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The energy metabolism of the brain is poorly understood partly due to the complex morphology of neurons and fluctuations in ATP demand over time. To investigate this, we used metabolic models that estimate enzyme usage per pathway, enzyme utilization over time, and enzyme transportation to evaluate how these parameters and processes affect ATP costs for enzyme synthesis and transportation. Our models show that the total enzyme maintenance energy expenditure of the human body depends on how glycolysis and mitochondrial respiration are distributed both across and within cell types in the brain. We suggest that brain metabolism is optimized to minimize the ATP maintenance cost by distributing the different ATP generation pathways in an advantageous way across cell types and potentially also across synapses within the same cell. Our models support this hypothesis by predicting export of lactate from both neurons and astrocytes during peak ATP demand, reproducing results from experimental measurements reported in the literature. Furthermore, our models provide potential explanation for parts of the astrocyte-neuron lactate shuttle theory, which is recapitulated under some conditions in the brain, while contradicting other aspects of the theory. We conclude that enzyme usage per pathway, enzyme utilization over time, and enzyme transportation are important factors for defining the optimal distribution of ATP production pathways, opening a broad avenue to explore in brain metabolism., Competing Interests: Competing interests statement:The authors declare no competing interest.

The tumor microenvironment is composed of a complex mixture of different cell types interacting under conditions of nutrient deprivation, but the metabolism therein is not fully understood due to difficulties in measuring metabolic fluxes and exchange of metabolites between different cell types in vivo . Genome-scale metabolic modeling enables estimation of such exchange fluxes as well as an opportunity to gain insight into the metabolic behavior of individual cell types. Here, we estimated the availability of nutrients and oxygen within the tumor microenvironment using concentration measurements from blood together with a metabolite diffusion model. In addition, we developed an approach to efficiently apply enzyme usage constraints in a comprehensive metabolic model of human cells. The combined modeling reproduced severe hypoxic conditions and the Warburg effect, and we found that limitations in enzymatic capacity contribute to cancer cells' preferential use of glutamine as a substrate to the citric acid cycle. Furthermore, we investigated the common hypothesis that some stromal cells are exploited by cancer cells to produce metabolites useful for the cancer cells. We identified over 200 potential metabolites that could support collaboration between cancer cells and cancer-associated fibroblasts, but when limiting to metabolites previously identified to participate in such collaboration, no growth advantage was observed. Our work highlights the importance of enzymatic capacity limitations for cell behaviors and exemplifies the utility of enzyme-constrained models for accurate prediction of metabolism in cells and tumor microenvironments., Competing Interests: The authors declare no competing interests., (© 2024 The Authors.)

Background: A 3D printing grid-based method was developed to construct anthropomorphic phantoms with non-uniform activity distributions, to be used for evaluation of quantitative SPECT images. The aims were to characterize the grid-based method and to evaluate its capability to provide realistically shaped phantoms with non-uniform activity distributions., Methods: Characterization of the grid structures was performed by printing grid-filled spheres. Evaluation was performed by micro-CT imaging to investigate the printing accuracy and by studying the modulation contrast ([Formula: see text]) in SPECT images for 177 Lu and 99m Tc as a function of the grid fillable-volume fraction (FVF) determined from weighing. The grid-based technique was applied for the construction of two kidney phantoms and two thyroid phantoms, designed using templates from the XCAT digital phantoms. The kidneys were constructed with a hollow outer container shaped as cortex, an inner grid-based structure representing medulla and a solid section representing pelvis. The thyroids consisted of two lobes printed as grid-based structures, with void hot spots within the lobes. The phantoms were filled with solutions of 177 Lu (kidneys) or 99m Tc (thyroids) and imaged with SPECT. For verification, Monte Carlo simulations of SPECT imaging were performed for activity distributions corresponding to those of the printed phantoms. Measured and simulated SPECT images were compared qualitatively and quantitatively., Results: Micro-CT images showed that printing inaccuracies were mainly uniform across the grid. The relationships between the FVF from weighing and [Formula: see text] were found to be linear (r = 0.9995 and r = 0.9993 for 177 Lu and 99m Tc, respectively). The FVF-deviations from the design were up to 15% for thyroids and 4% for kidneys, mainly related to possibilities of cleaning after printing. Measured and simulated SPECT images of kidneys and thyroids exhibited similar activity distributions and quantitative comparisons agreed well, thus verifying the grid-based method., Conclusions: We find the grid-based technique useful for the provision of 3D printed, realistically shaped, phantoms with non-uniform activity distributions, which can be used for evaluation of different quantitative methods in SPECT imaging., (© 2024. The Author(s).)

Background: Persons with hearing loss (HL) are a vulnerable group in working life. Studies have shown that they are more likely than the general population to be in part-time work, to be unemployed, receive disability pension, and to be on sick leave. Many workers with HL also experience unhealthy work conditions, such as jobs where they experience high demands combined with low control as well as safety concerns and social isolation. There is a lack of studies that focus on factors that promote a healthy, sustainable work situation for the target group., Objective: To investigate health factors that contribute to a sustainable work situation for employees with HL., Methods: The current study was a comparative, observational study with a cross-sectional design including a clinical population of adults with HL. Comparisons were made between workers with HL "in work" and workers with HL on "HL-related sick leave"., Results: Seven health factors were identified. Those "in work" experienced a healthier work environment as well as lower levels of mental strain, hearing-related work characteristics and content, cognitively demanding work content, hearing-related symptoms, energy-demanding activities, and bodily aches and pain than those on "HL-related sick leave"., Conclusion: The results demonstrate a clear pattern regarding health factors for a sustainable working life. The type of job was not related to whether an individual was on sick leave or working. Rather, the work climate and the content of the work mattered.

Introduction: The activity meter is used to determine the activity of delivered radiopharmaceuticals, administered activity to patients and reference activity when gamma-cameras are calibrated prior to imaged-based dosimetry. The aim is to describe a procedure for cross-calibration of activity meters at different clinical sites, and report on 177 Lu activity results when using factory-set calibration factors compared to when calibration is performed with traceability to a primary standard., Methods: Thirty activity meters placed at seven hospitals in Norway and Sweden from four manufacturers: Capintec, Commecer, NuviaTech and Veenstra were included. A stock solution with 177 Lu was prepared at the local sites and measured in each activity meter with factory settings. The solution was shipped to the reference site at Lund University for measurements in a secondary standard activity meter. Deviations between local and reference activity measurements were determined for three geometries: 25-mL vial, 10-mL syringe and 1-mL syringe., Results: The median of the deviations was 6.4 % for the 25 mL vial, 5.9 % for the 10 mL syringe and 6.8 % for the 1 mL syringe. The median of the deviations for the 25 mL vial, was 1.5 % for activity meters from Capintec, 7.0 % for Comecer, 11.0 % for NuviaTech and 2.4 % for Veenstra. The majority of the deviations were positive and the maximum deviation was 14.5 %., Conclusion: The activity of 177 Lu measured in an activity meter with factory-set dial settings may yield deviations up to 14.5%, compared to activities measured with traceability to a primary standard. This would imply an undertreatment of patients., 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 © 2023. Published by Elsevier Ltd.)

Molecular radiotherapy is rapidly expanding, and new radiotherapeutics are emerging. The majority of treatments is still performed using empirical fixed activities and not tailored for individual patients. Molecular radiotherapy dosimetry is often seen as a promising candidate that would allow personalisation of treatments as outcome should ultimately depend on the absorbed doses delivered and not the activities administered. The field of molecular radiotherapy dosimetry has made considerable progress towards the feasibility of routine clinical dosimetry with reasonably accurate absorbed-dose estimates for a range of molecular radiotherapy dosimetry applications. A range of challenges remain with respect to the accurate quantification, assessment of time-integrated activity and absorbed dose estimation. In this review, we summarise a range of technological and methodological advancements, mainly focussed on beta-emitting molecular radiotherapeutics, that aim to improve molecular radiotherapy dosimetry to achieve accurate, reproducible, and streamlined dosimetry. We describe how these new technologies can potentially improve the often time-consuming considered process of dosimetry and provide suggestions as to what further developments might be required., 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 © 2023 Associazione Italiana di Fisica Medica e Sanitaria. Published by Elsevier Ltd. All rights reserved.)

