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Abstract The subset of ovarian cancer (OC) diagnosed ≤ 30yo represents a distinct subgroup exhibiting disparities from late-onset OC in many aspects, including indefinite germline cancer predisposition. We performed DNA/RNA-WES with HLA-typing, PRS assessment and survival analysis in 123 early-onset OC-patients compared to histology/stage-matched late-onset and unselected OC-patients, and population-matched controls. Only 6/123(4.9%) early-onset OC-patients carried a germline pathogenic variant (GPV) in high-penetrance OC-predisposition genes. Nevertheless, our comprehensive germline analysis of early-onset OC-patients revealed two divergent trajectories of potential germline susceptibility. Firstly, overrepresentation analysis highlighted a connection to breast cancer (BC) that was supported by the CHEK2 GPV enrichment in early-onset OC(p = 1.2 × 10–4), and the presumably BC-specific PRS313, which successfully stratified early-onset OC-patients from controls(p = 0.03). The second avenue pointed towards the impaired immune response, indicated by LY75-CD302 GPV(p = 8.3 × 10–4) and diminished HLA diversity compared with controls(p = 3 × 10–7). Furthermore, we found a significantly higher overall GPV burden in early-onset OC-patients compared to controls(p = 3.8 × 10–4). The genetic predisposition to early-onset OC appears to be a heterogeneous and complex process that goes beyond the traditional Mendelian monogenic understanding of hereditary cancer predisposition, with a significant role of the immune system. We speculate that rather a cumulative overall GPV burden than specific GPV may potentially increase OC risk, concomitantly with reduced HLA diversity.

The "Cubes and Clouds" Massive Open Online Course (MOOC) addresses the growing challenges and opportunities in Earth Observation (EO) data analysis posed by the exponential growth of satellite missions and data volumes. This course introduces cloud-native EO concepts and open science principles, facilitating collaboration and data sharing within the EO community.Key topics covered in the MOOC include data discovery, processing workflows, and data sharing using real-world examples like snow cover mapping in the Alps. Participants engage with interactive lessons, videos, and hands-on coding exercises, leveraging freely available geospatial data and emphasizing open data principles and interoperability.The course infrastructure seamlessly integrates with cloud platforms like the Copernicus Data Space Ecosystem, enabling learners to apply concepts in a practical, cloud-based environment. Initial user statistics indicate strong interest, particularly among early-career professionals and researchers, with participant surveys suggesting increased confidence in using EO cloud platforms and embracing open science practices upon course completion.Overall, "Cubes and Clouds" serves as a valuable resource for the EO community, fostering transparency, collaboration, and innovation in geospatial science. Future developments aim to expand course content and attract diverse user groups, ensuring broader accessibility and long-term impact in advancing cloud-native EO and open science initiatives.

Abstract Background Monoallelic germline pathogenic variants (GPVs) in five Fanconi anemia (FA) genes (BRCA1/FANCS, BRCA2/FANCD1, PALB2/FANCN, BRIP1/FANCJ, and RAD51C/FANCO) confer an increased risk of breast (BC) and/or ovarian (OC) cancer, but the role of GPVs in 17 other FA genes remains unclear. Methods Here, we investigated the association of germline variants in FANCG/XRCC9 with BC and OC risk. Results The frequency of truncating GPVs in FANCG did not differ between BC (20/10,204; 0.20%) and OC (8/2966; 0.27%) patients compared to controls (6/3250; 0.18%). In addition, only one out of five tumor samples showed loss‐of‐heterozygosity of the wild‐type FANCG allele. Finally, none of the nine functionally tested rare recurrent missense FANCG variants impaired DNA repair activities (FANCD2 monoubiquitination and FANCD2 foci formation) upon DNA damage, in contrast to all tested FANCG truncations. Conclusion Our study suggests that heterozygous germline FANCG variants are unlikely to contribute to the development of BC or OC.

