Search

Background: Pituitary adenylate cyclase-activating peptide (PACAP) is a neuropeptide pivotal in migraine pathophysiology and is considered a promising new migraine drug target. Although intravenous PACAP triggers migraine attacks and a recent phase II trial with a PACAP-inhibiting antibody showed efficacy in migraine prevention, targeting the PACAP receptor PAC1 alone has been unsuccessful. The present study investigated the role of three PACAP receptors (PAC1, VPAC1 and VPAC2) in inducing migraine-relevant hypersensitivity in mice. Methods: Hindpaw hypersensitivity was induced by repeated PACAP38 injections. Tactile sensitivity responses were quantified using von Frey filaments in three knockout (KO) mouse strains, each lacking one of the PACAP-receptors (Ntotal = 160). Additionally, ex vivo wire myography was used to assess vasoactivity of the carotid artery, and gene expression of PACAP receptors was examined by qPCR. Results: PACAP38 induced hypersensitivity in WT controls (p < 0.01) that was diminished in VPAC1 and VPAC2 KO mice (p < 0.05). In contrast, PAC1 KO mice showed similar responses to WT controls (p > 0.05). Myograph experiments supported these findings showing diminished vasoactivity in VPAC1 and VPAC2 KO mice. We found no upregulation of the non-modified PACAP receptors in KO mice. Conclusions: This study assessed all three PACAP receptors in a migraine mouse model and suggests a significant role of VPAC receptors in migraine pathophysiology. The lack of hypersensitivity reduction in PAC1 KO mice suggests the involvement of other PACAP receptors or compensatory mechanisms. The results indicate that targeting only individual PACAP receptors may not be an effective migraine treatment. [ABSTRACT FROM AUTHOR]

Neurodegenerative diseases are often accompanied by neuroinflammation and impairment of the blood-brain barrier (BBB) mediated by activated glial cells through their release of proinflammatory molecules. To study the effects of glial cells on mouse brain endothelial cells (mBECs), we developed an in vitro BBB model with inflammation by preactivating mixed glial cells (MGCs) with lipopolysaccharide (LPS) before co-culturing with mBECs to study the influence of molecules released by activated MGCs. The response of the mBECs to activated MGCs was compared to direct stimulation with LPS. The cytokine profile of activated MGCs was analyzed together with their effects on the mBEC's integrity, expression of tight junction proteins, adhesion molecules, and BBB-specific transport proteins. Stimulation of MGCs significantly upregulated mRNA expression and secretion of several pro-inflammatory cytokines. Co-culturing mBECs with pre-stimulated MGCs significantly affected the barrier integrity of mBECs similar to direct stimulation with LPS. The gene expression levels of tight junction proteins were unaltered, but tight junction proteins revealed rearrangements with respect to subcellular distribution. Compared to direct stimulation with LPS, the expression of cell-adhesion molecules was significantly increased when mBECs were co-cultured with prestimulated MGCs and thus pre-activating MGCs transforms mBECs into a proinflammatory phenotype. [ABSTRACT FROM AUTHOR]

Arteriovenous malformations (AVM) are benign vascular anomalies prone to pain, bleeding, and progressive growth. AVM are mainly caused by mosaic pathogenic variants of the RAS-MAPK pathway. However, a causative variant is not identified in all patients. Using ultra-deep sequencing, we identified novel somatic RIT1 delins variants in lesional tissue of three AVM patients. RIT1 encodes a RAS-like protein that can modulate RAS-MAPK signaling. We expressed RIT1 variants in HEK293T cells, which led to a strong increase in ERK1/2 phosphorylation. Endothelial-specific mosaic overexpression of RIT1 delins in zebrafish embryos induced AVM formation, highlighting their functional importance in vascular development. Both ERK1/2 hyperactivation in vitro and AVM formation in vivo could be suppressed by pharmacological MEK inhibition. Treatment with the MEK inhibitor trametinib led to a significant decrease in bleeding episodes and AVM size in one patient. Our findings implicate RIT1 in AVM formation and provide a rationale for clinical trials with targeted treatments. [ABSTRACT FROM AUTHOR]

The structural complexity of high-tech industries is often compromised by a combination of thermal, mechanical, and geometric weaknesses. New generation materials and engineering the structure of materials are among the techniques that engineers employ to eliminate these effects. In this study, a comprehensive analysis solution is derived using Lekhnitskii's complex variable approach with the use of general mapping functions, the concept of functionally graded materials (FGMs), and holomorphic functions in the form of Laurent series. This general solution is used for the thermoelastic analysis of perforated functionally graded carbon nanotube-reinforced composite (FG-CNTRC) plates with polygonal hole. A refined-calibrated rule of mixtures is used to approximate the material property of FG-CNTRC plates according to gradational changes in direction of thickness and available molecular dynamics simulations results. After validation of present analytical solution results with finite element analysis results and available mechanical analysis of composite plates results, stress and moment resultants due to remoting heat flux-mechanical loading is studied. The effect of FG-CNTRC material properties, heat flux condition, and four parameters affecting the shape of the polygonal holes has been investigated. During the present parametric analysis, the results clearly show that the parameters related to the FG-CNTRC material properties, flux conditions, and hole geometry each provide a reliable tool for designers to influence the stress and moment resultants to minimize undesirable stresses. This general formulation is able to calculate thermoelastic parameters (thermal and mechanical parameters, separately) for the generalized problems of the FGM plate or composite laminates with a polygonal hole. [ABSTRACT FROM AUTHOR]

Neuromuscular blocking agents are used commonly to induce skeletal muscle relaxation during surgery. While muscle relaxation facilitates surgical procedures and tracheal intubation, adequate recovery of muscle function after surgery is required to support pulmonary function, and even mild residual neuromuscular block increases the risk of severe postoperative pulmonary complications. While recovery of muscle function after surgery involving neuromuscular blocking agents can be monitored and, in addition, be accelerated by use of current antagonists (reversal agents), there is a clear clinical need for a safe drug to antagonize all types of neuromuscular blocking agents. Here, we show that inhibition of the skeletal muscle-specific chloride ion (Cl-) channel, the ClC-1 channel, markedly accelerates recovery of both single contraction (twitch) and, important physiologically, sustained (tetanic) contractions in a rat model mimicking neuromuscular blocking agent-induced muscle block used during surgery. This suggests ClC-1 inhibition as a mechanism for fast and efficacious recovery of neuromuscular function induced by any neuromuscular blocking agents. Reversal agents are intravenous drugs used to accelerate recovery from neuromuscular block post-surgery. We report that inhibition of ClC-1, a skeletal muscle chloride channel, reverses any nondepolarizing blocking agent, providing a novel reversal (antagonism) mechanism. [ABSTRACT FROM AUTHOR]