Objectives: Self-assessment instruments are commonly used in audiological rehabilitation. However, several studies highlight the lack of multidimensionality in existing outcome measures, with the consequence that they only partially capture aspects of functioning in everyday life for people living with hearing loss. This study aimed to develop and investigate the content validity of a self-assessment instrument based on the validated Brief International Classification of Functioning, Disability, and Health Core Set for Hearing Loss., Design: The design was a two-part instrument development study. The first part focused on the item-generation process of the instrument, named the Hearing and Functioning in Everyday Life Questionnaire (HFEQ) during an experts' workshop. The second part focused on international content validation of the instrument using group interviews. Strategic sampling was used and 30 adults with hearing loss from India, South Africa, and the United States participated in the group interviews., Results: The expert's workshop resulted in the first version of the HFEQ containing 30 items. The results from group interviews show that the content of the HFEQ was considered to be valid concerning its relevance, comprehensiveness, and comprehensibility. A majority (73%) of the HFEQ items were perceived by the participants as relevant and easy to comprehend. For the remaining 27% of the items, the content was perceived to be relevant in all countries, but some terms and expressions were reported to require rewording or clearer examples. These modifications will be made in the next step of the development process., Conclusion: Content validation of the HFEQ demonstrates promising results, with participants perceiving the content as relevant and comprehensible. Further psychometric validation is required to investigate other psychometric properties, such as construct validity and reliability. The HFEQ has the potential to become a valuable new instrument for assessing everyday functioning in people with hearing loss in audiological rehabilitation and in research., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Dosimetry in radionuclide therapy often requires the calculation of average absorbed doses within and between spatial regions, for example, for voxel-based dosimetry methods, for paired organs, or across multiple tumors. Formation of such averages can be made in different ways, starting from different definitions., Purpose: The aim of this study is to formally specify different averaging strategies for absorbed doses, and to compare their results when applied to absorbed dose distributions that are non-uniform within and between regions., Methods: For averaging within regions, two definitions of the average absorbed dose are considered: the simple average over the region (the region average) and the average when weighting by the mass density (density-weighted region average). The latter is shown to follow from the definition of mean absorbed dose according to the ICRU, and to be consistent with the MIRD formalism. For averaging between different spatial regions, three definitions follow: the volume-weighted, the mass-weighted, and the unweighted average. With respect to characterizing non-uniformity, the different average definitions lead to the use of dose-volume histograms (DVHs) (region average), dose-mass histograms (DMHs) (density-weighted region average), and unweighted histograms (unweighted average). Average absorbed doses are calculated for three worked examples, starting from the different definitions. The first, schematic, example concerns the calculation of the average absorbed dose between two regions with different volumes or mass densities. The second, stylized, example concerns voxel-based dosimetry, for which the average absorbed-dose rate within a region is calculated. The geometries studied include three 177 Lu-filled voxelized spheres, where the sphere masses are held constant while the material compositions, densities, and volumes are varied. For comparison, the mean absorbed-dose rates obtained using unit-density sphere S-values are also included. The third example concerns SPECT/CT-based tumor dosimetry for five patients undergoing therapy with 177 Lu-PSMA and six patients undergoing therapy with 177 Lu-DOTA-TATE, for which the average absorbed-dose rates across multiple tumors are calculated. For the second and third examples, analyses also include representations by histograms., Results: Example 1 shows that the average absorbed doses, calculated using different definitions, can differ considerably if the masses and absorbed doses for two regions are markedly different. From example 2 it is seen that the density-weighted region average is stable under different activity and density distributions and is also in line with results using S-values. In contrast, the region average varies as function of the activity distribution. In example 3, the absorbed dose rates for individual tumors differ by (1.1 ± 4.3)% and (-0.1 ± 0.4)% with maximum deviations of +34.4% and -1.4% for 177 Lu-PSMA and 177 Lu-DOTA-TATE, respectively, when calculated as region averages or density-weighted region averages, with largest deviations obtained when the density is non-uniform. The average absorbed doses calculated across all tumors are similar when comparing mass-weighted and volume-weighted averages but these differ substantially from unweighted averages., Conclusion: Different strategies for averaging of absorbed doses within and between regions can lead to substantially different absorbed-dose estimates. At reporting of radionuclide therapy dosimetry, it is important to specify the averaging strategy applied., (© 2023 The Authors. Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

One example of a PET exam that suffers from noise problems is [ 68 Ga]Ga-DOTA-TOC, where patients are generally administered between 100 and 200 MBq [ 68 Ga]Ga-DOTA-TOC, irrespective of size. However, a fixed activity can result in low signal-to-noise ratios (SNRs) in larger patients. This study aimed to evaluate the impact on image quality with respect to injected activity and patient habitus through Monte Carlo (MC) simulation. Eight anthropomorphic computer phantoms with body mass indices (BMIs) between 19 kg/m 2 and 38 kg/m 2 and tumours distributed in the liver were simulated using the MC software Gate v8.2 with an activity distribution defined according to [ 68 Ga]Ga-DOTA-TOC standardised uptake values. Three activity-administration protocols were simulated: (i) with a fixed activity of 100 MBq, (ii) with the activity scaled by 2 MBq/kg, and (iii) with the activity scaled by a body size-dependent power-function based on the SNR obtained with (ii). BMI, weight, body surface area, and abdominal circumference were evaluated body size parameters. Images were reconstructed with the CASToR software and evaluated for background SNR and lesion contrast-to-noise ratio (CNR). Large SNR variabilities were obtained with protocols (i) and (ii), while (iii) generated good consistency. Several tumours failed to reach a CNR of 5 for large phantoms with protocol (i), but the CNR was generally improved by (ii) and (iii). An activity scaled by patient habitus generate better image quality consistency, which increases the likelihood that patients receive a similar standard of care., 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., (© 2023 The Authors.)

Background: Research has indicated that the effectiveness of intervention programs is affected by how well these programs are implemented, but key gaps remain in our understanding of the factors that promote or inhibit implementation. This study examined how demographic characteristics and perceived work environment among early childhood educators were associated with implementation outcomes of the Increased Health and Wellbeing in Preschools (DAGIS) intervention, which was conducted as a cluster randomized trial., Methods: Participants included 101 educators from 32 intervention preschool classrooms. Data were analyzed at the classroom level, as the DAGIS intervention was delivered in preschool classrooms consisting of several educators instead of individual implementers. Linear regression was used to estimate the associations of educators' demographic characteristics and perceived work environment with different aspects of implementation (i.e., dose delivered; dose received - exposure; dose received - satisfaction; and perceived quality, as well as a total sum score based on these four dimensions). Municipality was controlled in the adjusted models., Results: Findings indicated that having a higher proportion of educators with a Bachelor's or Master's degree in education within the classroom was associated with higher dose received - exposure and higher total degree of implementation, and the significance of the models was unaffected by adjustment for municipality. Moreover, having a higher proportion of educators younger than 35 years within the classroom was associated with higher dose received - exposure. However, the association was non-significant when adjusted for municipality. No other educator factor (i.e., work experience in years and perceived support from coworkers, group work, and innovative climate) predicted implementation outcomes., Conclusions: Higher educational attainment and younger age among educators at the classroom level were associated with higher scores for some of the implementation outcomes. Educators' work experience in years at the current preschool and in early childhood education, support from coworkers, group work, and innovative climate were not significantly associated with any implementation outcomes. Future research should explore ways to improve educators' implementation of interventions aimed at promoting children's health behaviors., (© 2023. The Author(s).)

Objective. The aim was to theoretically and experimentally investigate recovery in SPECT images with objects of different shapes. Furthermore, the accuracy of volume estimation by thresholding was studied for those shapes. Approach. Nine spheres, nine oblate spheroids, and nine prolate spheroids phantom inserts were used, of which the six smaller spheres were part of the NEMA IEC body phantom and the rest of the inserts were 3D-printed. The inserts were filled with 99m Tc and 177 Lu. When filled with 99m Tc, SPECT images were acquired in a Siemens Symbia Intevo Bold gamma camera and when filled with 177 Lu in a General Electric NM/CT 870 DR gamma camera. The signal rate per activity (SRPA) was determined for all inserts and represented as a function of the volume-to-surface ratio and of the volume-equivalent radius using VOIs defined according to the sphere dimensions and VOIs defined using thresholding. Experimental values were compared with theoretical curves obtained analytically (spheres) or numerically (spheroids), starting from the convolution of a source distribution with a point-spread function. Validation of the activity estimation strategy was performed using four 3D-printed ellipsoids. Lastly, the threshold values necessary to determine the volume of each insert were obtained. Main results. Results showed that SRPA values for the oblate spheroids diverted from the other inserts, when SRPA were represented as a function of the volume-equivalent radius. However, SRPA values for all inserts followed a similar behaviour when represented as a function of the volume-to-surface ratio. Results for ellipsoids were in agreement with those results. For the three types of inserts the volume could be accurately estimated using a threshold method for volumes larger than 25 ml. Significance. Determination of SRPA independently of lesion or organ shape should decrease uncertainties in estimated activities and thereby, in the long term, be beneficial to patient care., (© 2023 Institute of Physics and Engineering in Medicine.)

