-free screening strategy for hGPCR compatibility with the yeast mating pathway and enable hGPCR-signaling in the probiotic yeast Saccharomyces boulardii. Combined, our findings enable new means to study mating, hGPCR-signaling, and cell-cell communication in a model eukaryote and yeast probiotics. G protein-coupled receptors (GPCRs) enable cells to sense environmental cues and are indispensable for coordinating vital processes including quorum sensing, proliferation, and sexual reproduction. Here the authors, using heterologous GPCR expression and endogenous ligand production, enable synthetic mating in haploid yeast, and GPCR-mediated biosensing in diploid probiotic yeast. [ABSTRACT FROM AUTHOR]

This narrative review describes a new approach to navigation in a challenging landscape of clinical drug development in diabetes. Successful outcome studies in recent years have led to new indications and guidelines in type 2 diabetes, yet the number of clinical trials in diabetes is now declining. This is due to many environmental factors acting in concert, including the prioritisation of funding for other diseases, high costs of large randomised clinical trials, increase in regulatory requirements and limited entry of novel candidate drugs. There is a need for novel and cost-effective paradigms of clinical development to meet these and other challenges. The concept of registry-based randomised clinical trials (RRCTs) is an attractive option. In this review we focus on type 2 diabetes and the prevention of cardiovascular and microvascular comorbidities and mortality, using the Swedish SMARTEST trial as an example of an RRCT. We also give some examples from other disease areas. The RRCT concept is a novel, cost-effective and scientifically sound approach for conducting large-scale diabetes trials in a real-world setting. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the effects of weight loss treatment on physical fitness in patients with psoriatic arthritis (PsA) and obesity compared to matched controls. Methods: In total, 46 patients with PsA (CASPAR) and BMI ≥ 33 kg/m2 and 52 obese persons were included in this 12-month prospective open intervention study with a very low energy diet (640 kcal/day), followed by structured reintroduction of an energy-restricted diet and brief support for physical activity. The primary outcome was muscle strength assessed with hand-grip strength (Grippit) and leg muscle strength (timed stand test). Secondary outcomes were cardiorespiratory fitness, body composition, and physical functioning (SF-36PCS). Outcomes were assessed at baseline, 6 (M6), and 12 months (M12). Nonparametric statistics were used. Results: Median weight reduction at M6 was 18.9 kg in patients and 23.0 kg in controls, (p = 0.546). At M12, patients' median weight loss from baseline was 16.1 kg, corresponding with significant loss of total fat mass (− 30.1%), and lean mass (total − 7.0%, arm − 13.7%, and leg − 6.0%). Leg muscle strength improved in patients and controls at M6 (p < 0.001) and remained improved at M12 (p < 0.01), while hand-grip strength was unchanged in both groups. Cardiorespiratory fitness increased in controls at M6 (p = 0.018) and M12 (p = 0.028) but not in patients. Physical functioning improved in both groups at M6 (p < 0.001) and remained improved at M12 (p = 0.008) and (p < 0.01), respectively. Conclusion: The intervention resulted in positive effects on body weight and total body fat. Despite reduced lean body mass, the muscle strength did not deteriorate in patients with PsA and controls. Trial registration : ClinicalTrials.gov identifier: NCT02917434, registered on September 21, 2016-retrospectively registered. Key Points • Patients with PsA and obesity can benefit from weight loss treatment without the risk of deterioration in muscle strength and cardiorespiratory fitness. • Muscle strength and cardiorespiratory fitness were below suggested normative values for the majority of the patients at all time points, implying that more structured exercise strategies might be warranted to counteract physical fitness deficiencies in patients with PsA undergoing weight loss treatment. [ABSTRACT FROM AUTHOR]