Bracken ferns (genus Pteridium) are among the most prevalent plants worldwide, with their distribution expanding due to their invasive nature. The environmental implications of their proliferation in areas affected by human activity, natural disasters, or land-use changes are concerning, primarily because of the carcinogenic illudane glycosides they produce. These compounds cause domestic and wildlife animal poisoning, as well as contamination of dairy products and drinking water. Several illudane glycosides are known, but usually only ptaquiloside (PTA) is monitored. This study investigates the spatial and temporal variations in illudane glycosides PTA, caudatoside (CAU) and ptesculentoside (PTE) across two phenotypes of Pteridium aquilinum (vars. aquilinum and latiusculum) over a broad geographic range spanning Denmark, Sweden, and Finland, encompassing 66 locations. We analysed different parts of the fern fronds (the tips and the lowest pinnae) using LC–MS and statistically explored the influence of phenotype, frond part, geographic location, sunlight exposure, and the surrounding ecosystem on glycoside content. Our findings reveal that PTA accounts for approximately two-thirds of the total illudane glycoside content, followed by CAU at nearly one-third, and a minor contribution from PTE. Glycoside levels were not influenced by phenotypic varieties or the studied environmental factors, but were significantly affected by geographic location. Specifically, CAU levels increased progressively towards the northeast, while PTA concentrations were highest in Denmark and markedly decreased in northeastern countries by over threefold, presumably due to climatic gradient. It has been further supported by temporal analysis in selected PTA-dominant regions indicating a reduction in PTA towards the end of the growing season, aligning its levels with those of CAU. Our study highlights that CAU concentrations in bracken ferns may equal or surpass PTA, contesting the prevailing view that PTA is the only notable illudane glycoside in Bracken. To provide unbiased assessment of the potential risks posed by P. aquilinum in the region, environmental and toxicological research should include measurements of not only PTA, but also CAU and, if possible, PTE. [ABSTRACT FROM AUTHOR]

Since the fundamental works of Kachanov and Rabotnov, creep damage mechanics is an established field of research in solid mechanics. The starting point is the creep behavior of materials under moderate loads but elevated temperatures. The final stage of creep behavior is accompanied by damage and other microstructural changes such as embrittlement. In the present paper a detailed analysis of literature is given. A special focus is made on the different types of representation of damage by scalar, vectorial and tensorial variables. In addition, some Russian sources are presented which are not widely known yet. The survey is representative, but not complete - due to the large number of sources, it is not possible to provide a complete overview. Considering the huge number of parameters of tensorial damage variables which should be established experimentally in the second part of the paper a simple model for the high temperature creep and embrittlement in metals and alloys under conditions of the long-term usage is introduced. The model is an extension of R. Arutunyan's model developed in the 90th of the last century. The extension includes the consideration of a compressible medium, the introduction of the mass conservation law and true stress, and definition of the damage parameter as a relative change in the density of the material. The parameters are experimentally estimated and the comparison of simulations and experiments is given. [ABSTRACT FROM AUTHOR]

Purpose: To study the association between the use of drugs for hypertension or heart failure, particularly diuretics, and risk of death in COVID-19. Methods: We conducted a cohort study, based on record linked individual-based data from national registers, of all Swedish inhabitants 50 years and older (n = 3,909,321) at the start of the first SARS-CoV-2 wave in Sweden. The association between use of angiotensin-converting enzyme inhibitors (ACEI), angiotensin II receptor blockers (ARB), thiazides, loop diuretics, aldosterone antagonists, beta blocking agents and calcium channel blockers at the index date 6 March 2020, and death in COVID-19 during 7 March to 31 July 2020, was analysed using Cox-proportional hazards regression, adjusted for a wide range of possible confounders. Results: Use of loop diuretics was associated with higher risk [adjusted hazard ratio (HR) 1.26; 95% confidence interval (95% CI) 1.17–1.35] and thiazides with reduced risk (0.78; 0.69–0.88) of death in COVID-19. In addition, lower risk was observed for ACEI and higher risk for beta-blocking agents, although both associations were weak. For ARB, aldosterone antagonists and calcium channel blockers no significant associations were found. Conclusion: In this nationwide cohort of nearly 4 million persons 50 years and older, the use of loop diuretics was associated with increased risk of death in COVID-19 during the first SARS-CoV-2 wave in Sweden. This contrasted to the decreased risk observed for thiazides. As treatment with loop diuretics is common, particularly in the elderly, the group most affected by severe COVID-19, this finding merit further investigation. [ABSTRACT FROM AUTHOR]

Child abuse is a severe global problem associated with various negative consequences. It is therefore important that the services received at Child Advocacy Centers (CACs) are perceived as positive as possible by children affected by abuse. Preliminary research indicates that CACs are successful in terms of providing coordinated, professional services. However, existing research has primarily focused on service and criminal justice system outputs, rather than documenting the experiences of the target group: i.e., children undergoing the CAC proceedings. The present study seeks to investigate the children's experiences of the forensic procedures in a CAC. Qualitative interviews were conducted with 15 children undergoing case proceedings at a Danish CAC. The overall experiences of the children of the forensic interview and forensic medical examination were documented. Additionally, five overall themes were constructed using Thematic Analysis: Localities and surroundings, Relational and communicative work, Ambivalent experiences, Need of information and overview, and Missing out on everyday life. The findings of the current study underline the importance of the physical environment of the CAC, the need of information and overview as well as strong relational and communicative skills among professional as core elements in establishing positive encounters with the CAC. Furthermore, the results indicate how negative experiences of visiting a CAC are not necessarily directly linked to the CAC but may be a result of the children experiencing missing out on well-liked everyday activities. Altogether these results are important to consider when planning future CAC visits to support the well-being of the child. [ABSTRACT FROM AUTHOR]

Microbial carbon use efficiency (CUE) affects the fate and storage of carbon in terrestrial ecosystems, but its global importance remains uncertain. Accurately modeling and predicting CUE on a global scale is challenging due to inconsistencies in measurement techniques and the complex interactions of climatic, edaphic, and biological factors across scales. The link between microbial CUE and soil organic carbon relies on the stabilization of microbial necromass within soil aggregates or its association with minerals, necessitating an integration of microbial and stabilization processes in modeling approaches. In this perspective, we propose a comprehensive framework that integrates diverse data sources, ranging from genomic information to traditional soil carbon assessments, to refine carbon cycle models by incorporating variations in CUE, thereby enhancing our understanding of the microbial contribution to carbon cycling. Microbial carbon use efficiency (CUE) is crucial for carbon storage, but its variability is difficult to capture due to inconsistent measurements and complex interactions. This perspective proposes integrating diverse data and models to improve CUE in carbon cycle models [ABSTRACT FROM AUTHOR]

