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Desmosomes are dynamic complex protein structures involved in cellular adhesion. Disruption of these structures by loss-of-function variants in desmosomal genes leads to a variety of skin- and heart-related phenotypes. In this study, we report TUFT1 as a desmosome-associated protein, implicated in epidermal integrity. In two siblings with mild skin fragility, woolly hair, and mild palmoplantar keratoderma but without a cardiac phenotype, we identified a homozygous splice-site variant in the TUFT1 gene, leading to aberrant mRNA splicing and loss of TUFT1 protein. Patients’ skin and keratinocytes showed acantholysis, perinuclear retraction of intermediate filaments, and reduced mechanical stress resistance. Immunolabeling and transfection studies showed that TUFT1 is positioned within the desmosome and that its location is dependent on the presence of the desmoplakin carboxy-terminal tail. A Tuft1-knockout mouse model mimicked the patients’ phenotypes. Altogether, this study reveals TUFT1 as a desmosome-associated protein, whose absence causes skin fragility, woolly hair, and palmoplantar keratoderma.

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Background: Patient-reported outcome measures have become crucial in the clinical evaluation of patients. Appropriate selection, in a young population, of the instrument is vital to providing evidence-based patient-centered healthcare. This systematic review applies the COnsensus-based Standards for selection of health Measurement INstruments methodology to provide a critically appraised overview of patient-reported outcome measures targeted at pediatric orthopedic patients with lower limb impairment.Method: A systematic search of electronic databases was performed to identify original studies reporting the development and/or validation of patient-reported outcome measures evaluating children with impairment of the lower extremity. Data extraction, quality assessment, and risk of bias evaluation were performed following the COnsensus-based Standards for selection of health Measurement INstruments guidelines and Preferred Reporting Items for Systematic reviews and Meta-Analyses statement.Results: A total of 6919 articles were screened. Thirty-three studies were included, reporting evidence on the measurement properties of 13 different patient-reported outcome measures and 20 translations. Four studies reported on content validity and patient-reported outcome measure development. The methodological quality of studies on structural validity, content validity, or patient-reported outcome measure development was mostly rated as "doubtful" or "very good." The quality of evidence on measurement properties varied noticeably, with most studies needing to perform improve their methodological quality to justify their results.Conclusion: This review provides an extensive overview of all available patient-reported outcome measures for patients with lower extremity impairment within pediatric orthopedics. We cautiously advise the use of four patient-reported outcome measures. However, the scarce availability of research on content validity and patient-reported outcome measure dev

Autoimmune serology for the idiopathic inflammatory myopathies has over the years gained impact in the diagnostic work-up of these diseases. In The Netherlands the myositis line immuno-assay is offered by a limited number of laboratories, but the distinct phases from request to interpretation of results, are rather variable. These phases are explored by means of a questionnaire. Based on the results a consensus has been obtained about requesting, performing, reporting and interpreting the test results. The road to and the result of this harmonization initiative are reported in this article.

Item does not contain fulltext, Instrumented gait analysis was developed to assist in clinical decision-making to optimise treatment to improve walking in patients with complex gait problems. In this clinical lesson, two cases are presented in which instrumented gait analysis was used for a different goal. It was used to assist in finding the correct neurological or orthopaedic diagnosis in patients in whom symptoms occurred during walking. In both patients, an accurate diagnosis could not be found based on the symptoms they reported, despite a thorough analysis by the neurologist. Instead, the symptoms were caused by the compensations patients used to optimise walking and not directly by the health condition itself. Through instrumented gait analysis, the direct impact of a health condition on the gait pattern can be distinguished from compensations. It can be an asset in finding the correct diagnosis, especially in patients with complex gait problems or multiple health conditions.

