Danish population health measured by the EQ-5D-5L.

AIMS: The aims of this study were to provide Danish population norms for the EQ-5D-5L and to assess the measurement properties of the instrument in a Danish population setting. METHODS: We used data from the Danish 5L valuation study in which a representative sample of the Danish population completed the EQ-5D-5L and answered socio-demographic questions. We generated population norms for the five EQ-5D-5L dimensions, corresponding utility scores and the EQ-5D visual analogue scale (EQ VAS) according to age and sex. Measurement properties of ceiling effects, known-group construct validity and convergent validity were assessed. RESULTS: The mean EQ-5D-5L utility score for the 1014 respondents completing the EQ-5D-5L was 0.90 (standard deviation (SD)=0.16). No significant differences emerged across age groups (minimum mean utility score=0.88 (SD=0.19); maximum mean utility score=0.93 (SD=0.11)) or sex (mean utility score for women=0.89 (SD=0.17); mean utility score for men=0.91 (SD=0.15)). Statistical differences were found across educational level, occupational status, income and living situation. Similar patterns were observed for the EQ VAS. Generally, respondents most often reported problems with pain and discomfort, but young women most often reported problems with anxiety/depression. There was a significant strong correlation between EQ-5D-5L utility and the EQ VAS and a significant correlation between overall health and each of the five EQ-5D-5L dimensions. The overall ceiling effect for the EQ-5D-5L was 39% (compared to 56% for the EQ-5D-3L). CONCLUSIONS: Danish population norms for the EQ-5D-5L are now available. We found fewer ceiling effects for the EQ-5D-5L compared to the EQ-5D-3L, and we provide evidence for convergent and known-group validity of the EQ-5D-5L.

The ZFP-1(AF10)/DOT-1 complex opposes H2B ubiquitination to reduce Pol II transcription.

The inhibition of transcriptional elongation plays an important role in gene regulation in metazoans, including C. elegans. Here, we combine genomic and biochemical approaches to dissect a role of ZFP-1, the C. elegans AF10 homolog, in transcriptional control. We show that ZFP-1 and its interacting partner DOT-1.1 have a global role in negatively modulating the level of polymerase II (Pol II) transcription on essential widely expressed genes. Moreover, the ZFP-1/DOT-1.1 complex contributes to progressive Pol II pausing on essential genes during development and to rapid Pol II pausing during stress response. The slowing down of Pol II transcription by ZFP-1/DOT-1.1 is associated with an increase in H3K79 methylation and a decrease in H2B monoubiquitination, which promotes transcription. We propose a model wherein the recruitment of ZFP-1/DOT-1.1 and deposition of H3K79 methylation at highly expressed genes initiates a negative feedback mechanism for the modulation of their expression.

Diffusion tensor magnetic resonance imaging driven growth modeling for radiotherapy target definition in glioblastoma.

BACKGROUND: The clinical target volume (CTV) in radiotherapy is routinely based on gadolinium contrast enhanced T1 weighted (T1w + Gd) and T2 weighted fluid attenuated inversion recovery (T2w FLAIR) magnetic resonance imaging (MRI) sequences which have been shown to over- or underestimate the microscopic tumor cell spread. Gliomas favor spread along the white matter fiber tracts. Tumor growth models incorporating the MRI diffusion tensors (DTI) allow to account more consistently for the glioma growth. The aim of the study was to investigate the potential of a DTI driven growth model to improve target definition in glioblastoma (GBM). MATERIAL AND METHODS: Eleven GBM patients were scanned using T1w, T2w FLAIR, T1w + Gd and DTI. The brain was segmented into white matter, gray matter and cerebrospinal fluid. The Fisher-Kolmogorov growth model was used assuming uniform proliferation and a difference in white and gray matter diffusion of a ratio of 10. The tensor directionality was tested using an anisotropy weighting parameter set to zero (γ0) and twenty (γ20). The volumetric comparison was performed using Hausdorff distance, Dice similarity coefficient (DSC) and surface area. RESULTS: The median of the standard CTV (CTVstandard) was 180 cm3. The median surface area of CTVstandard was 211 cm2. The median surface area of respective CTVγ0 and CTVγ20 significantly increased to 338 and 376 cm2, respectively. The Hausdorff distance was greater than zero and significantly increased for both CTVγ0 and CTVγ20 with respective median of 18.7 and 25.2 mm. The DSC for both CTVγ0 and CTVγ20 were significantly below one with respective median of 0.74 and 0.72, which means that 74 and 72% of CTVstandard were included in CTVγ0 and CTVγ20, respectively. CONCLUSIONS: DTI driven growth models result in CTVs with a significantly increased surface area, a significantly increased Hausdorff distance and decreased overlap between the standard and model derived volume.