In this paper, we present a finite elasto-plasticity theory for large plastic deformations. For the elastic part of the model, we use the St. Venant–Kirchhoff elasticity. The plastic part is described by the isomorphy concept, the yield condition is covered by the isotropic J 2 theory of (Huber in Czas Techn 22:34,1904; von Mises in Math Phys 4:582–592, 1913) and (Hencky in ZAMM 9:215–220, 1924), and the yield condition uses the principle of maximum plastic dissipation. The numeric of this theory is discussed and finally implemented in a Fortran code to use it as material law in the UMAT subroutine of the finite element program Abaqus. The material law is validated using different test calculations like tensile and shear tests as well as a large deformation simulation compared to the Abaqus internal material law. Further, we apply this material model to determine the effective material stiffness tetrad of large deformed inhomogeneous materials. For these purposes, we additionally present an automated method for determining material stiffnesses of an arbitrary material in Abaqus. [ABSTRACT FROM AUTHOR]

Odense University Hospital is a major tertiary vascular hospital in Scandinavia, performing approx. 200 aortic repairs annually. This article presents the rationale behind this endeavor and the early outcomes of the initial implantation of locally processed homografts. All patients receiving a homograft were identified from the established homograft biobank database and their medical records were reviewed after obtaining consent. All surgeons in charge of homograft implantations were semi structured interviewed regarding the harvesting procedure, the tools for detecting available homografts, their quality and delivery. The National board of Health approved the biobank fulling the EU Directive of Tissues and Cells after 18 months of preparation. From May 6, 2021, to March 1, 2023, 26 patients had a homograft implantation, with 7 for mycotic aneurysms, 10 for aorto-iliac graft infection, 6 for infra-inguinal graft infection, and 3 for graft infection in thoracic aorta. Six (23%) were emergently performed. Two (7.7%) died within 30 days postoperatively, both following in situ replacement of an infected aortoiliac graft, corresponding to a 20% mortality in this subgroup. The incidence of reinfections was 19.2%; one each in the mycotic aneurysm group, the aortoiliac graft infection group, and the thoracic graft infection group. After 90 days, two patients were diagnosed with aorto-enteric fistula. All involved surgeons could easily identify available suitable homografts, and within 2 h have homografts of acceptable quality and requested dimensions. The establishment of the Danish Cardiovascular Homograft Biobank was straightforward and effectively serves cardiovascular procedures performed 24/7. Additionally, the initial experiences seem comparable to others experiences. [ABSTRACT FROM AUTHOR]

An alternative approach is proposed and applied to solve boundary value problems within the strain gradient elasticity theory. A mixed variation formulation of the finite element method (FEM) based on the concept of the Galerkin method is used. To construct finite-dimensional subspaces separate approximations of displacements, deformations, stresses, and their gradients are implemented by choosing the different sets of piecewise polynomial basis functions, interrelated by the stability condition of the mixed FEM approximation. This significantly simplifies the pre-requirement for approximating functions to belong to class C1 and allows one to use the simplest triangular finite elements with a linear approximation of displacements under uniform or near-uniform triangulation conditions. Global unknowns in a discrete problem are nodal displacements, while the strains and stresses and their gradients are treated as local unknowns. The conditions of existence, uniqueness, and continuous dependence of the solution on the problem's initial data are formulated for discrete equations of mixed FEM. These are solved by a modified iteration procedure, where the global stiffness matrix for classical elasticity problems is treated as a preconditioning matrix with fictitious elastic moduli. This avoids the need to form a global stiffness matrix for the problem of strain gradient elasticity since it is enough to calculate only the residual vector in the current approximation. A set of modeling plane crack problems is solved. The obtained solutions agree with the results available in the relevant literature. Good convergence is achieved by refining the mesh for all scale parameters. All three problems under study exhibit specific qualitative features characterizing strain gradient solutions namely crack stiffness increase with length scale parameter and cusp-like closure effect. [ABSTRACT FROM AUTHOR]

Tert-butyl hydroperoxide (t-BuOOH) is an organic hydroperoxide widely used as a model compound to induce oxidative stress. It leads to a plethora of cellular damage, including lipid peroxidation, DNA double-strand breaks (DNA DSBs), and breakdown of the mitochondrial membrane potential (MMP). We could show in several cell lines that t-BuOOH induces ferroptosis, triggered by iron-dependent lipid peroxidation. We have further revealed that not only t-BuOOH-mediated ferroptosis, but also DNA DSBs and loss of MMP are prevented by cell–cell contacts. The underlying mechanisms are not known. Here, we show in murine fibroblasts and a human colon carcinoma cell line that t-BuOOH (50 or 100 µM, resp.) causes an increase in intracellular Ca2+, and that this increase is key to lipid peroxidation and ferroptosis, DNA DSB formation and dissipation of the MMP. We further demonstrate that cell–cell contacts prevent t-BuOOH-mediated raise in intracellular Ca2+. Hence, we provide novel insights into the mechanism of t-BuOOH-triggered cellular damage including ferroptosis and propose a model in which cell–cell contacts control intracellular Ca2+ levels to prevent lipid peroxidation, DNA DSB-formation and loss of MMP. Since Ca2+ is a central player of toxicity in response to oxidative stress and is involved in various cell death pathways, our observations suggest a broad protective function of cell–cell contacts against a variety of exogenous toxicants. [ABSTRACT FROM AUTHOR]

In this article, the nonlinear coupled two-dimensional space-time fractional order reaction-advection–diffusion equations (2D-STFRADEs) with initial and boundary conditions is solved by using Shifted Legendre-Gauss-Lobatto Collocation method (SLGLCM) with fractional derivative defined in Caputo sense. The SLGLC scheme is used to discretize the coupled nonlinear 2D-STFRADEs into the shifted Legendre polynomial roots to convert it to a system of algebraic equations. The efficiency and efficacy of the scheme are confirmed through error analysis while applying the scheme on two existing problems having exact solutions. The impact of advection and reaction terms on the solution profiles for various space and time fractional order derivatives are shown graphically for different particular cases. A drive has been made to study the convergence of the proposed scheme, which has been applied on the proposed mathematical model. [ABSTRACT FROM AUTHOR]

This paper considers the problem of symmetrical three-point bending of a prismatic beam with an edge crack. The solution is obtained by the mixed finite element method within the simplified Toupin–Mindlin strain gradient elasticity theory. A mixed variational formulation of the boundary value problem for displacements–strains–stresses and their gradients is applied, simplifying the choice of approximating functions. The concept of energy balance is adopted to calculate the energy release rate with a virtual increase in crack length. The increment of the potential energy of an elastic body is determined by accounting for the strain and stress gradient contribution. Numerical calculations were performed using a quasi-uniform triangular mesh of the cross-type. The mesh refinement was applied in the vicinity of the crack tip, at the concentrated support, and the point of application of the transverse force, and uniform mesh partitioning was utilized in the rest of the beam. The fine-mesh analysis was carried out on the successively condensed meshes in the stress concentration domain for different values of the length scale parameter. The crack opening displacements and the distribution of strains and Cauchy stresses for various values of the length scale parameter are presented. An increase in this parameter increases the stiffness of the crack, which leads to a decrease in the crack opening displacements and a smooth closure of its faces at the crack tip. In addition, accounting for the scale parameter reduces the calculated values of strains and stresses near the crack tip. Based on the energy balance criterion, local fracture parameters such as the release rate of elastic energy at the crack tip and the stress intensity factor are determined for different values of the mesh step. The numerical calculations indicate the convergence of the obtained approximations. The main feature of solutions, which includes the strain gradient contribution, is the decrease in the values of the calculated parameters associated with the fracture energy compared to the classical elasticity theory. [ABSTRACT FROM AUTHOR]