01 augustus 2023, Item does not contain fulltext, BACKGROUND AND OBJECTIVE: Ultrasound based blood velocity estimation is a continuously developing frontier, where the vast number of possible acquisition setups and velocity estimators makes it challenging to assess which combination is better suited for a given imaging application. FLUST, the Flow-Line based Ultrasound Simulation Tool, may be used to address this challenge, providing a common platform for evaluation of velocity estimation schemes on in silico data. However, the FLUST approach had some limitations in its original form, including reduced robustness for phase sensitive setups and the need for manual selection of integrity parameters. In addition, implementation of the technique and therefore also documentation of signal integrity was left to potential users of the approach. METHODS: In this work, several improvements to the FLUST technique are proposed and investigated, and a robust, open source simulation framework developed. The software supports several transducer types and acquisition setups, in addition to a range of different flow phantoms. The main goal of this work is to offer a robust, computationally cheap and user-friendly framework to simulate ultrasound data from stationary blood velocity fields and thereby facilitate design and evaluation of estimation schemes, including acquisition design, velocity estimation and other post-processing steps. RESULTS: The technical improvements proposed in this work resulted in reduced interpolation errors, reduced variability in signal power, and also automatic selection of spatial and temporal discretization parameters. Results are presented illustrating the challenges and the effectiveness of the solutions. The integrity of the improved simulation framework is validated in an extensive study, with results indicating that speckle statistics, spatial and temporal correlation and frequency content all correspond well with theoretical predictions. Finally, an illustrative example shows how FLUST may be us

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Neurofibromatosis type 1 (NF1) and Legius syndrome (LS) are caused by inactivating variants in NF1 and SPRED1. NF1 encodes neurofibromin (NF), a GTPase-activating protein (GAP) for RAS that interacts with the SPRED1 product, Sprouty-related protein with an EVH (Ena/Vasp homology) domain 1 (SPRED1). Obtaining a clinical and molecular diagnosis of NF1 or LS can be challenging due to the phenotypic diversity, the size and complexity of the NF1 and SPRED1 loci, and uncertainty over the effects of some NF1 and SPRED1 variants on pre-mRNA splicing and/or protein expression and function. To improve NF1 and SPRED1 variant classification and establish pathogenicity for NF1 and SPRED1 variants identified in individuals with NF1 or LS, we analyzed patient RNA by RT-PCR and performed in vitro exon trap experiments and estimated NF and SPRED1 protein expression, RAS GAP activity, and interaction. We obtained evidence to support pathogenicity according to American College of Medical Genetics guidelines for 73/114 variants tested, demonstrating the utility of functional approaches for NF1 and SPRED1 variant classification and NF and LS diagnostics.

In this article, we describe to what extent culture-bound gender norms are reproduced in interactions between childcare workers and parents in daycare. This is important because more and more families want to share responsibilities for paid work and child rearing equally, but in many families this does not work out that way. Prevailing gender norms may provide an explanation for this. We used an online questionnaire to measure which implicit (gender/career IAT) and explicit gender beliefs (ideal amount of time spent on work or care for both father and mother) are held by childcare workers (n=259) and to what extent these beliefs and their different behaviour towards fathers and mothers is related. Although childcare workers with more traditional gender beliefs on the division of paid work by parents are more likely to inform and reach out to mothers, the relationships between beliefs and behaviour are not as strong as expected. An important finding is that the presence of more fathers in daycare is associated with more egalitarian behaviour of childcare workers. We suggest that the current tendency to approach mothers more often can be challenged by inviting more fathers and acknowledging them as the important parents they are.

Lateral humeral condyle fractures are frequently seen in pediatric patients and have a high risk of unfavorable outcomes. A fall on the outstretched arm with supination of the forearm is the most common trauma mechanism. A physical examination combined with additional imaging will confirm the diagnosis. Several classifications have been described to categorize these fractures based on location and comminution. Treatment options depend on the severity of the fracture and consist of immobilization in a cast, closed reduction with percutaneous fixation, and open reduction with fixation. These fractures can lead to notable complications such as lateral condyle overgrowth, surgical site infection, pin tract infections, stiffness resulting in decreased range of motion, cubitus valgus deformities, ‘fishtail’ deformities, malunion, non-union, avascular necrosis, and premature epiphyseal fusion. Adequate follow-up is therefore warranted.

