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Objective: To assess the potential contribution of large-scale food fortification (LSFF) towards meeting dietary micronutrient requirements in Tanzania., Design: We used household food consumption data from the National Panel Survey 2014-15 to estimate fortifiable food vehicle coverage and consumption (standardised using the adult female equivalent approach) and the prevalence at risk of inadequate apparent intake of five micronutrients included in Tanzania's fortification legislation. We modelled four LSFF scenarios: no fortification, status quo (i.e. compliance with current fortification contents) and full fortification with and without maize flour fortification., Setting: Tanzania., Participants: A nationally representative sample of 3290 Tanzanian households., Results: The coverage of edible oils and maize and wheat flours (including products of wheat flour and oil such as bread and cakes) was high, with 91 percent, 88 percent and 53 percent of households consuming these commodities, respectively. We estimated that vitamin A-fortified oil could reduce the prevalence of inadequate apparent intake of vitamin A (retinol activity equivalent) from 92 percent without LSFF to 80 percent with LSFF at current fortification levels. Low industry LSFF compliance of flour fortification limits the contribution of other micronutrients, but a hypothetical full fortification scenario shows that LSFF of cereal flours could substantially reduce the prevalence at risk of inadequate intakes of iron, zinc, folate and vitamin B 12 ., Conclusions: The current Tanzania LSFF programme likely contributes to reducing vitamin A inadequacy. Policies that support increased compliance could improve the supply of multiple nutrients, but the prominence of small-scale maize mills restricts this theoretical benefit.

Raman spectroscopy is widely used across scientific domains to characterize the chemical composition of samples in a nondestructive, label-free manner. Many applications entail the unmixing of signals from mixtures of molecular species to identify the individual components present and their proportions, yet conventional methods for chemometrics often struggle with complex mixture scenarios encountered in practice. Here, we develop hyperspectral unmixing algorithms based on autoencoder neural networks, and we systematically validate them using both synthetic and experimental benchmark datasets created in-house. Our results demonstrate that unmixing autoencoders provide improved accuracy, robustness, and efficiency compared to standard unmixing methods. We also showcase the applicability of autoencoders to complex biological settings by showing improved biochemical characterization of volumetric Raman imaging data from a monocytic cell., Competing Interests: Competing interests statement:M.M.S. holds part-time appointments at Imperial College London and the Karolinska Institute. M.M.S. is founder of Sparta Biodiscovery Ltd. which commercializes a technology for single particle Raman spectroscopy. M.M.S. is inventor in a patent describing a technique for SPARTA, a technique for single particle Raman spectroscopy (1810010.7), and in a patent describing Raman tags (2314282.1/GB/PRV). M.M.S. invested in, consults for (or was on scientific advisory boards or boards of directors), and conducts sponsored research funded by companies related to the biomaterials field.

Identifying biomarkers for Alzheimer's disease (AD) is crucial, due to its complex pathology, which involves dysfunction in lipid transport, contributing to neuroinflammation, synaptic loss, and impaired amyloid-β clearance. Nuclear magnetic resonance (NMR) is able to quantify and stratify lipoproteins. The study investigated lipoproteins in blood from AD patients, aiming to evaluate their diagnostic potential. Serum and plasma were collected from AD patients ( n = 25) and healthy individuals ( n = 25). We conducted a comprehensive lipoprotein profiling on serum samples using NMR spectroscopy, analysing 112 lipoprotein subfractions. In plasma, we measured unspecific markers of neuronal damage and AD hallmark proteins using single molecule array technology. Additionally, clinical data and cerebrospinal fluid biomarker levels were also collected to enrich our data. Our findings, after adjusting for age and sex differences, highlight significant alterations in two specific lipoproteins; high-density lipoprotein (HDL)-1 Apo-A2 (H1A2) and HDL-2 Apo-A2 (H2A2), both with area under the curve (AUC) values of 0.67, 95% confidence interval (CI) = 0.52-0.82). These results indicate that these lipoprotein subfractions may have potential as indicators of AD-related metabolic changes.

Atherosclerosis, a leading cause of coronary artery disease (CAD), is heavily influenced by hypercholesterolemia (HC). Proteomics research has shown promise in identifying biological markers for CAD diagnosis and prognosis. This cross-sectional study aimed to identify novel biomarkers for detecting HC and CAD. Through the analysis of proteome data from healthy controls (n = 45) and patients diagnosed with HC (n = 51) or CAD (n = 32), distinct protein patterns associated with each condition were identified. Significant alterations in protein levels were identified with a false discovery rate (FDR)-corrected q-value of <0.05. Subsequent receiver operating characteristic (ROC) analysis, with an area under the curve (AUC) greater than 0.75, was conducted. CAD patients exhibited significantly increased levels of the cholesterol-metabolizing protein proprotein convertase subtilisin/kexin type 9 (PCSK9) and varied levels of the angiogenesis-related protein stromal-cell-derived factor-1 (SDF-1) compared to controls. In pairwise comparisons among the study groups, 65 proteins showed significant differential expression. Notably, 14 of these proteins had significant correlations with blood cholesterol levels. Additionally, 22 of the identified proteins were associated with CAD or HC pathways, with nine proteins being common to both conditions (APO E, APO E3, MMP-3, PCSK9, SDF-1, APO B, PAFAH, 60 kDa heat shock protein, and TGF-beta-activated kinase 1 and MAP3K7-binding protein 1 fusion). Nevertheless, this is an exploratory study, and validation studies are needed to confirm these potential protein biomarkers for CAD in the context of HC.

Purpose: Hydrocephalus presents diagnostic and management challenges due to its heterogeneity. The ASPECT Hydrocephalus System, introduced in 2023, offers a comprehensive approach to describing patients with hydrocephalus. This study investigates the clinical applicability of the ASPECT Hydrocephalus System compared to the International Classification of Disease (ICD-10) and demonstrates its utility., Methods: Two hundred pediatric and adult patients with hydrocephalus treated at Copenhagen University Hospital between September 2019 and 2020 were described according to the ASPECT Hydrocephalus System. The latest brain imaging served as assessment point., Results: Forty-seven percent of patients had more than one ICD-10 code assigned, and 40.5% of patients had an unspecific ICD-10 code as the most recent. It was possible to apply factor A (anatomy), S (symptomatology), P (previous interventions), C (complications) and T (time of onset) to all patients. Factor E (etiology) categorized 15% of patients as 'unknown'. Combining factor A and S showed a similar incidence of acute high-pressure symptoms in patients with and without ventriculomegaly on imaging (39.7% vs 39.3%), demonstrating how symptoms and neuro-radiological findings do not necessarily correlate., Conclusion: The ASPECT Hydrocephalus System's applicability and utility were demonstrated in a large, diverse patient population. Except for 'Etiology', all factors could be applied to the entire population showing the system's robustness. While limitations in ICD-10 may force clinicians to choose between clinical measures, the ASPECT Hydrocephalus System allows comprehensive patient characterization, potentially aiding in clinical decision-making and research. Its use depends on registration quality. Application in prospective cohorts is warranted to assure feasibility., (© 2024. The Author(s).)

Background: Cardiac time intervals are sensitive markers of myocardial dysfunction that predispose to heart failure (HF). We aimed to investigate the association between cardiac time intervals and HF in patients with acute coronary syndrome (ACS)., Methods: This study included 386 ACS patients treated with percutaneous coronary intervention (PCI). Patients underwent an echocardiography examination a median of two days after PCI. Cardiac time intervals including isovolumic relaxation time (IVRT), isovolumic contraction time (IVCT), and systolic ejection time (ET), and myocardial performance index (MPI) were obtained by tissue Doppler echocardiography. The outcome was incident HF., Results: During follow-up (median 4.3, IQR:1.0-6.7 years), 140 (36%) developed HF. In unadjusted analyses, IVRT was not associated with HF (HR 1.02 (0.95-1.10), p = 0.61, per 10ms increase), and neither was IVCT (HR 0.07 (0.95-1.22), p = 0.26, per 10ms increase). Increasing MPI was associated with a higher risk of HF (HR 1.20 (1.08-1.34), P = 0.001, per 0.1 increase), and so was decreasing ET (HR 1.13 (1.07-1.18), P < 0.001 per 10ms decrease). After multivariable adjustment for cardiovascular risk factors, MPI (HR 1.13 (1.01-1.27), P = 0.034) and ET (HR 1.09 (1.01-1.17), P = 0.025) remained significantly associated with incident HF. LVEF modified the association between ET and HF (p for interaction = 0.002), such that ET was associated with HF in patients with LVEF ≥ 36% (HR = 1.15 (1.06-1.24), P = 0.001, per 10ms decrease)., Conclusion: In patients admitted with ACS, shortened ET and higher MPI were independently associated with an increased risk of incident HF. Additionally, ET was associated with incident HF in patients with LVEF above 36%., (© 2024. The Author(s).)