A conserved PHD finger protein and endogenous RNAi modulate insulin signaling in Caenorhabditis elegans.

Insulin signaling has a profound effect on longevity and the oxidative stress resistance of animals. Inhibition of insulin signaling results in the activation of DAF-16/FOXO and SKN-1/Nrf transcription factors and increased animal fitness. By studying the biological functions of the endogenous RNA interference factor RDE-4 and conserved PHD zinc finger protein ZFP-1 (AF10), which regulate overlapping sets of genes in Caenorhabditis elegans, we identified an important role for these factors in the negative modulation of transcription of the insulin/PI3 signaling-dependent kinase PDK-1. Consistently, increased expression of pdk-1 in zfp-1 and rde-4 mutants contributed to their reduced lifespan and sensitivity to oxidative stress and pathogens due to the reduction in the expression of DAF-16 and SKN-1 targets. We found that the function of ZFP-1 in modulating pdk-1 transcription was important for the extended lifespan of the age-1(hx546) reduction-of-function PI3 kinase mutant, since the lifespan of the age-1; zfp-1 double mutant strain was significantly shorter compared to age-1(hx546). We further demonstrate that overexpression of ZFP-1 caused an increased resistance to oxidative stress in a DAF-16-dependent manner. Our findings suggest that epigenetic regulation of key upstream signaling components in signal transduction pathways through chromatin and RNAi may have a large impact on the outcome of signaling and expression of numerous downstream genes.

High-resolution three-dimensional dosimetry in clinically relevant volumes utilizing optically stimulated luminescence.

BACKGROUND: The continued development of new radiotherapy techniques requires dosimetry systems that satisfy increasingly rigorous requirements, such as high sensitivity, wide dose range, and high spatial resolution. An emerging requirement is the ability to read out doses in three dimensions (3D) with high precision and spatial resolution. A few dosimetry systems with 3D capabilities are available, but their application in a clinical workflow is limited for various reasons, primarily originating from their chemical nature. The search for a 3D dosimetry system with potential for clinical implementation is thus ongoing. PURPOSE: To demonstrate the capabilities of a novel optically-stimulated-luminescence (OSL)-based 3D dosimetry system capable of measuring radiation doses in clinically relevant volumes. METHODS: A laser-based readout system was used to measure dose distributions delivered by both photons and protons, utilizing the OSL from a 50 × 50 × 50 $50\times 50\times 50$  mm 3 $^3$ YSO:Ce crystal. A homogeneous treatment plan consisting of two opposing photon fields was used to establish an inhomogeneity correction map of the crystal response and demonstrated the accuracy and precision of the system. The crystal was additionally irradiated with a photon treatment plan consisting of three overlapping 10 × 10 $10\times 10$  mm 2 $^2$ fields delivered from different angles, and a proton treatment plan consisting of four pencil beams with energies 90 MeV ( × 2 $\times 2$ ), 115 MeV, and 140 MeV. The system abilities were quantified by comparing the 3D-resolved measurements to Monte Carlo simulations. RESULTS: The dose map reproducibility of the system was found to be within 2% including both statistical and systematic errors. The measurements yielded integrated doses from a volume of 50 × 50 × 40 $50\times 50\times 40$  mm 3 $^3$ with voxel volumes of just 0.28 × 0.28 × 0.50 $0.28\times 0.28\times 0.50$  mm 3 $^3$ . An excellent agreement between the 3D-resolved measurements and the simulations was found for both photon- and proton-irradiation. CONCLUSIONS: The capabilities of the devised system for measuring clinically relevant fields of photons and proton pencil beams within a clinically relevant volume were demonstrated. The system poses as a promising candidate for clinical applications, and enables future research in the field of OSL-based tissue-equivalent 3D dosimetry.