We present a data structure that, given a graph G of n vertices and m edges, and a suitable pair of nested r-divisions of G, preprocesses G in O (m + n) time and handles any series of edge-deletions in O(m) total time while answering queries to pairwise biconnectivity in worst-case O(1) time. In case the vertices are not biconnected, the data structure can return a cutvertex separating them in worst-case O(1) time. As an immediate consequence, this gives optimal amortized decremental biconnectivity, 2-edge connectivity, and connectivity for large classes of graphs, including planar graphs and other minor free graphs. [ABSTRACT FROM AUTHOR]

Aqueous suspensions containing crystalline drug in the sub-micron range is a favorable platform for long-acting injectables where particle size can be used to obtain a desired plasma-concentration profile. Stabilizers are added to the suspensions and screened extensively to define the optimal formulation composition. In the initial formulation screening the amount of drug compound can be limited, necessitating milling methods for small-volume screening predictable for scale-up. Hence, adaptive focused ultrasound was investigated as a potential milling method for rapid small-volume suspensions by identifying the critical process parameters during preparation. Suspensions containing drug compounds with different mechanical properties and thereby grindability, i.e., cinnarizine, haloperidol, and indomethacin with brittle, elastic, and plastic properties, respectively, were investigated to gain an understanding of the manufacturing with adaptive focused acoustics as well as comparison to already established milling techniques. Using a DoE-design, peak incident power was identified as the most crucial process parameter impacting the milling process for all three compounds. It was possible to decrease the sizes of drug particles to micron range after one minute of focused ultrasound exposure which was superior compared to other milling techniques (e.g., non-focused ultrasound exposure). The addition of milling beads decreased the drug particle sizes even further, thus to a lower degree than other already established milling techniques such as milling by dual centrifugation. This study thereby demonstrated that adaptive focused ultrasonication was a promising method for rapid homogenization and particle size reduction to micron range for different compounds varying in grindability without altering the crystalline structure. [ABSTRACT FROM AUTHOR]

Radioguidance that makes use of β-emitting radionuclides is gaining in popularity and could have potential to strengthen the range of existing radioguidance techniques. While there is a strong tendency to develop new PET radiotracers, due to favorable imaging characteristics and the success of theranostics research, there are practical challenges that need to be overcome when considering use of β-emitters for surgical radioguidance. In this position paper, the EANM identifies the possibilities and challenges that relate to the successful implementation of β-emitters in surgical guidance, covering aspects related to instrumentation, radiation protection, and modes of implementation. [ABSTRACT FROM AUTHOR]

Minimal hepatic encephalopathy (MHE) is common in liver cirrhosis and is identified by psychometric tests. The portosystemic hepatic encephalopathy score (PHES) is the most widely used and serves as an inter-study comparator. PHES has not been standardised for use in the Danish population, where German normal values have been applied until now based on the notion that the populations are comparable. This study aimed to evaluate if German PHES normal values can be applied in the Danish population and establish Danish normal values if needed. 200 Danish and 217 German healthy persons underwent Number Connection Test A and B (NCT), Line Tracing Test (LTT), Digit Symbol Test (DST), and Serial Dotting Test (SDT), and based on performance, PHES was calculated. German and Danish PHES performance declined with age in all subtests but more rapidly in Danes. Both German and Danish norms were impacted by gender and education, but to a different extent in the single tests of the test battery. Accordingly, there was a need for specific Danish normal values, which are presented here. Applying the new Danish normal values instead of the German in patients with cirrhosis yielded a lower percentage of out-of-norm performances (58% vs. 66%) and, hence, a lower prevalence of MHE. Danes and Germans perform differently on PHES, and therefore, normal German values cannot be used in Danish patients. Danish normal values are presented here and yield a lower number of 'out of norm' performances. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to determine the organ-specific accuracy of [18F]FDG-PET/CT in identifying immune-related adverse events (irAEs) in patients with high-risk (stage III/IV) surgically resected melanoma treated with an adjuvant immune checkpoint inhibitor (ICI) and determine the incidence of irAEs within the first year after starting treatment. Materials and methods: This registry-based study included individuals who had undergone surgical removal of melanoma and were undergoing adjuvant ICI treatment (either nivolumab or pembrolizumab). The study specifically enrolled patients who had undergone both a baseline and at least one subsequent follow-up [18F]FDG-PET/CT scan. Follow-up scans were performed every third month in the first year after surgery to screen for disease recurrence. We retrospectively compared the follow-up scans with baseline scans to identify irAEs. Clinical information on irAEs was obtained from medical records and served as a reference standard for determining the accuracy of [18F]FDG-PET/CT. Results: A total of 123 patients with 363 [18F]FDG-PET/CT scans were included, and 65 patients (52.8%) developed irAEs. In decreasing order, the organ-specific incidences of irAEs were: skin 26/65 (40%), muscle and joints 21/65 (32.3%), intestines 13/65 (20%), thyroid gland 12/65 (18.5%), lungs 4/65 (6.2%), and heart 2/65 (3.1%). The sensitivities and specificities of [18F]FDG-PET/CT for diagnosing irAEs were: skin 19% (95% CI: 7–39%) and 95% (88–98%), muscles and joints 71% (48–89%) and 83% (75–90%), intestines 100% (75–100%) and 85% (77–91%); thyroid gland 92% (62–99%) and 95% (89–98%), lungs 75% (19–99%) and 90% (83–95%), and heart 50% (13–99%) and 97% (92–99%), respectively. Conclusion: [18F]FDG-PET/CT generally had moderate to high sensitivities (except for skin and heart) and specificities in diagnosing irAEs in patients receiving adjuvant ICI; this could be suggested to be systematically assessed and reported in scan reports. [ABSTRACT FROM AUTHOR]

