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Neuromodulation is present throughout the nervous system and serves a critical role for circuit function and dynamics. The computational investigations of neuromodulation in large scale networks require supportive software platforms. Snudda is a software for the creation and simulation of large scale networks of detailed microcircuits consisting of multicompartmental neuron models. We have developed an extension to Snudda to incorporate neuromodulation in large scale simulations. The extended Snudda framework implements neuromodulation at the level of single cells incorporated into large-scale microcircuits. We also developed Neuromodcell, a software for optimizing neuromodulation in detailed multicompartmental neuron models. The software adds parameters within the models modulating the conductances of ion channels and ionotropic receptors. Bath application of neuromodulators is simulated and models which reproduce the experimentally measured effects are selected. In Snudda, we developed an extension to accommodate large scale simulations of neuromodulation. The simulator has two modes of simulation – denoted replay and adaptive. In the replay mode, transient levels of neuromodulators can be defined as a time-varying function which modulates the receptors and ion channels within the network in a cell-type specific manner. In the adaptive mode, spiking neuromodulatory neurons are connected via integrative modulating mechanisms to ion channels and receptors. Both modes of simulating neuromodulation allow for simultaneous modulation by several neuromodulators that can interact dynamically with each other. Here, we used the Neuromodcell software to simulate dopaminergic and muscarinic modulation of neurons from the striatum. We also demonstrate how to simulate different neuromodulatory states with dopamine and acetylcholine using Snudda. All software is freely available on Github, including tutorials on Neuromodcell and Snudda-neuromodulation.

Abstract Background It is well established that drinking alcohol raises the risk of liver cancer (hepatocellular carcinoma). However, it has not been sufficiently established as to whether or not drinking cessation subsequently reduces the risk of liver cancer and if it does reduce the risk how long it takes for this heightened risk to fall to that of never drinkers. This question is important for effective policy design and evaluation, to establish causality and for motivational treatments. Methods A systematic review and meta-analysis using the current available evidence and a specific form of Generalised Least Squares is performed to assess how the risk of liver cancer changes with time for former drinkers. Results Four studies are found to have quantified the effect of drinking cessation on the risk of liver cancer. The meta-analysis suggests that the risk of liver cancer does indeed fall after cessation by 6-7% a year, but there remains a large uncertainty around this estimate both statistically and in its interpretation. As an illustration it is estimated that a time period of 23 years is required after drinking cessation, with a correspondingly large 95% confidence interval of 14 to 70 years, for the risk of liver cancer to be equal to that of never drinkers. Conclusion This is a relatively under researched area and this is reflected in the uncertainty of the findings. It is our view that it is not possible to extrapolate the results found here to the general population. Too few studies have addressed this question and of the studies that have, all have significant limitations. The key issue amongst the relevant studies is that it appears that current drinkers, abstainers and former drinkers are not composed of, or effectively adjusted to be, similar populations making inferences about risk changes impossible. This is a very difficult area to study effectively, but it is an important topic. More work is required to reduce both statistical uncertainty and tackle the various study limitations this paper highlights and until this is done, the current result should be considered preliminary.

Abstract Background Health inequality and its social determinants are well-studied, but the determinants of inequality of alcohol consumption are less well-investigated. Methods The total differential approach of decomposition of changes in the concentration index of the probability of participation in alcohol consumption was applied to 8-year longitudinal data for Swedish women aged 28-76 in 1988/89. Results Alcohol consumption showed a pro-rich inequality, with income being a strong contributor. Overall participation remained fairly constant, but the inequality decreased over time as abstinence became less common among the poor and more common among the rich. This was mainly due to changes in the relative weights of certain population groups, such as a decrease in the proportional size of the oldest cohorts. Conclusions Inequality in participation in alcohol consumption is pro-rich in Sweden. This inequality has tended to decrease over time, due to changes in population composition rather than to policy intervention.

Abstract Background Studies have found a positive effect of low/moderate alcohol consumption on wages. This has often been explained by referring to epidemiological research showing that alcohol has protective effects on certain diseases, i.e., the health link is normally justified using selected epidemiological information. Few papers have tested this link between alcohol and health explicitly, including all diseases where alcohol has been shown to have either a protective or a detrimental effect. Aim Based on the full epidemiological information, we study the effect of low alcohol consumption on health, in order to determine if it is reasonable to explain the positive effect of low consumption on wages using the epidemiological literature. Methods We apply a non-econometrical cost-of-illness approach to calculate the medical care cost and episodes attributable to low alcohol consumption. Results Low alcohol consumption carries a net cost for medical care and there is a net benefit only for the oldest age group (80+). Low alcohol consumption also causes more episodes in medical care then what is saved, although inpatient care for women and older men show savings. Conclusion Using health as an explanation in the alcohol-wage literature appears invalid when applying the full epidemiological information instead of selected information.

Background: The GOLD trial demonstrated that continuous glucose monitoring (CGM) in people with type 1 diabetes (T1D) managed with multiple daily insulin injections (MDI) improved not only glucose control but also overall well-being and treatment satisfaction. This analysis investigated which factors contributed to improved well-being and treatment satisfaction with CGM., Methods: The GOLD trial was a randomized crossover trial comparing CGM versus self-monitored blood glucose (SMBG) over 16 months. Endpoints included well-being measured by the World Health Organization-Five Well-Being Index (WHO-5) and treatment satisfaction by the Diabetes Treatment Satisfaction Questionnaire (DTSQ) as well as glucose metrics. Multivariable R 2 -decomposition was used to understand which variables contributed most to treatment satisfaction., Results: A total of 139 participants were included. Multivariable analyses revealed that increased convenience and flexibility contributed to 60% (95% confidence interval [CI] = 50%-69%) of the improvement in treatment satisfaction (Diabetes Treatment Satisfaction Questionnaire change version [DTSQ c ]) observed with CGM, whereas perceived effects on hypoglycemia and hyperglycemia only contributed to 6% (95% CI = 2%-11%) of improvements. Significant improvements in well-being (WHO-5) by CGM were observed for the following: feeling cheerful ( P = .025), calm and relaxed ( P = .024), being active ( P = .046), and waking up fresh and rested ( P = .044). HbA1c reductions and increased time in range (TIR) were associated with increased treatment satisfaction, whereas glycemic variability was not. HbA1c reduction showed also an association with increased well-being and increased TIR with less diabetes-related distress., Conclusions: While CGM improves glucose control in people with T1D on MDI, increased convenience and flexibility through CGM is of even greater importance for treatment satisfaction and patient well-being. These CGM-mediated effects should be taken into account when considering CGM initiation., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: D.P. has no conflict of interest to declare. W.P. has served as a consultant for Dexcom and Abbott Diabetes Care. H.I. has no conflict of interest to declare. H.H. has no conflict of interest to declare. J.H. has served on advisory boards or lectured for Abbot, AstraZeneca, Bayer, Boehringer Ingelheim, Lilly, Nordic Infucare, Novo Nordisk, Rubin Medical, and Sanofi. M.W. has served on advisory boards or lectured for MSD, Lilly, Novo Nordisk, and Sanofi, and has organized a professional regional meeting sponsored by Lilly, Rubin Medical, Sanofi, Novartis, and Novo Nordisk. J.B. has received honoraria for consulting and/or lecture fees from Abbott Diabetes Care, MannKind Corp, Nordic Infucare, NovoNordisk and Sanofi. T.H. has received research funds from Adocia, AstraZeneca, BD, Biocon, Boehringer Ingelheim, Dance Pharmaceuticals, Grünenthal, Eli Lilly, Medtronic, Novo Nordisk, Novartis, Sanofi, and Senseonics. T.H. has participated in advisory panels for Novo Nordisk and received speaker honoraria and travel grants from Eli Lilly, Mylan, and Novo Nordisk. S.D. has no conflict of interest to declare. T.N. has received honoraria on expert group participation from AstraZeneca, Merck Sharp & Dohme, Novo Nordisk, Eli Lilly and Company, Boehringer Ingelheim, Abbot and Amgen. E.S. has no conflict of interest to declare. I.H. has received research funding from Dexcom and Insulet. M.L. has received research grants from Eli Lilly and Novo Nordisk and served as a consultant or received honoraria from AstraZeneca, Eli Lilly, and Novo Nordisk.