Objectives: Use of handheld portable ultrasound is increasing and would improve access for people with rheumatic disease when conventional, cart-based ultrasound is unavailable. This study compared handheld and cart-based ultrasound for the assessment of gout lesions in people with gout., Methods: The lower limbs of 21 participants with gout were independently scanned at six sites (1st and 2nd metatarsophalangeal joints, knee, patellar ligament, Achilles tendon, and peroneal tendons) using cart-based (LOGIQ P9) and handheld (Vscan Air™) ultrasound by two rheumatologists. One rheumatologist was randomized to scan the right or left leg first with the cart-based or handheld ultrasound. The other rheumatologist scanned the legs in the opposite order with the imaging devices reversed. Images were saved and blinded images scored for double contour, tophus, erosion and aggregates using OMERACT definitions by two rheumatologists experienced in gout ultrasound., Results: On handheld ultrasound, 90% of participants had at least one site with double contour, tophus and erosions, and 100% had at least one site with aggregates. There were similar findings using cart-based ultrasound. However, site-level inter-device analysis showed only fair-good agreement: kappa (percentage agreement) for double contour 0.22 (67%), tophus 0.46 (77%), erosion 0.63 (83%) and aggregates 0.37 (75%). There were more aggregates detected by cart-based ultrasound in joints and more tophi detected by handheld ultrasound in ligaments and tendons., Conclusions: Handheld ultrasound can detect gout lesions in people with established gout. However, concordance between cart-based and handheld ultrasound in detection of some gout lesions is low, particularly double contour and aggregates., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Lene Terselv receives a Speaker's fee from Novarts, Pfizer, Eli Lilly and Janssen. Lene is on the Advisory board for UCB and Janssen. Nicola Dalbeth has received support from the Health research Council of New Zealand and is paid to the institution, has received grants or contracts from Novotech which is paid to the institution, has received personal consulting fees from AstraZeneca, Horizon, Selecta, Arthrosi, JW Pharmaceutical Corporation, PK Med, PTC Therapeutics, Protalix, Cello Health, JPI, Unlocked Labs, LG, Dexoligo Therapeutics, Shanton Pharma, Avalo, has received payment or honorarium from Novartis, Hikma, Horizon, has received personal fees for participating on a Data safety Monitoring Board or Advisory Board for Protalix, has had a Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid for New Zealand Rheumatology Associateion and Auckland Medical Research Foundation, has received a loan from Abbvie for ultrasound machine to clinical department via NZRA ultrasound loan programme., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Raman spectroscopy is an analytical method based on light-matter interactions that can interrogate the vibrational modes of matter and provide representative molecular fingerprints. Mediated by its label-free, non-invasive nature, and high molecular specificity, Raman-based techniques have become ubiquitous tools for in situ characterization of materials. This review comprehensively describes the theoretical and practical background of Raman spectroscopy and its advanced variants. The numerous facets of material characterization that Raman scattering can reveal, including biomolecular identification, solid-to-solid phase transitions, and spatial mapping of biomolecular species in bioactive materials, are highlighted. The review illustrates the potential of these techniques in the context of active biomedical material design and development by highlighting representative studies from the literature. These studies cover the use of Raman spectroscopy for the characterization of both natural and synthetic biomaterials, including engineered tissue constructs, biopolymer systems, ceramics, and nanoparticle formulations, among others. To increase the accessibility and adoption of these techniques, the present review also provides the reader with practical recommendations on the integration of Raman techniques into the experimental laboratory toolbox. Finally, perspectives on how recent developments in plasmon- and coherently-enhanced Raman spectroscopy can propel Raman from underutilized to critical for biomaterial development are provided., (© 2023 The Authors. Advanced Materials published by Wiley‐VCH GmbH.)

For people in homelessness, access to social services may appear difficult and alienating, which often contributes to poor health and a risk of accelerated marginalization. Historically, day centres for people in homelessness have been characterized by an emphasis on providing refuge and momentary restitution, accommodating urgent basic needs. In this article, we present a case study of the design of a new day centre in Denmark that aspires to move beyond the historical place-for-being . Rather, the new day centre is to be a place-for-being-and-becoming , focusing on bridging the varied needs of people in homelessness with easy access to social services at the day centre. This article explores the creation of new behaviour settings along with the challenges and considerations in designing enabling spaces for people in societally marginalized positions, concurrently offering and supporting a sense of inclusion, the possibility to develop one's agency and experience of lived citizenship. This article is part of the theme issue 'People, places, things, and communities: expanding behaviour settings theory in the twenty-first century'.

Background: The way in which children interact with food has a profound impact on their health and wellbeing. However, most research, strategy and policy where food is the focus are derived from adult perspectives. There is limited understanding of children's perspectives of the nature of their everyday food practices, and their level of involvement and influence. This work garnered children's (8-12 years old) descriptions of, and involvement in, their everyday food practices., Methods: Forty-two children from 28 families from across Brisbane (Australia) participated in qualitative creative draw-and-tell interviews and 20 of these children (from 15 families) also completed Photovoice data collection. Data were abductively analysed through a social practice theory lens., Results: Children reported engaging in food planning, acquisition, preparation, consumption and tidy-up practices, to varying degrees of 'less involved', 'in partnership with adults or other children' or 'independently'. This was influenced largely by the willingness of adults to relinquish control and children's desire to participate, as well as other contextual factors. Children were more independent in consumption practices, as well as packing lunchboxes and preparing food spaces (as preparation practices). Partnerships were established more so within food acquisition and preparation practices, with less involvement described within planning and tidy-up practices., Conclusions: The findings add new knowledge and depth and breadth to that already obtained from parents, teachers and adult researchers, highlighting the importance of privileging children's voices when investigating their food experiences. This work may be used to guide adults to invite and support children to be involved in food practices that they report being less involved in, as well as inform how best to work with and include children in future research and food and nutrition strategies and policies., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Environmental DNA (eDNA) is a technique increasingly used for monitoring organisms in the natural environment including riverine macroinvertebrates. However, the effectiveness of eDNA for monitoring riverine macroinvertebrates compared with the more traditional method of sampling the organisms directly and identifying them via morphological analysis, has not been well established. Furthermore, the ability of the various gene markers and PCR primer sets to detect the full range of riverine invertebrate taxa has not been quantified. Here we conducted a meta-analysis of the available literature, to assess the effectiveness of eDNA sampling for detecting riverine macroinvertebrates compared with sampling for the organisms directly and applying morphological analysis. We found, on average, eDNA sampling, irrespective of the gene marker used, detected fewer riverine invertebrates than morphological sampling. The most effective PCR primer set for identifying taxa was mlCOIintF/jgHCO2198, (mlCOIintF- forward primer, jgHCO2198, - reverse primer). Regardless of the gene marker or primer sets used, however, many taxa were not detected by eDNA metabarcoding that were detected by sampling directly for these invertebrates, including over 100 members of Arthropoda. eDNA sampling failed to detect any species belonging to Nematoda, Platyhelminthes, Cnidaria or Nematomorpha and these markers applied for eDNA sampling in terrestrial systems also do not detect members of Nematoda. In addition to these issues, uncertainties relating to false positives from upstream DNA sources, the stability of DNA from different species, differences in the propensity for DNA release into the environment for different organisms, and lack of available sequence information for numerous taxa illustrates the use of eDNA is not yet applicable as a robust stand-alone method for the monitoring of riverine invertebrates. As a primary consideration, further methodological developments are needed to ensure eDNA captures some of the key freshwater taxa, notably taxa belonging to the phyla Arthropoda, Nematoda, Platyhelminthes, Cnidaria and Nematomorpha., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Imogen Poyntz-Wright reports financial support was provided by Natural Environment Research Council. Imogen Poyntz-Wright reports financial support was provided by United Kingdom Department for Environment Food and Rural Affairs., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Modern therapies targeting the BRAF gene mutation in advanced melanoma have significantly improved patient outcomes but pose cardiovascular risks. This retrospective study in Eastern Denmark (2019-2022) assessed 108 melanoma patients treated with encorafenib and binimetinib. Patients were monitored for heart function using multigated acquisition (MUGA) scans. The study defined major cardiotoxicity as a decline in left ventricular ejection fraction (LVEF) by more than 10 percentage points to below 50%, and minor cardiotoxicity as a decrease in LVEF by more than 15 points but remaining above 50%. Results showed that 19 patients (18%) developed minor cardiotoxicity and were asymptomatic, while 7 (6%) experienced major cardiotoxicity, with two requiring intervention. Notably, no significant declines in LVEF were observed after six months of treatment. The study concluded that significant cardiotoxicity occurred in 6% of cases, mostly asymptomatic and reversible, and suggests that monitoring LVEF could potentially be reduced after 6-9 months if no early signs of cardiotoxicity are detected. This provides valuable insights into the cardiac safety of these treatments in real-world settings.

