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Mitochondrial dysfunction is a characteristic trait of human and rodent obesity, insulin resistance and fatty liver disease. Here we show that high-fat diet (HFD) feeding causes mitochondrial fragmentation in inguinal white adipocytes from male mice, leading to reduced oxidative capacity by a process dependent on the small GTPase RalA. RalA expression and activity are increased in white adipocytes after HFD. Targeted deletion of RalA in white adipocytes prevents fragmentation of mitochondria and diminishes HFD-induced weight gain by increasing fatty acid oxidation. Mechanistically, RalA increases fission in adipocytes by reversing the inhibitory Ser637 phosphorylation of the fission protein Drp1, leading to more mitochondrial fragmentation. Adipose tissue expression of the human homolog of Drp1, DNM1L, is positively correlated with obesity and insulin resistance. Thus, chronic activation of RalA plays a key role in repressing energy expenditure in obese adipose tissue by shifting the balance of mitochondrial dynamics toward excessive fission, contributing to weight gain and metabolic dysfunction.

When public services move online, citizens are expected to serve themselves on digital platforms and enrol in public services through self-service procedures. In this digital encounter, many citizens struggle to live up to the “self” in self-services and seek in-person assistance from public professionals. These professional actors play an essential role in enabling the co-production of self-services for citizens who struggle to be truly self-serving. This article explores the frontline workers’ roles in self-service co-production when interacting with citizens seeking help in the service procedures. Service interactions have been studied in two meeting centres of the Norwegian Labor and Welfare Administration. We have conducted observations of office interactions in general and at digital self-service stations in particular. Interviews with public officials have complemented these observations. We use intermediation and co-production theory as analytical lenses in our data analysis. The findings show that the role of frontline workers can be both flexible and narrow in nature and that they take on the role of intermediaries when acting as a bridge between the analogue world and the digital domain. We also see that the intermediating role frontline workers take will vary and is influenced by organisational, personal, and external circumstances that can enable or restrain the co-production of self-services.

Abstract Background For dosimetry, the demand for whole-body SPECT/CT imaging, which require long acquisition durations with dual-head Anger cameras, is increasing. Here we evaluated sparsely acquired projections and assessed whether the addition of deep-learning-generated synthetic intermediate projections (SIPs) could improve the image quality while preserving dosimetric accuracy. Methods This study included 16 patients treated with 177Lu-DOTATATE with SPECT/CT imaging (120 projections, 120P) at four time points. Deep neural networks (CUSIPs) were designed and trained to compile 90 SIPs from 30 acquired projections (30P). The 120P, 30P, and three different CUSIP sets (30P + 90 SIPs) were reconstructed using Monte Carlo-based OSEM reconstruction (yielding 120P_rec, 30P_rec, and CUSIP_recs). The noise levels were visually compared. Quantitative measures of normalised root mean square error, normalised mean absolute error, peak signal-to-noise ratio, and structural similarity were evaluated, and kidney and bone marrow absorbed doses were estimated for each reconstruction set. Results The use of SIPs visually improved noise levels. All quantitative measures demonstrated high similarity between CUSIP sets and 120P. Linear regression showed nearly perfect concordance of the kidney and bone marrow absorbed doses for all reconstruction sets, compared to the doses of 120P_rec (R2 ≥ 0.97). Compared to 120P_rec, the mean relative difference in kidney absorbed dose, for all reconstruction sets, was within 3%. For bone marrow absorbed doses, there was a higher dissipation in relative differences, and CUSIP_recs outperformed 30P_rec in mean relative difference (within 4% compared to 9%). Kidney and bone marrow absorbed doses for 30P_rec were statistically significantly different from those of 120_rec, as opposed to the absorbed doses of the best performing CUSIP_rec, where no statistically significant difference was found. Conclusion When performing SPECT/CT reconstruction, the use of SIPs can substantially reduce acquisition durations in SPECT/CT imaging, enabling acquisition of multiple fields of view of high image quality with satisfactory dosimetric accuracy.

