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Background: The aim was to compare bias and precision for 177 Lu-SPECT activity-concentration estimation using a dual-headed Anger SPECT system and a ring-configured CZT SPECT system. This was investigated for imaging at 208 keV and 113 keV, respectively., Methods: Phantom experiments were performed on a GE Discovery 670 system with 5/8'' NaI(Tl) crystal (dual-headed Anger system) and a GE StarGuide (ring-configured CZT system). Six spheres (1.2 mL to 113 mL) in a NEMA PET body phantom were filled with 99m Tc and 177 Lu, separately. Mean relative errors and coefficients of variation (CV) in estimated sphere activity concentration were studied over six timeframes of 10 min each for the two systems. For 177 Lu, similar acquisitions were also performed for an anthropomorphic phantom with two spheres (10 mL and 25 mL) in a liver with non-radioactive background and a sphere-to-background ratio of 15:1. Tomographic reconstruction was performed using OS-EM with 10 subsets with compensation for attenuation, scatter, and distance-dependent spatial resolution. For the Anger system, up to 40 iterations were used and for the ring-configured CZT system up to 30 iterations were used., Results: The two systems showed similar mean relative errors and CVs for 177 Lu when using an energy window around 208 keV, while the ring-configured system demonstrated a lower bias for a similar CV compared to the Anger system for 99m Tc and for 177 Lu when using an energy window around 113 keV. However, total activity in the phantom tended to be overestimated in both systems for these cases., Conclusions: The ring-configured CZT system is a viable alternative to the dual-headed Anger system equipped with medium-energy collimators for 177 Lu-SPECT and shows a potential advantage for activity-concentration estimation when operated at 113 keV. However, further consideration of the preservation of total activity is warranted., (© 2024. The Author(s).)

The genomic signature of an organism captures the characteristics of repeated oligonucleotide patterns in its genome 1 , such as oligomer frequencies, GC content, and differences in codon usage. Viruses, however, are obligate intracellular parasites that are dependent on their host cells for replication, and information about genomic signatures in viruses has hitherto been sparse.Here, we investigate the presence and specificity of genomic signatures in 2,768 eukaryotic viral species from 105 viral families, aiming to illuminate dependencies and selective pressures in viral genome evolution. We demonstrate that most viruses have highly specific genomic signatures that often also differ significantly between species within the same family. The species-specificity is most prominent among dsDNA viruses and viruses with large genomes. We also reveal consistent dissimilarities between viral genomic signatures and those of their host cells, although some viruses present slight similarities, which may be explained by genetic adaptation to their native hosts. Our results suggest that significant evolutionary selection pressures act upon viral genomes to shape and preserve their genomic signatures, which may have implications for the field of synthetic biology in the construction of live attenuated vaccines and viral vectors., (© 2024. The Author(s).)

The term 'RNA-seq' refers to a collection of assays based on sequencing experiments that involve quantifying RNA species from bulk tissue, single cells or single nuclei. The kallisto, bustools and kb-python programs are free, open-source software tools for performing this analysis that together can produce gene expression quantification from raw sequencing reads. The quantifications can be individualized for multiple cells, multiple samples or both. Additionally, these tools allow gene expression values to be classified as originating from nascent RNA species or mature RNA species, making this workflow amenable to both cell-based and nucleus-based assays. This protocol describes in detail how to use kallisto and bustools in conjunction with a wrapper, kb-python, to preprocess RNA-seq data. Execution of this protocol requires basic familiarity with a command line environment. With this protocol, quantification of a moderately sized RNA-seq dataset can be completed within minutes., (© 2024. Springer Nature Limited.)