Introduction: Traumatic elbow dislocations are among the most common injuries in sport climbing. They occur most frequently in bouldering (a climbing discipline with strong upward trend often performed indoors) due to the typical low-height backward fall into crashpads. There is still no data about the functional outcome and return to sport of this typical bouldering injury., Materials and Methods: All Patients with elbow dislocations due to a bouldering associated fall between 2011 and 2020 were identified retrospectively in our level I trauma centre. Trauma mechanisms, injury types and therapies were obtained. Follow-up was performed with an online questionnaire including sports-related effects, return to sport and the Elbow Self-Assessment Score (ESAS)., Results: 30 patients with elbow dislocations after bouldering accidents were identified. In 22 (73.3%) patients the injury was a simple dislocation. The questionnaire was completed by 20 patients. The leading mechanism was a low-height fall into crashpads. Surgical procedures were performed in every second patient. 18 patients (90%) reported return to bouldering after 4.7 ± 2.1 months. 12 patients (66.7%) regained their pre-injury level. Mid-/Long-term follow-up (mean 105 ± 37.5 months) showed excellent results in ESAS score (97.2 ± 3.9 points). Persistent limited range of motion or instability was reported by only 3 patients (15%)., Conclusion: Most athletes are able to return to bouldering but only two thirds regain their pre-injury performance level in this demanding upper-extremity sport. The unique low-height trauma mechanism may create a false sense of security. Specific awareness and safety features should be placed for climbing athletes to reduce elbow injuries., (© 2024. The Author(s).)

Muscle-enriched A-type lamin-interacting protein ( MLIP ) is an emerging protein involved in cellular homeostasis and stress adaptation. Eukaryotic cells regulate various cellular processes, including metabolism, DNA repair, and cell cycle progression, to maintain cellular homeostasis. Disruptions in this homeostasis can lead to diseases such as cancer, characterized by uncontrolled cell growth and division. This review aims to explore for the first time the unique role MLIP may play in cancer development and progression, given its interactions with the PI3K/Akt/mTOR pathway, p53 , MAPK9 , and FOXO transcription factors, all critical regulators of cellular homeostasis and tumor suppression. We discuss the current understanding of MLIP 's involvement in pro-survival pathways and its potential implications in cancer cells' metabolic remodeling and dysregulated homeostasis. Additionally, we examine the potential of MLIP as a novel therapeutic target for cancer treatment. This review aims to shed light on MLIP 's potential impact on cancer biology and contribute to developing innovative therapeutic strategies.

Advancements in lymphoma treatment have increased the number of long-term survivors who may experience late effects such as impaired sexual function and testosterone deficiency. The aim of this review was to determine the prevalence of testosterone deficiency and sexual dysfunction among male lymphoma survivors; and associations between the two. A systematic search identified 20 articles for inclusion. The prevalence of low total testosterone was 0%-50 %, with mean values within reference levels, and for luteinizing hormone above reference levels in 0%-80 %. Four studies included SHBG and free testosterone, with mixed results. Compromised sexual health was found in 23%-61 %. Overall, total testosterone and sexual health were associated. The risk of bias (ROBINS-E and RoB 2) was high/very high, leading to low/very low overall confidence in the bulk of evidence (GRADE). Longitudinal studies evaluating biologically active testosterone and sexual health are needed, to develop evidence based standard procedures for follow-up of sexual health., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interestsSigne Micas Pedersen reports equipment, drugs, or supplies was provided by Besins Healthcare. Peter de Nully Brown reports a relationship with Roche that includes: consulting or advisory. Peter de Nully Brown reports a relationship with Gilead Sciences Inc that includes: consulting or advisory. Peter de Nully Brown reports a relationship with Swedish Orphan Biovitrum that includes: consulting or advisory. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Background: The aim of this study was to investigate the effect of high load resistance training using barbell half squats compared with trap bar deadlifts on maximal strength, power performance, and lean mass in recreationally active females., Methods: Twenty-two recreationally active female participants (age: 26.9 ± 7.7 yrs.; height: 166.0 ± 5.1 cm; weight: 68.6 ± 9.9 kg) were randomly assigned to either a barbell half squat group (SG: n = 10) or trap bar deadlift group (DG: n = 12). Training consisted of twice-weekly sessions for eight weeks. Both groups completed one-repetition maximum (1RM) testing for both barbell half squat and trap bar deadlift groups. Countermovement jump (CMJ) and sprint performance were also assessed. Total body (TBLM) and leg lean mass (LLM) were measured with dual-energy x-ray absorptiometry. Between-group differences were analysed using analysis of covariance., Results: SG tended to improve 1RM half squat (21.0 ± 11.5 kg vs. 13.1 ± 7.5 kg) more than DG (mean difference (MD): 8.0 kg, 95% CI: -0.36 - 16.3 kg). A similar pattern in favour of DG (18.4 ± 11.2 vs. 11.7 ± 8.1 kg) compared to SG was observed (MD: 6.5 kg, 95% CI: -2.5 - 15.6 kg). No between-group differences for sprint, jump or lean body mass changes was observed. For groups combined, the following changes in CMJ (2.0 ± 2.4 cm), 5-m sprint (-0.020 ± 0.039 s), 15-m sprint (-0.055 ± 0.230 s), TBLM (0.84 ± 1.12 kg), and LLM (0.27 ± 0.59 kg) was observed., Conclusions: An exercise intervention consisting of half squats or trap bar deadlift were associated with improved muscle strength, power, and lean mass. Our findings suggests that in recreationally active females, exercise selection is less of a concern provided that heavy loads are applied, and relevant muscle groups are targeted., (© 2024. The Author(s).)

Data analysis for athletic performance optimization and injury prevention is of tremendous interest to sports teams and the scientific community. However, sports data are often sparse and hard to obtain due to legal restrictions, unwillingness to share, and lack of personnel resources to be assigned to the tedious process of data curation. These constraints make it difficult to develop automated systems for analysis, which require large datasets for learning. We therefore present SoccerMon, the largest soccer athlete dataset available today containing both subjective and objective metrics, collected from two different elite women's soccer teams over two years. Our dataset contains 33,849 subjective reports and 10,075 objective reports, the latter including over six billion GPS position measurements. SoccerMon can not only play a valuable role in developing better analysis and prediction systems for soccer, but also inspire similar data collection activities in other domains which can benefit from subjective athlete reports, GPS position information, and/or time-series data in general., (© 2024. The Author(s).)

Coronary artery disease (CAD) and atherosclerosis pose significant global health challenges, with intricate molecular changes influencing disease progression. Hypercholesterolemia (HC), hypertension (HT), and diabetes are key contributors to CAD development. Metabolomics, with its comprehensive analysis of metabolites, offers a unique perspective on cardiovascular diseases. This study leveraged metabolomics profiling to investigate the progression of CAD, focusing on the interplay of hypercholesterolemia, hypertension, and diabetes. We performed a metabolomic analysis on 221 participants from four different groups: (I) healthy individuals, (II) individuals with hypercholesterolemia (HC), (III) individuals with both HC and hypertension (HT) or diabetes, and (IV) patients with self-reported coronary artery disease (CAD). Utilizing data from the Qatar Biobank, we combined clinical information, metabolomic profiling, and statistical analyses to identify key metabolites associated with CAD risk. Our data identified distinct metabolite profiles across the study groups, indicating changes in carbohydrate and lipid metabolism linked to CAD risk. Specifically, levels of mannitol/sorbitol, mannose, glucose, and ribitol increased, while pregnenediol sulfate, oleoylcarnitine, and quinolinate decreased with higher CAD risk. These findings suggest a significant role of sugar, steroid, and fatty acid metabolism in CAD progression and point to the need for further research on the correlation between quinolinate levels and CAD risk, potentially guiding targeted treatments for atherosclerosis. This study provides novel insights into the metabolomic changes associated with CAD progression, emphasizing the potential of metabolites as predictive biomarkers.