Background Traumatic elbow injuries in children occur frequently and are among the most common traumatic injuries seen in the emergency department (ED) and in general practice. The use of a validated decision rule to enhance selective radiography in paediatric patients with possible elbow fractures may reduce unnecessary exposure to radiation in children. Method and analysis This study is designed as a multicentre prospective cohort study. An expert panel of orthopaedic elbow surgeons, paediatric orthopaedic surgeons and trauma surgeons will initially determine clinical parameters that provide a possible predictive value for elbow fractures. Four hundred children between the ages of 2 and 17 years visiting the ED with pain following elbow trauma will then be included. The clinical parameters will be collected via patient history and physical examination. Elbow radiographs will be obtained in all patients to identify fractures. The data will be processed in a multivariable logistic regression analysis to determine which clinical parameters predict the presence of an elbow fracture. Only the clinical parameters that predict a fracture will be used to formulate the new decision rule: the paediatric elbow trauma (PET) rules. Internal validation of the prediction model will take place after inclusion is complete and by means of a bootstrap analysis on the acquired data. A calculation will be made to determine how many radiographs can potentially be reduced by applying the PET rules and a cost analysis will be performed. Ethics and dissemination The study will be conducted according to the principles of the Declaration of Helsinki and in accordance with the Medical Research Involving Human Subjects Act. The Medical Research Ethics Committees United stated on 16 May 2022 that The Medical Research Involving Human Act (WMO) does not apply to this study and an official approval by the committee is not required, reference number; project W22.086.

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Contains fulltext : 282540.pdf (Publisher’s version ) (Open Access), INTRODUCTION/AIMS: Visual and quantitative muscle ultrasound are both valid diagnostic tools in neuromuscular diseases. To optimize muscle ultrasound evaluation and facilitate its use in neuromuscular disease, we examined the correlation between visual and quantitative muscle ultrasound analysis and their pitfalls. METHODS: Retrospective data from 994 patients with 13,562 muscle ultrasound images were analyzed. Differences in echogenicity z-score distribution per Heckmatt grade and corresponding correlation coefficients were calculated. RESULTS: Overall, there was a correlation of 0.60 between the two scoring systems, with a gradual increase in z-score with increasing Heckmatt grades and vice versa. Patients with a neuromuscular disorder had higher Heckmatt grades (p < 0.001) and z-scores (median z-score = 0.30, p < 0.001) than patients without. The highest Heckmatt grades and z-scores were found in patients with either a dystrophy or inflammatory myopathy (both median Heckmatt grade of 2 and median z score of 0.74 and 1.20, respectively). Discrepant scores were infrequent (<2%), but revealed important pitfalls in both grading systems. DISCUSSION: Visual and quantitative muscle ultrasound are complementary techniques to evaluate neuromuscular disease and have a moderate positive correlation. Importantly, we identified specific pitfalls for visual and quantitative muscle ultrasound and how to overcome them in clinical practice.

Contains fulltext : 285280.pdf (Publisher’s version ) (Open Access)

Contains fulltext : 251752.pdf (Publisher’s version ) (Open Access), BACKGROUND: In patients with primary mitochondrial disease (MD), screening with electrocardiogram (ECG) and transthoracic echocardiography (TTE) is warranted according to current guidelines as structural cardiac abnormalities are frequent. This study aims to evaluate the cardiac phenotype of a large Dutch cohort of patients with MD and investigates whether ECG alone is sufficient for predicting structural cardiac abnormalities on TTE. METHODS: In this retrospective cohort study, genetically confirmed MD patients >18 years old with an available ECG and TTE were included. Newcastle Mitochondrial Disease Scale for Adults (NMDAS) scores were assessed. ECG's were evaluated for rhythm and conduction disorders, voltage criteria for left ventricular hypertrophy (LVH) and repolarization disorders. Echocardiographic evaluation included left and right ventricular volumes and function, and presence of LVH or concentric remodeling. RESULTS: In total, 200 MD patients were included with a median age of 45 years (IQR; 37-57) of whom 36% were male. Of all MD patients, 35% had abnormalities on ECG and 61% on TTE. Most frequent structural cardiac abnormalities on TTE were: global longitudinal strain > - 18% (54%), concentric remodeling (27%) and left ventricular (LV) ejection fraction <52% (14%). Patients with maternally inherited diabetes and deafness (MIDD) and mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) had the highest prevalence of ECG abnormalities (50% and 47%). TTE abnormalities were most prevalent in patients with MIDD (75%), followed by mitochondrial myopathy (MM) (55%), MELAS (47%) and Mitochondrial Epilepsy and Ragged Red Fibers (MERRF) (47%). MD patients with a high disease severity (NMDAS ≥21) had a higher prevalence of ECG abnormalities (44%, p = 0.039) and structural cardiac abnormalities (72%, p = 0.004) compared to patients with a NMDAS score of 11-20 and ≤ 10 (ECG: 34% and 19%; TTE: 63% and 39%). ECG abnormalities had a positive