Background: The aim was to investigate the noise and bias properties of quantitative 177 Lu-SPECT with respect to the number of projection angles, and the number of subsets and iterations in the OS-EM reconstruction, for different total acquisition times., Methods: Experimental SPECT acquisition of six spheres in a NEMA body phantom filled with 177 Lu was performed, using medium-energy collimators and 120 projections with 180 s per projection. Bootstrapping was applied to generate data sets representing acquisitions with 20 to 120 projections for 10 min, 20 min, and 40 min, with 32 noise realizations per setting. Monte Carlo simulations were performed of 177 Lu-DOTA-TATE in an anthropomorphic computer phantom with three tumours (2.8 mL to 40.0 mL). Projections representing 24 h and 168 h post administration were simulated, each with 32 noise realizations. Images were reconstructed using OS-EM with compensation for attenuation, scatter, and distance-dependent resolution. The number of subsets and iterations were varied within a constrained range of the product number of iterations × number of projections ≤ 2400 . Volumes-of-interest were defined following the physical size of the spheres and tumours, the mean activity-concentrations estimated, and the absolute mean relative error and coefficient of variation (CV) over noise realizations calculated. Pareto fronts were established by analysis of CV versus mean relative error., Results: Points at the Pareto fronts with low CV and high mean error resulted from using a low number of subsets, whilst points at the Pareto fronts associated with high CV but low mean error resulted from reconstructions with a high number of subsets. The number of projection angles had limited impact., Conclusions: For accurate estimation of the 177 Lu activity-concentration from SPECT images, the number of projection angles has limited importance, whilst the total acquisition time and the number of subsets and iterations are parameters of importance., (© 2024. The Author(s).)

Purpose: Gender differences have been found in the outcomes of vocational rehabilitation (VR) and in Supported Employment (SE), therefore, the purpose of this study was to explore employment specialists' (ES) social representations of gender in relation to work and VR and how these social representations influence the ES's work in the VR process according to SE., Methods: The qualitative method of focus group discussions was employed. Ten focus groups were held with 39 ESs from four categories of SE organizations in Sweden. Topic analysis was applied to the transcribed material from the focus groups., Results: Five themes with different social representations about gender and disability in relation to VR and working life formed in the analysis: (1) differences in personal and health factors among VR-participants, (2) gender norms in society influencing VR, (3) energy-intensive environmental issues influencing VR, (4) gender-specific interactions in VR, and (5) gendered paths in the welfare system., Conclusion: Social representations of higher strains on women with disabilities compared to men with disabilities both in private and working life, which reflect the lived experiences of the ESs, is a possible explanation for gender differences in VR and working life for persons with disabilities.IMPLICATIONS FOR REHABILITATIONGender differences in the outcomes of vocational rehabilitation (VR) interventions have been noticed worldwide. In this study, pervasive social representations about gender and disability in relation to VR were found, but also unconsciousness about gender among VR professionals. Therefore, awareness of gender is necessary in VR.Individualized and person-centered approaches to VR like Supported Employment, although considered best practice, might hide structures like gender, which could lead to reproducing discriminating processes and therefore not achieving gender equality in VR. Therefore, knowledge of discrimination is important in VR.Gender-sensitivity in vocational rehabilitation models with a person-centered and individualized approach is needed and there might also be a need to systematically tailor vocational rehabilitation models to reach gender equality in the outcomes of the interventions. Therefore, gender equality indicators are needed for VR models, to evaluate model effectiveness from a gender perspective.

