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Epigenetic dysregulation has emerged as an important etiological mechanism of neurodevelopmental disorders (NDDs). Pathogenic variation in epigenetic regulators can impair deposition of histone post-translational modifications leading to aberrant spatiotemporal gene expression during neurodevelopment. The male-specific lethal (MSL) complex is a prominent multi-subunit epigenetic regulator of gene expression and is responsible for histone 4 lysine 16 acetylation (H4K16ac). Using exome sequencing, here we identify a cohort of 25 individuals with heterozygous de novo variants in MSL complex member MSL2. MSL2 variants were associated with NDD phenotypes including global developmental delay, intellectual disability, hypotonia, and motor issues such as coordination problems, feeding difficulties, and gait disturbance. Dysmorphisms and behavioral and/or psychiatric conditions, including autism spectrum disorder, and to a lesser extent, seizures, connective tissue disease signs, sleep disturbance, vision problems, and other organ anomalies, were observed in affected individuals. As a molecular biomarker, a sensitive and specific DNA methylation episignature has been established. Induced pluripotent stem cells (iPSCs) derived from three members of our cohort exhibited reduced MSL2 levels. Remarkably, while NDD-associated variants in two other members of the MSL complex (MOF and MSL3) result in reduced H4K16ac, global H4K16ac levels are unchanged in iPSCs with MSL2 variants. Regardless, MSL2 variants altered the expression of MSL2 targets in iPSCs and upon their differentiation to early germ layers. Our study defines an MSL2-related disorder as an NDD with distinguishable clinical features, a specific blood DNA episignature, and a distinct, MSL2-specific molecular etiology compared to other MSL complex-related disorders.

Abstract Background Pregnant women with obesity face heightened focus on weight during pregnancy due to greater risk of medical complications. Closer follow-up in maternety care may contribute to reduce risk and promote health in these women. The aim of this study was to gain a deeper insight in how pregnant women with obesity experience encounters with healthcare providers in maternity care. How is the received maternity care affected by their weight, and how do they describe the way healthcare providers express attitudes towards obesity in pregnancy? Methods We conducted in-depth interviews with 14 women in Trøndelag county in Norway with pre-pregnancy BMI of ≥ 30 kg/m2, between 3 and 12 months postpartum. The study sample was strategic regarding age, relationship status, education level, obesity class, and parity. Themes were developed using reflexive thematic analysis. The analysis was informed by contextual information from a prior study, describing the same participants’ weight history from childhood to motherhood along with their perceptions of childhood quality. Results This study comprised of an overarching theme supported by three main themes. The overarching theme, Being pregnant with a high BMI: a vulnerable condition, reflected the challenge of entering maternity care with obesity, especially for women unprepared to be seen as “outside the norm”. Women who had grown up with body criticism and childhood bullying were more prepared to have their weight addressed in maternity care. The first theme, Loaded conversations: a balancing act, emphasizes how pregnant women with a history of body criticism or obesity-related otherness proactively protect their integrity against weight bias, stigma and shame. The women also described how some healthcare providers balance or avoid weight and risk conversations for the same reasons. Dehumanization: an unintended drawback of standardized care makes apparent the pitfalls of prioritizing standardization over person-centered care. Finally, the third theme, The ambivalence of discussing weight and lifestyle, represent women’s underlying ambivalence towards current weight practices in maternity care. Conclusions Our findings indicate that standardized weight and risk monitoring, along with lifestyle guidance in maternity care, can place the pregnant women with obesity in a vulnerable position, contrasting with the emotionally supportive care that women with obesity report needing. Learning from these women’s experiences and their urge for an unloaded communication to protect their integrity highlights the importance of focusing on patient-centered practices instead of standardized care to create a safe space for health promotion.