Glucose-induced insulin secretion depends on β-cell electrical activity. Inhibition of ATP-regulated potassium (KATP) channels is a key event in this process. However, KATP channel closure alone is not sufficient to induce β-cell electrical activity; activation of a depolarizing membrane current is also required. Here we examine the role of the mechanosensor ion channel PIEZO1 in this process. Yoda1, a specific PIEZO1 agonist, activates a small membrane current and thereby triggers β-cell electrical activity with resultant stimulation of Ca2+-influx and insulin secretion. Conversely, the PIEZO1 antagonist GsMTx4 reduces glucose-induced Ca2+-signaling, electrical activity and insulin secretion. Yet, PIEZO1 expression is elevated in islets from human donors with type-2 diabetes (T2D) and a rodent T2D model (db/db mouse), in which insulin secretion is reduced. This paradox is resolved by our finding that PIEZO1 translocates from the plasmalemma into the nucleus (where it cannot influence the membrane potential of the β-cell) under experimental conditions emulating T2D (high glucose culture). β-cell-specific Piezo1-knockout mice show impaired glucose tolerance in vivo and reduced glucose-induced insulin secretion, β-cell electrical activity and Ca2+ elevation in vitro. These results implicate mechanotransduction and activation of PIEZO1, via intracellular accumulation of glucose metabolites, as an important physiological regulator of insulin secretion. Insulin secretion depends on action potential firing in pancreatic islet beta-cells, but the underlying mechanism is unclear. Here, the authors show that activation of the mechanosensor ion channel PIEZO1 plays a central role in beta-cell electrical activity and insulin release. [ABSTRACT FROM AUTHOR]

Although the increased risk of complications of type 2 diabetes (T2D) is well known, there is still little information about the long-term development of comorbidities in relation to risk factors. The purpose of the present study was to describe the risk trajectories of T2D complications over time in an observational cohort of newly diagnosed T2D patients, as well as to evaluate the effect of common risk factors on the development of comorbidities. This national cohort study investigated individuals with T2D in the Swedish National Diabetes Register regarding prevalence of comorbidities at the time of diagnosis, and the incidence of cardiovascular disease (CVD), chronic kidney disease (CKD) and heart failure in the entire patient cohort and stratified by HbA1c levels and age at baseline. Multivariable Cox regressions were used to evaluate risk factors predicting outcomes. We included 100,878 individuals newly diagnosed with T2D between 1998 and 2012 in the study, with mean 5.5 years follow-up (max 17 years). The mean age at diagnosis was 62.6 ± SD12.5 years and 42.7% of the patients were women. Prevalent CVD was reported for 17.5% at baseline. Although the prevalence of comorbidities was generally low for individuals 50 years or younger at diagnosis, the cumulative incidence of the investigated comorbidities increased over time. Newly diagnosed CVD was the most common comorbidity. Women were shown to have a lower risk of developing comorbid conditions than men. When following the risk trajectory of comorbidities over a period of up to 15 years in individuals with type 2 diabetes, we found that all comorbidities gradually increased over time. There was no distinct time point when onset suddenly increased. [ABSTRACT FROM AUTHOR]

The sequence of events for secreting insulin in response to glucose in pancreatic β-cells is termed "stimulus-secretion coupling". The core of stimulus-secretion coupling is a process which generates electrical activity in response to glucose uptake and causes Ca2+ oscillation for triggering exocytosis of insulin-containing secretory granules. Prior to exocytosis, the secretory granules are mobilized and docked to the plasma membrane and primed for fusion with the plasma membrane. Together with the final fusion with the plasma membrane, these steps are named the exocytosis process of insulin secretion. The steps involved in the exocytosis process are crucial for insulin release from β-cells and considered indispensable for glucose homeostasis. We recently confirmed a signature of defective exocytosis process in human islets and β-cells of obese donors with type 2 diabetes (T2D). Furthermore, cyclic AMP (cAMP) potentiates glucose-stimulated insulin secretion through mechanisms including accelerating the exocytosis process. In this mini-review, we aimed to organize essential knowledge of the secretory granule exocytosis and its amplification by cAMP. Then, we suggest the fatty acid translocase CD36 as a predisposition in β-cells for causing defective exocytosis, which is considered a pathogenesis of T2D in relation to obesity. Finally, we propose potential therapeutics of the defective exocytosis based on a CD36-neutralizing antibody and on Apolipoprotein A-I (ApoA-I), for improving β-cell function in T2D. [ABSTRACT FROM AUTHOR]