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Contains fulltext : 282596.pdf (Publisher’s version ) (Open Access), INTRODUCTION/AIMS: Diaphragm ultrasound is increasingly used in the diagnosis of diaphragm dysfunction and to guide respiratory management in patients with neuromuscular disorders and those who are critically ill. However, the association between diaphragm ultrasound variables and demographic factors like age, sex, and body mass index (BMI) are understudied. Such relationships are important for correct interpretation of normative values and comparison with selected patients groups. The aim of this study was to determine the associations between diaphragm ultrasound variables and subject characteristics. METHODS: B-mode ultrasound was used to image the diaphragm at the zone of apposition in 83 healthy subjects. Diaphragm thickness at resting end-expiration (T(end-exp) ), diaphragm thickness at maximal end-inspiration (T(max-insp) ), diaphragm thickening ratio (T(max-insp) /T(end-exp) ), and diaphragm echogenicity were measured. Multivariate linear regression was used to explore the associations between diaphragm ultrasound variables and subject characteristics. RESULTS: T(end-exp) , T(max-insp) , and thickening ratio do not change with age whereas diaphragm echogenicity increases with age. The thickening ratio had a weak negative association with BMI, while T(end-exp) was positively associated with BMI. Men had a larger T(end-exp) and T(max-insp) than women (T(end-exp) 1.6 ± 0.5 and 1.4 ± 0.3 mm; p = .011, T(max-insp) 3.8 ± 1.0 and 3.2 ± 0.9 mm; p = .004), but similar thickening ratios. DISCUSSION: Diaphragm thickness, thickening, and echogenicity measured with ultrasound are associated with factors such as age, BMI, and sex. Therefore, subject characteristics should be considered when interpreting diaphragm ultrasound measurements. In the absence of normative values, matched control groups are a prerequisite for research and in clinical practice.

Contains fulltext : 287507.pdf (Publisher’s version ) (Open Access), Ketogenic diets and orally administered exogenous ketone supplements are strategies to increase serum ketone bodies serving as an alternative energy fuel for high energy demanding tissues, such as the brain, muscles, and the heart. The ketogenic diet is a low-carbohydrate and fat-rich diet, whereas ketone supplements are usually supplied as esters or salts. Nutritional ketosis, defined as serum ketone concentrations of ≥ 0.5 mmol/L, has a fasting-like effect and results in all sorts of metabolic shifts and thereby enhancing the health status. In this review, we thus discuss the different interventions to reach nutritional ketosis, and summarize the effects on heart diseases, epilepsy, mitochondrial diseases, and neurodegenerative disorders. Interest in the proposed therapeutic benefits of nutritional ketosis has been growing the past recent years. The implication of this nutritional intervention is becoming more evident and has shown interesting potential. Mechanistic insights explaining the overall health effects of the ketogenic state, will lead to precision nutrition for the latter diseases.

Contains fulltext : 283331.pdf (Publisher’s version ) (Open Access), Ultrasound-based local pulse wave velocity (PWV) estimation, as a measure of arterial stiffness, can be based on fast focused imaging (FFI) or plane wave imaging (PWI). This study was aimed at comparing the accuracy of in vivo PWV estimation using FFI and PWI. Ultrasound radiofrequency data of carotid arteries were acquired in 14 healthy volunteers (25-57 y) by executing the FFI (12 lines, 7200 Hz) and PWI (128 lines, 2000 Hz) methods consecutively. PWV was derived at two time-reference points, dicrotic notch (DN) and systolic foot (SF), for multiple pressure cycles by fitting a linear function through the positions of the peaks of low-pass filtered wall acceleration curves as a function of time. The accuracy of PWV estimation was determined for various cutoff frequencies (10-200 Hz). No statistically significant difference was observed between PWVs estimated by both approaches. The PWV and R(2) at DN were higher, on average, than those at SF (PWV/R(2): FFI SF 5.5/0.92, FFI DN 6.1/0.92; PWI SF 5.4/0.89, PWI DN 6.3/0.95). The use of cutoff frequencies between 40 and 80 Hz provided the most accurate PWVs. Both methods seemed equally suitable for use in clinical practice, although we have a preference for the PWV at DN given the higher R(2) values.