Abstract Aims Acute heart failure (AHF) can result in worsening of heart failure (WHF), cardiogenic shock (CS), or death. Risk factors for these adverse outcomes are not well characterized. This study aimed to identify predictors for WHF or new‐onset CS in patients hospitalized for AHF. Methods and results Prospective cohort study enrolling consecutive patients with AHF admitted to a large tertiary care centre with follow‐up until death or discharge. WHF was defined by the RELAX‐AHF‐2 criteria. CS was defined as SCAI stages B–E. Potential predictors were assessed by fitting logistic regression models adjusted for age and sex. N = 233 patients were enrolled, median age was 78 years, and 80 were women (35.9%). Ischaemic cardiomyopathy was present in 82 patients (40.8%). Overall, 96 (44.2%) developed WHF and 18 (9.7%) CS. In‐hospital death (8/223, 3.6%) was related to both events (WHF: OR 6.64, 95% CI 1.21–36.55, P = 0.03; CS: OR 38.27, 95% CI 6.32–231.81, P

Abstract Background This study aimed at describing the epidemiology of (neuro)cysticercosis as well as its clinical and radiological characteristics in a Taenia solium endemic district of Zambia. Methods This was part of a cross-sectional community-based study conducted in Sinda district to evaluate an antibody-detecting T. solium point-of-care (TS POC) test for taeniosis and (neuro)cysticercosis. All TS POC cysticercosis positive (CC+) participants and a subset of the TS POC cysticercosis negative (CC-) received a clinical evaluation and cerebral computed tomography (CT) examination for neurocysticercosis (NCC) diagnosis and staging. Results Of the 1249 participants with a valid TS POC test result, 177 (14%) were TS POC CC+ . Cysticercosis sero-prevalence was estimated to be 20.1% (95% confidence intervals [CI] 14.6–27.0%). In total, 233 participants received a CT examination (151 TS POC CC+ , 82 TS POC CC-). Typical NCC lesions were present in 35/151 (23%) TS POC CC+ , and in 10/82 (12%) TS POC CC- participants. NCC prevalence was 13.5% (95% CI 8.4–21.1%) in the study population and 38.0% (95% CI 5.2–87.4%) among people reporting epileptic seizures. Participants with NCC were more likely to experience epileptic seizures (OR = 3.98, 95% CI 1.34–11.78, p = 0.01) than those without NCC, although only 7/45 (16%) people with NCC ever experienced epileptic seizures. The number of lesions did not differ by TS POC CC status (median: 3 [IQR 1–6] versus 2.5 [IQR 1–5.3], p = 0.64). Eight (23%) of the 35 TS POC CC+ participants with NCC had active stage lesions; in contrast none of the TS POC CC- participants was diagnosed with active NCC. Conclusion NCC is common in communities in the Eastern province of Zambia, but a large proportion of people remain asymptomatic.

Understanding and controlling the structure and function of liquid interfaces is a constant challenge in biology, nanoscience and nanotechnology, with applications ranging from molecular electronics to controlled drug release. X-ray reflectivity and grazing incidence diffraction provide invaluable probes for studying the atomic scale structure at liquid–air interfaces. The new time-resolved laser system at the LISA liquid diffractometer situated at beamline P08 at the PETRA III synchrotron radiation source in Hamburg provides a laser pump with X-ray probe. The femtosecond laser combined with the LISA diffractometer allows unique opportunities to investigate photo-induced structural changes at liquid interfaces on the pico- and nanosecond time scales with pump–probe techniques. A time resolution of 38 ps has been achieved and verified with Bi. First experiments include laser-induced effects on salt solutions and liquid mercury surfaces with static and varied time scales measurements showing the proof of concept for investigations at liquid surfaces.

Purpose Multiple knowledge sources inform healthcare. In healthcare encounters, patients and health professionals’ ideas intersect to understand illness and disease. Exploring what is thought of as legitimate knowledge, and where those reflections come from is central to the process of improving and developing healthcare. Within this context, we aim to explore how knowledge about hand osteoarthritis (OA) is constructed and negotiated in clinical consultations. Methodology The article is based on interviews with 21 patients and 14 health professionals in combination with observation in 16 clinical consultations. Reflexive thematic analysis was used to interpret the data. Results We generated four themes from codes to tell an interpretive story about how hand OA meaning-making is “talked into being” in patient-provider encounters: from the dominant voice of health professionals, from patients as knowers in the chronic healthcare dialogue, from health professionals and patients constructing knowledge together and from the construction of knowledge in hybrid positions when patients are health professionals and health professionals have hand OA. Conclusion New knowledge about hand OA is co-constructed in the situated context of the clinical encounter through a polyphony of voices—some of which are dominant, while others occupy the periphery—within and between the interactants in dialgue.