Passenger origin–destination data is an important input for public transport planning. In recent years, new data sources have become increasingly common through the use of the automatic collection of entry counts, exit counts and link flows. However, collecting such data can be sometimes costly. The value of additional data collection hence has to be weighed against its costs. We study the value of additional data for estimating time-dependent origin–destination matrices, using a case study from the London Piccadilly underground line. Our focus is on how the precision of the estimated matrix increases when additional data on link flow, destination count and/or average travel distance is added, starting from origin counts only. We concentrate on the precision of the most policy-relevant estimation outputs, namely, link flows and station exit flows. Our results suggest that link flows are harder to estimate than exit flows, and only using entry and exit data is far from enough to estimate link flows with any precision. Information about the average trip distance adds greatly to the estimation precision. The marginal value of additional destination counts decreases only slowly, so a relatively large number of exit station measurement points seem warranted. Link flow data for a subset of links hardly add to the precision, especially if other data have already been added. [ABSTRACT FROM AUTHOR]

Identification of biomarkers associated with protection from developing diabetic complications is a prerequisite for an effective prevention and treatment. The aim of the present study was to identify clinical and plasma metabolite markers associated with freedom from vascular complications in people with very long duration of type 1 diabetes (T1D). Individuals with T1D, who despite having longer than 30 years of diabetes duration never developed major macro- or microvascular complications (non-progressors; NP) were compared with those who developed vascular complications within 25 years from diabetes onset (rapid progressors; RP) in the Scandinavian PROLONG (n = 385) and DIALONG (n = 71) cohorts. The DIALONG study also included 75 healthy controls. Plasma metabolites were measured using gas and/or liquid chromatography coupled to mass spectrometry. Lower hepatic fatty liver indices were significant common feature characterized NPs in both studies. Higher insulin sensitivity and residual ß-cell function (C-peptide) were also associated with NPs in PROLONG. Protection from diabetic complications was associated with lower levels of the glycolytic metabolite pyruvate and APOCIII in PROLONG, and with lower levels of thiamine monophosphate and erythritol, a cofactor and intermediate product in the pentose phosphate pathway as well as higher phenylalanine, glycine and serine in DIALONG. Furthermore, T1D individuals showed elevated levels of picolinic acid as compared to the healthy individuals. The present findings suggest a potential beneficial shunting of glycolytic substrates towards the pentose phosphate and one carbon metabolism pathways to promote nucleotide biosynthesis in the liver. These processes might be linked to higher insulin sensitivity and lower liver fat content, and might represent a mechanism for protection from vascular complications in individuals with long-term T1D. [ABSTRACT FROM AUTHOR]

Purpose: Change in mammographic density has been suggested to be a proxy of tamoxifen response. We investigated the effect of additional adjuvant systemic therapy and CYP2D6 activity on MD change in a cohort of tamoxifen-treated pre- and postmenopausal breast cancer patients. Methods: Swedish breast cancer patients (n = 699) operated 2006–2014, genotyped for CYP2D6, having at least three months postoperative tamoxifen treatment, a baseline, and at least one follow-up digital mammogram were included in the study. Other systemic adjuvant treatment included chemotherapy, goserelin, and aromatase inhibitors. Change in MD, dense area, was assessed using the automated STRATUS method. Patients were stratified on baseline characteristics, treatments, and CYP2D6 activity (poor, intermediate, extensive, and ultrarapid). Relative density change was calculated at year 1, 2, and 5 during follow-up in relation to treatments and CYP2D6 activity. Results: Mean relative DA decreased under the follow-up period, with a more pronounced MD reduction in premenopausal patients. No significant effect of chemotherapy, aromatase inhibitors, goserelin, or CYP2D6 activity on DA change was found. DA did not revert to baseline levels after tamoxifen discontinuation. Conclusion: Our results indicate that other systemic adjuvant therapy does not further reduce MD in tamoxifen-treated breast cancer patients. We could not confirm the previously suggested association between CYP2D6 activity and MD reduction in a clinical setting with multimodality adjuvant treatment. No rebound effect on MD decline after tamoxifen discontinuation was evident. [ABSTRACT FROM AUTHOR]