Introduction Epilepsy surgery is the only curative treatment for patients with drug-resistant focal epilepsy. Stereoelectroencephalography (SEEG) is the gold standard to delineate the seizure-onset zone (SOZ). However, up to 40% of patients are subsequently not operated as no focal non-eloquent SOZ can be identified. The 5-SENSE Score is a 5-point score to predict whether a focal SOZ is likely to be identified by SEEG. This study aims to validate the 5-SENSE Score, improve score performance by incorporating auxiliary diagnostic methods and evaluate its concordance with expert decisions.Methods and analysis Non-interventional, observational, multicentre, prospective study including 200 patients with drug-resistant epilepsy aged ≥15 years undergoing SEEG for identification of a focal SOZ and 200 controls at 22 epilepsy surgery centres worldwide. The primary objective is to assess the diagnostic accuracy and generalisability of the 5-SENSE in predicting focality in SEEG in a prospective cohort. Secondary objectives are to optimise score performance by incorporating auxiliary diagnostic methods and to analyse concordance of the 5-SENSE Score with the expert decisions made in the multidisciplinary team discussion.Ethics and dissemination Prospective multicentre validation of the 5-SENSE score may lead to its implementation into clinical practice to assist clinicians in the difficult decision of whether to proceed with implantation. This study will be conducted in accordance with the Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans (2014). We plan to publish the study results in a peer-reviewed full-length original article and present its findings at scientific conferences.Trial registration number NCT06138808.

Germline CHEK2 pathogenic variants confer an increased risk of female breast cancer (FBC). Here we describe a recurrent germline intronic variant c.1009-118_1009-87delinsC, which showed a splice acceptor shift in RNA analysis, introducing a premature stop codon (p.Tyr337PhefsTer37).The variant was found in 21/10,204 (0.21%) Czech FBC patients compared to 1/3250 (0.03%) controls (p = 0.04) and in 4/3639 (0.11%) FBC patients from an independent German dataset. In addition, we found this variant in 5/2966 (0.17%) Czech (but none of the 443 German) ovarian cancer patients, three of whom developed early-onset tumors.Based on these observations, we classified this variant as likely pathogenic.

Insulinomas are rare gastrointestinal tumors with an incidence of 1–3 per million inhabitants annually. These tumors result in excessive insulin production, culminating in hypoglycemia. Such hypoglycemia triggers various central nervous system (CNS) manifestations, including headache, confusion, abnormal behavior, and epileptic seizures, which can lead to misdiagnosis as epilepsy. This case report documents a 46-year-old male who presented seizure-like episodes. Episodes occurred mainly during the night, lasting several minutes to hours. Initial seizures were characterized by bizarre behavior and altered responsiveness. Over time, seizure frequency, complexity, and severity escalated. We managed to record two episodes during long-term EEG and report, as the first ones, the detailed quantitative EEG analysis of these hypoglycemia-related events. EEG changes preceded the development of clear-cut pathological motor activity in tens of minutes and were present in all investigated frequency bands. The development of profound motor activity was associated with other increases in EEG power spectra in all frequencies except for delta. The most pronounced changes were found over the left temporal region, which can be the most susceptible to hypoglycemia. In our patient, the seizure-like episodes completely disappeared after the insulinoma removal, which demonstrates their relationship to hypoglycemia.

Abstract Vagus nerve stimulation (VNS) is a therapeutic option in drug-resistant epilepsy. VNS leads to ≥ 50% seizure reduction in 50 to 60% of patients, termed "responders". The remaining 40 to 50% of patients, "non-responders", exhibit seizure reduction

Abstract Early detection of highly infectious respiratory diseases, such as COVID-19, can help curb their transmission. Consequently, there is demand for easy-to-use population-based screening tools, such as mobile health applications. Here, we describe a proof-of-concept development of a machine learning classifier for the prediction of a symptomatic respiratory disease, such as COVID-19, using smartphone-collected vital sign measurements. The Fenland App study followed 2199 UK participants that provided measurements of blood oxygen saturation, body temperature, and resting heart rate. Total of 77 positive and 6339 negative SARS-CoV-2 PCR tests were recorded. An optimal classifier to identify these positive cases was selected using an automated hyperparameter optimisation. The optimised model achieved an ROC AUC of 0.695 ± 0.045. The data collection window for determining each participant’s vital sign baseline was increased from 4 to 8 or 12 weeks with no significant difference in model performance (F(2) = 0.80, p = 0.472). We demonstrate that 4 weeks of intermittently collected vital sign measurements could be used to predict SARS-CoV-2 PCR positivity, with applicability to other diseases causing similar vital sign changes. This is the first example of an accessible, smartphone-based remote monitoring tool deployable in a public health setting to screen for potential infections.