Abstract Background A multidrug-resistant lineage of Staphylococcus epidermidis named ST215 is a common cause of prosthetic joint infections and other deep surgical site infections in Northern Europe, but is not present elsewhere. The increasing resistance among S. epidermidis strains is a global concern. We used whole-genome sequencing to characterize ST215 from healthcare settings. Results We completed the genome of a ST215 isolate from a Swedish hospital using short and long reads, resulting in a circular 2,676,787 bp chromosome and a 2,326 bp plasmid. The new ST215 genome was placed in phylogenetic context using 1,361 finished public S. epidermidis reference genomes. We generated 10 additional short-read ST215 genomes and 11 short-read genomes of ST2, which is another common multidrug-resistant lineage at the same hospital. We studied recombination’s role in the evolution of ST2 and ST215, and found multiple recombination events averaging 30–50 kb. By comparing the results of antimicrobial susceptibility testing for 31 antimicrobial drugs with the genome content encoding antimicrobial resistance in the ST215 and ST2 isolates, we found highly similar resistance traits between the isolates, with 22 resistance genes being shared between all the ST215 and ST2 genomes. The ST215 genome contained 29 genes that were historically identified as virulence genes of S. epidermidis ST2. We established that in the nucleotide sequence stretches identified as recombination events, virulence genes were overrepresented in ST215, while antibiotic resistance genes were overrepresented in ST2. Conclusions This study features the extensive antibiotic resistance and virulence gene content in ST215 genomes. ST215 and ST2 lineages have similarly evolved, acquiring resistance and virulence through genomic recombination. The results highlight the threat of new multidrug-resistant S. epidermidis lineages emerging in healthcare settings.

Public welfare services and their reliable distribution to those in need of them are an important cornerstone of the Nordic welfare states. With the ‘digital-firstʼ paradigm, digital self-services have become the default channel in Norway also for welfare services. However, especially vulnerable citizens struggle to use these digital self-services, thus making it difficult for them to receive the welfare benefits they are dependent on. Instead, vulnerable citizens often turn to the local offices of public organisations to get help. We conducted 19 interviews and 11 observations with citizens coming to a local office of the Norwegian Welfare and Labour Administration (NAV) to understand vulnerable citizensʼ challenges with digital self-services as well as the way these challenges are attended to at the NAV office. We find that citizens struggle, amongst other things, with complex application procedures, language problems, executive functioning, and the anonymity of self-services. At the same time – while citizens often do get the required help at the NAV office – not all the challenges are solved, and new challenges arise, making vulnerable citizens prone to even more severe vulnerability.

Background: Hormone receptor positivity predicts benefit from endocrine therapy but the knowledge about the long-term survival of patients with different tumor receptor levels is limited. In this study, we describe the 25 years outcome of tamoxifen (TAM) treated patients. Patients and methods: Between 1983 and 1992, a total of 4,610 postmenopausal patients with early-stage breast cancer were randomized to receive totally 2 or 5 years of TAM therapy. After 2 years, 4,124 were alive and free of breast cancer recurrence. Among these, 2,481 had demonstrated estrogen receptor positive (ER+) disease. From 1988, the Abbot enzyme immunoassay became available and provided quantitative receptor levels for 1,210 patients, for which our analyses were done. Results: After 5 years of follow-up, when all TAM treatment was finished, until 15 years of follow-up, breast cancer mortality for patients with ER+ disease was significantly reduced in the 5-year group as compared with the 2-year group (hazard ratios [HR] 0.67, 95% confidence intervals [CI] 0.55–0.83, p

IntroductionPatients with clinically node-negative breast cancer have a negative sentinel lymph node status (pN0) in approximately 75% of cases and the necessity of routine surgical nodal staging by sentinel lymph node biopsy (SLNB) has been questioned. Previous prediction models for pN0 have included postoperative variables, thus defeating their purpose to spare patients non-beneficial axillary surgery. We aimed to develop a preoperative prediction model for pN0 and to evaluate the contribution of mammographic breast density and mammogram features derived by artificial intelligence for de-escalation of SLNB.Materials and methodsThis retrospective cohort study included 755 women with primary breast cancer. Mammograms were analyzed by commercially available artificial intelligence and automated systems. The additional predictive value of features was evaluated using logistic regression models including preoperative clinical variables and radiological tumor size. The final model was internally validated using bootstrap and externally validated in a separate cohort. A nomogram for prediction of pN0 was developed. The correlation between pathological tumor size and the preoperative radiological tumor size was calculated.ResultsRadiological tumor size was the strongest predictor of pN0 and included in a preoperative prediction model displaying an area under the curve of 0.68 (95% confidence interval: 0.63–0.72) in internal validation and 0.64 (95% confidence interval: 0.59–0.69) in external validation. Although the addition of mammographic features did not improve discrimination, the prediction model provided a 21% SLNB reduction rate when a false negative rate of 10% was accepted, reflecting the accepted false negative rate of SLNB.ConclusionThis study shows that the preoperatively available radiological tumor size might replace pathological tumor size as a key predictor in a preoperative prediction model for pN0. While the overall performance was not improved by mammographic features, one in five patients could be omitted from axillary surgery by applying the preoperative prediction model for nodal status. The nomogram visualizing the model could support preoperative patient-centered decision-making on the management of the axilla.