Stimulated Brillouin scattering experiments in the ionospheric plasma using a single electromagnetic pump wave have previously been observed to generate an electromagnetic sideband wave, emitted by the plasma, together with an ion- acoustic wave. Here we report results of a controlled, pump and probe beat-wave driven Brillouin scattering experiment, in which an ion-acoustic wave generated by the beating of electromagnetic pump and probe waves, results in electromagnetic sideband waves that are recorded on the ground. The experiment used the EISCAT facility in northern Norway, which has several high power electromagnetic wave transmitters and receivers in the radio frequency range. An electromagnetic pump consisting of large amplitude radio waves with ordinary (O) or extraordinary (X) mode polarization was injected into the overhead ionosphere, along with a less powerful probe wave, and radio sideband emissions observed on the ground clearly show stimulated Brillouin emissions at frequencies agreeing with, and changing with, the pump and probe frequencies. The experiment was simulated using a numerical full-scale model which clearly supports the interpretation of the experimental results. Such controlled beat-wave experiments demonstrate a way of remotely investigating the ionospheric plasma parameters. Nonlinear wave mixing has been explored in space plasma. Here the authors report beat-wave Brillouin scattering experiment at EISCAT, in which two radio waves at different transmitted frequencies are driving ion acoustic waves in the ionosphere, leading to stimulated Brillouin emissions escaping the plasma. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Tables reporting life expectancies by common risk factors are available for individuals with type 2 diabetes; however, there is currently no published equivalent for individuals with type 1 diabetes. We aimed to develop a life expectancy table using a recently published simulation model for individuals with type 1 diabetes. Methods: The simulation model was developed using data from a real-world population of patients with type 1 diabetes selected from the Swedish National Diabetes Register. The following six important risk factors were included in the life table: sex; age; current smoking status; BMI; eGFR; and HbA1c. For each of 1024 cells in the life expectancy table, a synthetic cohort containing 1000 individuals was created, with other risk factors assigned values representative of the real-world population. The simulations were executed for all synthetic cohorts and life expectancy for each cell was calculated as mean survival time of the individuals in the respective cohort. Results: There was a substantial variation in life expectancy across patients with different risk factor levels. Life expectancy of 20-year-old men varied from 29.3 years to 50.6 years, constituting a gap of 21.3 years between those with worst and best risk factor levels. In 20-year-old women, this gap was 18.9 years (life expectancy range 35.0–53.9 years). The variation in life expectancy was a function of the combination of risk factor values, with HbA1c and eGFR consistently showing a negative and positive correlation, respectively, with life expectancy at any level combination of other risk factors. Individuals with the lowest level (20 kg/m2) and highest level of BMI (35 kg/m2) had a lower life expectancy compared with those with a BMI of 25 kg/m2. Non-smokers and women had a higher life expectancy than smokers and men, respectively, with the difference in life expectancy ranging from 0.4 years to 2.7 years between non-smokers and smokers, and from 1.9 years to 5.9 years between women and men, depending on levels of other risk factors. Conclusions/interpretation: The life expectancy table generated in this study shows a substantial variation in life expectancy across individuals with different modifiable risk factors. The table allows for rapid communications of risk in an easily understood format between healthcare professionals, health economists, researchers, policy makers and patients. Particularly, it supports clinicians in their discussion with patients about the benefits of improving risk factors. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Concerns have been raised regarding a potential association of use of the incretin-based drugs dipeptidyl peptidase 4 (DPP4) inhibitors and glucagon-like peptide-1 (GLP-1)-receptor agonists with risk of cholangiocarcinoma. We examined this association in nationwide data from three countries. Methods: We used data from nationwide registers in Sweden, Denmark and Norway, 2007–2018, to conduct two cohort studies, one for DPP4 inhibitors and one for GLP-1-receptor agonists, to investigate the risk of incident cholangiocarcinoma compared with an active-comparator drug class (sulfonylureas). The cohorts included patients initiating treatment episodes with DPP4 inhibitors vs sulfonylureas, and GLP-1-receptor agonists vs sulfonylureas. We used Cox regression models, adjusted for potential confounders, to estimate hazard ratios from day 366 after treatment initiation to account for cancer latency. Results: The main analyses of DPP4 inhibitors included 1,414,144 person-years of follow-up from 222,577 patients receiving DPP4 inhibitors (median [IQR] follow-up time, 4.5 [2.6–7.0] years) and 123,908 patients receiving sulfonylureas (median [IQR] follow-up time, 5.1 [2.9–7.8] years) during which 350 cholangiocarcinoma events occurred. Use of DPP4 inhibitors, compared with sulfonylureas, was not associated with a statistically significant increase in risk of cholangiocarcinoma (incidence rate 26 vs 23 per 100,000 person-years; adjusted HR, 1.15 [95% CI 0.90, 1.46]; absolute rate difference 3 [95% CI -3, 10] events per 100,000 person-years). The main analyses of GLP-1-receptor agonists included 1,036,587 person-years of follow-up from 96,813 patients receiving GLP-1-receptor agonists (median [IQR] follow-up time, 4.4 [2.4–6.9] years) and 142,578 patients receiving sulfonylureas (median [IQR] follow-up time, 5.5 [3.2–8.1] years) during which 249 cholangiocarcinoma events occurred. Use of GLP-1-receptor agonists was not associated with a statistically significant increase in risk of cholangiocarcinoma (incidence rate 26 vs 23 per 100,000 person-years; adjusted HR, 1.25 [95% CI 0.89, 1.76]; absolute rate difference 3 [95% CI -5, 13] events per 100,000 patient-years). Conclusions/interpretation: In this analysis using nationwide data from three countries, use of DPP4 inhibitors and GLP-1-receptor agonists, compared with sulfonylureas, was not associated with a significantly increased risk of cholangiocarcinoma. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Research using data-driven cluster analysis has proposed five novel subgroups of diabetes based on six measured variables in individuals with newly diagnosed diabetes. Our aim was (1) to validate the existence of differing clusters within type 2 diabetes, and (2) to compare the cluster method with an alternative strategy based on traditional methods to predict diabetes outcomes. Methods: We used data from the Swedish National Diabetes Register and included 114,231 individuals with newly diagnosed type 2 diabetes. k-means clustering was used to identify clusters based on nine continuous variables (age at diagnosis, HbA1c, BMI, systolic and diastolic BP, LDL- and HDL-cholesterol, triacylglycerol and eGFR). The elbow method was used to determine the optimal number of clusters and Cox regression models were used to evaluate mortality risk and risk of CVD events. The prediction models were compared using concordance statistics. Results: The elbow plot, with values of k ranging from 1 to 10, showed a smooth curve without any clear cut-off points, making the optimal value of k unclear. The appearance of the plot was very similar to the elbow plot made from a simulated dataset consisting only of one cluster. In prediction models for mortality, concordance was 0.63 (95% CI 0.63, 0.64) for two clusters, 0.66 (95% CI 0.65, 0.66) for four clusters, 0.77 (95% CI 0.76, 0.77) for the ordinary Cox model and 0.78 (95% CI 0.77, 0.78) for the Cox model with smoothing splines. In prediction models for CVD events, the concordance was 0.64 (95% CI 0.63, 0.65) for two clusters, 0.66 (95% CI 0.65, 0.67) for four clusters, 0.77 (95% CI 0.77, 0.78) for the ordinary Cox model and 0.78 (95% CI 0.77, 0.78) for the Cox model with splines for all variables. Conclusions/interpretation: This nationwide observational study found no evidence supporting the existence of a specific number of distinct clusters within type 2 diabetes. The results from this study suggest that a prediction model approach using simple clinical features to predict risk of diabetes complications would be more useful than a cluster sub-stratification. [ABSTRACT FROM AUTHOR]