In this paper, I reflect on two of my intertwined research interests. The first is my professional engagement with researching drug use and abuse in Ireland, especially heroin addiction, in applied ethnographic projects, generally answering a specific set of questions on how services for ‘drug addiction’ work. My second interest is the historical construction of ‘addiction’ and the discursive intersections that produce various kinds of power, subjects, and techniques around this concept. I find the dialectical relationship between heroin and methadone in Ireland, especially the emergence of heroin ‘injecting rooms’, as a window into how drugs are social things. Drugs and the bodies who take them live in complex moral worlds; not as inert objects surrounded by abstract human creations. These worlds are an integral part of how ‘addiction’ works and how drugs treating addiction are actually used. Without a deeper understanding of such complexities, we will continue to miss key issues in the lives of people we hope to help.

Alternative splicing (AS) is crucial for cell-type-specific gene transcription and plays a critical role in neuronal differentiation and synaptic plasticity. De novo frameshift variants in NOVA2, encoding a neuron-specific key splicing factor, have been recently associated with a new neurodevelopmental disorder (NDD) with hypotonia, neurological features, and brain abnormalities. We investigated eight unrelated individuals by exome sequencing (ES) and identified seven novel pathogenic NOVA2 variants, including two with a novel localization at the KH1 and KH3 domains. In addition to a severe NDD phenotype, novel clinical features included psychomotor regression, attention deficit-hyperactivity disorder (ADHD), dyspraxia, and urogenital and endocrinological manifestations. To test the effect of the variants on splicing regulation, we transfected HeLa cells with wildtype and mutant NOVA2 complementary DNA (cDNA). The novel variants NM_002516.4:c.754_756delCTGinsTT p.(Leu252Phefs*144) and c.1329dup p.(Lys444Glnfs*82) all negatively affected AS events. The distal p.(Lys444Glnfs*82) variant, causing a partial removal of the KH3 domain, had a milder functional effect leading to an intermediate phenotype. Our findings expand the molecular and phenotypic spectrum of NOVA2-related NDD, supporting the pathogenic role of AS disruption by truncating variants and suggesting that this is a heterogeneous condition with variable clinical course.

Introduction As patient-reported outcome measures (PROMs) have become of significant importance in evaluation of care and clinical research, adequately selecting the appropriate instrument is an integral part of paediatric orthopaedic research and clinical practice. This systematic review aims to provide a comprehensive overview of PROMs targeted at children with impairment of the lower limb, and to critically appraise and summarise the quality of their measurement properties by applying the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) methodology. Method and analysis A systematic search of the MEDLINE and EMBASE databases will be performed to identify relevant publications reporting on the development and/or validation of PROMs used for evaluating children with impairment of the lower extremity. Data extraction and quality assessment of the included studies will be undertaken by two reviewers independently and in accordance with COSMIN guidelines. Ethics and dissemination It is not necessary to obtain ethical approval for this systematic review. The results will be published in a peer-reviewed journal and will be presented at relevant conferences to enhance information dissemination. PROSPERO registration number CRD42021287323.

Background: As patient-reported outcome measures (PROMs) have become of significant importance in patient evaluation, adequately selecting the appropriate instrument is an integral part of pediatric orthopedic research and clinical practice. This systematic review provides a comprehensive overview of PROMs targeted at children with impairment of the upper limb, and critically appraises and summarizes the quality of their measurement properties by applying the COnsensus-based Standards for selection of health Measurement INstruments (COSMIN) methodology. Methods: A systematic search of the MEDLINE and EMBASE databases was performed to identify relevant publications reporting on the development and/or validation of PROMs used for evaluating children with impairment of the upper extremity. Data extraction and quality assessment (including a risk of bias evaluation) of the included studies was undertaken by two reviewers independently and in accordance with COSMIN guidelines. Results: Out of 6423 screened publications, 32 original articles were eligible for inclusion in this review, reporting evidence on the measurement properties of 22 self- and/or proxy-reported questionnaires (including seven cultural adaptations) for various pediatric orthopedic conditions, including cerebral palsy (CP) and obstetric brachial plexus palsy (OBPP). The measurement property most frequently evaluated was construct validity. No studies evaluating content validity and only four PROM development studies were included. The methodological quality of these development studies was either ‘doubtful’ or ‘inadequate’. The quantity and quality of the evidence on the other measurement properties of the included questionnaires varied substantially with insufficient sample sizes and/or poor methodological quality resulting in significant downgrading of evidence quality. Conclusion: This review provides a comprehensive overview of currently available PROMs for evaluation of the pediatric upper limb