The Effectiveness of Modular Transdiagnostic Cognitive Behavioral Therapy Versus Treatment as Usual for Youths Displaying School Attendance Problems: A Randomized Controlled Trial.

School attendance problems (SAPs) are associated with negative short- and long-term outcomes. Despite high prevalence of SAPs, there is a shortage of evidence-based interventions. Existing approaches often target either school refusal or truancy, leaving a gap in effective interventions addressing both types of SAPs. This randomized controlled trial (RCT) assessed the effectiveness of Back2School (B2S), a modular transdiagnostic cognitive behavioral therapy (CBT) for SAPs, compared to treatment as usual (TAU). Outcomes included youths' school attendance and mental health. A group (B2S, TAU) × time (Pre, Post, 3-Month Follow-Up) design involving 152 youths (B2S; n = 74, TAU; n = 78) with SAPs (i.e., ≥ 10% absence in the past three months), aged 6-16 years (M = 12.2, SD = 2.2, males = 60%) were used. B2S comprised three months of CBT with youths, parents, and school involvement, while TAU comprised public and/or private intervention services. On average, youths in B2S received 15.0, (SD = 3.9) hours of intervention, while those in TAU received 13.4, (SD = 21.6). Intervention effects were investigated using mixed linear models. Both B2S and TAU exhibited significant within-group improvements in school attendance, with no significant differences between them. However, the B2S group significantly outperformed TAU in reducing youths' emotional problems, conduct problems, problems with peers, the overall impact of problems, and increasing youths self-efficacy for attending school and parent self-efficacy for dealing with a SAP. This RCT represents the first evaluation of a modular transdiagnostic CBT for youths displaying SAPs, showing significant mental health and self-efficacy benefits.  (Clinical trial registration: ClinicalTrials.gov: NCT03459677).

Adherence in Diabetes Questionnaire (ADQ) score as predictor of 11-year HbA1c trajectories in children and adolescents with type 1 diabetes: A population-based longitudinal study.

AIMS: To identify 11-year HbA1c trajectories in children/adolescents with type 1 diabetes and determine whether baseline caregiver- and/or child/adolescent-reported Adherence in Diabetes Questionnaire (ADQ) scores and multiple covariates predict HbA1c trajectory membership. METHODS: For a 2009 population-based cohort of children/adolescents with type 1 diabetes, we analyzed HbA1c follow-up (2010-2020) data from Danish diabetes registries. HbA1c trajectories were identified with group-based trajectory modeling. Using multinomial logistic regression, we tested whether ADQ scores predicted trajectory membership when adjusting for sex, age at diabetes diagnosis, diabetes duration, family structure, and caregiver education. RESULTS: For 671 children/adolescents (10-17 years at baseline) with 5644 HbA1c observations over 11 years, four trajectories/groups were identified: 1) "on target, gradual decrease" (27%), 2) "above target, mild increase then decrease" (39%), 3) "above target, moderate increase then decrease" (25%), and 4) "well above target, large increase then decrease" (9%). Using group one as the reference, lower caregiver-reported ADQ scores predicted group 2, 3, and 4 membership. Lower child/adolescent-reported ADQ scores predicted group 3 and 4 membership. Low caregiver education predicted group 3 and 4 membership. Single-parent status predicted group 4 membership. CONCLUSIONS: ADQ scores and socio-demographics may serve as tools to predict glycemic control in youth with type 1 diabetes.

Associations between disordered eating behaviors and HbA1c in young people with type 1 diabetes: a systematic review and meta-analysis.