Objectives To develop and validate the cut-offs in the Juvenile DermatoMyositis Activity Index (JDMAI) to distinguish the states of inactive disease (ID), low disease activity (LDA), moderate disease activity (MDA) and high disease activity (HDA) in children with juvenile dermatomyositis (JDM).Methods For cut-off definition, data from 139 patients included in a randomised clinical trial were used. Among the six versions of the JDMAI, JDMA1 (score range 0–40) and JDMAI2 (score range 0–39) were selected. Optimal cut-offs were determined against external criteria by calculating different percentiles of score distribution and through receiver operating characteristic curve analysis. External criteria included the modified Pediatric Rheumatology International Trials Organization (PRINTO) criteria for clinically ID in JDM (for ID) and PRINTO levels of improvement in the clinical trial (for LDA and HDA). MDA cut-offs were set at the score interval between LDA and HDA cut-offs. Cut-off validation was conducted by assessing construct and discriminative ability in two cohorts including a total of 488 JDM patients.Results The calculated JDMAI1 cut-offs were ≤2.4 for ID, ≤6.6 for LDA, 6.7–11 for MDA and >11 for HDA. The calculated JDMAI2 cut-offs were ≤5.2 for ID, ≤8.5 for LDA, 8.6–11.3 for MDA and >11.3 for HDA. The cut-offs discriminated strongly among disease activity states defined subjectively by caring physicians and parents, parents’ satisfaction or non-satisfaction with illness outcome, levels of pain, fatigue, physical functional impairment and physical well-being.Conclusions Both JDMAI1 and JDMAI2 cut-offs revealed good metrologic properties in validation analyses and are, therefore, suited for application in clinical practice and research.

The magnitude of innate inflammatory immune responses is dependent on interactions between peripheral neural and immune cells. In particular, a cholinergic anti-inflammatory pathway (CAP) has been identified in the spleen whereby noradrenaline (NA) released by splenic nerves binds to ß2-adrenergic receptors (β2-AR) on CD4+ T cells which, in turn, release acetylcholine (ACh). The binding of ACh to α7 acetylcholine receptors (α7-AChR) expressed by splenic macrophages inhibits the production of inflammatory cytokines, including tumor necrosis factor (TNF). However, the role of ACh-secreting CD4+ T-cells in the CAP is still controversial and largely based on the absence of this anti-inflammatory pathway in mice lacking T-cells (nude, FoxN1−/−). Using four conscious, non-lymphopenic transgenic mouse models, we found that, rather than acting on CD4+ T-cells, NA released by splenic nerve terminals acts directly onto β2-AR on splenic myeloid cells to exert this anti-inflammatory effect. We also show that, while larger doses of LPS are needed to trigger CAP in nude mouse strain compared to other strains, TNF production can be inhibited in these animals lacking CD4+ T-cell by stimulating either the vagus or the splenic nerve. We demonstrate that CD4+ T-cells are dispensable for the CAP after antibody-mediated CD4+ T-cell depletion in wild type mice. Furthermore, we found that NA-mediated inhibition of in vitro LPS-induced TNF secretion by human or porcine splenocytes does not require α7-AChR signaling. Altogether our data demonstrate that activation of the CAP by stimulation of vagus or splenic nerves in mice is mainly mediated by direct binding of NA to β2-AR on splenic macrophages, and suggest that the same mechanism is at play in larger species.

Objectives: To assess the impact of COVID-19 illness and pandemic era on sleep, general health, health care, and social status in patients with epilepsy in the Czech Republic. Methods: Our designed and approved questionnaire consisted of 23 questions. We focused on (1) patients' demographic and epidemiological data regarding COVID-19, (2) subjective assessment of sleep; (3) epilepsy, and (4) perception of general health during the first year of the COVID-19 pandemic in the Czech Republic from March 2020 to May 2021. We administered the questionnaires during outpatient visits or by phone calls in three major university Czech epilepsy centers (Ostrava, Brno, Pilsen). Results: We enrolled 227 (100%) patients. The mean age (±SD) was 41.2 ± 14.82 years (min 18, max 86 years), and 138 (61%) were women. COVID-19 was confirmed using the PCR test method in 57 (25.1%) patients. In the pre-pandemic era, 62 (27.3%) patients reported sleep disturbances. Insomnia in 46 (74.2%) and excessive daytime sleepiness in 6 (9.7%) were the most mentioned sleep abnormalities. Nocturnal seizures predispose to sleep impairment (p = 0.014) and vivid dreams and nightmares (p = 0.033). COVID-19 infection significantly increased the risk of vivid dreams and nightmares in patients with diurnal seizures (p = 0.006). Sleep quality impairment and seizure frequency worsening [(p