IntroductionThe Faroe Islands are a small archipelago located in the North Atlantic likely colonized by a small group of founders sometime between 50 and 300 CE. Post colonization, the Faroese people have been largely isolated from admixture with mainland and other island populations in the region. As such, the initial founder effect and subsequent genetic drift are likely major contributors to the modern genetic diversity found among the Faroese.MethodsIn this study, we assess the utility of Y-chromosomal microsatellites to detect founder effect in the Faroe Islands through the construction of haplotype networks and a novel empirical method, mutational distance from modal haplotype histograms (MDM), for the visualization and evaluation of population bottlenecks.ResultsWe compared samples from the Faroe Islands and Iceland to possible regional source populations and documented a loss of diversity associated with founder events. Additionally, within-haplogroup diversity statistics reveal lower haplotype diversity and richness within both the Faroe Islands and Iceland, consistent with a small founder population colonizing both regions. However, in the within haplogroup networks, the Faroe Islands are found within the larger set of potential source populations while Iceland is consistently found on isolated branches. Moreover, comparisons of within-haplogroup MDM histograms document a clear founder signal in the Faroes and Iceland, but the strength of this signal is haplogroup-dependent which may be indicative of more recent admixture or other demographic processes.DiscussionThe results of the current study and lack of conformity between Icelandic and Faroese haplotypes implies that the two populations were founded by different paternal gene pools and there is no detectable post-founder admixture between the two groups.

Abstract Background An increasingly complex healthcare system entails an urgent need for competent and resilient leadership. However, there is a lack of extensive research on leadership development within healthcare. The knowledge gaps extend to various frameworks and contexts, particularly concerning municipal healthcare, knowledge leadership, and the application of knowledge in the field of practice. This study is the first in a larger action research project that aims to co-create a knowledge-based continuous leadership development program for healthcare in a rural Arctic municipality. This present study aims to explore the knowledge and experiences of the participating healthcare leaders to develop a common basis for co-creating the program. Methods This hermeneutical study presents the first cycle of the larger action research project. An appreciative approach facilitated the project. Twenty-three healthcare leaders from three different leadership levels attended and evaluated two leadership development workshops and participated in four focus groups. The data were analyzed using Braun and Clarke’s reflexive thematic analysis. Results Two main themes were identified: (1) changing from striving solo players to team players, and (2) learning to handle a conflicting and complex context. These results influenced how the leadership development program based on the participants’ co-creation was organized as a collective and relational process rather than an individual competence replenishment. Conclusions The knowledge and experiences of healthcare leaders led to the co-creation of a knowledge-based continuous leadership development program based on the facilitated interaction of four essential elements: (1) competence development, (2) structures for interaction, (3) interpersonal safety, and (4) collective values and goals. The interaction was generated through trusted reflection facilitated by appreciative inquiry. The four elements and core played a crucial role in fostering relationships and facilitating learning, driving transformative change in this leadership development program. The study’s results provide a solid foundation for further co-creating the program. However, more research is needed to fully explore the practical application and overall significance.

Abstract Background Limited studies of multiple sclerosis (MS) exist whereby magnetic resonance imaging (MRI) of the brain with consistent imaging protocols occurs at the same time points as collection of healthy lifestyle measures. The aim of this study was to test the feasibility, acceptability and preliminary efficacy of acquiring MRI data as an objective, diagnostic and prognostic marker of MS, at the same time point as brain-healthy lifestyle measures including diet. Methods Participants living with relapsing remitting MS partook in one structural MRI scanning session of the brain, completed two online 24-hour dietary recalls and demographic and self-reported lifestyle questionnaires (e.g. self-reported disability, comorbidities, physical activity, smoking status, body mass index (BMI), stress). Measures of central tenancy and level of dispersion were calculated for feasibility and acceptability of the research protocols. Lesion count was determined by one radiologist and volumetric analyses by a data analysis pipeline based on FreeSurfer software suite. Correlations between white matter lesion count, whole brain volume analyses and lifestyle measures were assessed using Spearman’s rank-order correlation coefficient. Results Thirteen female participants were included in the study: eligibility rate 90.6% (29/32), recruitment rate 46.9% (15/32) and compliance rate 87% (13/15). The mean time to complete all required tasks, including MRI acquisition was 115.86 minutes $$($$ ( ± 23.04), over 4 days. Conversion to usual dietary intake was limited by the small sample. There was one strong, negative correlation between BMI and brain volume (r s = −0.643, p = 0.018) and one strong, positive correlation between physical activity and brain volume (r s = 0.670, p = 0.012) that were both statistically significant. Conclusions Acquiring MRI brain scans at the same time point as lifestyle profiles in adults with MS is both feasible and accepted among adult females living with MS. Quantification of volumetric MRI data support further investigations using semi-automated pipelines among people living with MS, with pre-processing steps identified to increase automated feasibility. This protocol may be used to determine relationships between elements of a brain-healthy lifestyle, including dietary intake, and measures of disease burden and brain health, as assessed by T1-weighted and T2-weighted lesion count and whole brain volume, in an adequately powered sample. Trial registration The study protocol was retrospectively registered in the Australia New Zealand Clinical Trials Registry (ACTRN12624000296538).