Purpose of Review: Devastating complications of the bladder outlet resulting from prostate cancer treatments are relatively uncommon. However, the combination of the high incidence of prostate cancer and patient longevity after treatment have raised awareness of adverse outcomes deteriorating patients' quality of life. This narrative review discusses the diagnostic work-up and management options for bladder outlet obstruction resulting from prostate cancer treatments, including those that require urinary diversion. Recent Findings: The devastated bladder outlet can be a consequence of the treatment of benign conditions, but more frequently from complications of pelvic cancer treatments. Regardless of etiology, the initial treatment ladder involves endoluminal options such as dilation and direct vision internal urethrotomy, with or without intralesional injection of anti-fibrotic agents. If these conservative strategies fail, surgical reconstruction should be considered. Although surgical reconstruction provides the best prospect of durable success, reconstructive procedures are also associated with serious complications. In the worst circumstances, such as prior radiotherapy, failed reconstruction, devastated bladder outlet with end-stage bladders, or patient's severe comorbidities, reconstruction may neither be realistic nor justified. Urinary diversion with or without cystectomy may be the best option for these patients. Thorough patient counseling before treatment selection is of utmost importance. Outcomes and repercussions on quality of life vary extensively with management options. Meticulous preoperative diagnostic evaluation is paramount in selecting the right treatment strategy for each individual patient. Summary: The risk of bladder outlet obstruction, and its severest form, devastated bladder outlet, after treatment of prostate cancer is not negligible, especially following radiation. Management includes endoluminal treatment, open or robot-assisted laparoscopic reconstruction, and urinary diversion in the worst circumstances, with varying success rates. [ABSTRACT FROM AUTHOR]

Obesity and systemic inflammation are associated with breast cancer (BC) outcomes. Systemic inflammation is increased in obesity. We examined the association between C-reactive protein (CRP) and disease-free survival (DFS) and overall survival (OS) overall, and according to body mass index (BMI). We assembled a cohort of women with BC (stage I–III) seen at Aarhus University Hospital between 2010 and 2020 who donated blood at BC diagnosis (N = 2673). CRP levels were measured and divided into quartiles. We followed patients from surgery to recurrence, contralateral BC, other malignancy, death, emigration, or end-of-follow-up. We used Cox regression to estimate hazard ratios (HRs) with 95% confidence intervals (95% CIs) to compare outcomes across CRP quartiles, overall and stratified by BMI (normal-weight (18.5 ≤ BMI < 25 kg/m2), overweight (25 ≤ BMI < 30 kg/m2), and obesity (BMI ≥ 30 kg/m2)). During follow-up, 368 events (212 recurrences, 38 contralateral BCs, and 118 deaths) occurred (median follow-up 5.55 years). For DFS, high CRP (CRP ≥ 3.19 mg/L) was associated with an increased risk of events (HRadj:1.62 [95% CI = 1.14–2.28]). In BMI-stratified analyses, high CRP was associated with elevated risk of events in normal-weight and overweight (HRadj:1.70 [95% CI = 1.09–2.66]; HRadj:1.75 [95% CI = 1.08–2.86]), but in obesity, the estimate was less precise (HRadj:1.73 [95% CI = 0.78–3.83]). For OS, high CRP was associated with increased risk of death (HRadj:2.47 [95% CI = 1.62–3.76]). The association was strong in normal-weight and overweight (HRadj:3.66 [95% CI = 1.95–6.87]; HRadj:1.92 [95% CI = 1.06–3.46]), but less clear in obesity (HRadj:1.40 [95% CI = 0.64–3.09]). To sum up, high CRP levels at BC diagnosis were associated with inferior prognosis in early BC irrespective of BMI, although less clear in patients with obesity. [ABSTRACT FROM AUTHOR]

We examined whether employees (N = 710) who experience low levels of political fit and who self-censor their political opinions at work, are more likely to display lower job satisfaction and perceived social community, and higher turnover intentions, burnout, and fear of social isolation. The results largely confirmed these associations and showed that the associations between perceived political fit and job satisfaction, social community, turnover intentions, and burnout were statistically mediated by willingness to self-censor. This suggests that employees who experience lower levels of person-organization fit with regards to their political ideology have a higher tendency to censure themselves, which is negatively related to their well-being, perceived social belonging, and job satisfaction. Furthermore, we found that the willingness to self-censor political opinions at work was slightly higher on average among those who were politically to the left, female, younger, and less educated. The findings point to the complexity of navigating political ideologies in the workplace. [ABSTRACT FROM AUTHOR]

Multisystem inflammatory syndrome in children (MIS-C) is a severe disease that emerged during the COVID-19 pandemic. Although recognized as an immune-mediated condition, the pathogenesis remains unresolved. Furthermore, the absence of a diagnostic test can lead to delayed immunotherapy. Using state-of-the-art mass-spectrometry proteomics, assisted by artificial intelligence (AI), we aimed to identify a diagnostic signature for MIS-C and to gain insights into disease mechanisms. We identified a highly specific 4-protein diagnostic signature in children with MIS-C. Furthermore, we identified seven clusters that differed between MIS-C and controls, indicating an interplay between apolipoproteins, immune response proteins, coagulation factors, platelet function, and the complement cascade. These intricate protein patterns indicated MIS-C as an immunometabolic condition with global hypercoagulability. Our findings emphasize the potential of AI-assisted proteomics as a powerful and unbiased tool for assessing disease pathogenesis and suggesting avenues for future interventions and impact on pediatric disease trajectories through early diagnosis. Proteomic profiling reveals diagnostic signatures and pathogenic insights in multisystem inflammatory syndrome in children. [ABSTRACT FROM AUTHOR]

Objectives: Fusobacterium necrophorum is a common cause of pharyngotonsillitis. However, no guidelines exist on when to diagnose or treat it. We aimed to investigate associations between clinical criteria and F. necrophorum-positivity in pharyngotonsillitis and assess the predictive potential of a simple scoring system. Methods: Pharyngotonsillitis patients who were tested for F. necrophorum (PCR) and presented to hospitals in the Skåne Region, Sweden, between 2013–2020 were eligible. Data were retrieved from electronic chart reviews and registries. By logistic regression we investigated associations between F. necrophorum-positivity and pre-specified criteria: age 13–30 years, symptom duration ≤ 3 days, absence of viral symptoms (e.g. cough, coryza), fever, tonsillar swelling/exudate, lymphadenopathy and CRP ≥ 50 mg/L. In secondary analyses, associated variables were weighted by strength of association into a score and its predictive accuracy of F. necrophorum was assessed. Results: Among 561 cases included, 184 (33%) had F. necrophorum, which was associated with the following criteria: age 13–30, symptom duration ≤ 3 days, absence of viral symptoms, tonsillar swelling/exudate and CRP ≥ 50 mg/L. Age 13–30 had the strongest association (OR5.7 95%CI 3.7–8.8). After weighting, these five variables had a sensitivity and specificity of 68% and 71% respectively to predict F. necrophorum-positivity at the proposed cut-off. Conclusion: Our results suggest that F. necrophorum cases presenting to hospitals might be better distinguished from other pharyngotonsillitis cases by a simple scoring system presented, with age 13–30 being the strongest predictor for F. necrophorum. Prospective studies, involving primary care settings, are needed to evaluate generalisability of findings beyond cases presenting to hospitals. [ABSTRACT FROM AUTHOR]