Background: The COVID-19 pandemic has had implications for adolescents' interpersonal relationships, communication patterns, education, recreational activities and well-being. An understanding of the impact of the pandemic on their mental health is crucial in measures to promote the post-pandemic recovery. Using a person-centered approach, the current study aimed to identify mental health profiles in two cross-sectional samples of Finnish adolescents before and after the peak of the pandemic, and to examine how socio-demographic and psychosocial factors, academic expectations, health literacy, and self-rated health are associated with the emerging profiles., Methods and Findings: Survey data from the Health Behaviour in School-aged Children (HBSC) study conducted in Finland in 2018 (N = 3498, age M = 13.44) and 2022 (N = 3838, age M = 13.21) were analyzed. A four-profile model using cluster analysis was selected for both samples. In Sample 1, the identified profiles were (1) "Good mental health", (2) "Mixed psychosocial health", (3) "Somatically challenged", and (4) "Poor mental health". In Sample 2, the identified profiles were (1) "Good mental health", (2) "Mixed psychosomatic health", (3) "Poor mental health and low loneliness", and (4) "Poor mental health and high loneliness". The results of the mixed effect multinomial logistic regression analysis showed that in both samples, being a girl and reporting lower maternal monitoring; lower family, peer, and teacher support; higher intensity of online communication; a less positive home atmosphere and school climate; and poor self-rated health were most strongly linked to belonging to a poorer mental health profile. In addition, in Sample 2, low subjective health literacy was a key factor associated with poorer mental health profiles, and teacher support was more important than before COVID., Conclusions: The current study stresses the importance of identifying those vulnerable to developing poor mental health. To maximize post-pandemic recovery, the role of schools, especially teacher support and health literacy, along with the factors that remained important over time should be taken into account in public health and health promotion interventions., (© 2023. The Author(s).)

Single-cell RNA sequencing combined with genome-scale metabolic models (GEMs) has the potential to unravel the differences in metabolism across both cell types and cell states but requires new computational methods. Here, we present a method for generating cell-type-specific genome-scale models from clusters of single-cell RNA-Seq profiles. Specifically, we developed a method to estimate the minimum number of cells required to pool to obtain stable models, a bootstrapping strategy for estimating statistical inference, and a faster version of the task-driven integrative network inference for tissues algorithm for generating context-specific GEMs. In addition, we evaluated the effect of different RNA-Seq normalization methods on model topology and differences in models generated from single-cell and bulk RNA-Seq data. We applied our methods on data from mouse cortex neurons and cells from the tumor microenvironment of lung cancer and in both cases found that almost every cell subtype had a unique metabolic profile. In addition, our approach was able to detect cancer-associated metabolic differences between cancer cells and healthy cells, showcasing its utility. We also contextualized models from 202 single-cell clusters across 19 human organs using data from Human Protein Atlas and made these available in the web portal Metabolic Atlas, thereby providing a valuable resource to the scientific community. With the ever-increasing availability of single-cell RNA-Seq datasets and continuously improved GEMs, their combination holds promise to become an important approach in the study of human metabolism.

Hydroxylated polybrominated diphenyl ethers (OH-PBDEs) are formed by metabolism from the flame retardants polybrominated diphenyl ethers (PBDEs). In the aquatic environment, they are also produced naturally. OH-PBDEs are known for their potential to disrupt energy metabolism, the endocrine system, and the nervous system. This is the first study focusing on the effects of OH-PBDEs at the metabolite level in vivo. The aim of the current study was to investigate the metabolic effects of exposure to OH-PBDEs using metabolomics, and to identify potential biomarker(s) for energy disruption of OH-PBDEs. Zebrafish (Danio rerio) embryos were exposed to two different concentrations of 6-OH-BDE47 and 6-OH-BDE85 and a mixture of these two compounds. In total, 342 metabolites were annotated and 79 metabolites were affected in at least one exposure. Several affected metabolites, e.g. succinic acid, glutamic acid, glutamine, tyrosine, tryptophan, adenine, and several fatty acids, could be connected to known toxic mechanisms of OH-PBDEs. Several phospholipids were strongly up-regulated with up to a six-fold increase after exposure to 6-OH-BDE47, a scarcely described effect of OH-PBDEs. Based on the observed metabolic effects, a possible connection between disruption of the energy metabolism, neurotoxicity and potential immunotoxicity of OH-PBDEs was suggested. Single compound exposures to 6-OH-BDE47 and 6-OH-BDE85 showed little overlap in the affected metabolites. This shows that compounds of similar chemical structure can induce different metabolic effects, possibly relating to their different toxic mechanisms. There were inter-concentration differences in the metabolic profiles, indicating that the metabolic effects were concentration dependent. After exposure to the mixture of 6-OH-BDE47 and 6-OH-BDE85, a new metabolic profile distinct from the profiles obtained from the single compounds was observed. Succinic acid was up-regulated at the highest, but still environmentally relevant, concentration of 6-OH-BDE47, 6-OH-BDE85, and the mixture. Therefore, succinic acid is suggested as a potential biomarker for energy disruption of OH-PBDEs., 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 © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Supported Employment (SE) has shown better results in the employment rate for persons with disabilities than other methods within vocational rehabilitation, but how SE affects the employment rate for subgroups in the interventions needs further attention., Objective: To examine previous research regarding the influence of intersecting statuses on the employment rate in SE for people with psychiatric, neuropsychiatric, or intellectual disabilities according to type of diagnosis, sex, race/ethnicity, age, level of education and previous work history., Methods: A systematic literature search was conducted in nine databases including peer-reviewed articles from 2000 to April 2021. Articles presenting the employment rate in SE interventions according to the intersecting statuses listed in the objective were included., Results: The searches identified 3777 unique records, of which 53 articles were included in data extraction. In most of the included articles, intersecting statuses did not affect the employment rate for people in the SE interventions with psychiatric disabilities. Few studies have examined neuropsychiatric and intellectual disabilities. A majority of the studies subjected to full-text analysis were excluded due to a lack of reporting of the effects of intersecting statuses on the employment rate. The studies that reported on the effects of intersecting statuses on the employment rate often had small samples and lacked statistical power., Conclusions: Intersecting statuses do not appear to affect the employment rate for people receiving SE interventions, but systematic reviews with pooled samples need to be undertaken because of the low reporting rate and underpowered sample sizes in existing studies.

Background: Somatostatin receptor 68 Ga PET imaging is standard for evaluation of a patient's suitability for 177 Lu peptide receptor radionuclide therapy of neuroendocrine tumours (NETs). The 68 Ga PET serves to ensure sufficient somatostatin receptor expression, commonly evaluated qualitatively. The aim of this study is to investigate the quantitative relationships between uptake in 68 Ga PET and absorbed doses in 177 Lu therapy., Method: Eighteen patients underwent [ 68 Ga]Ga-DOTA-TATE PET imaging within 20 weeks prior to their first cycle of [ 177 Lu]Lu-DOTA-TATE. Absorbed doses for therapy were estimated for tumours, kidney, spleen, and normal liver parenchyma using a hybrid SPECT/CT-planar method. Gallium-68 activity concentrations were retrieved from PET images and also used to calculate SUVs and normalized SUVs, using blood and tissue for normalization. The 68 Ga activity concentrations per injected activity, SUVs, and normalized SUVs were compared with 177 Lu activity concentrations 1 d post-injection and 177 Lu absorbed doses. For tumours, for which there was a variable number per patient, both inter- and intra-patient correlations were analysed. Furthermore, the prediction of 177 Lu tumour absorbed doses based on a combination of tumour-specific 68 Ga activity concentrations and group-based estimates of the effective half-lives for grade 1 and 2 NETs was explored., Results: For normal organs, only spleen showed a significant correlation between the 68 Ga activity concentration and 177 Lu absorbed dose (r = 0.6). For tumours, significant, but moderate, correlations were obtained, with respect to both inter-patient (r = 0.7) and intra-patient (r = 0.45) analyses. The correlations to absorbed doses did not improve when using 68 Ga SUVs or normalized SUVs. The relationship between activity uptakes for 68 Ga PET and 177 Lu SPECT was stronger, with correlation coefficients r = 0.8 for both inter- and intra-patient analyses. The 177 Lu absorbed dose to tumour could be predicted from the 68 Ga activity concentrations with a 95% coverage interval of - 65% to 248%., Conclusions: On a group level, a high uptake of [ 68 Ga]Ga-DOTA-TATE is associated with high absorbed doses at 177 Lu-DOTA-TATE therapy, but the relationship has a limited potential with respect to individual absorbed dose planning. Using SUV or SUV normalized to reference tissues do not improve correlations compared with using activity concentration per injected activity., (© 2022. The Author(s).)