In recent years, the salmon farming industry has grown significantly worldwide, and in the Faroe Islands, it has become a major industry with an annual production of over 94,000 tonnes, yielding 24% of the GDP. According to environmental regulations, the ocean floor is monitored during every production cycle at all farming sites, involving macrofaunal, sensory, and chemical analyses. However, the impact of farming activity on microorganisms in the Faroe Islands remains unknown. This study aimed to assess the impact of Atlantic salmon farming on benthic microbial communities, giving a better understanding of the effects on the foundation of the benthic food web and to assess if these are more prone to environmental impact than traditional macrofaunal biomonitoring. Sediment cores were sampled along a transect from directly below the salmon cages to a background reference site. The sampling occurred prior to the release of salmon into the cages (‘before stocking’) and immediately before the salmon were harvested (‘peak biomass’). The 16S rRNA (V4-V5) gene was sequenced on an Illumina MiSeq from our sediment samples at the surface, 3 cm, and 10 cm depth. Significant shifts in microbial community composition were observed between ‘before stocking’ and ‘peak biomass’, as well as between different depth layers. Microbial diversity increased with increasing distance from the cages and was at its highest ‘before stocking’, indicating a significant impact of the salmon farming on the microbial community structure. In contrast to the regularly executed environmental monitoring, the results from this study showed an impact on the sediments by the salmon farming, underlining the powerful alternative of DNA-metabarcoding when biomonitoring an aquaculture area.

Vocabulary knowledge is essential for successful language learning. However, little is known about young learners' vocabulary learning in a Thai EFL context and the teaching methods that facilitate vocabulary learning. The current study examined whether songs and total physical response (TPR) can facilitate preschoolers' vocabulary acquisition in a Thai EFL context. Seventy-two preschoolers, aged four to five, were taught 12 target words using TPR, songs, and a mix of both methods (TPR&S) in three classrooms for six weeks. A mixed-method research design was used to triangulate data collected from two tests and video recordings. The tests were administered as a pre-test and a post-test. Moreover, video recordings from hidden cameras captured the participants' interactions during the intervention. The findings revealed that singing and TPR and the mix of both methods significantly improved the participants' vocabulary acquisition, with the TPR&S method having a more positive impact on the participants' vocabulary acquisition than either singing or TPR alone. In conclusion, the current findings indicate that singing and TPR, specifically, a combination of the two, are effective methods to teach young learners English vocabulary in EFL contexts.

Abstract Background The 2017 ATS/ERS technical standard for measuring the single-breath diffusing capacity (DLCO) proposed the “rapid-gas-analyzer” (RGA) or, equivalently, “total-breath” (TB) method for the determination of total lung capacity (TLC). In this study, we compared DLCO and TLC values estimated using the TB and conventional method, and how estimated TLC using these two methods compared to that determined by body plethysmography. Method A total of 95 people with COPD (GOLD grades 1–4) and 23 healthy subjects were studied using the EasyOne Pro (ndd Medical Technologies, Switzerland) and Master Screen Body (Vyaire Medical, Höchberg, Germany). Results On average the TB method resulted in higher values of DLCO (mean ± SD Δ = 0.469 ± 0.267; 95%CI: 0.420; 0.517 mmol*min-1*kPa-1) and TLC (Δ = 0.495 ± 0.371; 95%CI: 0.427; 0.562 L) compared with the conventional method. In healthy subjects the ratio between TB and conventional DLCO was close to one. TLC estimated using both methods was lower than that determined by plethysmography. The difference was smaller for the TB method (Δ = 1.064 ± 0.740; 95%CI: 0.929; 1.199 L) compared with the conventional method (Δ = 1.558 ± 0.940; 95%CI: 1.387; 1.739 L). TLC from body plethysmography could be estimated as a function of TB TLC and FEV1 Z-Score with an accuracy (normalized root mean square difference) of 9.1%. Conclusion The total-breath method yielded higher values of DLCO and TLC than the conventional analysis, especially in subjects with COPD. TLC from the total-breath method can also be used to estimate plethysmographic TLC with better accuracy than the conventional method. The study is registered under clinicaltrial.gov NCT04531293.