Background: Clinical trials have demonstrated promising outcomes for adjuvant immunotherapy in patients with resected melanoma. Real-life data provide valuable insights to support patient guidance and treatment decisions., Methods: Observational population-based study examining a national cohort of patients with resected stage III-IV melanoma referred for adjuvant therapy. Data were extracted from the Danish Metastatic Melanoma Database (DAMMED)., Results: Between November 2018 and January 2022, 785 patients received adjuvant anti-PD-1. The majority had stage III resected melanoma (87%), normal LDH levels (80%), and performance score 0 (87%). Patients were followed for a median of 25.6 months (95%CI 24-28). The median recurrence-free survival (RFS) and melanoma-specific survival (MSS) were not reached. The RFS was 78% (95%CI 75-81), 66% (63-70), and 59% (55-63); MSS was 97% (95-98), 93% (91-95), and 87% (84-90) at 1-, 2-, and 3-year; respectively. Less than half (42%) of the patients finalized planned therapy, 32% discontinued due to toxicity, and 19% due to melanoma recurrence. Patients discontinuing adjuvant treatment prematurely, without recurrence, had similar outcomes as patients finalizing therapy. In a multivariable analysis, ipilimumab plus nivolumab did not improve outcomes compared to ipilimumab monotherapy as a first-line metastatic treatment after adjuvant anti-PD-1., Conclusion: Survival outcomes in real-world patients with melanoma treated with adjuvant anti-PD-1 align with results from the randomized controlled trials. Patients discontinuing therapy prematurely, for other reasons than recurrence, had similar outcomes as patients finalizing planned treatment. First-line metastatic treatment with ipilimumab and nivolumab post-adjuvant anti-PD-1 did not show improved outcomes compared to ipilimumab/anti-PD-1 monotherapy., Competing Interests: Declaration of Competing Interest Within the last two years: RJ has received travel/conference expenses from Pierre Fabre. MD has received proprietary data access from Bristol Myers Squibb and Genentech and is an advisor of Achilles Therapeutics. CR reports grants from Novo Nordisk Foundation and Helsinn Healthcare SA, and personal fees from Bristol-Myers Squibb, Helsinn Healthcare SA, and Pharmanovia, outside the submitted work. CAH has received honoraria for lectures from BMS and GSK. IMS has received honoraria for consultancies and lectures from IO Biotech, Novartis, MSD, Pierre Fabre, BMS, Novo Nordisk, TILT Bio; research grants from IO Biotech, BMS, Lytix, Adaptimmune, and TILT Bio. EE received honoraria from BMS, Pierre Fabre, and Novartis for consultancies, lectures, and travel/conference expenses from Pierre Fabre and MSD. No potential conflict of interest was reported by the other author(s)., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Hypertension is a pervasive and widespread health condition that poses a significant risk factor for cardiovascular disease, which includes conditions such as heart attack, stroke, and heart failure. Despite its widespread occurrence, the exact cause of hypertension remains unknown, and the mechanisms underlying the progression from prehypertension to hypertension require further investigation. Recent proteomic studies have shown promising results in uncovering potential biomarkers related to disease development. In this study, serum proteomic data collected from Qatar Biobank were analyzed to identify altered protein expression between individuals with normal blood pressure, prehypertension, and hypertension and to elucidate the biological pathways contributing to this disease. The results revealed a cluster of proteins, including the SRC family, CAMK2B, CAMK2D, TEC, GSK3, VAV, and RAC, which were markedly upregulated in patients with hypertension compared to those with prehypertension (fold change ≥ 1.6 or ≤-1.6, area under the curve ≥ 0.8, and q -value < 0.05). Pathway analysis showed that the majority of these proteins play a role in actin cytoskeleton remodeling. Actin cytoskeleton reorganization affects various biological processes that contribute to the maintenance of blood pressure, including vascular tone, endothelial function, cellular signaling, inflammation, fibrosis, and mechanosensing. Therefore, the findings of this study suggest a potential novel role of actin cytoskeleton-related proteins in the progression from prehypertension to hypertension. The present study sheds light on the underlying pathological mechanisms involved in hypertension and could pave the way for new diagnostic and therapeutic approaches for the treatment of this disease.

Background: Transgender and gender diverse (TGD) individuals face barriers, including harassment and discrimination, when accessing healthcare services. Medical imaging procedures require personal information to be shared, such as date of last menstrual cycle and/or pregnancy status; some imaging exams are also invasive or intimate in nature. Terminology is based on binary sex creating an inherently cis-heteronormative environment. TGD patients fear being outed and often feel a need to function as educators and advocates for their care. Incorporation of inclusive healthcare curriculum related to TGD populations is an effective means of educating new health providers and promotes safer and more inclusive spaces in healthcare settings. Educators face barriers which hinder the creation and implementation of TGD content. The purpose of this study was to examine the impacts educators are faced with when creating and delivering TGD content in their medical imaging curriculum., Methods: A case study of medical imaging programs at a Canadian post-secondary institute was undertaken. Data was collected via semi-structured interviews with faculty. Relevant institutional documents such as strategic plans, policies/procedures, websites, and competency profiles were accessed. Framework analysis was used to analyze the data., Results: The study found seven themes that influence the development of TGD curriculum as follows: familiarity and comfort with the curriculum and content change process; collaboration with other healthcare programs; teaching expertise; management of course workload and related. duties; connections to the TGD community; knowledge of required TGD content and existing gaps in curriculum; and access to supports., Conclusions: Understanding educators' perspectives can lead to an increased sense of empowerment for them to create and incorporate TGD curriculum in the future. Many post- secondary institutions are incorporating an inclusive lens to educational plans; this research can be used in future curriculum design projects. The goal is improved medical imaging experiences for the TGD population., (© 2024. The Author(s).)

Introduction: Telemetric monitoring of intracranial pressure (ICP) in children with a complex cerebrospinal disorder might help parents distinguish acute and potential life-threatening symptoms of hydrocephalus from other illnesses., Research Question: What is patient and parent perceptions of system utility of telemetric ICP monitoring, and how does a long-term telemetric implant influence daily life of both patients and their families?, Material and Methods: A qualitative case study design with a focus group interview including parents of children with a complex cerebrospinal fluid disorder and an implanted telemetric ICP sensor., Results: Three parents participated. Based on thematic analysis, three themes were created: 'Daily living with telemetric ICP monitoring', 'Parenting a child with a CSF disorder', and 'The healthy sibling'. The ICP sensor provided the parents with security and made them trust their intuition, while the possibility of home monitoring ensured stability for the entire family and had a calming effect on healthy siblings. Home monitoring was seen as the system's greatest advantages, whereas size, weight, and functionality of the external monitoring equipment were highlighted as disadvantages., Discussion and Conclusion: All parents supported the telemetric ICP sensor as a valued tool in treatment guidance of their child and stated that advantages exceeded disadvantages. It was stated that the possibility of conducting ICP measurements at home reduced the need for acute hospital admissions, which consequently led to a more stable daily life for the entire family. Suggestions regarding technical improvements with focus on more compatible external monitoring equipment were raised by all parents included., Competing Interests: None of the authors have any conflict of interest to declare., (© 2024 The Authors.)

Limited research exists on how the transition towards more sustainable eating takes place at the meso-level of family decision-making, or how children and adolescents engage in and possibly influence the process towards more sustainable diets in families. In this paper, we study how public recommendations that encourage reducing the consumption of meat for the benefit of both health and climate are interpreted, negotiated, and acted upon in Danish families with adolescents (aged 15-20) residing at home. We use novel methodological stimuli, including vignettes and a visual sorting task, embedded in qualitative, in-depth interviews to elicit data on parents' and adolescents' everyday meat consumption/reduction behaviours. Findings reveal that a desire to uphold harmony and family cohesion serves as simultaneous drivers and barriers to reducing meat consumption. Further, we identify barriers to change in the gendered work hidden in the tasks of planning the integration of more sustainable, green dishes into the meal repertoires. Implications are drawn for social marketers, marketers, and public policymakers, encouraging these to use insights into family food decision-making processes as a lever to facilitate the needed green transition of diets in family households., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

This observational study aimed to analyze external training load in highly trained female football players, comparing starters and non-starters across various cycle lengths and training days., Method: External training load [duration, total distance [TD], high-speed running distance [HSRD], sprint distance [SpD], and acceleration- and deceleration distance [AccDecdist] from 100 female football players (22.3 ± 3.7 years of age) in the Norwegian premier division were collected over two seasons using STATSports APEX. This resulted in a final dataset totaling 10498 observations after multiple imputation of missing data. Microcycle length was categorized based on the number of days between matches (2 to 7 days apart), while training days were categorized relative to match day (MD, MD+1, MD+2, MD-5, MD-4, MD-3, MD-2, MD-1). Linear mixed modeling was used to assess differences between days, and starters vs. non-starters., Results: In longer cycle lengths (5-7 days between matches), the middle of the week (usually MD-4 or MD-3) consistently exhibited the highest external training load (~21-79% of MD TD, MD HSRD, MD SpD, and MD AccDecdist); though, with the exception of duration (~108-120% of MD duration), it remained lower than MD. External training load was lowest on MD+2 and MD-1 (~1-37% of MD TD, MD HSRD, MD SpD, MD AccDecdist, and ~73-88% of MD peak speed). Non-starters displayed higher loads (~137-400% of starter TD, HSRD, SpD, AccDecdist) on MD+2 in cycles with 3 to 7 days between matches, with non-significant differences (~76-116%) on other training days., Conclusion: Loading patterns resemble a pyramid or skewed pyramid during longer cycle lengths (5-7 days), with higher training loads towards the middle compared to the start and the end of the cycle. Non-starters displayed slightly higher loads on MD+2, with no significant load differentiation from MD-5 onwards., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 K. Winther et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

We report a case of Mismatch Repair Deficiency (MMRD) caused by germline homozygous EPCAM deletion leading to tissue-specific loss of MSH2. Through the use of patient-derived cells and organoid technologies, we performed stepwise in vitro differentiation of colonic and brain organoids from reprogrammed EPCAM del iPSC derived from patient fibroblasts. Differentiation of iPSC to epithelial-colonic organoids exhibited continuous increased EPCAM expression and hypermethylation of the MSH2 promoter. This was associated with loss of MSH2 expression, increased mutational burden, MMRD signatures and MS-indel accumulation, the hallmarks of MMRD. In contrast, maturation into brain organoids and examination of blood and fibroblasts failed to show similar processes, preserving MMR proficiency. The combined use of iPSC, organoid technologies and functional genomics analyses highlights the potential of cutting-edge cellular and molecular analysis techniques to define processes controlling tumorigenesis and uncovers a new paradigm of tissue-specific MMRD, which affects the clinical management of these patients., (© 2024. The Author(s).)