Introduction: Lipid-lowering therapy (LLT) reduces the risk of cardiovascular disease (CVD) in patients with type 1 diabetes (T1D). However, socioeconomic factors and gender may have an impact on the adherence to and non-persistence with LLT. Methods: This was a nationwide register-based cohort study that included 6192 individuals with T1D aged ≥ 18 years who were registered in the Swedish National Diabetes Register and had initiated novel use of LLT. Information on socioeconomic parameters (source: Statistics Sweden) and comorbidity (source: National Patient Register) was collected. The individuals were followed for 36 months, and adherence to LLT was analyzed according to age, socioeconomics and gender. The medication possession ratio (MPR; categorized into ≤ 80% and > 80%) and non-persistence (discontinuation) with medication was calculated after 18 and 36 months. Results: Individuals older than 53 years were more adherent to LLT (MPR > 80%) than those younger than 36 years (odds ratio [(OR] 1.30, p < 0.0001) at 36 months. Women were more adherent and less prone to discontinue LLT at 18 months (OR 1.05, p = 0.0005 and OR 0.95, p = 0.0004, respectively), but not at 36 months. Divorced individuals were less adherent than married ones (OR 0.93, p = 0.0005) and discontinued LLT more often than the latter (OR 1.06, p = 0.003). Education had no impact on adherence, but individuals with higher incomes discontinued LLT less frequently than those with lower incomes. Individuals with a country of origin other than Sweden discontinued LLT more often. Conclusion: Lower adherence to LLT in individuals with T1D was associated with male gender, younger age, marital status and country of birth. These factors should be considered when evaluating adherence to LLT in clinical practice, with the aim to help patients achieve full cardioprotective treatment. [ABSTRACT FROM AUTHOR]