Abstract Background The demand for plasma products is growing, necessitating an increase in plasma collection by plasmapheresis. While the 20th edition of the European Guidelines permits plasma donors in Europe to donate with 96-h donation intervals, the potential short- and long-term consequences of high-frequency plasma donations on donor health remain unknown. This study aims to measure the effect of plasma donation frequency on plasma protein composition, including total serum protein (TSP) and immunoglobulin G (IgG), in Norwegian male blood donors. Methods This randomized controlled trial (RCT) included 120 male blood donors who were randomized into two intervention groups and one control group: high-frequency plasma donors (HFPDs) who donated 650 mL of plasma 3 times every 2 weeks, whereas regular-frequency plasma donors (RFPDs) who donated 650 mL of plasma 1 time every 2 weeks. The control group consisted of whole blood donors. The primary outcomes are the concentrations of TSP and IgG. Discussion The findings from this study may have implications for recommendations related to donor health and plasma donation frequencies and may contribute to supporting the strategic independence of plasma products in Norway and Europe without compromising donor health. Trial registration ClinicalTrials.gov: NCT05179200 . Registered December 20th, 2021.

Abstract Aims Cardiomyopathies (CMPs) are a heterogeneous group of diseases that are defined by structural and functional abnormalities of the cardiac muscle. Dilated cardiomyopathy (DCM), the most common CMP, is defined by left ventricular dilation and impaired contractility and represents a common cause of heart failure. Different phenotypes result from various underlying genetic and acquired causes with variable effects on disease development and progression, prognosis, and response to medical treatment. Current treatment algorithms do not consider these different aetiologies, due to lack of insights into treatable drivers of cardiac failure in patients with DCM. Our study aims to precisely phenotype and genotype the various subtypes of DCM and hereby lay the foundation for individualized therapy. Methods and results The Geno‐ And Phenotyping of PrImary Cardiomyopathy (GrAPHIC) is a currently ongoing prospective observational monocentric cohort study that recruits patients with DCM after exclusion of other causes such as coronary artery disease, valvular dysfunction, myocarditis, exposure to toxins, and peripartum CMP. Patients are enrolled at our heart failure outpatient clinic or during hospitalization at the University Hospital Hamburg. Clinical parameters, multimodal imaging and functional assessment, cardiac biopsies, and blood samples are obtained to enable an integrated genomic, functional, and biomarker analysis. Conclusions The GrAPHIC will contribute to a better understanding of the heterogeneous nature of primary CMPs focusing on DCM and provide improved prognostic approaches and more individualized therapies.

Abstract New Public Management-inspired reforms in the Norwegian hospital sector have introduced several features from the private sector into a predominantly public healthcare system. Since the late 1990s, several reforms have been carried out with the intention of improving the utilization of resources. There is, however, limited knowledge about the long-term, and sector-wide effects of these reforms. In this study, using a panel data set of all public hospital trusts spanning nine years, we provide an analysis of the efficiency of hospital trusts using data envelopment analysis (DEA), as well as a Malmquist productivity index. Thereafter we use the efficiency scores as the dependent variable in a second-stage panel data regression analysis. We show that during the period between 2011 and 2019, on average, efficiency has increased over time. Further, in the second-stage analysis, we show that New Public Management features related to incentivization are associated with the level of hospital efficiency. We find no association between degree of competition and efficiency.