Background: Pharmaceutical expenditures (PE) are increasing worldwide, raising concerns about sustainability. However, the current price index provides an incomplete picture of this trend due to the rapid introduction of new drugs on the market., Objective: The aim of this study is to decompose PE into their components and investigate the development in Sweden from 1990 to 2022., Methods: The PE index was broken down into separate indices for price, quantity, and a residual. The residual reflects changes in expenditure driven by shifts in drug treatment patterns., Results: PE increased by 227% during the study period. The decomposition showed that this increase was mainly driven by the residual (215%). Drug quantity increased by 105%, while the relative prices decreased by 50%. When dividing the whole study period into three 11-year-subperiods, the increase in real drug expenditure, drug quantity, and the residual was the highest from 1990 to 2000., Conclusions: The finding that the residual is the main driver indicates that the increase in PE is due to the introduction of and shift to more expensive pharmaceutical treatments, while existing treatments tend to become cheaper. Further research is needed to determine whether newer, more expensive drugs are indeed worth the extra cost.

Background: Advanced Therapy Medicinal Products (ATMPs) for human use have advanced globally with the rapid adoption of Chimeric Antigen Receptor T-cell (CAR-T) therapies in haemato-oncology. CAR-T cell therapy and ATMPs have unique, significant acute and chronic toxicities, and appropriate patient care is crucial. Significant challenges, including the need for nurse education and training, accompany optimal patient success and benefits., Objectives: This study aimed to describe nurses' training needs in relation to ATMP management and patient care., Methods: A cross-sectional online survey was performed by the European Society for Blood and Marrow Transplantation, based on a previously tested questionnaire developed in the UK., Findings: 109 complete responses from 86 different centers from 24 countries were returned (1207 distributed). Over 1/3 reported experience delivering licensed ATMPs (CAR-T). High-priority training areas included a general introduction to ATMPs, toxicity management, product-specific information, and regulatory frameworks for ATMPs. A clear need for ATMP-specific training exists and is regarded as important. Training prior to implementation is key and should be supported by ongoing competency maintenance. Counseling, patient support, and long-term follow-up are identified for future training and opportunities for nurse experience sharing in this rapidly evolving field., Competing Interests: Michelle Kenyon: Mallinkrodt, Jazz, Sanofi Sarah Jayne Liptrott: No competing interests were disclosed. Annika Kisch: No competing interests were disclosed. Jarl Mooyaart: No competing interests were disclosed. Brian Piepenbroek: No competing interests were disclosed. Daphna Hutt: No competing interests were disclosed. Isabel Salcedo: No competing interests were disclosed. Annalisa Ruggeri: No competing interests were disclosed. Christian Chabannon: Bellicum Pharmaceuticals, BMS, Jazz, Janssen Pharmaceuticals, Kite / Pharma, Novartis, Sanofi SA Rose Ellard: Kite Gilead, Novartis, Janssen, BMS Celgene. John Murray: Therakos, Jazz Pharmaceuticals, Janssen and Gilead/Kite

Studying inflammatory responses induced by vaccination can contribute to a more detailed understanding of underlying immune mechanisms in lumpfish (Cyclopterus lumpus). Tissue samples from lumpfish intraperitoneally immunized with a divalent oil-adjuvanted vaccine (Aeromonas salmonicida and Vibrio salmonicida) at water temperatures of 5, 10, and 15°C were collected at 630 day degrees and 18 weeks post injection. The relative amount of secretory and membrane-bound immunoglobulin M (IgM) gene transcripts in the head kidney was determined by qPCR. Vaccine-induced inflammatory lesions were assessed on histological sections of abdominal pancreatic/intestinal tissue from vaccinated fish in all three temperature groups. Inflammatory cells forming dense aggregations in lesions showed proliferative activity, many of which were identified as eosinophilic-granulocyte-like cells. IgM+ cells were scattered in inflammatory tissue dominated by connective tissue, showing no difference in numbers between lesions from fish vaccinated at 5, 10, and 15°C. Relative gene expression analysis of secretory and membrane-bound IgM revealed low overall expression in the head kidney of vaccinated fish at both 630 day-degrees and 18 weeks post injection. The results of this study indicate that the vaccine stimulated prolonged local inflammatory responses at the injection site, which were not influenced by temperature., (© 2024 The Author(s). Journal of Fish Diseases published by John Wiley & Sons Ltd.)

In this study, we investigated the prevalence of mental disorders and the use of psychopharmacologic drugs among individuals with cerebral palsy (CP). We studied how the association between CP and mental illness develops over the life course (between ages 5 and 65 years), and how it varies across disability specific factors (intellectual disability, gross motor function and communicative ability). We used logistic regression models on a longitudinal matched case-control data material on all persons with CP in Sweden linked to several administrative registers including, the national patient registers and the pharmaceutical registers. Our results showed that the probability of being diagnosed with mental disorders and being dispensed psychopharmacologic drug was significantly higher among persons with CP compared to persons without CP across the different outcomes [OR = 1.52-4.7]. For some mental and neurodevelopmental disorders including sleep disorders, autism, and ADHD, and for the use of anxiolytics and sedatives, there was a sizeable gap already in childhood. However, the excess burden of mental illness appeared to grow over the life course, indicating that adults with CP may be a particularly disadvantaged group. Diagnosis for mental disorders and dispensation for psychopharmacologic drugs were not consistent with respect to disability specific factors, especially communicative and intellectual function, which indicates the need for systematic approaches in the mental health care of individuals with CP., Competing Interests: Conflict of interest The authors declare that they have no known conflicts or interests or details of conflicts of interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Individuals with psychotic disorders face an increased risk of physical health issues, leading to reduced life expectancy. Despite recommendations to integrate physical health promotion into mental healthcare, challenges persist, and mortality from somatic diseases continues to rise. Understanding healthcare providers' perspectives is crucial to overcoming these barriers. This study aims to explore the experiences of healthcare providers working in direct patient care and as unit heads regarding factors influencing health promotion in Swedish psychosis outpatient units., Methods: A qualitative descriptive study was conducted in two specialized psychosis outpatient units. Thirteen healthcare providers, including clinical case managers and three heads of units, were individually interviewed. Thematic analysis was used to analyze the data., Results: Three main themes were generated: (1) Health care providers' attitudes and competence. The health care provider's values and beliefs influenced the engagement in health promotion. (2) Patient-related aspects. Understanding how different patient life components shaped the physical health and need for measurements (3) Organizational prerequisites. Prioritizing resources and leadership impact the experience of health promotion. Clinical case management appeared as a promising approach to coordinate/integrate physical and mental health care, evident in themes 1 and 3., Conclusions: Beyond organizational factors, healthcare providers' skills, patient understanding, and ethical reflection influence their motivation to engage in physical health promotion. The study included only 13 participants, representing various professions, including managers who provided specific leadership perspectives. Clinical case managers appear well-suited to address physical health promotion due to their proficiency in shared decision-making and coordination.

Competing Interests: Author Disclosures Author disclosure forms can be accessed below in the Supplemental Material section.