To date, the energy-intensive production and high-water content severely limits nanocellulose applications on a large scale off-site. In this study, adding water-soluble polysaccharides (PS) to achieve an integrated process of water-redispersible nanocellulose production was well established. The addition of PS, in particular carboxymethylated-galactoglucomannan (cm-GGM), facilitates fibre fibrillation enabling homogenization at a higher solid content at 1.5 wt% compared with around 0.4 wt% for neat fibre. More importantly, the addition of cm-GGM saved 73 % energy in comparison without PS addition. Good water redispersibility of thus-prepared nanocellulose was validated in viewpoints of size distribution, morphology, viscosity and film properties as compared with neat nanocellulose. The tensile strength and optical transmittance of nanocellulose films increased to 116 MPa and 77 % compared to those without PS addition of 62 MPa and 74 %, respectively. Collectively, this study provides a new avenue for large-volume production of redispersible nanocellulose at a high solid content with less energy-consumption., 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 © 2022. Published by Elsevier Ltd.)

Reliable forecast of COVID-19 hospital admissions in near-term horizons can help enable effective resource management which is vital in reducing pressure from healthcare services. The use of mobile network data has come to attention in response to COVID-19 pandemic leveraged on their ability in capturing people social behavior. Crucially, we show that there are latent features in irreversibly anonymized and aggregated mobile network data that carry useful information in relation to the spread of SARS-CoV-2 virus. We describe development of the forecast models using such features for prediction of COVID-19 hospital admissions in near-term horizons (21 days). In a case study, we verified the approach for two hospitals in Sweden, Sahlgrenska University Hospital and Södra Älvsborgs Hospital, working closely with the experts engaged in the hospital resource planning. Importantly, the results of the forecast models were used in year 2021 by logisticians at the hospitals as one of the main inputs for their decisions regarding resource management., (© 2022. The Author(s).)

Background: Digital transformation has influenced all areas of adolescents' lives, including the ways adolescents maintain friendships. Interpersonal communication is one of the most common activities while online. Online communication may provide adolescents with opportunities to expand their social contacts, but these encounters can be risky, especially when the communication is with unknown people on the internet. This study examined the associations between different forms of online communication behavior and well-being., Materials and Methods: Data were collected from Finnish adolescents as part of the Health Behavior in School-Aged Children (HBSC) study in 2018. The participants were 3,140 Finnish adolescents aged 11-15 years. Descriptive analyses were used to examine the frequency of different forms of online communication behaviors. The associations between online communications and individual factors were analyzed using the X 2 test and 95% confidence intervals. Structural equation modeling (SEM) was used to analyze the extent to which adolescents' online communication behavior explained the variance in adolescents' well-being indicators., Results: Overall, 60% of the adolescents reported communicating intensively with close friends, with higher rates of intensive communication reported by girls, higher age groups, and the high health literacy group. 22% of adolescents reported intensive communication with friends they got to know through the internet (online friends), while intensive online communication with unknown people was reported by 13% of adolescents. Overall, around one-fourth of adolescents preferred sharing personal matters online rather than in face-to-face encounters, and 10% of adolescents reported using the internet daily to get to know new people, and to look for like-minded company. The SEM analysis showed that keeping online contact with offline friends was linked to a positive outcome in all the measured well-being indicators; however, intensive communication with people contacted only online (online friends and unknown people) was negatively associated with well-being indicators (lower self-rated health, lower life satisfaction, higher loneliness, and problematic social media use)., Conclusion: Both positive and negative associations were observed between online communication and well-being, depending on the target and content of the communication. The results indicate that online communication has benefits for adolescents who have more offline social life. Overall, one should ensure that the impact of interventions is proportionately greater for adolescents at the bottom end of the health gradient., 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 © 2022 Lyyra, Junttila, Gustafsson, Lahti and Paakkari.)

This study aimed to investigate how maternal birthweight is related to early pregnancy obesity, gestational diabetes mellitus (GDM), and offspring birthweight. Females born term and singleton in Sweden between 1973 and 1995 (N = 305,893) were studied at their first pregnancy. Information regarding their birthweight, early pregnancy body mass index, and pregnancy complications was retrieved from the Swedish Medical Birth Register, as were data on their mothers and offspring. High maternal birthweights (2-3 standard deviation scores (SDS) and >3 SDS) were associated with greater odds of early pregnancy obesity, odds ratio (OR) 1.52 (95% confidence interval (CI) 1.42-1.63) and OR 2.06 (CI 1.71-2.49), respectively. A low maternal birthweight (<2 SDS) was associated with greater odds of GDM (OR 2.49, CI 2.00-3.12). No association was found between high maternal birthweight and GDM. A maternal birthweight 2-3 SDS was associated with offspring birthweight 2-3 SDS (OR 3.83, CI 3.44-4.26), and >3 SDS (OR 3.55, CI 2.54-4.97). Corresponding ORs for a maternal birthweight >3 SDS were 5.38 (CI 4.12-7.01) and 6.98 (CI 3.57-13.65), respectively. In conclusion, a high maternal birthweight was positively associated with early pregnancy obesity and offspring macrosomia. A low, but not a high maternal birthweight, was associated with GDM.

Background: In recent years, a lot of effort has been put in the enhancement of medical imaging using artificial intelligence. However, limited patient data in combination with the unavailability of a ground truth often pose a challenge to a systematic validation of such methodologies. The goal of this work was to investigate a recently proposed method for an artificial intelligence-based generation of synthetic SPECT projections, for acceleration of the image acquisition process based on a large dataset of realistic SPECT simulations., Methods: A database of 10,000 SPECT projection datasets of heterogeneous activity distributions of randomly placed random shapes was simulated for a clinical SPECT/CT system using the SIMIND Monte Carlo program. Synthetic projections at fixed angular increments from a set of input projections at evenly distributed angles were generated by different u-shaped convolutional neural networks (u-nets). These u-nets differed in noise realization used for the training data, number of input projections, projection angle increment, and number of training/validation datasets. Synthetic projections were generated for 500 test projection datasets for each u-net, and a quantitative analysis was performed using statistical hypothesis tests based on structural similarity index measure and normalized root-mean-squared error. Additional simulations with varying detector orbits were performed on a subset of the dataset to study the effect of the detector orbit on the performance of the methodology. For verification of the results, the u-nets were applied to Jaszczak and NEMA physical phantom data obtained on a clinical SPECT/CT system., Results: No statistically significant differences were observed between u-nets trained with different noise realizations. In contrast, a statistically significant deterioration was found for training with a small subset (400 datasets) of the 10,000 simulated projection datasets in comparison with using a large subset (9500 datasets) for training. A good agreement between synthetic (i.e., u-net generated) and simulated projections before adding noise demonstrates a denoising effect. Finally, the physical phantom measurements show that our findings also apply for projections measured on a clinical SPECT/CT system., Conclusion: Our study shows the large potential of u-nets for accelerating SPECT/CT imaging. In addition, our analysis numerically reveals a denoising effect when generating synthetic projections with a u-net. Clinically interesting, the methodology has proven robust against camera orbit deviations in a clinically realistic range. Lastly, we found that a small number of training samples (e.g., ~ 400 datasets) may not be sufficient for reliable generalization of the u-net., (© 2022. The Author(s).)

Objective: To investigate and summarize the literature on the validation of International Classification of Functioning, Disability and Health (ICF) core sets from 2001 to 2019 and explore what research methods have been used when validating ICF core sets. Methods: The current study is a scoping review using a structured literature search. Results: In total, 66 scientific articles were included, of which 23 ICF core sets were validated. Most validation studies were conducted in Europe using a quantitative methodology and were validated from the perspective of patients. Analysis methods differed considerably between the studies, and most ICF core sets were validated only once for a single target population or from a single perspective. The comprehensive core sets were validated more often than the brief core sets, and core sets for stroke and low back pain were validated most often. Conclusion: The results of the current study show that only 66% of the existing ICF core sets are validated. Many of the validation studies are conducted in a European context and from a single perspective. More validation studies of ICF core sets from the perspective of both patients and professionals are needed.Implications for rehabilitationICF core sets aim to facilitate assessments in clinical settings and research.Validation studies indicate in general that the ICF core sets are valid and relevant for patients and professionals in the specific areas explored and thus can be used in rehabilitation settings.To improve the quality of ICF core sets, more validation studies are needed for ICF core sets not yet tested and for ICF core sets that have been validated only in one study or for one specific population or target group.