Whole-head segmentation from Magnetic Resonance Images (MRI) establishes the foundation for individualized computational models using finite element method (FEM). This foundation paves the path for computer-aided solutions in fields, particularly in non-invasive brain stimulation. Most current automatic head segmentation tools are developed using healthy young adults. Thus, they may neglect the older population that is more prone to age-related structural decline such as brain atrophy. In this work, we present a new deep learning method called GRACE, which stands for G eneral, R apid, A nd C omprehensive whole-h E ad tissue segmentation. GRACE is trained and validated on a novel dataset that consists of 177 manually corrected MR-derived reference segmentations that have undergone meticulous manual review. Each T1-weighted MRI volume is segmented into 11 tissue types, including white matter, grey matter, eyes, cerebrospinal fluid, air, blood vessel, cancellous bone, cortical bone, skin, fat, and muscle. To the best of our knowledge, this work contains the largest manually corrected dataset to date in terms of number of MRIs and segmented tissues. GRACE outperforms five freely available software tools and a traditional 3D U-Net on a five-tissue segmentation task. On this task, GRACE achieves an average Hausdorff Distance of 0.21, which exceeds the runner-up at an average Hausdorff Distance of 0.36. GRACE can segment a whole-head MRI in about 3 seconds, while the fastest software tool takes about 3 minutes. In summary, GRACE segments a spectrum of tissue types from older adults T1-MRI scans at favorable accuracy and speed. The trained GRACE model is optimized on older adult heads to enable high-precision modeling in age-related brain disorders. To support open science, the GRACE code and trained weights are made available online and open to the research community at https://github.com/lab-smile/GRACE., Competing Interests: Declaration of competing interest The authors report no conflicts of interest.

Introduction: Pre-hypertension is a prevalent condition among the adult population worldwide. It is characterized by asymptomatic elevations in blood pressure beyond normal levels but not yet reaching the threshold for hypertension. If left uncontrolled, pre-hypertension can progress to hypertension, thereby increasing the risk of serious complications such as heart disease, stroke, kidney damage, and others., Objective: The precise mechanisms driving the progression of hypertension remain unknown. Thus, identifying the metabolic changes associated with this condition can provide valuable insights into potential markers or pathways implicated in the development of hypertension., Methods: In this study, we utilized untargeted metabolomics profiling, which examines over 1,000 metabolites to identify novel metabolites contributing to the progression from pre-hypertension to hypertension. Data were collected from 323 participants through Qatar Biobank., Results: By comparing metabolic profiles between pre-hypertensive, hypertensive and normotensive individuals, six metabolites including stearidonate, hexadecadienoate, N6-carbamoylthreonyladenosine, 9 and 13-S-hydroxyoctadecadienoic acid (HODE), 2,3-dihydroxy-5-methylthio- 4-pentenoate (DMTPA), and linolenate were found to be associated with increased risk of hypertension, in both discovery and validation cohorts. Moreover, these metabolites showed a significant diagnostic performance with area under curve >0.7., Conclusion: These findings suggest possible biomarkers that can predict the risk of progression from pre-hypertension to hypertension. This will aid in early detection, diagnosis, and management of this disease as well as its associated complications., 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., (© 2024 Al Ashmar, Anwardeen, Anlar, Pedersen, Elrayess and Zeidan.)

Objectives: Abnormalities in mismatch repair have been described in ovarian cancer, but few studies have examined the causes of mismatch repair deficiency (MMRd). To address this, we completed targeted mutational and methylation sequencing on MMRd ovarian cancer cases. The objective of this study was to explore the molecular mechanism of MMRd using our targeted next generation sequencing panel., Methods: Newly diagnosed non-serous/mucinous ovarian cancers (n=215) were prospectively recruited from three cancer centers in Ontario, Canada, between 2015 and 2018. Tumors were reflexively assessed for mismatch repair protein by immunohistochemistry. Matched tumor-normal MMRd cases were analyzed on a custom next generation sequencing panel to identify germline and somatic mutations, copy number variants, rearrangements, and promoter methylation in mismatch repair and associated genes., Results: Of 215 cases, 28 (13%) were MMRd. The MMRd cohort had a median age of 52.3 years (range 33.6-62.2), with mostly stage I (50%) and grade 1 or 2 endometrioid histotype (57%). Of the 28 cases, 22 were available for molecular analysis, and Lynch syndrome was detected in 50% of MMRd cases (11/22; seven ovarian cancer and four synchronous ovarian and endometrial cancer: seven MSH6 , two MLH1 , one PMS2 , and one MSH2) . An explanation for the observed mismatch repair phenotype was available for 22/22 deficient cases, including 12 MLH1/PMS2 deficient (nine somatic methylation, one bi-allelic somatic deletion, and two pathogenic germline variant), one PMS2 deficient (one pathogenic germline variant), seven MSH6 deficient (seven pathogenic germline variant), and two MSH2/MSH6 deficient (one pathogenic germline variant and one bi-allelic somatic mutation). Concordance between clinical germline testing and panel sequencing results was 100%., Conclusions: Use of our custom next generation sequencing panel allowed for the streamlined assessment of hereditary and somatic causes of MMRd in ovarian cancers., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

The ratio of early transmitral filling velocity to early diastolic strain rate (E/SRe) has been proposed as a new non-invasive measurement of left ventricular filling pressure. We aimed to investigate the ability of E/SRe to predict atrial fibrillation (AF) after ST-elevation myocardial infarction (STEMI). This was a prospective cohort study of patients (n = 369) with STEMI. Patients underwent an echocardiographic examination a median of two days after pPCI. By echocardiography, transmitral early filling velocity (E) was measured by pulsed-wave Doppler, and early diastolic strain rate (SRe) was measured by speckle tracking of the left ventricle. E was indexed to SRe and the early myocardial relaxation velocity (e') to obtain the E/SRe and E/e', respectively. The endpoint was new-onset AF. During follow-up (median 5.6 years, IQR: 5.0-6.1 years), 23 (6%) of the 369 patients developed AF. In unadjusted analyses, both E/SRe and E/e' were significantly associated with AF [E/SRe: HR = 1.06; (1.03-1.10); p < 0.001, per 10 increase] and [E/e': HR = 1.11 (1.05-1.17); p < 0.001, per 1 increase] and had equal Harrell's C-statistic of 0.71. However, only E/SRe remained an independent predictor after multivariable adjustments for clinical and echocardiographic parameters [E/SRe: HR = 1.06 (1.00-1.11); p = 0.044, per 10 increase]. E/SRe was further significantly associated with AF in patients with E/e' < 14 HR = 1.09 (1.01-1.17); p = 0.030, per 10 increase), also after multivariable adjustments. E/SRe is an independent predictor of AF in STEMI patients, even in subjects with seemingly normal filling pressure., (© 2023. The Author(s).)

Objective: To compare the agreement and cost of two recall methods for estimating children's minimum dietary diversity (MDD)., Design: We assessed child's dietary intake on two consecutive days: an observation on day one, followed by two recall methods (list-based recall and multiple-pass recall) administered in random order by different enumerators at two different times on day two. We compared the estimated MDD prevalence using survey-weighted linear probability models following a two one-sided test equivalence testing approach. We also estimated the cost-effectiveness of the two methods., Setting: Cambodia (Kampong Thom, Siem Reap, Battambang, and Pursat provinces) and Zambia (Chipata, Katete, Lundazi, Nyimba, and Petauke districts)., Participants: Children aged 6-23 months: 636 in Cambodia and 608 in Zambia., Results: MDD estimations from both recall methods were equivalent to the observation in Cambodia but not in Zambia. Both methods were equivalent to the observation in capturing most food groups. Both methods were highly sensitive although the multiple-pass method accurately classified a higher proportion of children meeting MDD than the list-based method in both countries. Both methods were highly specific in Cambodia but moderately so in Zambia. Cost-effectiveness was better for the list-based recall method in both countries., Conclusion: The two recall methods estimated MDD and most other infant and young child feeding indicators equivalently in Cambodia but not in Zambia, compared to the observation. The list-based method produced slightly more accurate estimates of MDD at the population level, took less time to administer and was less costly to implement.