This case study introduces a green, 1 h single-step method using water-rich natural deep eutectic solvent (WRNADES) for ultrasound-assisted extraction (UAE) of polyphenols from Saccharina latissima , a commercially cultivated brown seaweed. The extraction efficiency was evaluated using a selective quantitative NMR method (s-qNMR) and the traditional nonselective colorimetric total phenolic content assay (TPC). Initial 6 h extractions in traditional solvents (methanol, ethanol, acetone, and ethyl acetate) showed a 40-60% increase in polyphenolic yields in 50% aqueous solutions measured by the TPC method. Six different water-rich (50%) NADES (WRNADES) combinations were tested (choline chloride/betaine with lactic acid, citric acid, and 1,3-butanediol), with betaine and 1,3-butanediol (1:1) proving most effective. Parameters for the WRNADES were optimized using Box-Behnken design response surface methodology, resulting in a 1:20 w/w biomass to solvent ratio and a 1 h extraction time at 50 °C. The WRNADES extraction process was refined into a scalable, single-step procedure and compared with traditional solvent extractions (6 h, 50% aqueous methanol and acetone). A final XAD-7 polyphenol recovery step was included in all extractions. The optimized WRNADES extraction yielded 15.97 mg GAE/g of the dry weight recovered polyphenolic extract (s-qNMR), exceeding the 6 h 50% aqueous methanol (12.4 mg GAE/g) and acetone (11.4 mg GAE/g) extractions. Thus, the UAE-WRNADES method presented in this case study provides a cost-effective, sustainable, and eco-friendly alternative for the extraction of phenolic compounds from seaweed. It promotes the development of environmentally friendly production processes within the seaweed biorefinery., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Noise barriers are path interventions between noise sources and human receivers used mainly along road corridors to improve the acoustic environment for affected residents. Despite their widespread use, the impact of these interventions on community perception is still insufficiently investigated. This paper presents findings from a longitudinal study evaluating the efficacy of noise barriers in three residential areas alongside highways, compared to a reference case in a relatively quiet area. Noise exposure was objectively quantified via acoustic measurements and noise modelling, while socio-acoustic surveys measured the residents' subjective response in terms of noise annoyance as well as other aspects of quality of life. While noise exposure (L day ) decreased on average by 4.4-11.7 dBA at near-barrier points, direct reductions in pre to post-intervention noise annoyance were observed only in one case. Additionally, only in this particular case were the appraisals of the acoustic environment restored to a condition similar to low-level noise emissions (reference case). Contextual factors potentially downgrading the interventions' effectiveness are discussed, such as the history of complaints and coping, mistrust towards road authorities, high expectations, and the impacts of the COVID-19 pandemic. While noise exposure reductions did not directly lead to noise annoyance decreases, an ordinal regression pooling all cases revealed that larger reductions in noise exposure were associated with a higher likelihood of residents reporting decreased traffic noise annoyance in the post-survey. No evidence was found regarding noise barriers' impact on the subjective assessment of other aspects of quality of life, such as health complaints, concentration disturbance, and sleep quality., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Aims/hypothesis: Previous studies have shown that individuals with similar mean glucose levels (MG) or percentage of time in range (TIR) may have different HbA 1c values. The aim of this study was to further elucidate how MG and TIR are associated with HbA 1c ., Methods: Data from the randomised clinical GOLD trial (n=144) and the follow-up SILVER trial (n=98) of adults with type 1 diabetes followed for 2.5 years were analysed. A total of 596 paired HbA 1c /continuous glucose monitoring measurements were included. Linear mixed-effects models were used to account for intra-individual correlations in repeated-measures data., Results: In the GOLD trial, the mean age of the participants (± SD) was 44±13 years, 63 (44%) were female, and the mean HbA 1c (± SD) was 72±9.8 mmol/mol (8.7±0.9%). When correlating MG with HbA 1c , MG explained 63% of the variation in HbA 1c (r=0.79, p<0.001). The variation in HbA 1c explained by MG increased to 88% (r=0.94, p value for improvement of fit <0.001) when accounting for person-to-person variation in the MG-HbA 1c relationship. Time below range (TBR; <3.9 mmol/l), time above range (TAR) level 2 (>13.9 mmol/l) and glycaemic variability had little or no effect on the association. For a given MG and TIR, the HbA 1c of 10% of individuals deviated by >8 mmol/mol (0.8%) from their estimated HbA 1c based on the overall association between MG and TIR with HbA 1c . TBR and TAR level 2 significantly influenced the association between TIR and HbA 1c . At a given TIR, each 1% increase in TBR was related to a 0.6 mmol/mol lower HbA 1c (95% CI 0.4, 0.9; p<0.001), and each 2% increase in TAR level 2 was related to a 0.4 mmol/mol higher HbA 1c (95% CI 0.1, 0.6; p=0.003). However, neither TIR, TBR nor TAR level 2 were significantly associated with HbA 1c when accounting for MG., Conclusions/interpretation: Inter-individual variations exist between MG and HbA 1c , as well as between TIR and HbA 1c , with clinically important deviations in relatively large groups of individuals with type 1 diabetes. These results may provide important information to both healthcare providers and individuals with diabetes in terms of prognosis and when making diabetes management decisions., (© 2024. The Author(s).)

Background: This study investigates the excess costs of dementia from healthcare, social care services, and prescription drugs 3 years before to 6 years after diagnosis. Further, sociodemographic cost differences are explored., Methods: Using Swedish register data from 2013 to 2016 to compare individuals diagnosed with dementia (n = 15,339) with population controls, the excess formal care costs for people with a dementia diagnosis are obtained with longitudinal regression analysis., Results: People with dementia incur higher formal care costs for all years studied compared to people without dementia. The excess costs vary from €3400 3 years before diagnosis to €49,700 6 years after diagnosis. The costs are mainly driven by institutional care, and solitary living is a strong predictor of high excess costs., Conclusion: The results show that the formal care costs of individuals with dementia are substantial, and that the economic burden of dementia in Sweden is larger than previously estimated., (© 2024. The Author(s).)