This work presents a new approach for more effective valorization of sawmill wastes (Beech and Cedar sawdusts), which were used as new sources for the extraction of lignin-containing and lignin-free cellulose II nanocrystals (L-CNCs and CNCs). It was shown that the properties of the extracted nanocrystals depend on the nature of the used sawdust (softwood or hardwood sawdusts). L-CNCs and CNCs derived from Beech fibers were long and thin and also had a higher crystallinity, compared with those obtained from Cedar fibers. Thanks to their interesting characteristics and their high crystallinity, these nanocrystals have been used without changing their surfaces as template cores for nanostructured hollow silica-free-surfactant synthesis for photocatalysis to degrade methylene blue (MB) dye. The synthesis was performed with a simple and efficient sol-gel method using tetraethyl orthosilicate as the silica precursor followed by calcination at 650 °C. The obtained materials were denoted as B/L-CNC/nanoSiO 2 , B/CNC/nanoSiO 2 , C/L-CNC/nanoSiO 2 , and C/CNC/nanoSiO 2 , when the used L-CNC and CNC cores are from Beech and Cedar, respectively. By comprehensive analysis, it was demonstrated that the nanostructured silica were quite uniform and had a similar morphology as the templates. Also, the pore sizes were closely related to the dimensions of L-CNC and CNC templates, with high specific surface areas. The photocatalytic degradation of MB dye was about 94, 98, 74, and 81% for B/L-CNC/nanoSiO 2 , B/CNC/nanoSiO 2 , C/L-CNC/nanoSiO 2 , and C/CNC/nanoSiO 2 , respectively. This study provides a simple route to extract L-CNCs and CNCs as organic templates to prepare nanostructured silica. The different silica structures showed excellent photodegradation of MB.

Background and Aims: Elevated circulating levels of CathepsinD (CatD) have been linked to metabolic deviations including liver inflammation. We investigated 1) whether supplementation with probiotics and/or fish oil affects CatD and 2) whether the CatD concentration would associate with gestational diabetes (GDM), low-grade inflammation, lipid metabolism, body fat % and dietary composition., Methods and Results: Overweight/obese pregnant women (n = 438) were randomized into fish oil + placebo, probiotics + placebo, fish oil + probiotics or placebo + placebo groups. Fish oil contained 1.9 g docosahexaenoic acid and 0.22 g eicosapentaenoic acid and probiotics were Lacticaseibacillusrhamnosus HN001 (formerly Lactobacillusrhamnosus HN001) and Bifidobacteriumanimalis ssp. lactis 420, 10 10 colony-forming units each). Serum CatD levels were analysed by ELISA, GlycA and lipid metabolites by NMR, high sensitive C-reactive protein (hsCRP) by immunoassay, and intakes of energy yielding nutrients and n-3 and n-6 fatty acids from food diaries at both early and late pregnancy. GDM was diagnosed by OGTT. CatD concentrations did not differ between the intervention groups or by GDM status. Multivariable linear models revealed that body fat % and GlycA affected CatD differently in healthy women and those with GDM., Conclusion: The serum CatD concentration of pregnant women was not modified by this dietary intervention. Serum CatD was influenced by two parameters, body fat and low grade inflammation, which were dependent on the woman's GDM status. CLINICAL TRIAL REG. NO: NCT01922791, clinicaltrials.gov (secondary analysis)., Competing Interests: Declaration of competing interest None., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

The study aimed to create a pipeline from Monte Carlo simulated projections of a Gate PET system to reconstructed images. The PET system was modelled after the GE Discovery MI (DMI) PET/CT, and the simulated projections were reconstructed with the stand-alone reconstruction software CASToR. Attenuation correction, normalisation calibration, random estimation, and scatter estimation for the simulations were computed with in-house programs. The pipeline was compared in both projection and image space with data acquired on a clinical DMI and reconstructed with GE's off-line PET reconstruction software (PET Toolbox) and CASToR. The simulated and measured data were compared for the number of prompt coincidences, scatter fraction, contrast recovery coefficient (CRC), signal-to-noise ratio (SNR), background variability, residual lung error, and image profiles. A slight discrepancy was noted in the projection space, but good agreements were generally achieved in image space between simulated and measured data. The CRC was found to be 81 % for Gate - CASToR, 84 % for GE - CASToR, and 84 % for GE - PET Toolbox for the largest sphere of the NEMA image quality (IQ) phantom, and the SNR was found to be 98 for Gate - CASToR, 91 for GE - CASToR, and 93 for GE - PET Toolbox. Profiles drawn over the spheres for the NEMA IQ phantom and the Data Spectrum (DS) phantom show a good match between measurement and simulation. The results indicate feasibility to utilise the pipeline as a tool for off-line simulation-based studies. A complete pipeline introduces possibilities to study the impact of single parameters in the whole chain from simulation to reconstructed images., Competing Interests: The authors declare no conflict of interest., (© 2022 The Authors.)

Tumor dosimetry was performed for 177 Lu-DOTATATE with the aims of better understanding the range and variation of the tumor-absorbed doses (ADs), how different dosimetric quantities evolve over the treatment cycles, and whether this evolution differs depending on the tumor grade. Such information is important for radiobiologic interpretation and may inform the design of alternative administration schemes. Methods: The data came from 41 patients with neuroendocrine tumors (NETs) of grade 1 ( n = 23) or 2 ( n = 18) who had received between 2 and 9 treatment cycles. Dosimetry was performed for 182 individual lesions, giving a total of 880 individual AD assessments across all cycles. Hybrid planar-SPECT/CT imaging was used, including quantitative SPECT reconstruction, voxel-based absorbed-dose-rate calculation, semiautomatic image segmentation, and partial-volume correction. Linear mixed-effect models were used to analyze changes in tumor ADs over cycles, absorbed-dose rates and activity concentrations on day 1, effective half-times, and tumor volumes. Tumors smaller than 8 cm 3 were excluded from analyses. Results: Tumor ADs ranged between 2 and 77 Gy per cycle. On average, the AD decreased over the cycles, with significantly different rates ( P < 0.05) of 6% and 14% per cycle for grade 1 and 2 NETs, respectively. The absorbed-dose rates and activity concentrations on day 1 decreased by similar amounts. The effective half-times were less variable but shorter for grade 2 than for grade 1 ( P < 0.001). For grade 2 NETs, the tumor volumes decreased, with a similar tendency in grade 1. Conclusion: The tumor AD, absorbed-dose rate, and activity uptake decrease, in parallel with tumor volumes, between 177 Lu-DOTATATE treatment cycles, particularly for grade 2 NETs. The effective half-times vary less but are lower for grade 2 than grade 1 NETs. These results may indicate the development of radiation-induced fibrosis and could have implications for the design of future treatment and dosimetry protocols., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

Objective . This study considers the error distributions for time-integrated activity (TIA) of single-time-point (STP) methods for patient-specific dosimetry in radionuclide therapy. Approach . The general case with the same pharmaceutical labelled with different radionuclides for imaging and therapy are considered for a mono-exponential time-activity curve. Two methods for STP dosimetry, both based on the combination of one activity estimate with the population-mean effective decay constant, are investigated. The cumulative distribution functions (CDFs) and the probability density functions for the two methods are analytically derived for arbitrary distributions of the biological decay constant. The CDFs are used for determining 95% coverage intervals of the relative errors for different combinations of imaging time points, physical decay constants, and relative standard deviations of the biological decay constant. Two examples, in the form of kidney dosimetry in [ 177 Lu]Lu-DOTA-TATE therapy and tumour dosimetry for Na[ 131 I]I therapy for thyroid cancer with dosimetry based on imaging of Na[ 124 I]I, are also studied in more detail with analysis of the sensitivity with respect to errors in the mean biological decay constant and to higher moments of the distribution. Main results . The distributions of the relative errors are negatively skewed, potentially leading to the situation that some TIA estimates are highly underestimated even if the majority of estimates are close to the true value. Significance . The main limitation of the studied STP dosimetry methods is the risk of large underestimations of the TIA., (Creative Commons Attribution license.)