Peptide receptor radionuclide therapy presents the possibility of tracing and quantifying the uptake of the drug in the body and performing dosimetry, potentially allowing individualization of treatment schemes. However, the details of how neuroendocrine tumors (NETs) respond to different absorbed doses are insufficiently known. Here, we investigated the relationship between tumor-absorbed dose and tumor response in a cohort of patients with NETs treated with [ 177 Lu]Lu-DOTATATE. Methods: This was a retrospective study based on 69 tumors in 32 patients treated within a clinical trial. Dosimetry was performed at each cycle of [ 177 Lu]Lu-DOTATATE, rendering 366 individual absorbed dose assessments. Hybrid planar-SPECT/CT imaging using [ 177 Lu]Lu-DOTATATE was used, including quantitative SPECT reconstruction, voxel-based absorbed dose rate calculation, semiautomatic image segmentation, and partial-volume correction. Changes in tumor volume were used to determine tumor response. The volume for each tumor was manually delineated on consecutive CT scans, giving a total of 712 individual tumor volume assessments. Tumors were stratified according to grade. The relationship between absorbed dose and response was investigated using mixed-effects models and logistic regression. Tumors smaller than 4 cm 3 were excluded. Results: In grade 2 NETs, a clear relationship between absorbed dose and volume reduction was observed. Our observations suggest a 90% probability of partial tumor response for an accumulated tumor-absorbed dose of at least 135 Gy. Conclusion: Our findings are in accordance with previous observations regarding the relationship between tumor shrinkage and absorbed dose. Moreover, our data suggest an absorbed dose threshold for partial response in grade 2 NETs. These observations provide valuable insights for the design of dosimetry-guided peptide receptor radionuclide therapy schemes., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: Although the importance of quantitative SPECT has increased tremendously due to newly developed therapeutic radiopharmaceuticals, there are still no accreditation programs to harmonize SPECT imaging. Work is currently underway to develop an accreditation for quantitative 177 Lu SPECT/CT. The aim of this study is to verify whether the positioning of the spheres within the phantom has an influence on the recovery and thus needs to be considered in SPECT harmonization. In addition, the effects of these recovery coefficients on a potential partial volume correction as well as absorbed-dose estimates are investigated., Methods: Using a low-dose CT of a SPECT/CT acquisition, a computerized version of the NEMA body phantom was created using a semi-automatic threshold-based method. Based on the mass-density map, the detector orbit, and the sphere centers, realistic SPECT acquisitions of all possible 720 sphere configurations of both the PET and the SPECT versions of the NEMA Body Phantom were generated using Monte Carlo simulations. SPECT reconstructions with different numbers of updates were performed without (CASToR) and with resolution modeling (STIR). Recovery coefficients were calculated for all permutations, reconstruction methods, and phantoms, and their dependence on the sphere positioning was investigated. Finally, the simulation-based findings were validated using SPECT/CT acquisitions of six different sphere configurations., Results: Our analysis shows that sphere positioning has a significant impact on the recovery for both of the reconstruction methods and the phantom type. Although resolution modeling resulted in significantly higher recovery, the relative variation in recovery within the 720 permutations was even larger. When examining the extreme values of the recovery, reconstructions without resolution modeling were influenced primarily by the sphere position, while with resolution modeling the volume of the two adjacent spheres had a larger influence. The SPECT measurements confirmed these observations, and the recovery curves showed good overall agreement with the simulated data., Conclusion: Our study shows that sphere positioning has a significant impact on the recovery obtained in NEMA sphere phantom measurements and should therefore be considered in a future SPECT accreditation. Furthermore, the single-measurement method normally performed for PVC should be reconsidered to account for the position dependency., (© 2024. The Author(s).)

Purpose: The aim of the current study was to explore the construct validity and internal consistency reliability of the International Classification of Functioning, Disability and Health (ICF)-based original English version of the Hearing and Functioning in Everyday Life Questionnaire (HFEQ) and to revise the HFEQ based on the results., Method: This study used a cross-sectional survey design. The data were collected using an online survey. Adults with self-reported hearing disability ( n = 513) from the United States were included. The ICF components of body functions, activity and participation, and environmental factors were tested as the underlying structure of the HFEQ using confirmatory factor analysis and then adjusted by triangulation with previous content validation., Results: The results of the current study confirmed the ICF components of body functions, activity and participation, and environmental factors as underlying constructs of the HFEQ. However, after triangulation with previous content validation, fine adjustments were made. The revised version of the HFEQ includes two removed items and a fine-tuned factor structure., Conclusion: The results confirm that the structure of the HFEQ aligns with the ICF, and the overall results indicate that HFEQ has acceptable construct validity and internal consistency.