Abstract The 9th Cardiovascular Outcome Trial (CVOT) Summit: Congress on Cardiovascular, Kidney, and Metabolic Outcomes was held virtually on November 30-December 1, 2023. This reference congress served as a platform for in-depth discussions and exchange on recently completed outcomes trials including dapagliflozin (DAPA-MI), semaglutide (SELECT and STEP-HFpEF) and bempedoic acid (CLEAR Outcomes), and the advances they represent in reducing the risk of major adverse cardiovascular events (MACE), improving metabolic outcomes, and treating obesity-related heart failure with preserved ejection fraction (HFpEF). A broad audience of endocrinologists, diabetologists, cardiologists, nephrologists and primary care physicians participated in online discussions on guideline updates for the management of cardiovascular disease (CVD) in diabetes, heart failure (HF) and chronic kidney disease (CKD); advances in the management of type 1 diabetes (T1D) and its comorbidities; advances in the management of CKD with SGLT2 inhibitors and non-steroidal mineralocorticoid receptor antagonists (nsMRAs); and advances in the treatment of obesity with GLP-1 and dual GIP/GLP-1 receptor agonists. The association of diabetes and obesity with nonalcoholic steatohepatitis (NASH; metabolic dysfunction-associated steatohepatitis, MASH) and cancer and possible treatments for these complications were also explored. It is generally assumed that treatment of chronic diseases is equally effective for all patients. However, as discussed at the Summit, this assumption may not be true. Therefore, it is important to enroll patients from diverse racial and ethnic groups in clinical trials and to analyze patient-reported outcomes to assess treatment efficacy, and to develop innovative approaches to tailor medications to those who benefit most with minimal side effects. Other keys to a successful management of diabetes and comorbidities, including dementia, entail the use of continuous glucose monitoring (CGM) technology and the implementation of appropriate patient-physician communication strategies. The 10th Cardiovascular Outcome Trial Summit will be held virtually on December 5–6, 2024 ( http://www.cvot.org ).

Estimation of so-called return levels for environmental extremes is of importance for risk assessment. A particular challenge is to find estimates corresponding to long return periods, as uncertainties in the form of confidence intervals became too wide for practical use when applying conventional methodology where large portions of data are not used. A recently proposed technique, the Average Conditional Exceedance Rate (ACER), makes effective use of all available data. For risk analysis related to nuclear infrastructure, usually located along a coastline, extreme sea levels are of concern. We demonstrate, for measurements of the sea level along the Swedish coast at locations close to nuclear power plants, that the methodology results in considerably shorter confidence intervals compared to conventional approaches.

Abstract Background Sarcopenia is associated with multiple adverse outcomes. Traditional methods to determine low muscle mass for the diagnosis of sarcopenia are mainly based on dual‐energy X‐ray absorptiometry (DXA), whole‐body magnetic resonance imaging (MRI) and bioelectrical impedance analysis. These tests are not always available and are rather time consuming and expensive. However, many brain and head diseases require a head MRI. In this study, we aim to provide a more accessible way to detect sarcopenia by comparing the traditional method of DXA lean mass estimation versus the tongue and masseter muscle mass assessed in a standard brain MRI. Methods The H70 study is a longitudinal study of older people living in Gothenburg, Sweden. In this cross‐sectional analysis, from 1203 participants aged 70 years at baseline, we included 495 with clinical data and MRI images available. We used the appendicular lean soft tissue index (ALSTI) in DXA images as our reference measure of lean mass. Images from the masseter and tongue were analysed and segmented using 3D Slicer. For the statistical analysis, the Spearman correlation coefficient was used, and concordance was estimated with the Kappa coefficient. Results The final sample consisted of 495 participants, of which 52.3% were females. We found a significant correlation coefficient between both tongue (0.26) and masseter (0.33) with ALSTI (P