Background: Thanks to improved medical care, individuals with spina bifida (SB) live well into adulthood and go through the process of reproductive maturation and the development of sexual desires. However, access to reproductive counselling and contraceptive use has been reported to be lower for women with physical and intellectual disabilities compared to the general population., Objective: We investigated oral contraceptive use in women with SB, residing in Sweden and how use varies based on the level of lesion and demographic factors., Methods: This was a population-based case-control study using annual data from national registers from 2006 to 2015. The sample consisted of 7045 women aged 15-49 years, of which 1173 had a diagnosis of SB. χ 2 tests and logistic regression were used to investigate the study objective., Results: The rate of oral contraceptive use in women with SB was 24.6 % compared to 34.5 % among the general population. After adjusting for potential confounders women with SB were found to have a lower probability of using oral contraceptives (OR 0.63 95 % CI 0.56-0.71) compared to women without SB. Among women with SB, those with diagnoses Q05.8 (Sacral SB without hydrocephalus) and Q05.9 (SB unspecified) had a higher likelihood of using oral contraceptives compared to other Q05 diagnoses., Conclusion: Women with SB had a lower likelihood of being on oral contraceptives compared to the control group. Further research should investigate if the lower use indicates that oral contraceptives are not an inappropriate method of contraception for women with SB., Competing Interests: Declaration of Competing interest The authors declare that they have no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Variants in the MYBPC3 gene are a frequent cause of hypertrophic cardiomyopathy (HCM) but display a large phenotypic heterogeneity. Founder mutations are often believed to be more benign as they prevailed despite potential negative selection pressure. We detected a pathogenic variant in MYBPC3 (del exon 23-26) in several probands. We aimed to assess the presence of a common haplotype and to describe the cardiac characteristics, disease severity and long-term outcome of mutation carriers., Methods: Probands with HCM caused by a pathogenic deletion of exon 23-26 of MYBPC3 were identified through genetic screening using a gene panel encompassing 59 genes associated with cardiomyopathies in a single genetic center in Belgium. Cascade screening of first-degree relatives was performed, and genotype positive relatives were further phenotyped. Clinical characteristics were collected from probands and relatives. Cardiac outcomes included death, heart transplantation, life-threatening arrhythmia, heart failure hospitalization or septal reduction therapy. Haplotype analysis, using microsatellite markers surrounding MYBPC3 , was performed in all index patients to identify a common haplotype. The age of the founder variant was estimated based on the size of the shared haplotype using a linkage-disequilibrium based approach., Results: We identified 24 probands with HCM harbouring the MYBPC3 exon 23-26 deletion. Probands were on average 51 ± 16 years old at time of clinical HCM diagnosis and 62 ± 10 years old at time of genetic diagnosis. A common haplotype of 1.19 Mb was identified in all 24 probands, with 19 of the probands sharing a 13.8 Mb haplotype. The founder event was estimated to have happened five generations, or 175-200 years ago, around the year 1830 in central Flanders. Through cascade screening, 59 first-degree relatives were genetically tested, of whom 37 (62.7%) were genotype positive (G+) and 22 (37.3%) genotype negative (G-). They were on average 38 ± 19 years old at time of genetic testing. Subsequent clinical assessment revealed a HCM phenotype in 19 (51.4%) G+ relatives. Probands were older (63 ± 10 vs. 42 ± 21 years; p < 0.001) and had more severe phenotypes than G+ family members, presenting with more symptoms (50% vs. 13.5%; p = 0.002), arrhythmia (41.7% vs. 12.9%, p = 0.014), more overt hypertrophy and left ventricular outflow tract obstruction (43.5% vs. 3.0%; p < 0.001). Male G+ relatives more often had a HCM phenotype (78.6% vs. 34.8%; p = 0.010) and were more severely affected than females. At the age of 50, a penetrance of 78.6% was observed, defined as the presence of HCM in 11 of 14 G+ relatives with age ≥50 years. Overall, 20.3% of all variant carriers developed one of the predefined cardiac outcomes after a median follow-up of 5.5 years with an average age of 50 (±21) years., Conclusion: A Belgian founder variant, an exon 23-26 deletion in MYBPC3 , was identified in 24 probands and 37 family members. The variant is characterized by a high penetrance of 78.6% at the age of 50 years but has variable phenotypic expression. Adverse outcomes were observed in 20.3% of patients during follow-up., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Boen, Alaerts, Van Laer, Saenen, Goovaerts, Bastianen, Koopman, Vanduynhoven, De Vuyst, Rosseel, Heidbuchel, Van Craenenbroeck and Loeys.)

Background: Blood levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) has been suggested as a future guidance tool for the selection of patients for aortic valve replacement. This study aimed to examine how levels of NT-proBNP pre-transcatheter aortic valve implantation (TAVI) is associated with one-year rates of heart failure (HF) admission and mortality following TAVI., Methods: With Danish nationwide registries, we identified all patients undergoing TAVI from 2014 to 2021 who had at least one recorded NT-pro-BNP measurement within one year before TAVI. Patients were compared by quartiles of pre-TAVI NT-proBNP: quartile 4 (high NT-proBNP group) vs quartile 1-3 (low NT-proBNP group). Comparisons of all-cause mortality and HF-admissions were conducted using Kaplan-Meier analysis, cumulative incidence, and Cox analysis, as appropriate., Results: We identified 1,140 patients undergoing first-time TAVI with a recorded NT-pro-BNP; 846 (74.2 %) with a low NT-proBNP (<420 pmol/L) (55.0 % male, median age 81 year) and 294 (25.8 %) with a high NT-proBNP (≥420 pmol/L) (53.1 % male, median age 82 year). A high versus low NT-proBNP was associated with increased one-year cumulative incidence of HF-admissions (9.1 % vs. 23.1 %, adjusted HR 2.00 [95 % CI, 1.40-2.85]) and all-cause mortality (6.0 % vs. 14.6 %, adjusted HR 1.95 [95 % CI: 1.24-3.07]). A high NT-proBNP was associated with higher rates of outcomes irrespective of previously known atrial fibrillation, HF, chronic kidney disease, and hypertension., Conclusion: In patients undergoing TAVI, a baseline NT-proBNP ≥ 420 pmol/L was associated with increased one-year rates of HF-admission and mortality post-TAVI and may be utilized to identify a high-risk population., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Cardiovascular outcome in Marfan syndrome (MFS) patients most prominently depends on aortic aneurysm progression with subsequent aortic dissection. Angiotensin II receptor blockers (ARBs) prevent aneurysm formation in MFS mouse models. In patients, ARBs only slow down aortic dilation. Downstream signalling from the angiotensin II type 1 receptor (AT1R) is mediated by G proteins and β-arrestin recruitment. AT1R also interacts with the monocyte chemoattractant protein-1 (MCP-1) receptor, resulting in inflammation. In this study, we explore the targeting of β-arrestin signalling in MFS mice by administering TRV027. Furthermore, because high doses of the ARB losartan, which has been proven beneficial in MFS, cannot be achieved in humans, we investigate a potential additive effect by combining lower concentrations of losartan (25 mg/kg/day and 5 mg/kg/day) with barbadin, a β-arrestin blocker, and DMX20, a C-C chemokine receptor type 2 (CCR2) blocker. A high dose of losartan (50 mg/kg/day) slowed down aneurysm progression compared to untreated MFS mice (1.73 ± 0.12 vs. 1.96 ± 0.08 mm, p = 0.0033). TRV027, the combination of barbadin with losartan (25 mg/kg/day), and DMX-200 (90 mg/kg/day) with a low dose of losartan (5 mg/kg/day) did not show a significant beneficial effect. Our results confirm that while losartan effectively halts aneurysm formation in Fbn1 C1041G/+ MFS mice, neither TRV027 alone nor any of the other compounds combined with lower doses of losartan demonstrate a notable impact on aneurysm advancement. It appears that complete blockade of AT1R function, achieved by administrating a high dosage of losartan, may be necessary for inhibiting aneurysm progression in MFS.

Purpose: To understand the current practice in relation to the management of topical therapy for cutaneous chronic Graft versus Host Disease (ccGvHD) and access to extracorporeal photopheresis (ECP) within European allogeneic haematopoietic cell transplantation centres by a survey of nurses., Method: This was a multicentre cross-national study at eligible European Blood and Marrow Transplant centres. Eligibility required more than 30% of treated patients having allogeneic haematopoietic cell transplant. Centres performing only autologous stem cell transplants were excluded from the study., Results: 12% of respondents were unaware of whether their centre had a policy or not for monitoring chronic cutaneous graft versus host disease. Over half had the affiliation of a dermatologist for referral, but only 19% had access to a specialist nurse. Patient education was routinely provided in most of the centres (86%). Results suggested as the severity of a patient's chronic cutaneous graft versus host disease increased, there was a reduction in the amount of topical emollients and steroids employed. Following topical therapies, systemic treatments, and other modalities such as ECP were employed with less focus directed towards topical care., Conclusions: Topical treatment is the backbone of any treatment paradigm for chronic cutaneous graft versus host disease, however, there is no universally agreed algorithm. Improved skin care may lead to a reduction in the amount of systemic therapy required, thus increasing patients' quality of life. There is little standardisation in the topical management of chronic cutaneous graft versus host disease, despite skin being the most cited organ affected by chronic graft versus host disease, this should be addressed., Competing Interests: Declaration of competing interest John Murray reports speaker honorarium from Therakos. The rest of the authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objectives: Head and neck cancer (HNC) is the sixth most common cancer worldwide. The condition and its treatment often lead to marked morbidities and, for some patients, premature death. Inferentially, HNC imposes a significant economic burden on society. This study aims to provide a comprehensive and detailed estimation of the cost of illness of HNC for Sweden in 2019., Methods: This is a prevalence-based cost of illness study. Resource utilization and related costs are quantified using national registry data. A societal perspective is applied, including (1) direct costs for healthcare utilization, (2) costs for informal care from family and friends, and (3) costs for productivity loss due to morbidity and premature death. The human capital approach is used when estimating productivity losses., Results: The societal cost of HNC for Sweden in 2019 was estimated at €92 million, of which the direct costs, costs for informal care, and costs for productivity loss represented 34%, 2%, and 64%, respectively. Oral cavity cancer was the costliest HNC, followed by oropharyngeal cancer, whereas nasopharyngeal cancer was the costliest per person. The cost of premature mortality comprised 60% of the total cost of productivity loss. Males accounted for 65% of direct costs and 67% of costs for productivity loss., Conclusions: The societal cost of HNC is substantial and constitutes a considerable burden to Swedish society. The results of the present study may be used by policymakers for planning and allocation of resources. Furthermore, the information may be used for future cost-effectiveness analyses., Competing Interests: Author Disclosures Links to the disclosure forms provided by the authors are available here., (Copyright © 2024. Published by Elsevier Inc.)