With the development of new radiopharmaceutical therapies, quantitative SPECT/CT has progressively emerged as a crucial tool for dosimetry. One major obstacle of SPECT is its poor resolution, which results in blurring of the activity distribution. Especially for small objects, this so-called partial-volume effect limits the accuracy of activity quantification. Numerous methods for partial-volume correction (PVC) have been proposed, but most methods have the disadvantage of assuming a spatially invariant resolution of the imaging system, which does not hold for SPECT. Furthermore, most methods require a segmentation based on anatomic information. Methods: We introduce DL-PVC, a methodology for PVC of 177 Lu SPECT/CT imaging using deep learning (DL). Training was based on a dataset of 10,000 random activity distributions placed in extended cardiac-torso body phantoms. Realistic SPECT acquisitions were created using the SIMIND Monte Carlo simulation program. SPECT reconstructions without and with resolution modeling were performed using the CASToR and STIR reconstruction software, respectively. The pairs of ground-truth activity distributions and simulated SPECT images were used for training various U-Nets. Quantitative analysis of the performance of these U-Nets was based on metrics such as the structural similarity index measure or normalized root-mean-square error, but also on volume activity accuracy, a new metric that describes the fraction of voxels in which the determined activity concentration deviates from the true activity concentration by less than a certain margin. On the basis of this analysis, the optimal parameters for normalization, input size, and network architecture were identified. Results: Our simulation-based analysis revealed that DL-PVC (0.95/7.8%/35.8% for structural similarity index measure/normalized root-mean-square error/volume activity accuracy) outperforms SPECT without PVC (0.89/10.4%/12.1%) and after iterative Yang PVC (0.94/8.6%/15.1%). Additionally, we validated DL-PVC on 177 Lu SPECT/CT measurements of 3-dimensionally printed phantoms of different geometries. Although DL-PVC showed activity recovery similar to that of the iterative Yang method, no segmentation was required. In addition, DL-PVC was able to correct other image artifacts such as Gibbs ringing, making it clearly superior at the voxel level. Conclusion: In this work, we demonstrate the added value of DL-PVC for quantitative 177 Lu SPECT/CT. Our analysis validates the functionality of DL-PVC and paves the way for future deployment on clinical image data., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Aim: We aimed to evaluate the occurrence of, and risk factors for precocious and early puberty in a retrospective cohort study of girls with shunted infantile hydrocephalus., Methods: The study population comprised 82 girls with infantile hydrocephalus, born between 1980 and 2002, and treated with a ventriculoperitoneal shunt. Data were available for 39 girls with myelomeningocele and 34 without. Medical records were analysed regarding clinical data and timing of puberty. Precocious and early puberty was defined as the appearance of pubertal signs before 8 years and 0 months and 8 years and 9 months, respectively., Results: Median age at last admission was 15.8 years (range 10.0-18.0). In total, 15 girls (21%) had precocious puberty, and another 21 (29%) had early puberty. Three or more shunt revisions had been performed in 26/36 girls with early or precocious puberty and in 3/37 girls without (p = 0.01). The number of shunt revisions correlated negatively with age at the start of puberty in the girls with myelomeningocele (Spearman's correlation coefficient = -0.512, p = 0.001)., Conclusion: Girls with shunted infantile hydrocephalus have a high risk of precocious or early puberty. Repeated shunt revisions seemed to be associated with early puberty., (© 2024 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Purpose: The aim was to investigate the use of multiple small VOIs for kidney dosimetry in [ 177 Lu]Lu-DOTA-TATE therapy., Method: The study was based on patient and simulated SPECT images in anthropomorphic geometries. Images were reconstructed using two reconstruction programs (local LundaDose and commercial Hermia) using OS-EM with and without resolution recovery (RR). Five small VOIs were placed to determine the average activity concentration (AC) in each kidney. The study consisted of three steps: (i) determination of the number of iterations for AC convergence based on simulated images; (ii) determination of recovery-coefficients (RCs) for 2 mL VOIs using a separate set of simulated images; (iii) assessment of operator variability in AC estimates for simulated and patient images. Five operators placed the VOIs, using for guidance: a) SPECT/CT with RR, b) SPECT/CT without RR, and c) CT only. For simulated images, time-integrated ACs (TIACs) were evaluated. For patient images, estimated ACs were compared with results of a previous method based on whole-kidney VOIs., Results: Eight iterations and ten subsets were sufficient for both programs and reconstruction settings. Mean RCs (mean ± SD) with RR were 1.03 ± 0.02 (LundaDose) and 1.10 ± 0.03 (Hermia), and without RR 0.91 ± 0.03 (LundaDose) and 0.94 ± 0.03 (Hermia). Most stable and accurate estimates of the AC were obtained using five 2-mL VOIs guided by SPECT/CT with RR, applying them to images without RR, and including an explicit RC for recovery correction., Conclusion: The small VOI method based on five 2-mL VOIs was found efficient and sufficiently accurate for kidney dosimetry in [ 177 Lu]Lu-DOTA-TATE therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Single-cell technologies have been widely used in biological studies and generated a plethora of single-cell data to be interpreted. Due to the inclusion of the priori metabolic network knowledge as well as gene-protein-reaction associations, genome-scale metabolic models (GEMs) have been a powerful tool to integrate and thereby interpret various omics data mostly from bulk samples. Here, we first review two common ways to leverage bulk omics data with GEMs and then discuss advances on integrative analysis of single-cell omics data with GEMs. We end by presenting our views on current challenges and perspectives in this field., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Genome-scale metabolic models (GEMs) are computational representations that enable mathematical exploration of metabolic behaviors within cellular and environmental constraints. Despite their wide usage in biotechnology, biomedicine and fundamental studies, there are many phenotypes that GEMs are unable to correctly predict. GECKO is a method to improve the predictive power of a GEM by incorporating enzymatic constraints using kinetic and omics data. GECKO has enabled reconstruction of enzyme-constrained metabolic models (ecModels) for diverse organisms, which show better predictive performance than conventional GEMs. In this protocol, we describe how to use the latest version GECKO 3.0; the procedure has five stages: (1) expansion from a starting metabolic model to an ecModel structure, (2) integration of enzyme turnover numbers into the ecModel structure, (3) model tuning, (4) integration of proteomics data into the ecModel and (5) simulation and analysis of ecModels. GECKO 3.0 incorporates deep learning-predicted enzyme kinetics, paving the way for improved metabolic models for virtually any organism and cell line in the absence of experimental data. The time of running the whole protocol is organism dependent, e.g., ~5 h for yeast., (© 2024. Springer Nature Limited.)

