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Abstract Ocean ecosystems have been subjected to anthropogenic influences for centuries, but the scale of past ecosystem changes is often unknown. For centuries, the European flat oyster (Ostrea edulis), an ecosystem engineer providing biogenic reef habitats, was a culturally and economically significant source of food and trade. These reef habitats are now functionally extinct, and almost no memory of where or at what scales this ecosystem once existed, or its past form, remains. The described datasets present qualitative and quantitative extracts from written records published between 1524 and 2022. These show: (1) locations of past flat oyster fisheries and/or oyster reef habitat described across its biogeographical range, with associated levels of confidence; (2) reported extent of past oyster reef habitats, and; (3) species associated with these habitats. These datasets will be of use to inform accelerating flat oyster restoration activities, to establish reference models for anchoring adaptive management of restoration action, and in contributing to global efforts to recover records on the hidden history of anthropogenic-driven ocean ecosystem degradation.

Abstract Background The presence and burden of coronary artery calcium (CAC) is a strong predictor of cardiovascular events. Current guidelines of the European Society of Cardiology (ESC) for cardio-oncology do not recommend the use of the CAC score to determine the status of risk in cancer patients. The aim of this study is to evaluate the presence and burden of CAC on cardiac tomography and the distribution of the cardiovascular toxicity risk factors in patients with moderate and high baseline risk of cancer therapy-related cardiovascular toxicity. Methods The study prospectively included cancer patients, diagnosed and qualified for systemic treatment with anthracycline chemotherapy. Clinical data and blood samples were collected from all patients. Additionally, the echocardiography and coronary computed tomography (CCTA) with the calculation of the coronary artery calcium (CAC) score were performed. Results A total of 80 patients (mean age 60.5 years, 75 female) were included in the study. The majority of patients (62, 77.5%) had breast cancer, 11 (13.8%) were diagnosed with sarcoma, and 7 (8.8%) with lymphoma. There were 42 (52.5%) patients classified as having moderate (MR) and 38 (47.5%) as having high risk (HR) of cancer therapy-related cardiovascular toxicity according to current ESC guidelines. In comparison with moderate risk, high risk patients were older and more likely to have hypertension, hyperlipidaemia and chronic kidney disease. The mean coronary artery calcium score was significantly higher in the HR group (150.4 vs. 24.8; p = 0.000). Furthermore, cardiac biomarkers were also higher in high-risk patients (p = 0.000). In echocardiographic parameters global longitudinal strain (GLS) was lower (p = 0.012), and diastolic dysfunction was more common in the HR group. However, the left ventricle ejection fraction (LVEF) was similar in the MR and HR groups. Conclusions In patients at high and moderate risk for cancer therapy-related cardiovascular toxicity, cardiovascular toxicity risk factors were common and more prevalent in the high-risk group. The coronary artery calcium score was also significantly higher in the high-risk group. Assessing the presence and burden of coronary artery calcium is an attractive option to assess additional cardiovascular risk in cancer patients.

Liquid biopsy (LBx) provides diagnostic, prognostic and predictive insights for malignant diseases and offers promising applications regarding tumor burden, tumor heterogeneity and clonal evolution.