People with Li-Fraumeni syndrome (LFS) harbor a germline pathogenic variant in the TP53 tumor suppressor gene, face a near 100% lifetime risk of cancer, and routinely undergo intensive surveillance protocols. Liquid biopsy has become an attractive tool for a range of clinical applications, including early cancer detection. Here, we provide a proof-of-principle for a multimodal liquid biopsy assay that integrates a targeted gene panel, shallow whole-genome, and cell-free methylated DNA immunoprecipitation sequencing for the early detection of cancer in a longitudinal cohort of 89 LFS patients. Multimodal analysis increased our detection rate in patients with an active cancer diagnosis over uni-modal analysis and was able to detect cancer-associated signal(s) in carriers prior to diagnosis with conventional screening (positive predictive value = 67.6%, negative predictive value = 96.5%). Although adoption of liquid biopsy into current surveillance will require further clinical validation, this study provides a framework for individuals with LFS., Significance: By utilizing an integrated cell-free DNA approach, liquid biopsy shows earlier detection of cancer in patients with LFS compared with current clinical surveillance methods such as imaging. Liquid biopsy provides improved accessibility and sensitivity, complementing current clinical surveillance methods to provide better care for these patients. See related commentary by Latham et al., p. 23. This article is featured in Selected Articles from This Issue, p. 5., (©2023 The Authors; Published by the American Association for Cancer Research.)

Objective: To examine the dose-response association between estimated cardiorespiratory fitness (eCRF) and risk of myocardial infarction (MI)., Patients and Methods: Adults who attended Tromsø Study surveys 4-6 (Janurary 1,1994-December 20, 2008) with no previous cardiovascular disease were followed up through December 31, 2014 for incident MI. Associations were examined using restricted cubic splines Fine and Gray regressions, adjusted for education, smoking, alcohol, diet, sex, adiposity, physical activity, study survey, and age (timescale) in the total cohort and subsamples with hyperlipidemia (n=2956), hypertension (n=8290), obesity (n=5784), metabolic syndrome (n=1410), smokers (n=3823), and poor diet (n=3463) and in those who were physically inactive (n=6255)., Results: Of 14,285 participants (mean age ± SD, 53.7±11.4 years), 979 (6.9%) experienced MI during follow-up (median, 7.2 years; 25th-75th, 5.3-14.6 years). Females with median eCRF (32 mL/kg/min) had 43% lower MI risk (subdistributed hazard ratio [SHR], 0.57; 95% CI, 0.48-0.68) than those at the 10th percentile (25 mL/kg/min) as reference. The lowest MI risk was observed at 47 mL/kg/min (SHR, 0.02; 95% CI, 0.01-0.11). Males had 26% lower MI risk at median eCRF (40 mL/kg/min; SHR, 0.74; 95% CI, 0.63-0.86) than those at the 10th percentile (32 mL/kg/min), and the lowest risk was 69% (SHR, 0.31; 95% CI, 0.14-0.71) at 60 mL/kg/min. The associations were similar in subsamples with cardiovascular disease risk factors., Conclusion: Higher eCRF associated with lower MI risk in females and males, but associations were more pronounced among females than those in males. This suggest eCRF as a vital estimate to implement in medical care to identify individuals at high risk of future MI, especially for females., Competing Interests: M.L.L. has received lecture fees from 10.13039/100004326Bayer, 10.13039/100004339Sanofi, and 10.13039/100002491BMS/10.13039/100004319Pfizer not related to this study. The remaining authors declare no conflict of interest., (© 2023 The Authors.)

Introduction: Alzheimer's Disease (AD) is complex and novel approaches are urgently needed to aid in diagnosis. Blood is frequently used as a source for biomarkers; however, its complexity prevents proper detection. The analytical power of metabolomics, coupled with statistical tools, can assist in reducing this complexity., Objectives: Thus, we sought to validate a previously proposed panel of metabolic blood-based biomarkers for AD and expand our understanding of the pathological mechanisms involved in AD that are reflected in the blood., Methods: In the validation cohort serum and plasma were collected from 25 AD patients and 25 healthy controls. Serum was analysed for metabolites using nuclear magnetic resonance (NMR) spectroscopy, while plasma was tested for markers of neuronal damage and AD hallmark proteins using single molecule array (SIMOA)., Results: The diagnostic performance of the metabolite biomarker panel was confirmed using sparse-partial least squares discriminant analysis (sPLS-DA) with an area under the curve (AUC) of 0.73 (95% confidence interval: 0.59-0.87). Pyruvic acid and valine were consistently reduced in the discovery and validation cohorts. Pathway analysis of significantly altered metabolites in the validation set revealed that they are involved in branched-chain amino acids (BCAAs) and energy metabolism (glycolysis and gluconeogenesis). Additionally, strong positive correlations were observed for valine and isoleucine between cerebrospinal fluid p-tau and t-tau., Conclusions: Our proposed panel of metabolites was successfully validated using a combined approach of NMR and sPLS-DA. It was discovered that cognitive-impairment-related metabolites belong to BCAAs and are involved in energy metabolism., (© 2024. The Author(s).)

In the current study, we report the prevalence of male testosterone deficiency in a cohort of 60 male long-term survivors of malignant lymphoma with normal total testosterone but in the lower part of the reference level. Testosterone deficiency was defined as subnormal concentrations of total testosterone or subnormal concentrations of calculated free testosterone. The aim was to clarify whether total testosterone was sufficient for identification of testosterone deficiency in male survivors of malignant lymphoma. Hormonal analyses taken at follow-up were compared with samples taken at diagnosis for a subgroup of 20 survivors, for evaluation of changes in hormones over time. Another group of 83 similar survivors of malignant lymphoma with testosterone in the high end of reference levels were also used for comparison, to identify groups of increased risk of testosterone deficiency. A total group of 143 survivors were therefore included in the study. Our findings indicate that for screening purposes an initial total testosterone is sufficient in some survivors because sexual hormone binding globulin concentration was found stable over time. However, 15% were found with subnormal calculated free testosterone. Survivors intensely treated for Hodgkin lymphoma and older survivors were identified as high-risk groups for testosterone deficiency necessitating endocrinological attention during follow-up. Some evidence of pituitary downregulation was also found, because of uncompensated decreases in testosterone concentration over time. In conclusion, longitudinal measurements of total testosterone alone do not seem adequate for the screening of testosterone deficiency for all long-term lymphoma survivors., (© 2023. The Author(s).)