Abstract Background Pre-pregnancy obesity increases the risk of perinatal complications. Post-pregnancy is a time of preparation for the next pregnancy and lifestyle advice in antenatal care and postpartum follow-up is therefore recommended. However, behavioral changes are difficult to achieve, and a better understanding of pregnant women’s perspectives and experiences of pre-pregnancy weight development is crucial. Methods We used a qualitative design and conducted semi-structured interviews with 14 women in Norway with pre-pregnancy obesity 3–12 months postpartum. Data were analyzed using thematic analysis. Results Four themes addressing women’s experiences and understanding of their weight development were generated: (1) Unmet essential needs, (2) Genetic predisposition for obesity, challenging life course transitions and turning points, (3) Under a critical eye: an ever-present negative bodily awareness, and (4) Wrestling with food. Parents’ inability to meet children’s essential needs caused weight gain through an unbalanced diet, increased stress, and emotional eating patterns. Body criticism and a feeling of not belonging led to negative body awareness that influenced behavioral patterns and relationships. Participants reporting having had a good childhood more often described their weight development as a result of genetic predisposition, challenging life course transitions and turning points, such as illness and injuries. Nevertheless, these participants also described how eating patterns were influenced by stress and negative emotions. Conclusions Healthcare providers should pay attention to the insider perspectives of pre-pregnancy weight development. An open and shared understanding of the root causes of these women’s weight development can form a basis for more successful lifestyle guidance.

Disorders affecting the neurological and musculoskeletal systems represent international health priorities. A significant impediment to progress in trials of new therapies is the absence of responsive, objective, and valid outcome measures sensitive to early disease changes. A key finding in individuals with neuromuscular and musculoskeletal disorders is the compositional changes to muscles, evinced by the expression of fatty infiltrates. Quantification of skeletal muscle composition by MRI has emerged as a sensitive marker for the severity of these disorders; however, little is known about the composition of healthy muscles across the lifespan. Knowledge of what is ‘typical’ age-related muscle composition is essential to accurately identify and evaluate what is ‘atypical’. This innovative project, known as the MuscleMap, will achieve the first important steps towards establishing a world-first, normative reference MRI dataset of skeletal muscle composition with the potential to provide valuable insights into various diseases and disorders, ultimately improving patient care and advancing research in the field.

Oral tongue squamous cell carcinoma (OTSCC) is the most common cancer of the oral cavity and is associated with high morbidity due to local invasion and lymph node metastasis. Tumor infiltrating lymphocytes (TILs) are associated with good prognosis in oral cancer patients and dictate response to treatment. Ectopic sites for immune activation in tumors, known as tertiary lymphoid structures (TLS), and tumor-associated high-endothelial venules (TA-HEVs), which are specialized lymphocyte recruiting vessels, are associated with a favorable prognosis in OSCC. Why only some tumors support the development of TLS and HEVs is poorly understood. In the current study we explored the infiltration of lymphocyte subsets and the development of TLS and HEVs in oral epithelial lesions using the 4-nitroquinoline 1-oxide (4NQO)-induced mouse model of oral carcinogenesis. We found that the immune response to 4NQO-induced oral epithelial lesions was dominated by T cell subsets. The number of T cells (CD4+, FoxP3+, and CD8+), B cells (B220+) and PNAd+ HEVs increased from the earliest to the latest endpoints. All the immune markers increased with the severity of the dysplasia, while the number of HEVs and B cells further increased in SCCs. HEVs were present already in early-stage lesions, while TLS did not develop at any timepoint. This suggests that the 4NQO model is applicable to study the dynamics of the tumor immune microenvironment at early phases of oral cancer development, including the regulation of TA-HEVs in OTSCC.

Human fetal development has been associated with brain health at later stages. It is unknown whether growth in utero, as indexed by birth weight (BW), relates consistently to lifespan brain characteristics and changes, and to what extent these influences are of a genetic or environmental nature. Here we show remarkably stable and lifelong positive associations between BW and cortical surface area and volume across and within developmental, aging and lifespan longitudinal samples (N = 5794, 4–82 y of age, w/386 monozygotic twins, followed for up to 8.3 y w/12,088 brain MRIs). In contrast, no consistent effect of BW on brain changes was observed. Partly environmental effects were indicated by analysis of twin BW discordance. In conclusion, the influence of prenatal growth on cortical topography is stable and reliable through the lifespan. This early-life factor appears to influence the brain by association of brain reserve, rather than brain maintenance. Thus, fetal influences appear omnipresent in the spacetime of the human brain throughout the human lifespan. Optimizing fetal growth may increase brain reserve for life, also in aging.