Purpose: Automated endoscopy video analysis is essential for assisting surgeons during medical procedures, but it faces challenges due to complex surgical scenes and limited annotated data. Large-scale pretraining has shown great success in natural language processing and computer vision communities in recent years. These approaches reduce the need for annotated data, which is of great interest in the medical domain. In this work, we investigate endoscopy domain-specific self-supervised pretraining on large collections of data. Methods: To this end, we first collect Endo700k, the largest publicly available corpus of endoscopic images, extracted from nine public Minimally Invasive Surgery (MIS) datasets. Endo700k comprises more than 700,000 images. Next, we introduce EndoViT, an endoscopy-pretrained Vision Transformer (ViT), and evaluate it on a diverse set of surgical downstream tasks. Results: Our findings indicate that domain-specific pretraining with EndoViT yields notable advantages in complex downstream tasks. In the case of action triplet recognition, our approach outperforms ImageNet pretraining. In semantic segmentation, we surpass the state-of-the-art (SOTA) performance. These results demonstrate the effectiveness of our domain-specific pretraining approach in addressing the challenges of automated endoscopy video analysis. Conclusion: Our study contributes to the field of medical computer vision by showcasing the benefits of domain-specific large-scale self-supervised pretraining for vision transformers. We release both our code and pretrained models to facilitate further research in this direction: https://github.com/DominikBatic/EndoViT. [ABSTRACT FROM AUTHOR]

The learning context, consisting of the school children's families, teachers, and peers, has effect on their mathematics learning. The concern of students' socioeconomic status (SES) affecting negatively their learning outcomes is increasing worldwide. This study investigates whether Finnish elementary school students' SES affects their mathematical competence and success expectancy on individual and class levels. Additionally, the role of teachers' beliefs on mathematics learning and class composition on the mathematics competence and success expectancy on the class level is explored. To analyze the nested data from student questionnaires and mathematics tests, and their teachers' questionnaires, we used multilevel structural equation modelling with two levels (1, individual; 2, class). The results indicate that on the individual level, the gender and SES affect students' mathematical competence and success expectancy in mathematics. On the class level, the teacher's evaluations of academic class composition predicted students' mathematical competence, and the teachers' constructivist beliefs of mathematics learning and class composition regarding students' special needs predicted students' success expectancy. We conclude that students with disadvantaged SES need support on success expectancy to flourish in mathematics. On the class level, this support can be conveyed through teachers' constructivist pedagogical beliefs. [ABSTRACT FROM AUTHOR]

We present a geometric approach to portfolio theory with a focus on risk-adjusted returns, in particular Jensen's alpha. We find that while the alpha/beta approach has severe limitations, especially in higher dimensions, only minor conceptual modifications (e.g., using orthogonal Sharpe ratios rather than risk-adjusted returns) are needed to identify the efficient trading strategies. We further show that, in a complete market, the so-called market price of risk vector is identical to the growth optimal Kelly vector, albeit expressed in coordinates of a different basis. This implies that a derivative, having an orthogonal Sharpe ratio of zero, has a price given by the minimal martingale measure. [ABSTRACT FROM AUTHOR]

Despite major advances in linking single genetic variants to single causal genes, the significance of genetic variation on transcript-level regulation of expression, transcript-specific functions, and relevance to human disease has been poorly investigated. Strawberry notch homolog 2 (SBNO2) is a candidate gene in a susceptibility locus with different variants associated with Crohn's disease and bone mineral density. The SBNO2 locus is also differentially methylated in Crohn's disease but the functional mechanisms are unknown. Here we show that the isoforms of SBNO2 are differentially regulated by lipopolysaccharide and IL-10. We identify Crohn's disease associated isoform quantitative trait loci that negatively regulate the expression of the noncanonical isoform 2 corresponding with the methylation signals at the isoform 2 promoter in IBD and CD. The two isoforms of SBNO2 drive differential gene networks with isoform 2 dominantly impacting antimicrobial activity in macrophages. Our data highlight the role of isoform quantitative trait loci to understand disease susceptibility and resolve underlying mechanisms of disease. Genetic variants in the SBNO2 locus are associated with Crohns's disease. Here the authors show that those variants cause a cell type and isoform specific effect were transcription of SBNO2 isoform 2 impacts on antimicrobial activity in macrophages providing a plausible gene-mechanism-phenotype model. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to examine the effects of intravenous (IV) fluid restriction on time to resolution of hyperlactatemia in septic shock. Hyperlactatemia in sepsis is associated with worse outcome. Sepsis guidelines suggest targeting lactate clearance to guide fluid therapy despite the complexity of hyperlactatemia and the potential harm of fluid overload. Methods: We conducted a post hoc analysis of serial plasma lactate concentrations in a sub-cohort of 777 patients from the international multicenter clinical CLASSIC trial (restriction of intravenous fluids in intensive care unit (ICU) patients with septic shock). Adult ICU patients with septic shock had been randomized to restrictive (n = 385) or standard (n = 392) intravenous fluid therapy. The primary outcome, time to resolution of hyperlactatemia, was analyzed with a competing-risks regression model. Death and discharge were competing outcomes, and administrative censoring was imposed 72 h after randomization if hyperlactatemia persisted. The regression analysis was adjusted for the same stratification variables and covariates as in the original CLASSIC trial analysis. Results: The hazard ratios (HRs) for the cumulative probability of resolution of hyperlactatemia, in the restrictive vs the standard group, in the unadjusted analysis, with time split, were 0.94 (confidence interval (CI) 0.78–1.14) at day 1 and 1.21 (0.89–1.65) at day 2–3. The adjusted analyses were consistent with the unadjusted results. Conclusion: In this post hoc retrospective analysis of a multicenter randomized controlled trial (RCT), a restrictive intravenous fluid strategy did not seem to affect the time to resolution of hyperlactatemia in adult ICU patients with septic shock. [ABSTRACT FROM AUTHOR]

This paper explores the interplay of surface and bulk elasticity on the evolution of surface relief within nanosized thin-film coatings, driven by the relaxation of misfit stresses through surface diffusion mechanism. The proposed theoretical approach incorporates the constitutive equations of surface elasticity theory developed by Gurtin and Murdoch into the Asaro–Tiller–Grinfeld model of morphological instability, which takes into account the stress sensitivity of the local gradient in chemical potential driving mass transport along the perturbed surface. Linear stability analysis, based on the solution of the linearized evolution equation representing the amplitude change of surface perturbation with time, predicts the conditions leading to the early growth of surface topological defects. These conditions depend on factors, such as the initial shape and wavelength of the surface undulations, misfit stresses, tension at the surface and interface, and the elastic properties governing the deformation of the surface, interface, film, and substrate. [ABSTRACT FROM AUTHOR]