Objectives: This study aimed to analyze the relationships among exclusion from PE, gender, and bullying in adolescents with specific developmental disorder of scholastic skills (SDDSS) aged 11, 13, and 15 years in Czechia.Methods: In total, the final research sample consisted of 13,953 students (49.4% boys) from the 2013/2014 Health Behaviour in School-aged Children survey. Chi-square tests and regression models stratified by presence of SDDSS diagnosis were used to assess the relationships between non-involvement in PA and bullying.Results: Students diagnosed with SDDSS (12.4% of the sample) were more likely to be excluded from physical education (PE) than students without this diagnosis. This exclusion was associated with higher odds of bullying victimization and perpetration. Our findings further showed that male gender plays a significant role for bullying perpetration for both groups (with and without SDDSS) investigated in the present study.Conclusion: Higher likelihood of aggressive behavior occurs in students who are excluded from PE, including students with SDDSS.

A nuclear accident (e.g., Fukushima), and, in particular, the transport of animals within a radiation-affected area can lead to a whole-body, or partial external irradiation, followed by oxidative stress, which could result in subsequent meat quality changes. In this experiment, live pigs were exposed to half-body irradiation by an external dose of 1.0 Gy. The caudal half of the animal's body was irradiated. After their slaughter, samples from the muscle tissue of musculus semimembranosus and musculus longissimus lumborum et thoracis at the upper margin of musculus gluteus medius (irradiated body half) and at the 3rd-4th thoracic vertebra (non-irradiated half) were collected to determine the meat quality parameters. A significant difference (P < 0.05) was observed only in the meat colour parameter (a*) in the irradiated group of pigs. If there is no internal contamination, and the half-body exposure to the external radiation dose does not exceed 1 Gy, pigs from an irradiation-affected area may be used for human consumption.

Background and Aims: COVID-19 has infected more than 77 million people worldwide and impacted the lives of many more, with a particularly devastating impact on vulnerable populations, including people with substance use disorders (SUDs). Quarantines, travel bans, regulatory changes, social distancing, and “lockdown” measures have affected drug and alcohol supply chains and subsequently their availability, price, and use patterns, with possible downstream effects on presentations of SUDs and demand for treatment. Given the lack of multicentric epidemiologic studies, we conducted a rapid global survey within the International Society of Addiction Medicine (ISAM) network in order to understand the status of substance-use patterns during the current pandemic.Design: Cross-sectional survey.Setting: Worldwide.Participants: Starting on April 4, 2020 during a 5-week period, the survey received 185 responses from 77 countries.Measurements: To assess addiction medicine professionals' perceived changes in drug and alcohol supply, price, use pattern, and related complications during the COVID-19 pandemic.Findings: Participants reported (among who answered “decreased” or “increased”) a decrease in drug supply (69.0%) and at the same time an increase in price (95.3%) globally. With respect to changes in use patterns, an increase in alcohol (71.7%), cannabis (63.0%), prescription opioids (70.9%), and sedative/hypnotics (84.6%) use was reported, while the use of amphetamines (59.7%), cocaine (67.5%), and opiates (58.2%) was reported to decrease overall.Conclusions: The global report on changes in the availability, use patterns, and complications of alcohol and drugs during the COVID-19 pandemic should be considered in making new policies and in developing mitigating measures and guidelines during the current pandemic (and probable future ones) in order to minimize risks to people with SUD.