Cortisol is a steroid hormone involved in a wide range of medical conditions. The level of the hormone fluctuates over time, but with traditional laboratory-based assays, such dynamics cannot be monitored in real time. Here, a reversible cortisol sensor is reported that allows continuous monitoring of cortisol in blood plasma using sampling by microdialysis. The sensor is based on measuring single-molecule binding and unbinding events of tethered particles. The particles are functionalized with antibodies and the substrate with cortisol-analogues, causing binding and unbinding events to occur between particles and substrate. The frequency of binding events is reduced when cortisol is present in the solution as it blocks the binding sites of the antibodies. The sensor responds to cortisol in the high nanomolar to low micromolar range and can monitor cortisol concentrations over multiple hours. Results are shown for cortisol monitoring in filtered and in microdialysis-sampled human blood plasma.

Adolescent and young adult (AYA) cancer survivors (18–39 years at diagnosis) often experience negative body changes such as scars, amputation, and disfigurement. Understanding which factors influence body image among AYA survivors can improve age-specific care in the future. Therefore, we aim to examine the prevalence, and association of a negative body image with sociodemographic, clinical, and psychosocial factors, among AYA cancer survivors (5–20 years after diagnosis). A population-based cross-sectional cohort study was conducted among AYA survivors (5–20 years after diagnosis) registered within the Netherlands Cancer Registry (NCR) (SURVAYA-study). Body image was examined via the EORTC QLQ-C30 and QLQ-SURV100. Multivariable logistic regression models were used. Among 3735 AYA survivors who responded, 14.5% (range: 2.6–44.2%), experienced a negative body image. Specifically, AYAs who are female, have a higher Body Mass Index (BMI) or tumor stage, diagnosed with breast cancer, cancer of the female genitalia, or germ cell tumors, treated with chemotherapy, using more maladaptive coping strategies, feeling sexually unattractive, and having lower scores of health-related Quality of Life (HRQoL), were more likely to experience a negative body image. Raising awareness and integrating supportive care for those who experience a negative body image into standard AYA survivorship care is warranted. Future research could help to identify when and how this support for AYA survivors can be best utilized.

Neurofibromatosis type 1 (NF1) is caused by inactivating mutations in NF1. Due to the size, complexity, and high mutation rate at the NF1 locus, the identification of causative variants can be challenging. To obtain a molecular diagnosis in 15 individuals meeting diagnostic criteria for NF1, we performed transcriptome analysis (RNA-seq) on RNA obtained from cultured skin fibroblasts. In each case, routine molecular DNA diagnostics had failed to identify a disease-causing variant in NF1. A pathogenic variant or abnormal mRNA splicing was identified in 13 cases: 6 deep intronic variants and 2 transposon insertions causing noncanonical splicing, 3 postzygotic changes, 1 branch point mutation and, in 1 case, abnormal splicing for which the responsible DNA change remains to be identified. These findings helped resolve the molecular findings for an additional 17 individuals in multiple families with NF1, demonstrating the utility of skin-fibroblast-based transcriptome analysis for molecular diagnostics. RNA-seq improves mutation detection in NF1 and provides a powerful complementary approach to DNA-based methods. Importantly, our approach is applicable to other genetic disorders, particularly those caused by a wide variety of variants in a limited number of genes and specifically for individuals in whom routine molecular DNA diagnostics did not identify the causative variant.