The High-Mobility Group Box-1 (HMGB1), a non-histone chromatin-associated protein, plays a crucial role in cancer growth and response to therapy as it retains a pivotal role in promoting both cell death and survival. HMGB1 has been reported to regulate several signaling pathways engaged in inflammation, genome stability, immune function, cell proliferation, cell autophagy, metabolism, and apoptosis. However, the association between HMGB1 and cancer is complex and its mechanism in tumorigenesis needs to be further elucidated. This review aims to understand the role of HMGB1 in human malignancies and discuss the signaling pathways linked to this process to provide a comprehensive understanding on the association of HMGB1 with carcinogenesis. Further, we will review the role of HMGB1 as a target/biomarker for cancer therapy, the therapeutic strategies used to target this protein, and its potential role in preventing or treating cancers. In light of the recent growing evidence linking HMGB1 to cancer progression, we think that it may be suggested as a novel and emergent therapeutic target for cancer therapy. Hence, HMGB1 warrants paramount investigation to comprehensively map its role in tumorigenesis., Competing Interests: Declaration of Competing Interest The authors declare that this work was conducted in the absence of any financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The introduction of modern therapies improved the median survival of patients with metastatic melanoma (MM). Here, we determined the real-world impact of modern treatments on the long-term survival of MM., Methods: In a population-based study, we extracted all cases of MM diagnosed in four non-consecutive years marked by major changes in available 1st line treatments (2012, 2014, 2016, and 2018) from the Danish MM Database. Patients were grouped into "trial-like" and "trial-excluded" based on common trial eligibility criteria., Results: We observed a sustained improved survival of "trial-like" patients diagnosed in 2016 or in 2018, compared to 2012 or 2014, but no major differences in 2018 versus 2016. In contrast, while survival of "trial-excluded" patients in 2016 was better compared to 2014 and 2012, survival in 2018 was improved over all previous years. We then developed a prognostic model based on multivariable stratified Cox regression, to predict the survival of newly diagnosed MM patients. Internal validation showed excellent discrimination and calibration, with a time-area-under-the-curve above 0.79 at multiple time horizons, for up to four years after diagnosis., Conclusions: The introduction of modern treatments such as anti-PD-1 has led to a sustained, improved survival of real-world patients with MM, regardless of their eligibility for clinical trials. We provide an updateable prognostic model that can be used to improve patient information. Overall, these data highlight a positive population-based impact of modern treatments and can help health technology assessment agencies worldwide to evaluate the appropriateness of drug pricing based on known cost-benefit data., Competing Interests: Declaration of Competing Interest MD (past two years) has received proprietary data access from Bristol Myers Squibb and Genentech, and is advisor of Achilles Therapeutics. IMS has received honoraria for consultancies and lectures from Novartis, Roche, Merck, and Bristol Myers Squibb; a restricted research grant from Novartis; and financial support for attending symposia from Bristol Myers Squibb, Merck, Novartis, Pfizer, and Roche. LB served on the advisory board of Bristol-Myers Squibb, Roche, Novartis, Merck, EISAI, and Bayer Healthcare. HS received honoraries for consultancies and lectures from Novartis, Merck, Bristol-Myers Squibb, and Incyte; and restricted research grants from MSD. EE received honoraries for consultancies and lectures from Novartis, Merck, Bristol-Myers Squibb, and Pierre Fabre, and conference and travel coverage from Pierre Fabre and Merck. CAH received honoraries for lectures from GSK and Bristol Myers Squibb. All remaining authors have declared no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Aligning with the United Nations Convention on the Rights of the Child, amplification of children's voice in food practice research aims to inform initiatives that cater to children's needs and thus improve nutritional outcomes. The aim of this study was to describe children's (aged 6-11 years) involvement across qualitative research investigating their food practice perspectives., Design: A scoping review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Scoping Reviews (PRISMA-ScR). Six electronic databases were searched up until March 2023 (Cochrane, CINAHL, Embase, ERIC, Medline and PsychInfo). The Wellcome Framework for young people's involvement in health research guided data extraction. Data were described according to inclusiveness, geography, food-related study topic, research stage and method, and child involvement., Results: The search identified 120 peer-reviewed studies (134 papers). Active participation was only seen within research implementation stages (i.e. data collection ( n 134), analysis ( n 31), dissemination ( n 9) and re-design ( n 7)). More passive forms of participation were identified in research design stages (i.e. agenda setting, resourcing and design). Studies that utilised participatory research methodologies and developmentally appropriate and engaging methods (e.g. PhotoVoice) saw more active participation by children., Conclusion: This review identified a lack of opportunities for children's active participation in all stages of food practice research. Without a radical shift towards providing these opportunities, food and nutrition initiatives, policies or further research that do not meet the needs of children's food-related worlds will continue to be developed. Instead, researchers and their institutions need to advocate for and, where possible, provide voluntary opportunities for children to actively participate in food practice research.

Apolipoproteins (APOs) are vital structural components of plasma lipoproteins that are involved in lipid metabolism and transport. Recent studies have reported an association between apolipoprotein dysregulation and the onset of a variety of human cancers; however, the role of certain APOs in cancer development remains unknown. Based on recent work, we hypothesize that APOs might be involved in the onset of cancer, with a focus on the most common cancers, including breast, lung, gynecological, colorectal, thyroid, gastric, pancreatic, hepatic, and prostate cancers. This review will focus on the evidence supporting this hypothesis, the mechanisms linking APOs to the onset of cancer, and the potential clinical relevance of its various inhibitors.

Background: Person-specific computational models can estimate transcranial direct current stimulation (tDCS) current dose delivered to the brain and predict treatment response. Artificially created electrode models derived from virtual 10-20 EEG measurements are typically included in these models as current injection and removal sites. The present study directly compares current flow models generated via artificially placed electrodes ("artificial" electrode models) against those generated using real electrodes acquired from structural MRI scans ("real" electrode models) of older adults., Methods: A total of 16 individualized head models were derived from cognitively healthy older adults (mean age = 71.8 years) who participated in an in-scanner tDCS study with an F3-F4 montage. Visible tDCS electrodes captured within the MRI scans were segmented to create the "real" electrode model. In contrast, the "artificial" electrodes were generated in ROAST. Percentage differences in current density were computed in selected regions of interest (ROIs) as examples of stimulation targets within an F3-F4 montage., Main Results: We found significant inverse correlations ( p < 0.001) between median current density values and brain atrophy in both electrode pipelines with slightly larger correlations found in the artificial pipeline. The percent difference (PD) of the electrode distances between the two models predicted the median current density values computed in the ROIs, gray, and white matter, with significant correlation between electrode distance PDs and current density. The correlation between PD of the contact areas and the computed median current densities in the brain was found to be non-significant., Conclusions: This study demonstrates potential discrepancies in generated current density models using real versus artificial electrode placement when applying tDCS to an older adult cohort. Our findings strongly suggest that future tDCS clinical work should consider closely monitoring and rigorously documenting electrode location during stimulation to model tDCS montages as closely as possible to actual placement. Detailed physical electrode location data may provide more precise information and thus produce more robust tDCS modeling results., 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Indahlastari, Dunn, Pedersen, Kraft, Someya, Albizu and Woods.)

The accurate diagnosis of small-cell lung cancer (SCLC) is crucial, as treatment strategies differ from those of other lung cancers. This systematic review aims to identify proteins differentially expressed in SCLC compared to normal lung tissue, evaluating their potential utility in diagnosing and prognosing the disease. Additionally, the study identifies proteins differentially expressed between SCLC and large cell neuroendocrine carcinoma (LCNEC), aiming to discover biomarkers distinguishing between these two subtypes of neuroendocrine lung cancers. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a comprehensive search was conducted across PubMed/MEDLINE, Scopus, Embase, and Web of Science databases. Studies reporting proteomics information and confirming SCLC and/or LCNEC through histopathological and/or cytopathological examination were included, while review articles, non-original articles, and studies based on animal samples or cell lines were excluded. The initial search yielded 1705 articles, and after deduplication and screening, 16 articles were deemed eligible. These studies revealed 117 unique proteins significantly differentially expressed in SCLC compared to normal lung tissue, along with 37 unique proteins differentially expressed between SCLC and LCNEC. In conclusion, this review highlights the potential of proteomics technology in identifying novel biomarkers for diagnosing SCLC, predicting its prognosis, and distinguishing it from LCNEC.

Animal habitat selection-central in both theoretical and applied ecology-may depend on behavioural motivations such as foraging, predator avoidance, and thermoregulation. Step-selection functions (SSFs) enable assessment of fine-scale habitat selection as a function of an animal's movement capacities and spatiotemporal variation in extrinsic conditions. If animal location data can be associated with behaviour, SSFs are an intuitive approach to quantify behaviour-specific habitat selection. Fitting SSFs separately for distinct behavioural states helped to uncover state-specific selection patterns. However, while the definition of the availability domain has been highlighted as the most critical aspect of SSFs, the influence of accounting for behaviour in the use-availability design has not been quantified yet. Using a predator-free population of high-arctic muskoxen Ovibos moschatus as a case study, we aimed to evaluate how (1) defining behaviour-specific availability domains, and/or (2) fitting separate behaviour-specific models impacts (a) model structure, (b) estimated selection coefficients and (c) model predictive performance as opposed to behaviour-unspecific approaches. To do so, we first applied hidden Markov models to infer different behavioural modes (resting, foraging, relocating) from hourly GPS positions (19 individuals, 153-1062 observation days/animal). Using SSFs, we then compared behaviour-specific versus behaviour-unspecific habitat selection in relation to terrain features, vegetation and snow conditions. Our results show that incorporating behaviour into the definition of the availability domain primarily impacts model structure (i.e. variable selection), whereas fitting separate behaviour-specific models mainly influences selection strength. Behaviour-specific availability domains improved predictive performance for foraging and relocating models (i.e. behaviours with medium to large spatial displacement), but decreased performance for resting models. Thus, even for a predator-free population subject to only negligible interspecific competition and human disturbance we found that accounting for behaviour in SSFs impacted model structure, selection coefficients and predictive performance. Our results indicate that for robust inference, both a behaviour-specific availability domain and behaviour-specific model fitting should be explored, especially for populations where strong spatiotemporal selection trade-offs are expected. This is particularly critical if wildlife habitat preferences are estimated to inform management and conservation initiatives., (© 2023 The Authors. Journal of Animal Ecology published by John Wiley & Sons Ltd on behalf of British Ecological Society.)