Pathogenic loss-of-function variants in BGN, an X-linked gene encoding biglycan, are associated with Meester-Loeys syndrome (MRLS), a thoracic aortic aneurysm/dissection syndrome. Since the initial publication of five probands in 2017, we have considerably expanded our MRLS cohort to a total of 18 probands (16 males and 2 females). Segregation analyses identified 36 additional BGN variant-harboring family members (9 males and 27 females). The identified BGN variants were shown to lead to loss-of-function by cDNA and Western Blot analyses of skin fibroblasts or were strongly predicted to lead to loss-of-function based on the nature of the variant. No (likely) pathogenic missense variants without additional (predicted) splice effects were identified. Interestingly, a male proband with a deletion spanning the coding sequence of BGN and the 5' untranslated region of the downstream gene (ATP2B3) presented with a more severe skeletal phenotype. This may possibly be explained by expressional activation of the downstream ATPase ATP2B3 (normally repressed in skin fibroblasts) driven by the remnant BGN promotor. This study highlights that aneurysms and dissections in MRLS extend beyond the thoracic aorta, affecting the entire arterial tree, and cardiovascular symptoms may coincide with non-specific connective tissue features. Furthermore, the clinical presentation is more severe and penetrant in males compared to females. Extensive analysis at RNA, cDNA, and/or protein level is recommended to prove a loss-of-function effect before determining the pathogenicity of identified BGN missense and non-canonical splice variants. In conclusion, distinct mechanisms may underlie the wide phenotypic spectrum of MRLS patients carrying loss-of-function variants in BGN., (© 2024. The Author(s).)

Natural products obtained from marine organisms continue to be a rich source of novel structural architecture and of importance in drug discovery, medicine, and health. However, the success of such endeavors depends on the exact structural elucidation and access to sufficient material, often by stereoselective total synthesis, of the isolated natural product of interest. (-)-Mucosin ( 1 ), a fatty acid derivative, previously presumed to contain a rare cis -bicyclo[4.3.0]non-3-ene moiety, has since been shown to be the trans -congener. Analytically, the fused bicyclic ring system in (-)- 1 constitutes a particular challenge in order to establish its relative and absolute stereochemistry. Herein, data from biological evaluations, NMR and molecular modeling studies of (-)- 1 are presented. An overview of the synthetic strategies enabling the exact structural elucidation of (-)-mucosin ( 1 ) is also presented.

Background: Treatment for resectable oral cavity cancer (OCC) often includes combinations of surgery and radiotherapy (RT), but there is no conclusive information on the preferred treatment order. The aim of this study was to assess the costs and cost-effectiveness of two alternative treatment regimens for patients with OCC, reflecting pre- and post-operative RT, from a societal perspective., Methods: The study used data from the ARTSCAN 2 randomised controlled trial, which compares pre-operative accelerated RT with post-operative conventionally fractionated RT. Two-hundred-forty patients were included in the analysis of treatment outcomes. Direct costs were retrieved from the hospital's economic systems, while indirect costs were obtained from national registries. Cost-effectiveness was assessed and a sensitivity analysis was performed. Overall survival (OS) at 5 years, was used as effect measure in the analysis., Results: Two-hundred-nine patients completed the treatments and had retrievable data on costs. Mean direct costs (inpatient and outpatient care) were € 47,377 for pre-operative RT and € 39,841 for post-operative RT (p = 0.001), while corresponding indirect costs were € 19,854 and € 20,531 (p = 0.89). The incremental cost, i.e., the mean difference in total cost between the treatment regimens, was € 6859 paralleled with a 14-percentage point lower OS-rate at 5 years for pre-operative RT (i.e., 58 vs. 72%). Thus, pre-operative RT was dominated by post-operative RT., Conclusions: From a societal perspective, post-operative RT for patients with resectable OCC is the dominant strategy compared to pre-operative RT., (© 2023. The Author(s).)

Background: People with type 1 diabetes generally view it easier to exercise when having continuous information of the glucose levels. We evaluated whether patients with type 1 diabetes managed with multiple daily insulin injections (MDI) exercised more after initiating continuous glucose monitoring (CGM) and whether the improved glycemic control and well-being associated with CGM translates into improved blood lipids and markers of inflammation., Method: The GOLD trial was a randomized cross-over trial over 16 months where patients used either CGM or capillary self-monitoring of blood glucose (SMBG) over six months, with a four-month wash-out period between the two treatment periods. We compared grade of physical activity, blood lipids, apolipoproteins, and high-sensitivity C-reactive protein (hsCRP) levels during CGM and SMBG., Results: There were 116 patients with information of physical activity estimated by the International Physical Activity Questionnaire (IPAQ) during both CGM and SMBG. No changes were found during CGM or SMBG, IPAQ scores 3305 versus 3878 ( P = .16). In 136 participants with information of blood lipid levels with no change in lipid-lowering medication during the two treatment periods, HbA1c differed by 4.2 mmol/mol (NGSP 0.39%) between SMBG and CGM treatment ( P < .001). No significant changes existed in low-density lipoprotein, high-density lipoprotein, triglycerides, total cholesterol, apolipoprotein A1, apolipoprotein B1, or hsCRP, during CGM and SMBG., Conclusion: Although many patients experience it easier to perform physical activity when monitoring glucose levels with CGM, it does not influence the amount of physical activity in persons with type 1 diabetes. Blood lipids, apolipoprotein, and hsCRP levels were similar during CGM and SMBG., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: TN has received unrestricted grants from AstraZeneca and NovoNordisk and has served on national advisory boards of Abbot, Amgen, Novo Nordisk, Sanofi-Aventis, Eli Lilly, MSD, and Boehringer Ingelheim. ML has received research grants from Eli Lilly and Novo Nordisk and been consultant or received honoraria from Astra Zeneca, Boehringer Ingelheim, Eli Lilly, and Novo Nordisk. JH has served on advisory boards or lectured for Novo Nordisk, Sanofi, Lilly, Abbot, Rubin Medical, MSD, and Boehringer Ingelheim. MW has served on advisory boards or lectured for MSD, Lilly, Novo Nordisk, and Sanofi and has organized a professional regional meeting sponsored by Lilly, Rubin Medical, Sanofi, Novartis, and Novo Nordisk. JB has received honoraria for consulting and/or lecture fees from Abbott Diabetes Care, Novo Nordisk, and Sanofi.