Physiologically based pharmacokinetic (PBPK) models offer the ability to simulate and predict the biodistribution of radiopharmaceuticals and have the potential to enable individualised treatment planning in molecular radiotherapy. The objective of this study was to develop and implement a whole-body compartmental PBPK model for peptide receptor radionuclide therapy (PRRT) with [ 177 Lu]Lu-DOTA-TATE in SimBiology to allow for more complex analyses. The correctness of the model implementation was ensured by comparing its outputs, such as the time-integrated activity (TIA), with those of a PBPK model implemented in SAAM II software., Methods: A combined PBPK model for [ 68 Ga]Ga-DOTA-TATE and [ 177 Lu]Lu-DOTA-TATE was developed and implemented in both SAAM II and SimBiology. A retrospective analysis of 12 patients with metastatic neuroendocrine tumours (NETs) was conducted. First, time-activity curves (TACs) and TIAs from the two software were calculated and compared for identical parameter values. Second, pharmacokinetic parameters were fitted to activity concentrations, analysed and compared., Results: The PBPK model implemented in SimBiology produced TIA results comparable to those generated by the model implemented in SAAM II, with a relative deviation of less than 0.5% when using the same input parameters. The relative deviation of the fitted TIAs was less than 5% when model parameter values were fitted to the measured activity concentrations., Conclusion: The proposed PBPK model implemented in SimBiology can be used for dosimetry in radioligand therapy and TIA prediction. Its outputs are similar to those generated by the PBPK model implemented in SAAM II, confirming the correctness of the model implementation in SimBiology., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Associazione Italiana di Fisica Medica e Sanitaria. Published by Elsevier Ltd. All rights reserved.)

