Sophia Genetics (Switzerland)

e13088 Background: CDK4/6i combined with ET is 1L standard of care treatment for HR+/HER2- for mBC patients, however duration of response varies with some patients experiencing disease progression within 12-months. Limited predictive factors related to ET+CDK4/6i treatment response exist. This pilot aims to assess the feasibility of developing a ML derived risk score for CDK4/6i+ET across 5 different data modalities to inform escalation and de-escalation therapeutic strategies. Methods: A pilot study on a retrospective cohort of 131 patients with mBC from the Memorial Sloan Kettering Cancer Center (MSK) treated with CDK4/6i and ET in the 1L setting was carried out to develop a ML based algorithm for predicting rwPFS at an individual patient level. Baseline multimodal data (including clinical, demographic, histopathological, genomic and radiomic) alongside clinical outcomes were collected. For radiomic analysis, up to 5 lesions were segmented in 3D on baseline PET/CT scans per patient using the SOPHiA DDMTM Radiomics platform. Radiomic features, extracted per IBSI standards, were combined with other data modalities. Baseline tumor genomic analysis was performed using the MSK-IMPACT assay, including genes with an alteration frequency > 5% in the cohort. A filter-based variable selection method was applied prior to training multiple ML algorithms, with the optimization criteria being the Brier score for rwPFS prediction. Due to the limited cohort size, a nested cross-validation approach was employed to ensure robust performance estimation. Results: A Random Forest survival model, combined with k-Nearest Neighbor (k-NN) imputation techniques for handling missing data, achieved an AUC of 0.787 (95% CI, 0.716–0.859) at 12 months for predicting rwPFS. Presence of liver metastases, SUVmax, total tumor volume, CEA, CA 15-3, TP53 mutation and PET uptake heterogeneity were among the top weighted features. These clinically plausible features, combined into a multimodal algorithm, allowed to stratify patients into two risk groups based on their predicted rwPFS with a median rwPFS of 45.2 (95% CI, 27.1-n/a) in low-risk vs 11.3m (95% CI, 9.1-16.1m) in high-risk group (hazard ratio: 4.10, 95% CI, 2.64–6.37). Conclusions: This pilot study demonstrates the feasibility of a ML, multimodal approach to predict rwPFS for patients with HR+/HER2- mBC treated with 1L CDK4/6i + ET. This approach could be implemented in the clinical setting to guide treatment choice and to inform clinical trial design by identifying high-risk individuals. Further training and validation of the model is planned in a larger, multicentric cohort.

Stressed, damaged or very aged skin is predominantly characterized by a malfunctioning skin barrier. Underlying skin barrier malfunction is a reduced or defective calcium gradient in the epidermis. Consequently, replenishing the compromised skin's calcium stores with topical calcium could be a potential therapeutic approach. We investigated the effect of our novel Ca2+ double cone vector system on improving the differentiation and barrier function of reconstructed human epidermis (RHE), cultured at low basal calcium (0.3 mM) to represent very aged skin. Furthermore, in a randomized placebo-controlled clinical study the skin barrier of 20 healthy volunteers was challenged with 2% sodium lauryl sulphate (SLS) for 24 h under occlusion, following and/or prior to treatment with a gel containing 2% of our calcium vector system. Culture in reduced basal calcium conditions (0.3 mM) strongly impeded the formation of a dense stratified epidermis. The apical treatment with 1.1 mM CaCl2 was not able to restore a functional differentiation. Treatment with 0.1% of the Ca2+ delivery system rescued the differentiation process and resulted in a normal stratified epidermis. Clinically, application of the Ca2+ vector system prior to and following SLS stress prevented increases in skin irritation and transepidermal water loss (TEWL) compared to placebo controls. Importantly, the treatment also significantly accelerated the recovery time following SLS stress. With our novel Ca2+ vector system, we highlight the delivery of bioavailable Ca2+ ions into the skin as a new and successful approach to treat a damaged barrier present in stressed, aged or atopic skin.