BACKGROUND: In type 1 diabetes, disordered eating behaviors (DEBs) can adversely impact HbA1c. Diabetes-adapted DEB questionnaires assess intentional insulin omission, whereas generic questionnaires do not. Given the number of studies describing DEB-HbA1c associations published over the past decade, an updated systematic review is warranted. OBJECTIVE: The study aimed to examine the associations between disordered eating behaviors (DEBs) assessed by generic and diabetes-adapted questionnaires (and subscales) and HbA1c among young people (<29 years) with type 1 diabetes. METHODS: A systematic search was conducted in PubMed, Embase, PsycInfo, and CINAHL databases. Observational studies examining associations between DEB as assessed by questionnaires and HbA1c were included. Publication information, DEB and HbA1c characteristics, and DEB-HbA1c associations were extracted. Hedges' g was calculated for mean HbA1c differences between groups with and without DEB. RESULTS: The systematic search yielded 733 reports, of which 39 reports representing 35 unique studies met the inclusion criteria. Nineteen studies assessing DEB by diabetes-adapted questionnaires (n=5,795) and seven using generic questionnaires (n=2,162) provided data for meta-analysis. For diabetes-adapted questionnaires, DEB was associated with higher HbA1c (g=0.62 CI=0.52; 0.73) with a similar effect size when restricted to validated questionnaires (g=0.61; CI=0.50; 0.73). DEB was not associated with HbA1c for generic questionnaires (g=0.19; CI=-0.17; 0.55), but significantly associated with higher HbA1c for validated generic questionnaires (g=0.32; 95% CI=0.16-0.48). Participant and HbA1c collection characteristics were often inadequately described. CONCLUSION: Diabetes-adapted DEB questionnaires should be used in youth with type 1 diabetes because they capture intentional insulin omission and are more strongly associated with HbA1c than generic DEB questionnaires.

Responses to the Strengths and Difficulties Questionnaire predict HbA1c trajectories in children and adolescents with type 1 diabetes: a population-based study.

INTRODUCTION: We aimed to determine whether caregiver responses to the Strengths and Difficulties Questionnaire (SDQ) are predictive of HbA1c trajectory membership in children and adolescents with type 1 diabetes, when adjusting for covariates. RESEARCH DESIGN AND METHODS: For a Danish 2009 national cohort of children and adolescents with type 1 diabetes, we analyzed yearly HbA1c follow-up data during 2010-2020 including sociodemographic data from Danish national registries. Using group-based trajectory modeling and multinomial logistic regression, we tested whether caregiver SDQ scores predicted HbA1c trajectory membership when adjusting for sex, age at diabetes diagnosis, diabetes duration, family structure, and caregiver education. RESULTS: In total, 835 children and adolescents (52% females) with a mean (SD) age of 12.5 (3.3) years, and a mean diabetes duration of 5.2 (3.1) years, were included. Based on 7247 HbA1c observations, four HbA1c trajectories were identified: (1) 'on target, gradual decrease' (26%), (2) 'above target, mild increase then decrease' (41%), (3) 'above target, moderate increase then decrease' (24%), and (4) 'well above target, large increase then decrease' (9%). Higher SDQ total difficulties scores predicted trajectories 3 and 4 (p=0.0002 and p<0.0001, respectively). Regarding the SDQ subscale scores, emotional symptoms predicted trajectories 3 and 4, and conduct problems and hyperactivity/inattention predicted trajectories 2, 3, and 4. Single-parent family and low caregiver education level both predicted trajectories 3 and 4. CONCLUSIONS: Caregiver SDQ responses and sociodemographic information may help detect children and adolescents with type 1 diabetes, who need intensive multidisciplinary medical and psychological interventions.

Competitive tenders on analogue hospital pharmaceuticals in Denmark 2017-2020.

BACKGROUND: Competitive tenders on pharmaceuticals are one of the most effective cost-containment instruments in healthcare systems. Its effectiveness has been demonstrated, among other things, in markets for generic medicine and biosimilars. In Denmark, an internationally unique model for competitive tenders on analogue substitutable pharmaceuticals has been developed and implemented for all public hospitals. METHODS: We obtained data on all analogue competitive tenders carried out by the Danish Medicines Council from its foundation on January 1, 2017, to October 9, 2020. We calculated univariate descriptive statistics, pairwise correlations and made a multiple regression analysis on tender savings. RESULTS: Average annual saving on hospital pharmaceutical purchase prices was 44.1% ranging from 0.4% to 92.8% between therapeutic areas and areas of indication. There was a significant positive correlation between tender savings and the number of competitors participating in the tender, and a significant negative correlation between tender savings and the number of days since market authorization. CONCLUSIONS: This study finds analogue tenders to be similar in effect and mechanism to competitive tenders in markets for generic medicine and biosimilars. It supports the increasing number of empirical findings that competitive tendering has a high potential to generate substantial savings on healthcare budgets.

Sociodemographic and clinical characteristics of youths and parents seeking psychological treatment for school attendance problems.