Ketogenic diets and orally administered exogenous ketone supplements are strategies to increase serum ketone bodies serving as an alternative energy fuel for high energy demanding tissues, such as the brain, muscles, and the heart. The ketogenic diet is a low-carbohydrate and fat-rich diet, whereas ketone supplements are usually supplied as esters or salts. Nutritional ketosis, defined as serum ketone concentrations of ≥ 0.5 mmol/L, has a fasting-like effect and results in all sorts of metabolic shifts and thereby enhancing the health status. In this review, we thus discuss the different interventions to reach nutritional ketosis, and summarize the effects on heart diseases, epilepsy, mitochondrial diseases, and neurodegenerative disorders. Interest in the proposed therapeutic benefits of nutritional ketosis has been growing the past recent years. The implication of this nutritional intervention is becoming more evident and has shown interesting potential. Mechanistic insights explaining the overall health effects of the ketogenic state, will lead to precision nutrition for the latter diseases.

Context: Adipose tissue (AT) transcriptome studies provide holistic pictures of adaptation to weight and related bioclinical settings changes.Objective: To implement AT gene expression profiling and investigate the link between changes in bioclinical parameters and AT gene expression during three steps of a two-phase dietary intervention (DI).Methods: AT transcriptome profiling was obtained from sequencing 1051 samples, corresponding to 556 distinct individuals enrolled in a weight loss intervention (8-week low calorie diet (LCD) at 800 kcal/d) followed with a 6-month ad libitum randomized DI. Transcriptome profiles obtained with QuantSeq sequencing were benchmarked against Illumina RNAseq. Reverse transcription quantitative polymerase chain reaction was used to further confirm associations. Cell specificity was assessed using freshly isolated cells and THP-1 cell line.Results: During LCD, 5 modules were found, of which 3 included at least 1 bioclinical variable. Change in body mass index (BMI) connected with changes in mRNA level of genes with inflammatory response signature. In this module, change in BMI was negatively associated to changes in expression of genes encoding secreted protein (GDF15, CCL3, and SPP1). Through all phases of the DI, change in GDF15 was connected to changes in SPP1, CCL3, LIPA and CD68. Further characterization showed that these genes were specific to macrophages (with LIPA, CD68 and GDF15 expressed in anti-inflammatory macrophages) and GDF15 also expressed in preadipocytes.Conclusion: Network analyses identified a novel AT feature with GDF15 upregulated with calorie restriction induced weight loss, concomitantly to macrophage markers. In AT, GDF15 was expressed in preadipocytes and macrophages where it was a hallmark of anti-inflammatory cells.

The aim of this article is to describe neurovascular findings in patients with Loeys Dietz syndrome type III and their possible clinical impact. Loeys Dietz syndrome type III, caused by pathogenic SMAD3 variants, is an autosomal dominant syndrome characterized by aneurysms and arterial tortuosity in combination with osteoarthritis. Neurovascular abnormalities have been described in other heritable aortic syndromes, however, reliable data in Loeys Dietz syndrome type III is missing. In our tertiary center, all adult patients with confirmed Loeys Dietz syndrome type III are followed in a standardized aorta outpatient clinic including Computed Tomography Angiography (CTA) of the head and neck region at baseline and (tri) yearly during follow-up. We performed an analysis of the neurovascular imaging findings and clinical follow-up. The primary outcome was a combined endpoint of mortality, dissection, cerebral vascular event and intervention. In addition, tortuosity and vascular growth were assessed. In total 26 patients (mean age 38.4 years, 38.5% males) underwent 102 (mean 3.9 (1-8) per patient) neurovascular Computed Tomography Angiography scans between 2010 and 2021. In 84.6% some form of neurovascular abnormality was found. The abnormalities at baseline were aneurysm (26.9%) dissection flap (7.7%), arterial tortuosity (61.5%), arterial coiling (23.1%) and arterial kinking (3.8%). During follow up (mean 8.85 (1-11) years) one patient suffered from sudden death and one patient needed a neuro-radiological intervention. No cerebral bleeding or stroke occurred. In conclusion, neurovascular imaging in Loeys Dietz syndrome type III patients revealed abnormalities such as aneurysm, tortuosity, coiling and kinking in the vast majority of patients, but clinical events were rare. Neurovascular screening and follow up is advised in all Loeys Dietz syndrome type III patients.