Abstract Background Increased risk of severe tachyarrhythmias is reported in patients with type 2 diabetes mellitus (T2DM). The aim of this study was to explore if treatment with cardiac implantable electronic device (CIED) such as implantable cardioverter defibrillator (ICD), cardiac resynchronization therapy- pacemaker and -defibrillator (CRT-P/CRT-D) differed in patients with vs. without T2DM. A secondary aim was to identify patient characteristics indicating an increased CIED treatment. Method 416 162 adult patients with T2DM from the Swedish National Diabetes Registry and 2 081 087 controls from the Swedish population, matched for age, sex and living area, were included between 1/1/1998 and 31/12/2012 and followed until 31/12/2013. They were compared regarding prevalence of ventricular tachycardia (VT) at baseline and the risk of receiving a CIED during follow-up. Multivariable Cox regression analysis was performed to estimate the risk of CIED-treatment and factors identifying patients with such risk. Results Ventricular fibrillation (VF) (0.1% vs 0.0004%) and (VT) (0.2% vs. 0.1%) were more frequent among patients with T2DM compared to controls. CIED-treatment was significantly increased in patients with T2DM both in unadjusted and adjusted analyses. HR and 95% CI, after adjustment for sex, age, marital status, income, education, country of birth, coronary artery disease and congestive heart failure, were 1.32 [1.21–1.45] for ICD, 1.74 [1.55–1.95] for CRT-P and 1.69 [1.43–1.99] for CRT-D. Blood-pressure and lipid lowering therapies were independent risk factors associated to receiving CIED, while female sex was protective. Conclusions Although the proportion of VT/VF was low, patients with T2DM had a higher prevalence of these conditions and increased risk for treatment with CIED compared to controls. This underlines the importance of recognizing that T2DM patients have an increased need of CIED.

Abstract Background Surgical sentinel lymph node biopsy (SLNB) is routinely used to reliably stage axillary lymph nodes in early breast cancer (BC). However, SLNB may be associated with postoperative arm morbidities. For most patients with BC undergoing SLNB, the findings are benign, and the procedure is currently questioned. A decision-support tool for the prediction of benign sentinel lymph nodes based on preoperatively available data has been developed using artificial neural network modelling. Methods This was a retrospective geographical and temporal validation study of the noninvasive lymph node staging (NILS) model, based on preoperatively available data from 586 women consecutively diagnosed with primary BC at two sites. Ten preoperative clinicopathological characteristics from each patient were entered into the web-based calculator, and the probability of benign lymph nodes was predicted. The performance of the NILS model was assessed in terms of discrimination with the area under the receiver operating characteristic curve (AUC) and calibration, that is, comparison of the observed and predicted event rates of benign axillary nodal status (N0) using calibration slope and intercept. The primary endpoint was axillary nodal status (discrimination, benign [N0] vs. metastatic axillary nodal status [N+]) determined by the NILS model compared to nodal status by definitive pathology. Results The mean age of the women in the cohort was 65 years, and most of them (93%) had luminal cancers. Approximately three-fourths of the patients had no metastases in SLNB (N0 74% and 73%, respectively). The AUC for the predicted probabilities for the whole cohort was 0.6741 (95% confidence interval: 0.6255–0.7227). More than one in four patients (n = 151, 26%) were identified as candidates for SLNB omission when applying the predefined cut-off for lymph node-negative status from the development cohort. The NILS model showed the best calibration in patients with a predicted high probability of healthy axilla. Conclusion The performance of the NILS model was satisfactory. In approximately every fourth patient, SLNB could potentially be omitted. Considering the shift from postoperatively to preoperatively available predictors in this validation study, we have demonstrated the robustness of the NILS model. The clinical usability of the web interface will be evaluated before its clinical implementation. Trial registration Registered in the ISRCTN registry with study ID ISRCTN14341750. Date of registration 23/11/2018.