BACKGROUND: Knowledge of school attendance problems (SAPs) is needed to inform treatments targeting SAPs and protecting youths from negative outcomes associated with SAPs. OBJECTIVES: This study examined the school absence, absence categories (i.e., absence due to illness, excused, non-excused), sociodemographic characteristics, and mental health problems among youths seeking psychological treatment for SAPs. METHODS: The study used a cross-sectional design. Sociodemographic and clinical characteristics of 152 help-seeking youths with SAPs (i.e., >10% absenteeism) and their parents were examined. The data were derived from the baseline assessment conducted before treatment start. RESULTS: Older youths, youths with mental health problems, and youths whose parents had mental health problems exhibited higher levels of absence. Lower levels of non-excused absence were found among youths with highly educated fathers, and youths living with both parents. Many youths had clinical levels of anxiety, depression, or 'emotional and behavioral difficulties'. CONCLUSION: The study highlights the need for early intervention, addressing a broad range of mental health problems. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT03459677.

Non-ablative doses of focal ionizing radiation alters function of central neural circuits.

BACKGROUND: Modulation of pathological neural circuit activity in the brain with a minimum of complications is an area of intense interest. OBJECTIVE: The goal of the study was to alter neurons' physiological states without apparent damage of cellular integrity using stereotactic radiosurgery (SRS). METHODS: We treated a 7.5 mm-diameter target on the visual cortex of Göttingen minipigs with doses of 40, 60, 80, and 100 Gy. Six months post-irradiation, the pigs were implanted with a 9 mm-wide, eight-shank multi-electrode probe, which spanned the radiation focus as well as the low-exposure neighboring areas. RESULTS: Doses of 40 Gy led to an increase of spontaneous firing rate, six months post-irradiation, while doses of 60 Gy and greater were associated with a decrease. Subjecting the animals to visual stimuli resulted in typical visual evoked potentials (VEP). At 40 Gy, a significant reduction of the P1 peak time, indicative of higher network excitability was observed. At 80 Gy, P1 peak time was not affected, while a minor reduction at 60 Gy was seen. No distance-dependent effects on spontaneous firing rate, or on VEP were observed. Post-mortem histology revealed no evidence of necrosis at doses below 60 Gy. In an in vitro assay comprising of iPS-derived human neuron-astrocyte co-cultures, we found a higher vulnerability of inhibitory neurons than excitatory neurons with respect to radiation, which might provide the cellular mechanism of the disinhibitory effect observed in vivo. CONCLUSION: We provide initial evidence for a rather circuit-wide, long-lasting disinhibitory effect of low sub-ablative doses of SRS.

Overeating, binge eating, quality of life, emotional difficulties, and HbA1c in adolescents with type 1 diabetes: A Danish national survey.

AIMS: To determine 1) the prevalence of symptoms of overeating (OE), subclinical binge eating (SBE) and clinical binge eating (CBE), in adolescents with type 1 diabetes (T1D), and 2) their associations with quality of life (QoL), anxiety, depression, HbA1c, and body mass index standard deviation score (BMISDS). METHODS: In total 506 adolescents (age 12-17 years; mean 14.7 years; girls 49%) from the Danish Registry for Diabetes in Childhood and Adolescence (DanDiabKids) were included. Participants completed questionnaires on disordered eating, QoL, and emotional difficulties. A blood sample was sent for HbA1c determination. BMISDS was determined from the DanDiabKids data. RESULTS: Prevalence rates of OE, SBE, and CBE were 8.4%, 18% and 7.9% respectively. Youth with CBE symptoms scored lowest on generic and diabetes specific QoL, highest on anxiety and depression symptoms, and had a higher HbA1c. Youth with CBE had borderline increased BMISDS. CONCLUSIONS: In a Danish national survey of adolescents with T1D, approximately one-third of participants had overeating or binge eating symptoms, comparable with the numbers in a U.S T2D population. Increased binge eating symptoms associated with lower QoL, higher depression scores, higher anxiety scores, and poorer clinical outcomes. Binge eating symptoms were markers for poor mental and somatic health.

Applicant Fairness Perceptions of a Robot-Mediated Job Interview: A Video Vignette-Based Experimental Survey.