Aim: To evaluate whether both bolus insulin injection frequency and smart pen engagement were associated with changes in glycaemic control, using real-world data from adults with type 1 diabetes (T1D)., Materials and Methods: Adults using a smart pen (NovoPen 6) to administer bolus insulin (fast-acting insulin aspart or insulin aspart) alongside continuous glucose monitoring were eligible for inclusion. Smart pen engagement was characterized by number of days with pen data uploads over the previous 14 days. Glycaemic control was evaluated by analysing glucose metrics., Results: Overall, data from 1194 individuals were analysed. The number of daily bolus injections was significantly associated with time in range (TIR; 3.9-10.0 mmol/L [70-180 mg/dL]; P < 0.0001). Individuals administering, on average, three daily bolus insulin injections had an estimated 11% chance of achieving >70% TIR. The probability of achieving >70% TIR increased with the mean number of daily bolus injections. However, the percentage of TIR was lower on days when individuals administered higher-than-average numbers of injections. The observed mean number of daily bolus injections administered across the study population was lower than the optimal number required to reach glycaemic targets (4.8 injections vs. 6-8 injections). Smart pen engagement was significantly associated with improved TIR., Conclusions: Glycaemic control was associated with daily bolus insulin injection frequency and smart pen engagement. A treatment regimen combining an optimal bolus injection strategy, and effective smart pen engagement, may improve glycaemic control among adults with T1D., (© 2023 Novo Nordisk A/S and The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

The scavenger endothelial cells (SECs) of vertebrates are an important class of endocytic cells responsible for clearance of foreign and physiological waste macromolecules, partitioning in the immune system, functioning as a cellular powerplant by producing high energy metabolites like lactate and acetate. All animal phyla possess SECs, but the tissue localization of SECs has only been investigated in a limited number of species. By using a specific ligand for scavenger receptors (formalin treated bovine serum albumin), the study revealed that in all tetrapod species (amphibia, reptiles, birds and mammals) the SECs were found lining the sinusoids of the liver. No SECs were found in the liver of any of the bony fishes (Osteichthyes) investigated. Interestingly, we found the SECs not only to be located in the heart of marine species but also in some freshwater species such as Lota lota, Percichthys trucha and Perca fluviatilis. In some fish species, the SECs were found both in the heart and/or kidney in a number of marine and freshwater fishes, whereas in some marine, diadromous and freshwater fishes the SECs were confined only to the kidney tissue. However, from these results it can be suggested that there is neither a clear phylogenetic trend when it came to anatomical localization of SECs nor any pattern in terms of habitat (salinity preferences)., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Investigating prevalence of child abuse in sport is a relatively new field of research, born from the need for credible data on this phenomenon., Objective: To establish prevalence rates of interpersonal violence against children in sport in six European countries., Participants and Setting: The sample (N = 10,302) consists of individuals aged 18-30 who had participated in organized sport prior to age 18 (49.3 % male, 50 % female)., Methods: A self-report questionnaire was developed (the Interpersonal Violence Against Children in Sport Questionnaire or IVACS-Q) to measure prevalence of five categories of interpersonal violence (neglect, psychological violence, physical violence, non-contact sexual violence, and contact sexual violence) against children who participate in sport. Validation testing (published separately) showed reasonable levels of convergent and divergent validity. Prevalence rates are calculated by national context, whether inside or outside sport, and by sex (male/female)., Results: Prevalence of IVACS inside sport differed by category: psychological violence (65 %, n = 6679), physical violence (44 %, n = 4514), neglect (37 %, n = 3796), non-contact sexual violence (35 %, n = 3565), and contact sexual violence (20 %, n = 2060). Relatively small geographical differences were found. Across all categories, males (79 %, n = 4018) reported significantly more experiences inside sport than females (71 %, n = 3653) (χ 2 (1) = 92.507, p < .000). Strong correlations were found between experiencing violence inside and outside sport., Conclusions: Interpersonal violence against children in sport is widespread. The sector's approach to prevention must recognize the risks to female and male children (and all children) and the additional vulnerabilities of abused children. Further comparative and longitudinal research within sport is required., Competing Interests: Declaration of competing interest None., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: To analyse survival rates and causes of death in adults with spina bifida in Sweden compared with a matched control group., Design and Methods: This population-based study included 11,900 adults born between 1950 and 1997. Three national Swedish registers were used to identify individuals with a diagnosis of spina bifida and a matched control group without spina bifida in the period 1990-2015. International Classification of Diseases codes were used to identify causes of death. Survival analysis was conducted and causes of death in the 2 groups were compared., Results: There was a lower probability of survival for people with spina bifida in all age groups (p < 0.001) compared with the control group. The most prevalent causes of death in people with spina bifida were congenital, respiratory, nervous, cardiovascular, genitourinary, and injuries. People with spina bifida had a higher probability of dying from congenital (p < 0.001), respiratory (p = 0.002), genitourinary (p < 0.002), and nervous-related (p < 0.001) and lower probability of injury-related deaths (p < 0.001)., Conclusion: Adults with spina bifida in Sweden have a lower survival rate compared with the general population, with the frequency of certain causes of death differing between the two groups. In order to reduce excess premature mortality, prevention and careful management of potentially fatal conditions are essential throughout a patient's lifespan.

Objective: Mental illness is increasing among young people and likewise the request for health care services. At the same time, somatic comorbidity is common in children and adolescents with psychiatric disorders. There is a lack of studies on health care use in children and adolescents, and the hypothesis was that children and adolescents with psychiatric disorders use more primary-, and specialized somatic health care compared to children without psychiatric disorders., Methods: In this retrospective population-based register study, all individuals aged 3-17 years living in Västra Götaland region in Sweden in 2017 were included (n = 298,877). Linear and Poisson regression were used to compare health care use during 2016-2018 between children with and without psychiatric diagnoses, controlling for age and gender. The results were reported as unstandardised beta coefficient (ß) and adjusted prevalence ratio (aPR) respectively., Results: Having a psychiatric diagnosis was associated with more primary care visits (ß 2.35, 95% CI 2.30-2.40). This applied to most diagnoses investigated. Girls had more primary care visits than boys. Likewise, individuals with psychiatric diagnoses had more specialized somatic outpatient care (ß 1.70, 95% CI 1.67-1.73), both planned and unplanned (ß 1.23, 95% CI 1.21-1.25; ß 0.18, 95% CI 0.17-0.19). Somatic inpatient care was more common in those having a psychiatric diagnosis (aPR 1.65, 95% CI 1.58-1.72), with the diagnoses of psychosis and substance use exerting the greatest risk., Conclusions: Psychiatric diagnoses were associated with increased primary-, somatic outpatient- as well as somatic inpatient care. Increased awareness of comorbidity and easy access to relevant health care could be beneficial for patients and caregivers. The results call for a review of current health care systems with distinct division between medical disciplines and levels of health care., (© 2023 The Authors. Acta Psychiatrica Scandinavica published by John Wiley & Sons Ltd.)