Background: There is limited evidence about diet quality and associated factors in a representative population-based sample of preschool-aged children in Finland., Objective: The aims of this study were to investigate (1) the extent to which child diet quality and the consumption of health indicator foods (vegetables, fruits, berries, vegetable oil-based spread, nonfat milk) are in accordance with Finnish recommendations for preschool-aged children, (2) whether diet quality differs between children with underweight or normal weight compared with children with overweight or obesity, and (3) whether parental or child factors are related to children's diet quality., Design: This was a cross-sectional study., Participants/setting: Healthy children aged 2 to 6 years (n = 766) were recruited from child health clinics across Finland from February to June 2016., Main Outcome Measures: Diet quality and consumption of the health indicator foods were assessed by the Children's Index of Diet Quality (CIDQ, score 0-21, values < 10 indicate poor; 10-13.5, moderate; and ≥14, good diet quality). Parental information was collected with a self-administered questionnaire. Child weight and height were measured by child health clinic nurses., Statistical Analyses: The overweight/obesity status and diet quality of the children were compared with 1-way analysis of variance. One-way analysis of variance was used as the preliminary analysis between child and parental factors and CIDQ scores, and linear mixed model analysis to further analyze the relationship between child and parental factors and CIDQ data., Results: Only a small minority (13.7%) of the children had a good diet quality, 55.4% had a moderate diet quality, and 30.9% had a poor diet quality. Only 1% of the children consumed the key health indicator foods, namely vegetables, fruits, and berries, as recommended. Diet quality did not differ between children with underweight/normal weight and overweight/obesity. Instead, the child's younger age, parents' higher education, and parents' self-perceived healthy diet were related to good diet quality in the child., Conclusions: The diet quality was moderate or poor in the majority of the children. Parental characteristics were the main factors related to the child's diet quality. The results suggest that future efforts to improve preschool-aged children's diet quality are needed including efforts to counsel families in pediatric care. Whether the findings from the current study also apply to Finnish school-aged children should be investigated further., (Copyright © 2022 Academy of Nutrition and Dietetics. Published by Elsevier Inc. All rights reserved.)

Standardisation of genetic parts has become a topic of increasing interest over the last decades. The promise of simplifying molecular cloning procedures, while at the same time making them more predictable and reproducible has led to the design of several biological standards, one of which is modular cloning (MoClo). The Yeast MoClo toolkit provides a large library of characterised genetic parts combined with a comprehensive and flexible assembly strategy. Here we aimed to (1) simplify the adoption of the standard by providing a simple design tool for including new parts in the MoClo library, (2) characterise the toolkit further by demonstrating the impact of a BglII site in promoter parts on protein expression, and (3) expand the toolkit to enable efficient construction of gRNA arrays, marker-less integration cassettes and combinatorial libraries. These additions make the toolkit more applicable for common engineering tasks and will further promote its adoption in the yeast biological engineering community.

Hydroxylated polybrominated diphenyl ethers (OH-PBDEs), naturally produced by algae and cyanobacteria in the Baltic Sea, are potent disrupters of energy metabolism as well as endocrine disruptors and neurotoxins. In this study, European perch (Perca fluviatilis) from the Baltic Sea were sampled from May until October. OH-PBDEs and ten biomarkers were measured in each individual (n = 84 over 18 sampling time points) to study potential correlations between exposure to OH-PBDEs and changes in biomarkers. Several biomarkers showed significant non-linear seasonal variation. In the perch, ethoxyresorufin-O-deethylase (EROD) activity, plasma lactate concentration, and plasma glucose concentration showed a significant positive log-linear correlation with OH-PBDEs, whereas lipid percentage and liver somatic index showed a significant negative log-linear correlation with OH-PBDEs. These results strengthen the concern that OH-PBDEs could cause negative health effects for fish in the Baltic Sea., (Copyright © 2021. Published by Elsevier B.V.)

Background: Alignment-free methods are a popular approach for comparing biological sequences, including complete genomes. The methods range from probability distributions of sequence composition to first and higher-order Markov chains, where a k-th order Markov chain over DNA has [Formula: see text] formal parameters. To circumvent this exponential growth in parameters, variable-length Markov chains (VLMCs) have gained popularity for applications in molecular biology and other areas. VLMCs adapt the depth depending on sequence context and thus curtail excesses in the number of parameters. The scarcity of available fast, or even parallel software tools, prompted the development of a parallel implementation using lazy suffix trees and a hash-based alternative., Results: An extensive evaluation was performed on genomes ranging from 12Mbp to 22Gbp. Relevant learning parameters were chosen guided by the Bayesian Information Criterion (BIC) to avoid over-fitting. Our implementation greatly improves upon the state-of-the-art even in serial execution. It exhibits very good parallel scaling with speed-ups for long sequences close to the optimum indicated by Amdahl's law of 3 for 4 threads and about 6 for 16 threads, respectively., Conclusions: Our parallel implementation released as open-source under the GPLv3 license provides a practically useful alternative to the state-of-the-art which allows the construction of VLMCs even for very large genomes significantly faster than previously possible. Additionally, our parameter selection based on BIC gives guidance to end-users comparing genomes., (© 2021. The Author(s).)

Genome-scale metabolic models (GEMs) are used extensively for analysis of mechanisms underlying human diseases and metabolic malfunctions. However, the lack of comprehensive and high-quality GEMs for model organisms restricts translational utilization of omics data accumulating from the use of various disease models. Here we present a unified platform of GEMs that covers five major model animals, including Mouse1 ( Mus musculus ), Rat1 ( Rattus norvegicus ), Zebrafish1 ( Danio rerio ), Fruitfly1 ( Drosophila melanogaster ), and Worm1 ( Caenorhabditis elegans ). These GEMs represent the most comprehensive coverage of the metabolic network by considering both orthology-based pathways and species-specific reactions. All GEMs can be interactively queried via the accompanying web portal Metabolic Atlas. Specifically, through integrative analysis of Mouse1 with RNA-sequencing data from brain tissues of transgenic mice we identified a coordinated up-regulation of lysosomal GM2 ganglioside and peptide degradation pathways which appears to be a signature metabolic alteration in Alzheimer's disease (AD) mouse models with a phenotype of amyloid precursor protein overexpression. This metabolic shift was further validated with proteomics data from transgenic mice and cerebrospinal fluid samples from human patients. The elevated lysosomal enzymes thus hold potential to be used as a biomarker for early diagnosis of AD. Taken together, we foresee that this evolving open-source platform will serve as an important resource to facilitate the development of systems medicines and translational biomedical applications., Competing Interests: The authors declare no competing interest., (Copyright © 2021 the Author(s). Published by PNAS.)

Aim: To investigate the prevalence of vitamin D deficiency among children with non-haematological malignancies and to explore possible causes of low vitamin D levels among these patients., Methods: We performed a cross-sectional study of 458 children diagnosed with solid tumours, brain tumours, non-Hodgkin lymphoma or Hodgkin disease at the University Children's Hospital, Uppsala, Sweden. Serum 25-hydroxyvitamin D and parathyroid hormone levels were measured in samples taken at the time of cancer diagnosis and related to clinical data. Vitamin D deficiency was defined as a 25-hydroxyvitamin D level below 50 nmol/L., Results: The prevalence rate of vitamin D deficiency among children with non-haematological malignancies was 41%. There was no association between sex or diagnosis and vitamin D status. Vitamin D deficiency was more common among school children than preschool children (51% vs. 24%). Older age, season outside summer, and a more recent calendar year were significant predictors of lower 25-hydroxyvitamin D. There was a significant, albeit weak, negative correlation between 25-hydroxyvitamin D and parathyroid hormone., Conclusion: Vitamin D deficiency is common among children diagnosed with cancer, particularly among school-aged children diagnosed outside summer. The prevalence appears to be increasing, underlining the need for adequate replacement of vitamin D in these patients., (© 2021 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Regular access to green space has been shown to provide several health benefits for children. However, children today spend less time outdoors. Thus, it has become important to understand what drives and limits children's activities in nature. Based on a Finnish online survey of 1463 parents of children aged 2-7 conducted in 2019, the current study examined parents' perceived barriers to visiting nature with their children. It also examined how parental mental well-being is related to families' frequency of nature visits, and whether this association is mediated by different categories of parents' perceived barriers. Eleven out of 12 barriers were largely perceived by parents as reasons that did not prevent them from visiting nature with their children. Next, factor analysis indicated a three-factor solution to the barriers. The results of a multiple mediation analysis showed that better parental mental well-being was associated with more frequent adult-child nature visits, and this relationship was partially mediated by a "lack of competence and logistics" and a "lack of time and interest", but not by "insecurity and fear". The results indicated that parents with poor mental well-being were more likely to perceive barriers to visiting nature, which in turn appeared to be related to a higher likelihood of having children who visited nature less frequently.