Abstract Background Waist-to-height ratio (WHtR) has been proposed as a simple and effective screening tool for assessing central obesity and cardiometabolic risk in both adult and pediatric populations. However, evidence suggests that the use of a uniform WHtR cut-off of 0.50 may not be universally optimal for pediatric populations globally. We aimed to determine the optimal cut-offs of WHtR in children and adolescents with increased cardiometabolic risk across different countries worldwide. Methods We used ten population-based cross-sectional data on 24,605 children and adolescents aged 6–18 years from Brazil, China, Greece, Iran, Italy, Korea, South Africa, Spain, the UK, and the USA for establishing optimal WHtR cut-offs. We performed an external independent test (9,619 children and adolescents aged 6–18 years who came from other six countries) to validate the optimal WHtR cut-offs based on the predicting performance for at least two or three cardiometabolic risk factors. Results Based on receiver operator characteristic curve analyses of various WHtR cut-offs to discriminate those with ≥ 2 cardiometabolic risk factors, the relatively optimal percentile cut-offs of WHtR in the normal weight subsample population in each country did not always coincide with a single fixed percentile, but varied from the 75th to 95th percentiles across the ten countries. However, these relatively optimal percentile values tended to cluster irrespective of sex, metabolic syndrome (MetS) criteria used, and WC measurement position. In general, using ≥ 2 cardiometabolic risk factors as the predictive outcome, the relatively optimal WHtR cut-off was around 0.50 in European and the US youths but was lower, around 0.46, in Asian, African, and South American youths. Secondary analyses that directly tested WHtR values ranging from 0.42 to 0.56 at 0.01 increments largely confirmed the results of the main analyses. In addition, the proposed cut-offs of 0.50 and 0.46 for two specific pediatric populations, respectively, showed a good performance in predicting ≥ 2 or ≥ 3 cardiometabolic risk factors in external independent test populations from six countries (Brazil, China, Germany, Italy, Korea, and the USA). Conclusions The proposed international WHtR cut-offs are easy and useful to identify central obesity and cardiometabolic risk in children and adolescents globally, thus allowing international comparison across populations.

Hege Johanne Magnussen,1,2 Ingvild Kjeken,1– 3 Irma Pinxsterhuis,1 Trine Amalie Sjøvold,4 Marte Feiring1– 3 1Department of Rehabilitation Science and Health Technology, Faculty of Health Sciences, Oslo Metropolitan University, Oslo, Norway; 2Norwegian National Advisory Unit on Rehabilitation in Rheumatology, Diakonhjemmet Hospital, Oslo, Norway; 3REMEDY - Center for Treatment of Rheumatic and Musculoskeletal Diseases, Diakonhjemmet Hospital, Oslo, Norway; 4REMEDY Patient Council, Diakonhjemmet hospital, Oslo, NorwayCorrespondence: Hege Johanne Magnussen, Email hegejoha@oslomet.noPurpose: Societal change and rise in demand for healthcare call for new health professional practices and task redistribution. Through negotiated order theory, this study explores how hospital rheumatologists (RT) and occupational therapists (OT) negotiate professional tasks in the clinical management of hand osteoarthritis.Methodology: Fourteen qualitative interviews and 16 observations in clinical consultations were conducted in two hospitals specialized in rheumatology in Norway. Participants included eight OTs, six RTs, and patients in consultations. Data were analyzed using reflexive thematic analysis.Results: Three themes were developed from codes: hierarchical ordering of hospital work impacts interprofessional negotiations; diagnostic organization of tasks preserves RT authority; and evidence-based recommendations in rheumatology enhance OT responsibilities. Overall, RTs and OTs enact tasks in succession where higher-ranking RTs establish a diagnosis and decide the subsequent in-hospital trajectory entrenched in a medical knowledge system. When medicine does not hold evidence-based treatment alternatives for patients, OTs respond by providing therapeutic interventions that are legitimized through international recommendations in rheumatology when they equip patients with tools to cope with chronic illness.Conclusion: Negotiations over tasks do not take place from equal power positions when status and knowledge hierarchies frame professional practices. The enactment of tasks is concurrently highly influenced by the arena of the workplace, where the two professional groups both cross boundaries and work together in concert despite professional differences in order to meet patient interests and provide relevant healthcare.Keywords: professional boundaries, negotiated order, disease trajectory, hand osteoarthritis, reflexive thematic analysis