Background: Cyanobacteria are emerging as green cell factories for sustainable biofuel and chemical production, due to their photosynthetic ability to use solar energy, carbon dioxide and water in a direct process. The model cyanobacterial strain Synechocystis sp. PCC 6803 has been engineered for the isobutanol and 3-methyl-1-butanol production by introducing a synthetic 2-keto acid pathway. However, the achieved productions still remained low. In the present study, diverse metabolic engineering strategies were implemented in Synechocystis sp. PCC 6803 for further enhanced photosynthetic isobutanol and 3-methyl-1-butanol production., Results: Long-term cultivation was performed on two selected strains resulting in maximum cumulative isobutanol and 3-methyl-1-butanol titers of 1247 mg L -1 and 389 mg L -1 , on day 58 and day 48, respectively. Novel Synechocystis strain integrated with a native 2-keto acid pathway was generated and showed a production of 98 mg isobutanol L -1 in short-term screening experiments. Enhanced isobutanol and 3-methyl-1-butanol production was observed when increasing the kivd S286T copy number from three to four. Isobutanol and 3-methyl-1-butanol production was effectively improved when overexpressing selected genes of the central carbon metabolism. Identified genes are potential metabolic engineering targets to further enhance productivity of pyruvate-derived bioproducts in cyanobacteria., Conclusions: Enhanced isobutanol and 3-methyl-1-butanol production was successfully achieved in Synechocystis sp. PCC 6803 strains through diverse metabolic engineering strategies. The maximum cumulative isobutanol and 3-methyl-1-butanol titers, 1247 mg L -1 and 389 mg L -1 , respectively, represent the current highest value reported. The significantly enhanced isobutanol and 3-methyl-1-butanol production in this study further pave the way for an industrial application of photosynthetic cyanobacteria-based biofuel and chemical synthesis from CO 2 ., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: The development of entrustable professional activities (EPAs) as a framework for work-based training and assessment in undergraduate medical education has become popular. EPAs are defined as units of a professional activity requiring adequate knowledge, skills, and attitudes, with a recognized output of professional labor, independently executable within a time frame, observable and measurable in its process and outcome, and reflecting one or more competencies. Before a new framework is implemented in a specific context, it is valuable to explore social validity, that is, the acceptability by relevant stakeholders., Aim: The aim of our work was to define Core EPAs for undergraduate medical education and further explore the social validity of the constructs., Method and Material: In a nationwide collaboration, EPAs were developed using a modified Delphi procedure and validated according to EQual by a group consisting of teachers nominated from each of the seven Swedish medical schools, two student representatives, and an educational developer (n = 16). In the next step, social validity was explored in a nationwide survey. The survey introduced the suggested EPAs. For each EPA, the importance of the EPA was rated, as was the rater's perception of the present graduates' required level of supervision when performing the activity. Free-text comments were also included and analyzed., Results: Ten Core EPAs were defined and validated. The validation scores for EQual ranged from 4.1 to 4.9. The nationwide survey had 473 responders. All activities were rated as "important" by most responders, ranging from 54 to 96%. When asked how independent current graduates were in performing the ten activities, 6 to 35% reported "independent". The three themes of the free text comments were: 'relevant target areas and content'; 'definition of the activities'; and 'clinical practice and learning'., Conclusion: Ten Core EPAs were defined and assessed as relevant for Swedish undergraduate medical education. There was a consistent gap between the perceived importance and the certainty that the students could perform these professional activities independently at the time of graduation. These results indicate that the ten EPAs may have a role in undergraduate education by creating clarity for all stakeholders., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Introduction: This study utilized continuous glucose monitoring data to analyze the effects of switching to treatment with fast-acting insulin aspart (faster aspart) in adults with type 1 diabetes (T1D) in clinical practice., Methods: A noninterventional database review was conducted in Sweden among adults with T1D using multiple daily injection (MDI) regimens who had switched to treatment with faster aspart as part of basal-bolus treatment. Glycemic data were retrospectively collected during the 26 weeks before switching (baseline) and up to 32 weeks after switching (follow-up) to assess changes in time in glycemic range (TIR; 70-180 mg/dL), mean sensor glucose, glycated hemoglobin (HbA1c) levels, coefficient of variation, time in hyperglycemia (level 1, > 180 to ≤ 250 mg/dL; level 2, > 250 mg/dL), and time in hypoglycemia (level 1, ≥ 54 to < 70 mg/dL; level 2, < 54 mg/dL) (ClinicalTrials.gov Identifier NCT03895515)., Results: Overall, 178 participants were included in the study cohort. The analysis population included 82 individuals (mean age 48.5 years) with adequate glucose sensor data. From baseline to follow-up, statistically significant improvements were reported for TIR (mean increase 3.3%-points [approximately 48 min/day]; p = 0.006) with clinically relevant improvement (≥ 5%) in 43% of participants. Statistically significant improvements from baseline were observed for mean sensor glucose levels, HbA1c levels, and time in hyperglycemia (levels 1 and 2), with no statistically significant changes in time spent in hypoglycemia., Conclusions: Switching to faster aspart was associated with improvements in glycemic control without increasing hypoglycemia in adults with T1D using MDI in this real-world setting., (© 2023. The Author(s).)

Using a dynamic optimisation model for juvenile fish in stochastic food environments, we investigate optimal hormonal regulation, energy allocation and foraging behaviour of a growing host infected by a parasite that only incurs an energetic cost. We find it optimal for the infected host to have higher levels of orexin, growth and thyroid hormones, resulting in higher activity levels, increased foraging and faster growth. This growth strategy thus displays several of the fingerprints often associated with parasite manipulation: higher levels of metabolic hormones, faster growth, higher allocation to reserves (i.e. parasite-induced gigantism), higher risk-taking and eventually higher predation rate. However, there is no route for manipulation in our model, so these changes reflect adaptive host compensatory responses. Interestingly, several of these changes also increase the fitness of the parasite. Our results call for caution when interpreting observations of gigantism or risky host behaviours as parasite manipulation without further testing., (© 2023 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

This study aimed to estimate the healthcare costs of kidney transplantation compared with dialysis using a propensity score approach to handle potential treatment selection bias. We included 693 adult wait-listed patients who started renal replacement therapy between 1998 and 2012 in Region Skåne and Stockholm County Council in Sweden. Healthcare costs were measured as annual and monthly healthcare expenditures. In order to match the data structure of the kidney transplantation group, a hypothetical kidney transplant date of persons with dialysis were generated for each dialysis patient using the one-to-one nearest-neighbour propensity score matching method. Applying propensity score matching and inverse probability-weighted regression adjustment models, the potential outcome means and average treatment effect were estimated. The estimated healthcare costs in the first year after kidney transplantation were €57,278 (95% confidence interval (CI) €54,467-60,088) and €47,775 (95% CI €44,313-51,238) for kidney transplantation and dialysis, respectively. Thus, kidney transplantation leads to higher healthcare costs in the first year by €9,502 (p = 0.066) compared to dialysis. In the following two years, kidney transplantation is cost saving [€36,342 (p < 0.001) and €44,882 (p < 0.001)]. For patients with end-stage renal disease, kidney transplantation reduces healthcare costs compared with dialysis over three years after kidney transplantation, even though the healthcare costs are somewhat higher in the first year. Relating the results of existing estimates of costs and health benefits of kidney transplantation shows that kidney transplantation is clearly cost-effective compared to dialysis in Sweden., (© 2023. The Author(s).)

Background: Pain is a global health concern with substantial societal costs and limits the activity participation of individuals. The prevalence of pain is estimated to be high among individuals with cerebral palsy (CP)., Objectives: To estimate the association between pain and labor outcomes for adults with CP in Sweden., Methods: A longitudinal cohort study based on data from Swedish population-based administrative registers of 6899 individuals (53,657 person-years) with CP aged 20-64 years. Individual fixed effects regression models were used to analyze the association between pain and labor outcomes (employment and earnings from employment), as well as potential pathways through which pain might affect employment and earnings., Results: Pain was associated with adverse outcomes varying across severity, corresponding to a reduction of 7-12% in employment and 2-8% in earnings if employed. Pain might affect employment and earnings through increased likelihood of both sickness leave and early retirement., Conclusion: Pain management could potentially be important to improve labor outcomes for adults with CP, in addition to improving the quality of life., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

This study contributes to the research on agency positioning in psychotherapy by looking at how clients and therapists, when discussing the client's difficulties, made use of two specific conversational practices, i.e., different grammatical forms of person reference and changes in footing, and what the consequences of this were for how the clients were positioned in relation to their problematic experiences. A data corpus of the first sessions of nine psychotherapies at a university training clinic in Finland was utilized. The uses of person references and changes in footing in therapists' initiative turns, clients' responses, and therapists' third position (recipient) actions were examined. The analysis showed that in initiative turns therapists usually used the second-person singular, as an invitation for the client to respond from his/her personal point of view, thus ascribing active agency to the client. When telling their problematic experiences, clients typically used so-called zero-person constructions, presenting such experiences as common to people in general, thus lessening their agency and inviting the therapist to share their experiential position. In recipient actions, therapists could use a combination of zero and active person reference which served to communicate an empathic stance and an invitation to the client to take an agentic observer position. Almost exclusively, only therapists used changes in footing. This could happen rapidly within single utterances and serve to express affiliation with the client's emotional experience and to invite or challenge the client to take an observer position. The study supplemented the CA change model with the DA and DSA notions of changes in agency positions as core elements in therapy talk and showed how variations in person references and changes in footing had a decisive influence on how different types of turns functioned within the overall conversational structure of the psychotherapy institution., Competing Interests: The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wahlström.)