Local adaptation to annually changing environments has evolved in numerous species. Seasonal coat colour change is an adaptation that has evolved in multiple mammal and bird species occupying areas that experience seasonal snow cover. It has a critical impact on fitness as predation risk may increase when an individual is mismatched against its habitat's background colour. In this paper, we investigate the correlation between landscape covariates and moult timing in a native winter-adapted herbivore, the mountain hare ( Lepus timidus ), throughout Norway. Data was collected between 2011 and 2019 at 678 camera trap locations deployed across an environmental gradient. Based on this data, we created a Bayesian multinomial logistic regression model that quantified the correlations between landscape covariates and coat colour phenology and analysed among season and year moult timing variation. Our results demonstrate that mountain hare moult timing is strongly correlated with altitude and latitude with hares that live at higher latitudes and altitudes keeping their winter white coats for longer than their conspecifics that inhabit lower latitudes and altitudes. Moult timing was also weakly correlated with climate zone with hares that live in coastal climates keeping their winter white coats for longer than hares that live in continental climates. We found evidence of some among year moult timing variation in spring, but not in autumn. We conclude that mountain hare moult timing has adapted to local environmental conditions throughout Norway., Competing Interests: We confirm that there are no conflicts of interest., (© 2023 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

Background: Small cell lung cancer (SCLC) is highly aggressive with limited therapeutic options and a poor prognosis. Moreover, noninvasive biomarker tools for detecting disease and monitoring treatment response are lacking. To address this, we evaluated serum biomarkers of extracellular matrix proteins not previously explored in SCLC., Methods: We measured biomarkers in the serum of 16 patients with SCLC before and after chemotherapy as well as in the serum of 11 healthy individuals., Results: Our findings demonstrated that SCLC serum had higher levels of collagen type I degradation, collagen type III formation, and collagen type XI formation than healthy controls. In addition, we observed higher levels of type XIX and XXII collagens, fibrinogen, and von Willebrand factor A formation in SCLC serum. The formation of type I collagen did not exhibit any discernible variation. However, we observed a decrease in the degradation of type I collagen following chemotherapy., Conclusion: Overall, our findings revealed elevated levels of collagen and blood-clotting markers in the serum of SCLC patients, indicating the potential of ECM proteins as noninvasive biomarkers for SCLC., (© 2023 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Summary: This case report describes a rare presentation of ectopic Cushing's syndrome (CS) due to ectopic corticotropin-releasing hormone (CRH) production from a medullary thyroid carcinoma (MTC). The patient, a 69-year-old man, presented with symptoms of muscle weakness, facial plethora, and easy bruising. An inferior petrosal sinus sampling test (IPSS) demonstrated pituitary adrenocorticotrophic hormone (ACTH) secretion, but a whole-body somatostatin receptor scintigraphy (68Ga-DOTATOC PET/CT) revealed enhanced uptake in the right thyroid lobe which, in addition to a grossly elevated serum calcitonin level, was indicative of an MTC. A 18F-DOPA PET/CT scan supported the diagnosis, and histology confirmed the presence of MTC with perinodal growth and regional lymph node metastasis. On immunohistochemical analysis, the tumor cell stained positively for calcitonin and CRH but negatively for ACTH. Distinctly elevated plasma CRH levels were documented. The patient therefore underwent thyroidectomy and bilateral adrenalectomy. This case shows that CS caused by ectopic CRH secretion may masquerade as CS due to a false positive IPSS test. It also highlights the importance of considering rare causes of CS when diagnostic test results are ambiguous., Learning Points: Medullary thyroid carcinoma may secrete CRH and cause ectopic CS. Ectopic CRH secretion entails a rare pitfall of inferior petrosal sinus sampling yielding a false positive test. Plasma CRH measurements can be useful in selected cases.

Background: Northern small mammal populations are renowned for their multi-annual population cycles. Population cycles are multi-faceted and have extensive impacts on the rest of the ecosystem. In 2011, we started a student-based research activity to monitor the variation of small rodent density along an elevation gradient following the Birkebeiner Road, in southeast Norway. Fieldwork was conducted by staff and students at the University campus Evenstad, Inland Norway University of Applied Sciences, which has a long history of researching cyclic population dynamics. The faculty has a strong focus on engaging students in all parts of the research activities, including data collection. Small rodents were monitored using a set of snap trap stations. Trapped animals were measured (e.g. body mass, body length, sex) and dissected to assess their reproductive status. We also characterised the vegetation at trapping sites., New Information: We provide a dataset of small rodent observations that show fluctuating population dynamics across an elevation gradient (300 m to 1,100 m a.s.l) and in contrasting habitats. This dataset encompasses three peaks of the typical 3-4-year vole population cycles; the number of small rodents and shrews captured show synchrony and peaked in years 2014, 2017 and 2021. The bank vole Myodesglareolus was by far (87%) the most common species trapped, but also other species were observed (including shrews). We provide digital data collection forms and highlight the importance of long-term data collection., (Magne Neby, Harry Andreassen, Cyril Pierre Milleret, Simen Pedersen, Ana-Maria Peris Tamayo, David Carriondo Sánchez, Erik Versluijs, Barbara Zimmermann.)

Objective: To examine the potential influence of a ketogenic diet on serum concentrations of antiseizure medications (ASMs) in children with drug resistant epilepsy., Methods: We investigated the serum concentrations of ASMs in 25 children with drug resistant epilepsy, 2-13 years of age, treated with a classical ketogenic diet for 12 weeks. The patients were recruited from the National Centre for Epilepsy from August 15th, 2017, to January 24th, 2022. Changes in ASM serum concentrations were analyzed using a mixed effect model analysis. Significance level was set at P < 0.05 for all comparisons., Results: The participants used 12 different ASMs during the study. The mean number of ASMs was 2.4 (±SD 0.7). None of the participants changed the type or dose of the ASMs during the intervention period. The serum concentrations of clobazam (n = 9, P = 0.002), desmethylclobazam (n = 9, P = 0.010), and lamotrigine (n = 6, P = 0.016) decreased significantly during the dietary treatment. The analytes with the largest reduction in serum concentration after 12 weeks of dietary treatment were clobazam (mean change -38%) and desmethylclobazam (mean change -37%). We found no significant change in the serum concentrations of levetiracetam, topiramate, and valproic acid., Significance: We identified a significant decrease in the serum concentrations of clobazam, desmethylclobazam, and lamotrigine following a 12-week ketogenic diet intervention in children with drug resistant epilepsy. An unintended decrease in the serum concentrations of ASMs may render the patient prone to seizures. Measurements of ASM serum concentrations might be useful in patients on a ketogenic diet, especially in patients with lack of efficacy of the dietary treatment., (© 2023 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Gliomas, which arise from glial cells in the brain, remain a significant challenge due to their location and resistance to traditional treatments. Despite research efforts and advancements in healthcare, the incidence of gliomas has risen dramatically over the past two decades. The dysregulation of microRNAs (miRNAs) has prompted the creation of therapeutic agents that specially target them. However, it has been reported that they are involved in complex signaling pathways that contribute to the loss of expression of tumor suppressor genes and the upregulation of the expression of oncogenes. In addition, numerous miRNAs promote the development, progression, and recurrence of gliomas by targeting crucial proteins and enzymes involved in metabolic pathways such as glycolysis and oxidative phosphorylation. However, the complex interplay among these pathways along with other obstacles hinders the ability to apply miRNA targeting in clinical practice. This highlights the importance of identifying specific miRNAs to be targeted for therapy and having a complete understanding of the diverse pathways they are involved in. Therefore, the aim of this review is to provide an overview of the role of miRNAs in the progression and prognosis of gliomas, emphasizing the different pathways involved and identifying potential therapeutic targets.

Background: The global shortage of donor hearts available for transplantation is a major problem for the treatment of end-stage heart failure. The ischemic time for donor hearts using traditional preservation by standard static cold storage (SCS) is limited to approximately 4 hours, beyond which the risk for primary graft dysfunction (PGD) significantly increases. Hypothermic machine perfusion (HMP) of donor hearts has been proposed to safely extend ischemic time without increasing the risk of PGD., Methods: Using our sheep model of 24 hours brain death (BD) followed by orthotopic heart transplantation (HTx), we examined post-transplant outcomes in recipients following donor heart preservation by HMP for 8 hours, compared to donor heart preservation for 2 hours by either SCS or HMP., Results: Following HTx, all HMP recipients (both 2 hours and 8 hours groups) survived to the end of the study (6 hours after transplantation and successful weaning from cardiopulmonary bypass), required less vasoactive support for hemodynamic stability, and exhibited superior metabolic, fluid status and inflammatory profiles compared to SCS recipients. Contractile function and cardiac damage (troponin I release and histological assessment) was comparable between groups., Conclusions: Overall, compared to current clinical SCS, recipient outcomes following transplantation are not adversely impacted by extending HMP to 8 hours. These results have important implications for clinical transplantation where longer ischemic times may be required (e.g., complex surgical cases, transport across long distances). Additionally, HMP may allow safe preservation of "marginal" donor hearts that are more susceptible to myocardial injury and facilitate increased utilization of these hearts for transplantation., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)