Abstract Background Females are generally less prone to cardiovascular (CV) events than males, but this protection is trumped by diabetes. The mechanism behind the increased relative risk in females with diabetes is not fully understood. Insulin resistance (IR) is suggested to be a more important contributor to CV morbidity in females than in males. We aim to investigate differences in the association between IR indexes (Homeostatic Model Assessment of IR - HOMA-IR, visceral adiposity index – VAI, and triglycerides/high-density lipoprotein-cholesterol - TG/HDL-C index), and a first non-fatal myocardial infarction (MI) across different glycaemic states. Methods IR indexes were calculated in a population with (n = 696) and without (n = 707) a first non-fatal MI, free from known diabetes. MI cases were investigated at least six weeks after the event. All participants were categorized by an oral glucose tolerance test as having normal glucose tolerance, impaired fasting glucose, impaired glucose tolerance, or newly diagnosed diabetes. Comparison of proportion of glycaemic states by sex was tested by chi-square test. The associations between sex, a first non-fatal MI, IR indexes, and traditional CV risk factors were analysed by multivariate logistic regression models. Continuous variables were logarithmically transformed. Results Of the total population 19% were females and 81% males, out of whom 47% and 50% had a first non-fatal MI, respectively. Compared with males, females were older, less often smokers, with lower body mass index and higher total cholesterol and high-density lipoprotein cholesterol levels. The proportion of glycaemic states did not differ between the sexes (p = 0.06). Females were less insulin resistant than males, especially among cases and with normal glucose tolerance. In logistic regression models adjusted for major CV risk factors including sex, the associations between VAI and TG/HDL-C index and a first non-fatal MI remained significant only in females (odds ratios and 95% confidence intervals: 1.7, 1.0-2.9, and 1.9, 1.1–3.4 respectively). Conclusions These results support the assumption that IR indexes based on anthropometrics and lipid panel, i.e., VAI and TG/HDL-C, could be a better measure of IR and CV-predictor for non-fatal MI in females, even without glycaemic perturbations.

Abstract Background The Otsu method and the Chan–Vese model are two methods proven to perform well in determining volumes of different organs and specific tissue fractions. This study aimed to compare the performance of the two methods regarding segmentation of active thyroid gland volumes, reflecting different clinical settings by varying the parameters: gland size, gland activity concentration, background activity concentration and gland activity concentration heterogeneity. Methods A computed tomography was performed on three playdough thyroid phantoms with volumes 20, 35 and 50 ml. The image data were separated into playdough and water based on Hounsfield values. Sixty single photon emission computed tomography (SPECT) projections were simulated by Monte Carlo method with isotope Technetium-99 m ( $$^{\text {99m}}$$ 99m Tc). Linear combinations of SPECT images were made, generating 12 different combinations of volume and background: each with both homogeneous thyroid activity concentration and three hotspots of different relative activity concentrations (48 SPECT images in total). The relative background levels chosen were 5 %, 10 %, 15 % and 20 % of the phantom activity concentration and the hotspot activities were 100 % (homogeneous case) 150 %, 200 % and 250 %. Poisson noise, (coefficient of variation of 0.8 at a 20 % background level, scattering excluded), was added before reconstruction was done with the Monte Carlo-based SPECT reconstruction algorithm Sahlgrenska Academy reconstruction code (SARec). Two different segmentation algorithms were applied: Otsu’s threshold selection method and an adaptation of the Chan–Vese model for active contours without edges; the results were evaluated concerning relative volume, mean absolute error and standard deviation per thyroid volume, as well as dice similarity coefficient. Results Both methods segment the images well and deviate similarly from the true volumes. They seem to slightly overestimate small volumes and underestimate large ones. Different background levels affect the two methods similarly as well. However, the Chan–Vese model deviates less and paired t-testing showed significant difference between distributions of dice similarity coefficients (p-value $$

Although there is a large body of research about emotional labour in workplace settings, such as the health professions and the service industry, less is known about the empirical processes through which emotional labour is taught in higher education and professional education. Using medical education as an example, a discursive psychological (DP) approach is used in this paper to detail how the feeling rules of the physician's profession are constructed by students and tutors in fiction, film, and poetry seminars. From a data set of 36 video- and audio-recorded fiction seminars from two medical schools, 29 sequences of discussions about emotional challenges for physicians were found. These examples have been transcribed in detail and analysed using DP. Analysis shows that students and tutors construct feeling rules as fluid, negotiable and changeable. Feeling rules are defined as the calibration of emotion to suit different situations as well as different physicians with different levels of emotionality. Students deploy constructions of feeling rules to manage student identities, and students and tutors construct emotion as a separation between subjective experience and observable behaviours, where the subject-side experience should be managed or controlled in the way it manifests externally.