Objective: As there is a lack of studies on adolescents and young adults with obesity, the Swedish Youth with Obesity cohort was set up to describe the long-term results of medical, as well as surgical, obesity interventions in youth. This article describes the study protocol., Methods: Since 2018, the study has continuously recruited patients aged between 16 and 25 years who have been admitted for obesity treatment at a specialist obesity clinic in Stockholm, Sweden. Participants provide data from blood tests, questionnaires, and anthropometric measurements. Data are collected longitudinally at enrollment and after 18 months and 3, 4, 5, and 10 years., Results: In the first 500 participants (76% female), the mean age was 21 (SD 3.0) years and the mean BMI was 41.3 (SD 6.1) kg/m 2 at enrollment. Almost half of the participants (44.4%) reported that both parents were born outside the Nordic countries. The proportion of participants who smoked at least sometimes was 28.4%., Conclusions: The longitudinally collected data from the Swedish Youth with Obesity cohort will become a valuable source for answering various research questions regarding long-term results of medical and surgical obesity treatment in adolescents and young adults with obesity., (© 2023 The Authors. Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society.)

The World Health Organization has rated alcohol abuse as one of the leading risk factors for population health worldwide and emphasises the relevance of alcohol affordability (AA) measures as important instruments to monitor alcohol control policy. The present study suggests an AA index that is suitable for measuring AA in Sweden, where off-premises alcohol is exclusively distributed by Systembolaget, the government-owned chain of liquor stores. Sweden provides uniform off-premises prices for alcohol and extensive register data, which profits the accuracy of this index. By allowing for AA comparisons across types of alcoholic beverages (beer, wine, spirits) and price categories, as well as across population groups (age, sex and family composition), and by being transferable to other Nordic countries with uniform off-premises prices, this study will facilitate governmental monitoring and supervision of the alcohol policy in Nordic countries. The suggested AA index is defined as the ratio of the median equivalised disposable income and the price per litre of 100% ethanol for alcohol, scaled to equal 100% in the base year. The income can be measured for the reviewed population or a subgroup, and the price measure can include all sold alcoholic beverages or separate them by beverage type and/or price category. Thereby, the index measures the number of litres of 100% ethanol that are affordable with the median income. Applying the index to the publicly available data for 2011-2019 from Statistics Sweden and Systembolaget reveals that alcohol in Sweden generally became more affordable, with high-priced alcoholic beverages becoming comparably more affordable than low-priced alcohol. However, low-priced beer became less affordable over the last decade. Future studies may validate the AA index against alcohol consumption., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Introduction: To improve the utilization of continuous- and flash glucose monitoring (CGM/FGM) data we have tested the hypothesis that a machine learning (ML) model can be trained to identify the most likely root causes for hypoglycemic events., Methods: CGM/FGM data were collected from 449 patients with type 1 diabetes. Of the 42,120 identified hypoglycemic events, 5041 were randomly selected for classification by two clinicians. Three causes of hypoglycemia were deemed possible to interpret and later validate by insulin and carbohydrate recordings: (1) overestimated bolus (27%), (2) overcorrection of hyperglycemia (29%) and (3) excessive basal insulin presure (44%). The dataset was split into a training (n = 4026 events, 304 patients) and an internal validation dataset (n = 1015 events, 145 patients). A number of ML model architectures were applied and evaluated. A separate dataset was generated from 22 patients (13 'known' and 9 'unknown') with insulin and carbohydrate recordings. Hypoglycemic events from this dataset were also interpreted by five clinicians independently., Results: Of the evaluated ML models, a purpose-built convolutional neural network (HypoCNN) performed best. Masking the time series, adding time features and using class weights improved the performance of this model, resulting in an average area under the curve (AUC) of 0.921 in the original train/test split. In the dataset validated by insulin and carbohydrate recordings (n = 435 events), i.e. 'ground truth,' our HypoCNN model achieved an AUC of 0.917., Conclusions: The findings support the notion that ML models can be trained to interpret CGM/FGM data. Our HypoCNN model provides a robust and accurate method to identify root causes of hypoglycemic events., (© 2023. The Author(s).)

Four different nuclear magnetic resonance (NMR) predictors have been evaluated for their ability to predict 600-MHz 1 H spectra of free fatty acids and fatty acid methyl esters of 20 common fatty acids. The predictors were evaluated on two main criteria: (1) their accuracy in direct prediction of the spectra (absolute accuracy) and (2) the ability to reveal trends or predict the change that occurs in the spectra as a result of a change in the fatty acid carbon chain, or by esterification of the free fatty acids to methyl esters (relative accuracy). The absolute accuracy in chemical shift prediction for fatty acids was good, compared with previous reports on a broader range of compounds. All four predictors had median prediction errors for chemical shifts of the signals in fatty acid methyl esters well below 0.1 ppm and as low as 0.015 ppm for one of the predictors. However, all predictors also had outliers with errors far above the upper interquartile range. In general, they also fail to reproduce trends of diagnostic value that were observed in the experimental data or properly predict the result of a minor change in molecular structure. All four predictors depend on experimental data from different origins. This may be a limiting factor for the relative accuracy of the predictors., (© 2023 John Wiley & Sons Ltd.)

Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Background: Mitral valve surgery is associated with substantial perioperative risk and long-term complications. Data on long-term outcomes following surgery remain scarce and are hypothetically modified by age and comorbidities., Methods: This Danish nationwide study included patients ≥60 years of age undergoing mitral valve surgery from 2000-2018. Patients were observed from day of surgery until outcome of interest (ie, rehospitalization or death) or maximum 1 year of follow-up. The absolute risks of outcomes were assessed, and associated factors were evaluated. Based on age and comorbidities, patients were stratified in 4 groups: low (<75 years + 0 comorbidities), low intermediate (≥75 years/1 comorbidity), high intermediate (≥75 years + 1 comorbidity/2 comorbidities), and high risk of death (≥75 years + ≥2 comorbidities)., Results: In total, 4,202 patients (62.9% men) were identified. Within 1 year after surgery, 504 (12.0%) died and 2,456 (58.5%) were rehospitalized. Factors associated with death included older age (>75 years), chronic obstructive lung disease, heart failure, prior myocardial infarction, prior stroke, liver disease, and kidney disease. The 1-year risks of death among patients in low, low-intermediate, high-intermediate, and high risk of death were 3.6%, 10.3%, 19.6%, and 27.7%, respectively. Diabetes mellitus and chronic obstructive lung disease were associated with an increased incidence of rehospitalization, and the incidence of rehospitalization was similar among the 4 abovementioned groups (57.8%-62.8%)., Conclusions: Mortality and rehospitalization risks after mitral valve surgery varied substantially with age and comorbidities. High-risk patients with >25% 1-year mortality may be easily identified using readily available clinical features., Trial Registration: In Denmark, registry-based studies that are conducted for the sole purpose of statistics and scientific research do not require ethical approval or informed consent by law. However, the study is approved by the data responsible institute (the Capital Region of Denmark [approval number: P-2019-348]) in accordance with the general data protection regulation., Competing Interests: Conflicts of Interest Køber serves as a consultant for Boehringer Ingelheim, and has received other support from AstraZeneca, Novartis, and Novo Nordisk. Fosbøl, Havers-Borgersen, Carranza Butt, and Strange reported no financial interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)