The incorporation of unique molecular identifiers (UMIs) in single-cell RNA-seq assays makes possible the identification of duplicated molecules, thereby facilitating the counting of distinct molecules from sequenced reads. However, we show that the naïve removal of duplicates can lead to a bias due to a "pooled amplification paradox," and we propose an improved quantification method based on unseen species modeling. Our correction called BUTTERFLY uses a zero truncated negative binomial estimator implemented in the kallisto bustools workflow. We demonstrate its efficacy across cell types and genes and show that in some cases it can invert the relative abundance of genes.

Objective: Hearing loss (HL) affects the everyday functioning of millions of people worldwide. The Brief International Classification of Functioning Disability and Health (ICF) core sets for HL was developed to meet the complex health care needs of adults with HL. Because the brief core set for HL has not yet been validated internationally, this study aimed to investigate its validity from an international perspective., Design: A cross-sectional validation study based on data from structured interviews with adults with HL., Study Sample: Participants ( n  = 571) from India, South Africa, Sweden and the US were included., Results: A six-factor solution explained 71% of the variance, focussing on issues related to communication, the social environment, participation in society, health care services, support, relationships and emotions ( α  = 0.915). Three ICF categories demonstrated low reliability - temperament and personality functions, seeing functions and school education ., Conclusion: The Brief ICF core set for HL is valid for adults with HL internationally. However, to further increase its international validity, we recommend adding the categories d920 recreation and leisure and replacing d850 school education with the more inclusive block, d810-d839 education.

Over the last two decades, the occurrence of hydroxylated polybrominated diphenyl ethers (OH-PBDEs) has been observed to be nearly ubiquitous among Baltic Sea filamentous macroalgae. High concentrations are continuously recorded among red, green, and brown filamentous algae. Several of these algae species are ephemeral, and when large parts of the colonies decay at the end of their lifecycles, the OH-PBDEs are expected to largely partition to the sediment. In this study, the fate of OH-PBDEs in Baltic Sea sediment was investigated, with focus on the effect of reductive debromination. During chemical debromination, it was observed that the half-life could differ with as much as two orders of magnitude between a pentabrominated and a tetrabrominated congener. Using collected Baltic Sea sediment, it was further observed that the half-life of spiked pentabrominated OH-PBDEs spanned from a few days up to a few weeks in room temperature. At 4 °C, it took 6 months to achieve a 50% decrease in concentration of the fasted degrading congener. Clear differences in selectivity between chemical debromination and debromination in sediment were also observed when studying the major reaction products. Baltic Sea sediment seems to have a good capacity for reducing naturally produced OH-PBDEs.

Objective: This scoping review investigated key findings about hearing loss (HL) in the working life (WL) from a well-being perspective., Design: A scoping review protocol was used to search the literature and to explore and extract key findings. A narrative analysis of key findings was used to group the data into themes. Study sample: Fifty-three articles from 29 different journals were included in the analysis., Results: The narrative analysis identified three broad themes; individual aspects, work environment and work organisation. Individual aspects concerned problems that workers with HL experienced in their working lives, strategies they used to manage their working lives and different aspects of health in relation to WL. Work environment focussed on the physical, organisational and social work environment. Work organisation identified aspects related to division of labour and employment status., Conclusions: Several of the included papers revealed lots of findings but did not substantially discuss the findings from a WL perspective. HL and well-being in WL is a multidimensional phenomenon due to the interplay between the individual and the environment. This interplay is rarely discussed in the included papers. Furthermore, intersectional aspects are infrequently highlighted and need to be further explored in future research.

Single-cell RNA sequencing has become a valuable tool for investigating cell types in complex tissues, where clustering of cells enables the identification and comparison of cell populations. Although many studies have sought to develop and compare different clustering approaches, a deeper investigation into the properties of the resulting populations is lacking. Specifically, the presence of misclassified cells can influence downstream analyses, highlighting the need to assess subpopulation purity and to detect such cells. We developed DSAVE (Down-SAmpling based Variation Estimation), a method to evaluate the purity of single-cell transcriptome clusters and to identify misclassified cells. The method utilizes down-sampling to eliminate differences in sampling noise and uses a log-likelihood based metric to help identify misclassified cells. In addition, DSAVE estimates the number of cells needed in a population to achieve a stable average gene expression profile within a certain gene expression range. We show that DSAVE can be used to find potentially misclassified cells that are not detectable by similar tools and reveal the cause of their divergence from the other cells, such as differing cell state or cell type. With the growing use of single-cell RNA-seq, we foresee that DSAVE will be an increasingly useful tool for comparing and purifying subpopulations in single-cell RNA-Seq datasets., Competing Interests: The authors have declared that no competing interests exist.

Cell-type specific gene expression profiles are needed for many computational methods operating on bulk RNA-Seq samples, such as deconvolution of cell-type fractions and digital cytometry. However, the gene expression profile of a cell type can vary substantially due to both technical factors and biological differences in cell state and surroundings, reducing the efficacy of such methods. Here, we investigated which factors contribute most to this variation. We evaluated different normalization methods, quantified the variance explained by different factors, evaluated the effect on deconvolution of cell type fractions, and examined the differences between UMI-based single-cell RNA-Seq and bulk RNA-Seq. We investigated a collection of publicly available bulk and single-cell RNA-Seq datasets containing B and T cells, and found that the technical variation across laboratories is substantial, even for genes specifically selected for deconvolution, and this variation has a confounding effect on deconvolution. Tissue of origin is also a substantial factor, highlighting the challenge of using cell type profiles derived from blood with mixtures from other tissues. We also show that much of the differences between UMI-based single-cell and bulk RNA-Seq methods can be explained by the number of read duplicates per mRNA molecule in the single-cell sample. Our work shows the importance of either matching or correcting for technical factors when creating cell-type specific gene expression profiles that are to be used together with bulk samples., Competing Interests: We hereby confirm that all authors have declared that no competing interests exist.

The maritime expansion of Scandinavian populations during the Viking Age (about AD 750-1050) was a far-flung transformation in world history 1,2 . Here we sequenced the genomes of 442 humans from archaeological sites across Europe and Greenland (to a median depth of about 1×) to understand the global influence of this expansion. We find the Viking period involved gene flow into Scandinavia from the south and east. We observe genetic structure within Scandinavia, with diversity hotspots in the south and restricted gene flow within Scandinavia. We find evidence for a major influx of Danish ancestry into England; a Swedish influx into the Baltic; and Norwegian influx into Ireland, Iceland and Greenland. Additionally, we see substantial ancestry from elsewhere in Europe entering Scandinavia during the Viking Age. Our ancient DNA analysis also revealed that a Viking expedition included close family members. By comparing with modern populations, we find that pigmentation-associated loci have undergone strong population differentiation during the past millennium, and trace positively selected loci-including the lactase-persistence allele of LCT and alleles of ANKA that are associated with the immune response-in detail. We conclude that the Viking diaspora was characterized by substantial transregional engagement: distinct populations influenced the genomic makeup of different regions of Europe, and Scandinavia experienced increased contact with the rest of the continent.

The aim of this paper is to investigate the feasibility and limitations of activity-concentration estimation for 223 Ra using SPECT. Phantom measurements are performed using spheres (volumes 5.5 mL to 26.4 mL, concentrations 1.6 kBq mL -1 to 4.5 kBq mL -1 ). Furthermore, SPECT projections are simulated using the SIMIND Monte Carlo program for two geometries, one similar to the physical phantom and the other being an anthropomorphic phantom with added lesions (volumes 34 mL to 100 mL, concentrations 0.5 kBq mL -1 to 4 kBq mL -1 ). Medium-energy and high-energy collimators, 60 projections with 55 s per projection and a 20% energy window at 82 keV are employed. For the Monte Carlo simulated images, Poisson-distributed noise is added in ten noise realizations. Reconstruction is performed (OS-EM, 40 iterations, 6 subsets) employing compensation for attenuation, scatter, and collimator-detector response. The estimated concentrations in the anthropomorphic phantom are also corrected using recovery coefficients. Errors for the largest sphere in the physical phantom range from -25% to -34% for the medium-energy collimator and larger deviations for smaller spheres. Corresponding results for the high-energy collimator are -15% to -31%. The corresponding Monte Carlo simulations show standard deviations of a few percentage points. For the anthropomorphic phantom, before application of recovery coefficients the bias ranges from -16% to -46% (medium-energy collimator) and -10% to -28% (high-energy collimator), with standard deviations of 2% to 14% and 1% to 16%. After the application of recovery coefficients, the biases range from -3% to -35% (medium energy collimator) and from 0% to -18%. The errors decrease with increasing concentrations. Activity-concentration estimation of 223 Ra with SPECT is feasible, but problems with repeatability need to be further studied.