The burden of depression and anxiety in the world is rising. Identification of individuals at increased risk of developing these conditions would help to target them for prevention and ultimately reduce the healthcare burden. We developed a 10-year predictive algorithm for depression and anxiety using the full cohort of over 400,000 UK Biobank (UKB) participants without pre-existing depression or anxiety using digitally obtainable information. From the initial 167 variables selected from UKB, processed into 429 features, iterative backward elimination using Cox proportional hazards model was performed to select predictors which account for the majority of its predictive capability. Baseline and reduced models were then trained for depression and anxiety using both Cox and DeepSurv, a deep neural network approach to survival analysis. The baseline Cox model achieved concordance of 0.7772 and 0.7720 on the validation dataset for depression and anxiety, respectively. For the DeepSurv model, respective concordance indices were 0.7810 and 0.7728. After feature selection, the depression model contained 39 predictors and the concordance index was 0.7769 for Cox and 0.7772 for DeepSurv. The reduced anxiety model, with 53 predictors, achieved concordance of 0.7699 for Cox and 0.7710 for DeepSurv. The final models showed good discrimination and calibration in the test datasets. We developed predictive risk scores with high discrimination for depression and anxiety using the UKB cohort, incorporating predictors which are easily obtainable via smartphone. If deployed in a digital solution, it would allow individuals to track their risk, as well as provide some pointers to how to decrease it through lifestyle changes.

Background: The coronavirus disease 2019 (COVID-19) pandemic has impacted people with substance use disorders (SUDs) worldwide, and healthcare systems have reorganized their services in response to the pandemic.Methods: One week after the announcement of the COVID-19 as a pandemic, in a global survey, 177 addiction medicine professionals described COVID-19-related health responses in their own 77 countries in terms of SUD treatment and harm reduction services. The health responses were categorized around (1) managerial measures and systems, (2) logistics, (3) service providers, and (4) vulnerable groups.Results: Respondents from over 88% of countries reported that core medical and psychiatric care for SUDs had continued; however, only 56% of countries reported having had any business continuity plan, and 37.5% of countries reported shortages of methadone or buprenorphine supplies. Participants of 41% of countries reported partial discontinuation of harm-reduction services such as needle and syringe programs and condom distribution. Fifty-seven percent of overdose prevention interventions and 81% of outreach services were also negatively impacted.Conclusions: Participants reported that SUD treatment and harm-reduction services had been significantly impacted globally early during the COVID-19 pandemic. Based on our findings, we highlight several issues and complications resulting from the pandemic concerning people with SUDs that should be tackled more efficiently during the future waves or similar pandemics. The issues and potential strategies comprise the following: (1) helping policymakers to generate business continuity plans, (2) maintaining the use of evidence-based interventions for people with SUDs, (3) being prepared for adequate medication supplies, (4) integrating harm reduction programs with other treatment modalities, and (5) having specific considerations for vulnerable groups such as immigrants and refugees.

Neuromodulation of the immune system has been proposed as a novel therapeutic strategy for the treatment of inflammatory conditions. We recently demonstrated that stimulation of near-organ autonomic nerves to the spleen can be harnessed to modulate the inflammatory response in an anesthetized pig model. The development of neuromodulation therapy for the clinic requires chronic efficacy and safety testing in a large animal model. This manuscript describes the effects of longitudinal conscious splenic nerve neuromodulation in chronically-implanted pigs. Firstly, clinically-relevant stimulation parameters were refined to efficiently activate the splenic nerve while reducing changes in cardiovascular parameters. Subsequently, pigs were implanted with a circumferential cuff electrode around the splenic neurovascular bundle connected to an implantable pulse generator, using a minimally-invasive laparoscopic procedure. Tolerability of stimulation was demonstrated in freely-behaving pigs using the refined stimulation parameters. Longitudinal stimulation significantly reduced circulating tumor necrosis factor alpha levels induced by systemic endotoxemia. This effect was accompanied by reduced peripheral monocytopenia as well as a lower systemic accumulation of CD16+CD14high pro-inflammatory monocytes. Further, lipid mediator profiling analysis demonstrated an increased concentration of specialized pro-resolving mediators in peripheral plasma of stimulated animals, with a concomitant reduction of pro-inflammatory eicosanoids including prostaglandins. Terminal electrophysiological and physiological measurements and histopathological assessment demonstrated integrity of the splenic nerves up to 70 days post implantation. These chronic translational experiments demonstrate that daily splenic nerve neuromodulation, via implanted electronics and clinically-relevant stimulation parameters, is well tolerated and is able to prime the immune system toward a less inflammatory, pro-resolving phenotype.