Purpose: It is unclear how the evidence from clinical trials best translates into complex clinical settings. The aim of this quality improvement (QI) project was to change prescribing practice for rapid tranquillization in inpatient mental health care services examining the effectiveness of the Plan-Do-Study-Act (PDSA) method. Methods: A prospective QI project was conducted to ensure that intramuscular (IM) diazepam was substituted with IM lorazepam for benzodiazepine rapid tranquillization in inpatient mental health care. We monitored the prescription and administration of medication for rapid tranquillization before (N = 371), during (N = 1130) and after (N = 364) the QI intervention. Seven iterative PDSA cycles with a multiple-component intervention approach were conducted to gradually turn the prescribing practice in the desired direction. Simultaneously, a standard monitoring regimen was introduced to ensure patient safety. Results: Lorazepam administrations gradually replaced diazepam during the intervention period which was sustained post-intervention where lorazepam comprised 96% of benzodiazepine administrations for rapid tranquillization. The mean dose of benzodiazepine administered remained stable from pre (14.40 mg diazepam equivalents) to post (14.61 mg) intervention phase. Close to full compliance (> 80%) with vital signs monitoring was achieved by the end of the observation period. Conclusion: It was possible to increase the quality of treatment of acute agitation in a large inpatient mental health care setting using a stepwise approach based on iterative PDSA cycles and continuous data feedback. This approach might be valuable in other prescribing practice scenarios with feedback from local stakeholders and opinion leaders. [ABSTRACT FROM AUTHOR]

Key message: We find evidence of selection for local adaptation and extensive genotype-by-environment interaction in the potato National Chip Processing Trial (NCPT). We present a novel method for dissecting the interplay between selection, local adaptation and environmental response in plant breeding schemes. Balancing local adaptation and the desire for widely adapted cultivars is challenging for plant breeders and makes genotype-by-environment interactions (GxE) an important target of selection. Selecting for GxE requires plant breeders to evaluate plants across multiple environments. One way breeders have accomplished this is to test advanced materials across many locations. Public potato breeders test advanced breeding material in the National Chip Processing Trial (NCPT), a public–private partnership where breeders from ten institutions submit advanced chip lines to be evaluated in up to ten locations across the country. These clones are genotyped and phenotyped for important agronomic traits. We used these data to interrogate the NCPT for GxE. Further, because breeders submitting clones to the NCPT select in a relatively small geographic range for the first 3 years of selection, we examined these data for evidence of incidental selection for local adaptation, and the alleles underlying it, using an environmental genome-wide association study (envGWAS). We found genomic regions associated with continuous environmental variables and discrete breeding programs, as well as regions of the genome potentially underlying GxE for yield. [ABSTRACT FROM AUTHOR]

Over the last 500 years, Europe (excluding Russia) consumed over 2500 million tonnes of ocean biomass. This is based on detailed historical data that we provide for human consumption per capita which was stable from 1500 to 1899 and tripled in the twentieth century. In the last 300 years, cod and herring dominated human seafood consumption. Whaling for non-food uses peaked in the 1830s and declined as cetaceans became scarce. Seafood consumption increased rapidly after 1900, and by the late 1930s, annual marine consumption in Atlantic Europe reached 7 million tonnes of biomass, facilitated by the globalisation of whaling. Atlantic European consumption, including fishmeal for animal feed, peaked at more than 12 million tonnes annually in the 1970s, but declined thereafter. The marine footprint of Atlantic Europe was significant well before modern fisheries statistics commenced. Our findings can inform future assessments of ocean health and marine life's importance for human society. [ABSTRACT FROM AUTHOR]

Reed beds can be managed for commercial or conservation purposes, with effects on its inhabitants. In this paper, we assess the effect of management on the reed bed Coleoptera community by investigating reed beds subject to winter cutting, winter harvest, short-term unmanaged (3 years), and long-term unmanaged (25 years). Using pit fall traps, we collected Coleoptera across a summer season to estimate Coleoptera biomass, abundance, size, richness, diversity, and community composition across the four types of management of reed beds. Cutting and harvest both show to increase Coleoptera biomass compared to unmanaged reed beds, with the highest Coleoptera abundance found in the harvested reed bed. The species richness and diversity, on the other hand, peaked in the long-term unmanaged reed bed. Community composition differed between the different management types, and across time. Species of conservation concern were most abundant in recently managed areas. These results have implications for the conservation of the reed bed Coleoptera community. First, to maintain a high Coleoptera diversity, some areas must be left unmanaged. Secondly, to secure habitats for species of conservation concern as well as boost the Coleoptera biomass, frequent management of other areas is advised. This mosaic management pattern will also create the overall most species rich reed bed, as unique Coleoptera communities were found in each management type. [ABSTRACT FROM AUTHOR]

The numbers of diagnostic and therapeutic nuclear medicine agents under investigation are rapidly increasing. Both novel emitters and novel carrier molecules require careful selection of measurement procedures. This document provides guidance relevant to dosimetry for first-in human and early phase clinical trials of such novel agents. The guideline includes a short introduction to different emitters and carrier molecules, followed by recommendations on the methods for activity measurement, pharmacokinetic analyses, as well as absorbed dose calculations and uncertainty analyses. The optimal use of preclinical information and studies involving diagnostic analogues is discussed. Good practice reporting is emphasised, and relevant dosimetry parameters and method descriptions to be included are listed. Three examples of first-in-human dosimetry studies, both for diagnostic tracers and radionuclide therapies, are given. [ABSTRACT FROM AUTHOR]

Background: Accurate diagnosis of axillary lymph node (ALN) metastases is essential for prognosis and treatment planning in breast cancer. Evaluation of ALN is done by ultrasound, which is limited by inter-operator variability, and by sentinel lymph node biopsy and/or ALN dissection, none of which are without risks and/or long-term complications. It is known that conventional 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT) has limited sensitivity for ALN metastases. However, a recently developed dynamic whole-body (D-WB) [18F]FDG PET/CT scanning protocol, allowing for imaging of tissue [18F]FDG metabolic rate (MRFDG), has been shown to have the potential to increase lesion detectability. The study purpose was to examine detectability of malignant lesions in D-WB [18F]FDG PET/CT compared to conventional [18F]FDG PET/CT. Results: This study prospectively included ten women with locally advanced breast cancer who were referred for an [18F]FDG PET/CT as part of their diagnostic work-up. They all underwent D-WB [18F]FDG PET/CT, consisting of a 6 min single bed dynamic scan over the chest region started at the time of tracer injection, a 64 min dynamic WB PET scan consisting of 16 continuous bed motion passes, and finally a contrast-enhanced CT scan, with generation of MRFDG parametric images. Lesion visibility was assessed by tumor-to-background and contrast-to-noise ratios using volumes of interest isocontouring tumors with a set limit of 50% of SUVmax and background volumes placed in the vicinity of tumors. Lesion visibility was best in the MRFDG images, with target-to-background values 2.28 (95% CI: 2.04–2.54) times higher than target-to-background values in SUV images, and contrast-to-noise values 1.23 (95% CI: 1.12–1.35) times higher than contrast-to-noise values in SUV images. Furthermore, five imaging experts visually assessed the images and three additional suspicious lesions were found in the MRFDG images compared to SUV images; one suspicious ALN, one suspicious parasternal lymph node, and one suspicious lesion located in the pelvic bone. Conclusions: D-WB [18F]FDG PET/CT with MRFDG images show potential for improved lesion detectability compared to conventional SUV images in locally advanced breast cancer. Further validation in larger cohorts is needed. Clinical trial registration: The trial is registered in clinicaltrials.gov, NCT05110443, https://www.clinicaltrials.gov/study/NCT05110443?term=NCT05110443&rank=1. [ABSTRACT FROM AUTHOR]