Background: Children and adolescents with leukemia are potentially at high risk of vitamin D inadequacy, which may have clinical relevance for skeletal morbidity, infections, and cancer outcome. This study aimed to evaluate vitamin D status at the time of diagnosis to investigate its predictors and association with overall survival in children with leukemia., Procedure: We included all 295 children and adolescents diagnosed with leukemia at our institution between 1990 and 2016 who had available serum sample from the time of diagnosis. We analyzed serum 25-hydroxyvitamin D and parathyroid hormone levels and correlated them with clinical data., Results: The 25-hydroxyvitamin D level was deficient (< 25 nmol/L), insufficient (25-50 nmol/L), sufficient (50-75 nmol/L), and optimal (> 75 nmol/L) in 6.4%, 26.8%, 39.7%, and 27.1% of the children, respectively. Older age and a more recent time of sampling (calendar year) predicted lower 25-hydroxyvitamin D level. In preschool children (age ≤6 years), lower 25-hydroxyvitamin D level was also associated with acute myeloid leukemia, and a 25-hydroxyvitamin D level < 50 nmol/L was associated with inferior overall survival. In school-aged children (age > 6 years), the 25-hydroxyvitamin D level showed significant seasonal variation., Conclusion: It remains unclear whether vitamin D supplementation in pediatric leukemia patients will improve outcome., (© 2020 Wiley Periodicals, Inc.)

Genome-scale metabolic models (GEMs) are valuable tools to study metabolism and provide a scaffold for the integrative analysis of omics data. Researchers have developed increasingly comprehensive human GEMs, but the disconnect among different model sources and versions impedes further progress. We therefore integrated and extensively curated the most recent human metabolic models to construct a consensus GEM, Human1. We demonstrated the versatility of Human1 through the generation and analysis of cell- and tissue-specific models using transcriptomic, proteomic, and kinetic data. We also present an accompanying web portal, Metabolic Atlas (https://www.metabolicatlas.org/), which facilitates further exploration and visualization of Human1 content. Human1 was created using a version-controlled, open-source model development framework to enable community-driven curation and refinement. This framework allows Human1 to be an evolving shared resource for future studies of human health and disease., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Introduction: Growth hormone (GH) is a central hormone for regulating linear growth during childhood and also highly involved in the metabolism of lipids, carbohydrates, and protein. However, few studies report on how treatment with GH during childhood influences metabolic parameters. Our aim was to investigate metabolic effects of different doses of GH in short children with GH peak levels in the low to normal range., Design: Thirty-five prepubertal short children (<-2.5 SDS), aged 7-10 years, with peak levels of GH between 7 and 14 μg/L during an arginine-insulin tolerance test, were randomized to 3 different doses (11/33/100 μg/kg/day) of GH treatment for 2 years. Auxological and metabolic investigations were performed. These included metabolites in blood and interstitial microdialysis fluid, dual-energy X-ray absorptiometry, frequently sampled intravenous glucose tolerance test (FSIVGTT), and stable isotope examinations of rates of glucose production and lipolysis., Results: At 24 months, the high-dose group (HD) had higher fasting insulin compared with the standard-dose (SD) and low-dose (LD) groups (HD: 111.7 vs. SD: 61.2 and LD: 46.0 pmol/L [p < 0.001]) and showed signs of insulin resistance (HOMA-IR, HD: 4.20 vs. SD: 2.17 and LD: 1.71 (LD) [p < 0.001]). The FSIVGTT also demonstrated higher acute insulin response (p < 0.05). Few other metabolic differences were found at 24 months, but a decreased insulin sensitivity index (Si) could already be seen at 12 months for both SD and HD compared with the LD group (p < 0.05)., Conclusion: Treatment with GH resulted in a dose-dependent decrease in insulin sensitivity, demonstrated by higher levels of fasting insulin and signs of insulin resistance in both HOMA indices and FSIVGTT examinations., (© 2021 S. Karger AG, Basel.)

Aim: To investigate whether a high birthweight was associated with an increased proportion of body fat or with impaired glucose tolerance in adulthood., Methods: Our cohort comprised 27 subjects with birthweights of 4500 g or more, and 27 controls with birthweights within ±1 standard deviation scores, born at Uppsala University Hospital 1975-1979. The subjects were 34-40 years old at the time of study. Anthropometric data was collected, and data on body composition was obtained by air plethysmography and bioimpedance and was estimated with a three-compartment model. Indirect calorimetry, blood sampling for fasting insulin and glucose as well as a 75 g oral glucose tolerance test were also performed. Insulin sensitivity was assessed using homoeostasis model assessment 2 and Matsuda index., Results: There were no differences in body mass index, body composition or insulin sensitivity between subjects with a high birthweight and controls., Conclusion: In this cohort of adult subjects, although limited in size, those born with a moderately high birthweight did not differ from those with birthweights within ±1 standard deviation scores, regarding body composition or glucose tolerance., (©2019 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Aim: To analyse levels and profiles of autism symptoms in children with Down Syndrome (DS) with and without diagnosed autism spectrum disorder (ASD) and to specifically study the groups with severe Intellectual Disability (ID)., Methods: From a population-based cohort of 60 children with DS (age 5-17 years) with 41 participating children, scores obtained from the Autism Diagnostic Observation Schedule (ADOS) Module-1 algorithm were compared between those with and without diagnosed ASD. Children with DS and ASD were also compared to a cohort of children with idiopathic ASD, presented in the ADOS manual., Results: Children with DS and ASD had significantly higher ADOS scores in all domains compared to those without ASD. When the groups with DS, with and without ASD, were restricted to those with severe ID, the difference remained. When the children with DS and ASD and the idiopathic autism group were compared, the ADOS profiles were similar., Conclusion: A considerable proportion of children with DS has ASD, but there is also a group of children with DS and severe ID without autism. There is a need to increase awareness of the high prevalence of autism in children with DS to ensure that appropriate measures and care are provided., (©2019 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Purpose: To evaluate whether an intervention, targeting deficits in social communication, interaction and restricted activities in children and adolescents with Down syndrome and autism could lead to enhanced participation in family and school activities., Methods: The intervention included education for parents and school staff about autism, and workshops to identify social-communication and daily living activities that would be meaningful for the child to practice at home and at school. Thereafter, a three-month period of training for the child followed. Outcome measures comprised evaluation of goal achievement for each child, the "Family Strain Index" questionnaire and a visual scale pertaining to the parents' general opinion about the intervention., Results: On average, more than 90% of the goals were (to some extent or completely) achieved at home and at school. The mean scores of the "Family Strain Index" were almost identical at the follow-up to those before intervention. The evaluation supported that the use of strategies, intended to facilitate activities and communication, remained largely 18 months after start of the intervention., Conclusion: Despite the group involved in this study being composed of older children and adolescents, most of whom had severe and profound intellectual disability, the goal achievements and parents' views on the intervention were encouraging., Competing Interests: The authors report no conflicts of interest in this work.

Aim: We investigated the severities and profiles of intellectual disability (ID) in a population-based group of children with Down syndrome and related the findings to coexisting autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD)., Methods: There were about 100 children with Down syndrome living in Uppsala County, Sweden, at the time of the study who all received medical services from the same specialist outpatient clinic. The 60 children (68% male) were aged 5-17 years at inclusion: 41 were assessed within the study and 19 had test results from previous assessments, performed within three years before inclusion. We compared two age groups: 5-12 and 13-18 years old., Results: Of the 60 children, 49 were assessed with a cognitive test and the 11 children who could not participate in formal tests had clinical assessments. Mild ID was found in 9% of the older children and in 35% of the younger children. Severe ID was found in 91% of the older children and 65% of the younger children. Verbal and nonverbal domains did not differ., Conclusion: Intellectual level was lower in the older children and patients with Down syndrome need to be followed during childhood with regard to their ID levels., (©2018 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)