The study of metabolomics has improved our knowledge of the biology behind type 2 diabetes and its related metabolic physiology. We aimed to investigate markers of adipose tissue morphology, as well as insulin and glucose metabolism in 53 non-obese male individuals. The participants underwent extensive clinical, biochemical and magnetic resonance imaging phenotyping, and we also investigated non-targeted serum metabolites. We used a multi-modal machine learning approach to evaluate which serum metabolomic compounds predicted markers of glucose and insulin metabolism, adipose tissue morphology and distribution. Fasting glucose was associated with metabolites of intracellular insulin action and beta-cell dysfunction, namely cysteine-s-sulphate and n-acetylgarginine, whereas fasting insulin was predicted by myristoleoylcarnitine, propionylcarnitine and other metabolites of beta-oxidation of fatty acids. OGTT-glucose levels at 30 min were predicted by 7-Hoca, a microbiota derived metabolite, as well as eugenol, a fatty acid. Both insulin clamp and HOMA-IR were predicted by metabolites involved in beta-oxidation of fatty acids and biodegradation of triacylglycerol, namely tartrate and 3-phosphoglycerate, as well as pyruvate, xanthine and liver fat. OGTT glucose area under curve (AUC) and OGTT insulin AUC, was associated with bile acid metabolites, subcutaneous adipocyte cell size, liver fat and fatty chain acids and derivates, such as isovalerylcarnitine. Finally, subcutaneous adipocyte size was associated with long chain fatty acids, markers of sphingolipid metabolism, increasing liver fat and dopamine-sulfate 1. Ectopic liver fat was predicted by methylmalonate, adipocyte cell size, glutathione derived metabolites and fatty chain acids. Ectopic heart fat was predicted visceral fat, gamma-glutamyl tyrosine and 2-acetamidophenol sulfate. Adipocyte cell size, age, alpha-tocopherol and blood pressure were associated with visceral fat. We identified several biomarkers associated with adipose tissue pathophysiology and insulin and glucose metabolism using a multi-modal machine learning approach. Our approach demonstrated the relative importance of serum metabolites and they outperformed traditional clinical and biochemical variables for most endpoints. [ABSTRACT FROM AUTHOR]