Purpose: Family-based treatment (FBT) has contributed significantly to the treatment of anorexia nervosa (AN) in young people (YP). However, parents are concerned that FBT and the active role of parents in the task of refeeding may have a negative impact on family relations. The aim of the review is to assess whether families engaged in FBT for AN are more or less impacted in their family wellbeing and caregiver burden, compared to families with a YP diagnosed with AN, who are not undergoing treatment with FBT. Method: Computerized searches across six databases complemented by a manual search resulted in 30 papers being included in the scoping review. Results: The review identified 19 longitudinal studies on change in family wellbeing in families in FBT-like treatments, and 11 longitudinal studies on change in family wellbeing in treatment where parents are not in charge of refeeding. Only three randomized controlled studies directly compare FBT to treatment without parent-led refeeding. Conclusion: The available research suggests no difference between intervention types regarding impact on family wellbeing. Approximately half of the studies find improvements in family wellbeing in both treatment with and without parent-led refeeding, while the same proportion find neither improvement nor deterioration. As parents play a pivotal role in FBT, there is a need for good quality studies to elucidate the impact of FBT on family wellbeing. Level of evidenceLevel V: Opinions of authorities, based on descriptive studies, narrative reviews, clinical experience, or reports of expert committees. [ABSTRACT FROM AUTHOR]

This article explores the differences between the equal-tempered scale, the Pythagorean scale, and the just scale in music. It explains how these scales are constructed using geometric methods and how they differ in terms of the ratios between notes. The article also discusses the concept of cents as a measure of the distance between notes and provides a table comparing the ratios and cents for the notes of the C major scale in each scale. Overall, the article highlights the historical and mathematical aspects of musical scales and their impact on our perception of music. [Extracted from the article]

The article discusses the impact of cachexia, a condition characterized by weight loss and muscle wasting, on the quality of life and survival of lung cancer patients. It highlights the high prevalence of cachexia in lung cancer patients and the need for effective treatment approaches. The article introduces a research project called LuCaPET, which aims to use advanced imaging techniques and artificial intelligence algorithms to detect metabolic patterns associated with cachexia in lung cancer patients. The project also addresses the ethical challenges of using AI in clinical decision-making and aims to make the AI-driven models transparent and comprehensible for clinicians. The ultimate goal of the project is to improve the diagnosis and treatment of cachexia in lung cancer patients and enhance their quality of life and survival. [Extracted from the article]

Midline CNS tumors are occasionally inaccessible for surgical biopsies. In these instances, cell-free DNA (cfDNA) may serve as a viable alternative for molecular analysis and identification of targetable mutations. Here, we report a young child with an inoperable brainstem tumor in whom a stereotactic biopsy was deemed unsafe. The tumor progressed on steroids and after radiotherapy the patient developed hydrocephalus and received a ventriculoperitoneal shunt. Droplet digital PCR analysis of cfDNA from an intraoperative cerebrospinal fluid liquid biopsy revealed a BRAF V600 mutation enabling targeted treatment with MEK and BRAF inhibitors. The patient, now on trametinib and dabrafenib for 1 year, has had substantial tumor volume regression and reduction of contrast enhancement on MRIs and is making remarkable clinical progress. This case highlights that in a subset of CNS tumors, access to liquid biopsy analysis may be crucial to identify actionable therapeutic targets that would otherwise go undiscovered. [ABSTRACT FROM AUTHOR]

Background and purpose: Primary mitochondrial diseases (PMDs) are rare diseases for which diagnosis is challenging, and management and training programs are not well defined in Europe. To capture and assess care needs, five different European Reference Networks have conducted an exploratory survey. Methods: The survey covering multiple topics relating to PMDs was sent to all ERNs healthcare providers (HCPs) in Europe. Results: We have collected answers from 220 members based in 24/27 European member states and seven non-European member states. Even though most of the responders are aware of neurogenetic diseases, difficulties arise in the ability to deliver comprehensive genetic testing. While single gene analysis is widely available in Europe, whole exome and genome sequencing are not easily accessible, with considerable variation between countries and average waiting time for results frequently above 6 months. Only 12.7% of responders were happy with the ICD-10 codes for classifying patients with PMDs discharged from the hospital, and more than 70% of them consider that PMDs deserve specific ICD codes to improve clinical management, including tailored healthcare, and for reimbursement reasons. Finally, 90% of responders declared that there is a need for further education and training in these diseases. Conclusions: This survey provides information on the current difficulties in the care of PMDs in Europe. We believe that the results of this survey are important to help rare disease stakeholders in European countries identify key care and research priorities. [ABSTRACT FROM AUTHOR]

Background: Surgical coastal expeditions (SCEs) have been organized in Greenland for many years. They aim to provide small coastal hospitals with specialist services, such as endoscopies (SCEEs), by deploying specialist personnel, surgeons, and the necessary equipment to the hospital temporarily. The purpose of this program is to increase accessibility for patients, while simultaneously reducing the costs associated with patient transport to the central hospital. Methods: This retrospective pilot review of medical records identified quality indicators, such as bowel cleansing (BP), cecal intubation rate (CIR), and adenoma and advanced adenoma detection rates (ADR, AADR), to investigate the status and establish a system for quality monitoring of SCEsE in Greenland. Results: During two SCEs (8 working days), 89 SCEE were performed at Qaqortoq and Sisimiut Hospitals. The 60 patients who underwent colonoscopy included 32 men and 28 women with a mean age of 61 years (range 24–80 years). The unadjusted CIR was 91.7%. In eight (13.3%) examinations, bowel preparation was rated as unsatisfactory, resulting in two incomplete procedures. The ADR and AADR were 35% and 11.7%, respectively, and one cancer was detected (1.7%). Conclusion: The results showed satisfactory ADR, AADR, and CIR levels. However, the review also highlighted the need for increased attention to BP by developing a new procedure that considers differences due to specific eating habits in Greenland and provides much better information for patients. The review provided a snapshot of the quality of colonoscopies in Greenland, highlighting the necessity to continue this process to ensure that the quality is up to standard. Furthermore, SCE helps reduce the environmental footprint of gastrointestinal endoscopy by avoiding the need for patient air transport; instead of 77 round trips (61,830 km), only 8 (6440 km) were required. [ABSTRACT FROM AUTHOR]