Children with hemato-oncological diseases may have significant skeletal morbidity, not only during and after treatment but also at the time of diagnosis before cancer treatment. This study was designed to evaluate the vitamin D status and circulating bone metabolic markers and their determinants in children at the time of diagnostic evaluation for hemato-oncological disease. This cross-sectional study included 165 children (91 males, median age 6.9 yr range 0.2-17.7 yr). Of them, 76 patients were diagnosed with extracranial or intracranial solid tumors, 83 with leukemia, and 6 with bone marrow failure. Bone metabolism was assessed by measuring serum 25OHD, PTH, bone alkaline phosphatase, intact N-terminal propeptide of type I procollagen, and C-terminal cross-linked telopeptide of type I collagen. Vitamin D deficiency was found in 30.9% of children. Lower 25OHD levels were associated with older age, lack of vitamin D supplementation, season outside summer, and a country of parental origin located between latitudes -45° and 45°. Children diagnosed with leukemia had lower levels of markers of bone formation and bone resorption than those who had solid tumors or bone marrow failure. In conclusion, vitamin D deficiency was observed in one-third of children with newly diagnosed cancer. Bone turnover markers were decreased in children with leukemia, possibly because of the suppression of osteoblasts and osteoclasts by leukemic cells. The identification of patients with suboptimal vitamin D status and compromised bone remodeling at cancer diagnosis may aid in the development of supportive treatment to reduce the adverse effects of cancer and its treatment., Competing Interests: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

Background: The prevalence of teenage pregnancy in Colombia is higher than the worldwide average. The identification of socio-geographical disparities might help to prioritize public health interventions., Aim: To describe variation in the probability of teenage maternity across geopolitical departments and socio-geographical intersectional strata in Colombia., Methods: A cross-sectional study based on live birth certificates in Colombia. Teenage maternity was defined as a woman giving birth aged 19 or younger. Multilevel analysis of individual heterogeneity and discriminatory accuracy (MAIHDA) was applied using multilevel Poisson and logistic regression. Two different approaches were used: (1) intersectional: using strata defined by the combination of health insurance, region, area of residency, and ethnicity as the second level (2) geographical: using geopolitical departments as the second level. Null, partial, and full models were obtained. General contextual effect (GCE) based on the variance partition coefficient (VPC) was considered as the measure of disparity. Proportional change in variance (PCV) was used to identify the contribution of each variable to the between-strata variation and to identify whether this variation, if any, was due to additive or interaction effects. Residuals were used to identify strata with potential higher-order interactions., Results: The prevalence of teenage mothers in Colombia was 18.30% (95% CI 18.20-18.40). The highest prevalence was observed in Vichada, 25.65% (95% CI: 23.71-27.78), and in the stratum containing mothers with Subsidized/Unaffiliated healthcare insurance, Mestizo, Rural area in the Caribbean region, 29.08% (95% CI 28.55-29.61). The VPC from the null model was 1.70% and 9.16% using the geographical and socio-geographical intersectional approaches, respectively. The higher PCV for the intersectional model was attributed to health insurance. Positive and negative interactions of effects were observed., Conclusion: Disparities were observed between intersectional socio-geographical strata but not between geo-political departments. Our results indicate that if resources for prevention are limited, using an intersectional socio-geographical approach would be more effective than focusing on geopolitical departments especially when focusing resources on those groups which show the highest prevalence. MAIHDA could potentially be applied to many other health outcomes where resource decisions must be made., (© 2024. The Author(s).)

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.)