Achilles tendons are mechanosensitive, and their complex hierarchical structure is in part the result of the mechanical stimulation conveyed by the muscles. To fully understand how their microstructure responds to mechanical loading a non-invasive approach for 3D high resolution imaging suitable for soft tissue is required. Here we propose a protocol that can capture the complex 3D organization of the Achilles tendon microstructure, using phase-contrast enhanced synchrotron micro-tomography (SR-PhC-μCT). We investigate the effects that sample preparation and imaging conditions have on the resulting image quality, by considering four types of sample preparations and two imaging setups (sub-micrometric and micrometric final pixel sizes). The image quality is assessed using four quantitative parameters. The results show that for studying tendon collagen fibers, conventional invasive sample preparations such as fixation and embedding are not necessary or advantageous. Instead, fresh frozen samples result in high-quality images that capture the complex 3D organization of tendon fibers in conditions as close as possible to natural. The comprehensive nature of this innovative study by SR-PhC-μCT breaks ground for future studies of soft complex biological tissue in 3D with high resolution in close to natural conditions, which could be further used for in situ characterization of how soft tissue responds to mechanical stimuli on a microscopic level. [ABSTRACT FROM AUTHOR]

Experimental studies of multiple shock wave interaction to study transition from regular to irregular reflection rely on the processing of a large amount of schlieren photographs. Here we present an automated algorithm to track individual shock fronts and triple points. First, correction to any optical distortions is applied to the photographs. Next, noise removal and edge detection algorithms are implemented to extract the pixel locations of the shocks. The edge detection algorithm takes advantage of the light intensity feature of the shock waves to distinguish shock fronts from background noise. This algorithm is also capable of separating entangled shock fronts through pattern recognition, which utilizes a discretization method to reduce complex shock geometries to localized linear patterns. Collectively, the algorithms can track shock wave characteristics to sub-pixel precision. This algorithm has been deployed for post processing of shock wave experiments to extract shock wave characteristics including positions and propagation velocities of shock fronts, vertical and horizontal velocities of Mach stems, and triple point trajectories during shock-shock interactions. Results show that the algorithm can process large volumes of data with minimal manual operations, making image processing more precise, efficient and productive while allowing for tracking of Mach stems and triple points. [ABSTRACT FROM AUTHOR]

In countries where headache services exist at all, their focus is usually on specialist (tertiary) care. This is clinically and economically inappropriate: most headache disorders can effectively and more efficiently (and at lower cost) be treated in educationally supported primary care. At the same time, compartmentalizing divisions between primary, secondary and tertiary care in many health-care systems create multiple inefficiencies, confronting patients attempting to navigate these levels (the "patient journey") with perplexing obstacles. High demand for headache care, estimated here in a needs-assessment exercise, is the biggest of the challenges to reform. It is also the principal reason why reform is necessary. The structured headache services model presented here by experts from all world regions on behalf of the Global Campaign against Headache is the suggested health-care solution to headache. It develops and refines previous proposals, responding to the challenge of high demand by basing headache services in primary care, with two supporting arguments. First, only primary care can deliver headache services equitably to the large numbers of people needing it. Second, with educational supports, they can do so effectively to most of these people. The model calls for vertical integration between care levels (primary, secondary and tertiary), and protection of the more advanced levels for the minority of patients who need them. At the same time, it is amenable to horizontal integration with other care services. It is adaptable according to the broader national or regional health services in which headache services should be embedded. It is, according to evidence and argument presented, an efficient and cost-effective model, but these are claims to be tested in formal economic analyses. [ABSTRACT FROM AUTHOR]

Purpose: Severely fractured sleep is mostly portrayed negatively, but investigations in extreme sports show that humans can maintain performance with a minimum of sleep. With two cases of long-lasting extreme sports performances, we demonstrate that severely fragmented sleep does not necessarily lead to a deterioration of physical and cognitive performance. Methods: We performed continuous polysomnography on a 34 year-old skier for 11 days and nights during a world record attempt in long-term downhill skiing and monitored a 32 year-old cyclist during the Race Across America for 8.5 days via sleep and activity logs. Results: The skier slept fractured fashion in 15–16 naps with a daily average of 6 h consisting of 77% in sleep stage 1 and 2, 11% in stage 3, and 13% in stage REM. The cyclist slept a total of 7 h and 52 min in 8.5 days, split up into 11 short naps and 6 sleep periods. The average duration of napping was 8.8 min and of sleep 64.2 min. Conclusions: These two cases demonstrate that outstanding performances are possible with severely fractured sleep and/or sleep deprivation. In well-trained athletes, breaking new recordsis possible despite extreme sleep habits. [ABSTRACT FROM AUTHOR]