Abstract Genetic signatures have added a molecular dimension to prognostics and therapeutic decision-making. However, tumour heterogeneity in prostate cancer and current sampling methods could confound accurate assessment. Based on previously published spatial transcriptomic data from multifocal prostate cancer, we created virtual biopsy models that mimic conventional biopsy placement and core size. We then analysed the gene expression of different prognostic signatures (OncotypeDx®, Decipher®, Prostadiag®) using a step-wise approach with increasing resolution from pseudo-bulk analysis of the whole biopsy, to differentiation by tissue subtype (benign, stroma, tumour), followed by distinct tumour grade and finally clonal resolution. The gene expression profile of virtual tumour biopsies revealed clear differences between grade groups and tumour clones, compared to a benign control, which were not reflected in bulk analyses. This suggests that bulk analyses of whole biopsies or tumour-only areas, as used in clinical practice, may provide an inaccurate assessment of gene profiles. The type of tissue, the grade of the tumour and the clonal composition all influence the gene expression in a biopsy. Clinical decision making based on biopsy genomics should be made with caution while we await more precise targeting and cost-effective spatial analyses.

Objectives: Malaria and sexually transmitted and reproductive tract infections (STIs/RTIs) are highly prevalent in sub-Saharan Africa and associated with poor pregnancy outcomes. We investigated the individual and combined effects of malaria and curable STIs/RTIs on fetal growth in Kenya, Tanzania, and Malawi. Methods: This study was nested within a randomized trial comparing monthly intermittent preventive treatment for malaria in pregnancy with sulfadoxine-pyrimethamine vs dihydroartemisinin-piperaquine, alone or combined with azithromycin. Fetal weight gain was assessed by serial prenatal ultrasound. Malaria was assessed monthly, and Treponema pallidum, Neisseria gonorrhoeae, Trichomonas vaginalis, Chlamydia trachomatis, and bacterial vaginosis at enrollment and in the third trimester. The effect of malaria and STIs/RTIs on fetal weight/birthweight Z-scores was evaluated using mixed-effects linear regression. Results: In total, 1435 pregnant women had fetal/birth weight assessed 3950 times. Compared to women without malaria or STIs/RTIs (n = 399), malaria-only (n = 267), STIs/RTIs only (n = 410) or both (n = 353) were associated with reduced fetal growth (adjusted mean difference in fetal/birth weight Z-score [95% confidence interval]: malaria = -0.18 [-0.31,-0.04], P = 0.01; STIs/RTIs = -0.14 [-0.26,-0.03], P = 0.01; both = -0.20 [-0.33,-0.07], P = 0.003). Paucigravidae experienced the greatest impact. Conclusion: Malaria and STIs/RTIs are associated with poor fetal growth especially among paucigravidae women with dual infections. Integrated antenatal interventions are needed to reduce the burden of both malaria and STIs/RTIs.

Delta opioid receptor (DOR) agonists alleviate nociceptive behaviors in various chronic pain models, including neuropathic pain, while having minimal effect on sensory thresholds in the absence of injury. The mechanisms underlying nerve injury-induced enhancement of DOR function are unclear. We used a peripheral nerve injury (PNI) model of neuropathic pain to assess changes in the function and localization of DORs in mice and rats. Intrathecal administration of DOR agonists reversed mechanical allodynia and thermal hyperalgesia. The dose-dependent thermal antinociceptive effects of DOR agonists were shifted to the left in PNI rats. Administration of DOR agonists produced a conditioned place preference in PNI, but not in sham, animals, whereas the DOR antagonist naltrindole produced a place aversion in PNI, but not in sham, mice, suggesting the engagement of endogenous DOR activity in suppressing pain associated with the injury. GTPγS autoradiography revealed an increase in DOR function in the dorsal spinal cord, ipsilateral to PNI. Immunogold electron microscopy and in vivo fluorescent agonist assays were used to assess changes in the ultrastructural localization of DORs in the spinal dorsal horn. In shams, DORs were primarily localized within intracellular compartments. PNI significantly increased the cell surface expression of DORs within lamina IV-V dendritic profiles. Using neonatal capsaicin treatment, we identified that DOR agonist-induced thermal antinociception was mediated via receptors expressed on primary afferent sensory neurons but did not alter mechanical thresholds. These data reveal that the regulation of DORs following PNI and suggest the importance of endogenous activation of DORs in regulating chronic pain states.