It is well-established in the literature that biases (e. g., related to body size, ethnicity, race etc.) can occur during the employment interview and that applicants' fairness perceptions related to selection procedures can influence attitudes, intentions, and behaviors toward the recruiting organization. This study explores how social robotics may affect this situation. Using an online, video vignette-based experimental survey (n = 235), the study examines applicant fairness perceptions of two types of job interviews: a face-to-face and a robot-mediated interview. To reduce the risk of socially desirable responses, desensitize the topic, and detect any inconsistencies in the respondents' reactions to vignette scenarios, the study employs a first-person and a third-person perspective. In the robot-mediated interview, two teleoperated robots are used as fair proxies for the applicant and the interviewer, thus providing symmetrical visual anonymity unlike prior research that relied on asymmetrical anonymity, in which only one party was anonymized. This design is intended to eliminate visual cues that typically cause implicit biases and discrimination of applicants, but also to prevent biasing the interviewer's assessment through impression management tactics typically used by applicants. We hypothesize that fairness perception (i.e., procedural fairness and interactional fairness) and behavioral intentions (i.e., intentions of job acceptance, reapplication intentions, and recommendation intentions) will be higher in a robot-mediated job interview than in a face-to-face job interview, and that this effect will be stronger for introvert applicants. The study shows, contrary to our expectations, that the face-to-face interview is perceived as fairer, and that the applicant's personality (introvert vs. extravert) does not affect this perception. We discuss this finding and its implications, and address avenues for future research.

Dose response of three-dimensional silicone-based radiochromic dosimeters for photon irradiation in the presence of a magnetic field.

The magnetic field in magnetic resonance imaging guided radiotherapy (MRgRT) delivery systems influences charged-particle trajectories and hence the three-dimensional (3D) radiation dose distributions. This study investigated the dose-response as well as dose-rate and fractionation dependencies of silicone-based 3D radiochromic dosimeters for photon irradiation in a magnetic field using a 0.35 T MRgRT system. We found a linear dose response up to 22.6 Gy and no significant dose-rate dependency as a function of depth. A difference in optical response was observed for dosimeters irradiated in a single compared to multiple fractions. The dosimeter showed clinical potential for verification of MRgRT delivery.

CO2 sorption on MgO and CaO surfaces: a comparative quantum chemical cluster study.

A comparative quantum chemical study of CO2 adsorption on MgO and CaO has been carried out. Theoretical infrared (IR) frequencies are calculated and compared with IR experiments from the literature. The results show that CO2 adsorbs as monodentate on edge sites and bidentate on corner sites on MgO. The former assignment contradicts the common assumption of adsorption of CO2 in a bidentate configuration. On CaO, CO2 adsorbs as monodentate on both edge and corner sites, which is a reinterpretation of earlier experimental work. On terrace (100) sites, none of the adsorption modes on MgO or CaO possess calculated frequencies in agreement with the experimental IR spectra. These experimental bands were tentatively assigned to some slightly perturbed double negatively charged carbonate ions at the surface, rather than the monodentate structure suggested in the literature.

Mechanisms of change in cognitive behaviour therapy for panic disorder: the role of panic self-efficacy and catastrophic misinterpretations.

The efficacy of cognitive behavioural therapy (CBT) for panic disorder with or without agoraphobia (PD) is well-established; however, little is known about the underlying change processes of clinical improvement during therapy. According to cognitive theories, CBT for PD primarily works by changing catastrophic misinterpretations of bodily symptoms and panic attacks. However, panic self-efficacy, i.e. the perceived ability to cope with panic attacks, has also been suggested as an important change mechanism in CBT for PD. The aim of the study was to investigate if change in catastrophic misinterpretations and panic self-efficacy mediated change in the level of anxiety during the course of thirteen sessions of group CBT for PD. Forty-five participants completed weekly self-report measures of the possible cognitive mediators and the level of anxiety throughout therapy. The results indicated that within-person change in panic self-efficacy in one session, but not in catastrophic misinterpretations, predicted within-person level of anxiety symptoms the following week. However, in a reversed analysis, prior change in level of anxiety symptoms also predicted change in panic self-efficacy the following session. These results support panic self-efficacy as a mediator of change in CBT for PD, although a reciprocal causal relationship between panic self-efficacy and level of anxiety seems to be implied.