The ability of next-generation sequencing (NGS) assays to interrogate thousands of genomic loci has revolutionized genetic testing. However, translation to the clinic is impeded by false-negative results that pose a risk to patients. In response, regulatory bodies are calling for reliability measures to be reported alongside NGS results. Existing methods to estimate reliability do not account for sample- and position-specific variability, which can be significant. Here, we report an approach that computes reliability metrics for every genomic position and sample interrogated by an NGS assay. Our approach predicts the limit of detection (LOD), the lowest reliably detectable variant fraction, by taking technical factors into account. We initially explored how LOD is affected by input material amount, library conversion rate, sequencing coverage, and sequencing error rate. This revealed that LOD depends heavily on genomic context and sample properties. Using these insights, we developed a computational approach to predict LOD on the basis of a biophysical model of the NGS workflow. We focused on targeted assays for cell-free DNA, but, in principle, this approach applies to any NGS assay. We validated our approach by showing that it accurately predicts LOD and distinguishes reliable from unreliable results when screening 580 lung cancer samples for actionable mutations. Compared with a standard variant calling workflow, our approach avoided most false negatives and improved interassay concordance from 94% to 99%. Our approach, which we name LAVA (LOD-aware variant analysis), reports the LOD for every position and sample interrogated by an NGS assay. This enables reliable results to be identified and improves the transparency and safety of genetic tests.

IntroductionNon-fatal health loss makes a substantial contribution to the total disease burden among children and adolescents. An analysis of these morbidity patterns is essential to plan interventions that improve the health and well-being of children and adolescents. Our objective was to describe current levels and trends in the non-fatal disease burden from 2000 to 2016 among children and adolescents aged 0–19 years.MethodsWe used years lost due to disability (YLD) estimates in WHO’s Global Health Estimates to describe the non-fatal disease burden from 2000 to 2016 for the age groups 0–27 days, 28 days–11 months, 1–4 years, 5–9 years, 10–14 years and 15–19 years globally and by modified WHO region. To describe causes of YLDs, we used 18 broad cause groups and 54 specific cause categories.ResultsIn 2016, the total number of YLDs globally among those aged 0–19 years was about 130 million, or 51 per 1000 population, ranging from 30 among neonates aged 0–27 days to 67 among older adolescents aged 15–19 years. Global progress since 2000 in reducing the non-fatal disease burden has been limited (53 per 1000 in 2000 for children and adolescents aged 0–19 years). The most important causes of YLDs included iron-deficiency anaemia and skin diseases for both sexes, across age groups and regions. For young children under 5 years of age, congenital anomalies, protein–energy malnutrition and diarrhoeal diseases were important causes of YLDs, while childhood behavioural disorders, asthma, anxiety disorders and depressive disorders were important causes for older children and adolescents. We found important variations between sexes and between regions, particularly among adolescents, that need to be addressed context-specifically.ConclusionThe disappointingly slow progress in reducing the global non-fatal disease burden among children and adolescents contrasts starkly with the major reductions in mortality over the first 17 years of this century. More effective action is needed to reduce the non-fatal disease burden among children and adolescents, with interventions tailored for each age group, sex and world region.

Additive manufacture (AM) technologies allow innovative structural design, including complex lattice structures. Selective laser melting (SLM) is an AM process that enables the manufacture of space filling lattice structures. Lattice structures are topologically ordered, three-dimensional open-celled structures composed of one or more repeating unit cells. From a mechanical designer viewpoint, a great advantage offered by cellular materials is high strength accompanied by a relatively low mass. Due to their complex structure, fine geometry and the absence of supports structures, the setting of the best parameters to print lattice structures is difficult and could negative influence their mechanical response. This study investigated how different parameters settings influence the compression behaviour of lattice structures in stainless steel 17-4PH (AISI-630) printed by SLM. A comparison between compressive response of structures printed with different parameters is presented and considerations about their behaviour exposed.

Congenital myasthenic syndromes (CMSs) are caused by mutations in genes that encode proteins involved in the organization, maintenance, function, or modification of the neuromuscular junction. Among these, the collagenic tail of endplate acetylcholinesterase protein (COLQ; MIM 603033) has a crucial role in anchoring the enzyme into the synaptic basal lamina. Here, we report on the first case of a patient with a homozygous deletion affecting the last exons of the COLQ gene in a CMS patient born to consanguineous parents of Pakistani origin. Electromyography (EMG), electroencephalography (EEG), clinical exome sequencing (CES), and single nucleotide polymorphism (SNP) array analyses were performed. The subject was born at term after an uneventful pregnancy and developed significant hypotonia and dystonia, clinical pseudoseizures, and recurring respiratory insufficiency with a need for mechanical ventilation. CES analysis of the patient revealed a homozygous deletion of the COLQ gene located on the 3p25.1 chromosome region. The SNP-array confirmed the presence of deletion that extended from exon 11 to the last exon 17 with a size of 19.5 Kb. Our results add new insights about the underlying pathogenetic mechanisms expanding the spectrum of causative COLQ mutations. It is relevant, considering the therapeutic implications, to apply suitable molecular approaches so that no type of mutation is missed: “each lost mutation means a baby treated improperly”.