Sessile intertidal organisms live in a harsh environment with challenging environmental conditions and increasing anthropogenic pressure such as microplastic (MP) pollution. This study focused on effects of environmentally relevant MP concentrations on the metabolism of intertidal Pacific oyster Crassostrea gigas, and its potential MP-induced vulnerability to warming during midday low tide. Oysters experienced a simulated semidiurnal tidal cycle based on their natural habitat, and were exposed to a mixture of polystyrene microbeads (4, 7.5 and 10 µm) at two environmentally relevant concentrations (0.025 µg L−1 and 25 µg L−1) for 16 days, with tissue samplings after 3 and 12 days to address dose-dependent effects over time. On the last day of exposure, the remaining oysters were additionally exposed to low tide warming (3 °C h−1) to investigate possible MP-induced susceptibility to aerial warming. Metabolites of digestive gland and gill tissues were analysed by using untargeted 1H nuclear magnetic resonance (NMR) based metabolomics. For the digestive gland metabolite profiles were comparable to each other independent of MP concentration, exposure time, or warming. In contrast, gill metabolites were significantly affected by high MP exposure and warming irrespective of MP, initiating the same cellular stress response to counteract induced oxidative stress. The activated cascade of antioxidant defence mechanisms required energy on top of the general energy turnover to keep up homeostasis, which in turn may lead to subtle, and likely sub-lethal, effects within intertidal oyster populations. Present results underline the importance of examining the effects of environmentally relevant MP concentrations not only alone but in combination with other environmental stressors.

BackgroundA dietary supplementation with conjugated linoleic acid (CLA) was shown to attenuate inflammation and increase the proportions of circulating regulatory T cells (Tregs) and M2-type macrophages in disease models such as autoimmune encephalitis and arteriosclerosis. Since Tregs and anti-inflammatory (M2-type) macrophages were found to enhance stroke recovery, we hypothesized that CLA-supplementation might improve stroke recovery via immune modulatory effects.MethodsFunctional assessment was performed over 90 days after induction of experimental photothrombotic stroke in wild type mice (n = 37, sham n = 10). Subsequently, immunological characterization of different immunological compartments (n = 16), ex vivo magnetic resonance (MR, n = 12) imaging and immunohistochemical staining (n = 8) was performed. Additionally, we tested the effect of CLA in vitro on peripheral blood mononuclear cells from human stroke patients and healthy controls (n = 12).ResultsMR diffusion tensor imaging (DTI) demonstrated enhanced microstructural reorganization of interhemispheric white matter tracts, dependent on lesion size. Functional recovery over 90 days remained unaffected. Detailed immunological analyses across various compartments revealed no significant long-term immunological alterations due to CLA. However, analyses of human blood samples post-stroke showed reduced levels of pro-inflammatory interferon-γ (IFN-γ) and tumor necrosis factor alpha (TNF-α) release by T-lymphocytes following in vitro treatment with CLA.ConclusionWe aimed to explore the efficacy of a dietary intervention with minimal known side effects that could be accessible to human stroke patients, regardless of the degree of disability, and without the risks associated with aggressive immunomodulatory therapies. Our main findings include improved microstructural reorganization in small infarcts and a reduced inflammatory response of human T cells in vitro.

Introduction Physical activity is an inseparable element of people’s lives. It reduces risk of cardiovascular diseases, hypertension, helps maintain physical well-being as well as mental health. Exercise is especially crucial in adults aged over 65 as this population leads a more sedentary lifestyle. Objective This article aims to evaluate the impact of exercise on mental health in elderly population. Methods A Literature review of articles published in Pubmed between 2000 and 2024 using the following words “physical activity”, “exercise”, “mental health”, “elderly population”. Results Physical activity has an impact on physical as well as mental health. In elderly population it especially influences the latter. Recent studies have shown that it can reduce a risk of dementia, enhance cognitive performance and improve social life by creating a stronger community and social network. Conclusion Physical activity is one of the crucial elements of overall well-being. It is particularly important in elderly population in maintaining mental health. It enhances cognition, reduces risk of dementia and improves social life.

Introduction: In the last few years, with over 422 million cases of diabetes worldwide and with an overload of healthcare, the development of new glucose monitoring approaches has become a crucial subject. This paper set out to explore the effectiveness of current glucose monitoring methods, their usage in the context of physical activity, and prospects for the future. Review methods: We conducted our study as a literature review, with data being gathered via PubMed and Embase. The state of knowledge: Currently, the two most popular methods of glucose monitoring are self-monitoring (SMBG) and continuous glucose monitoring (CGM) with real-time devices such as Dexcom G6, and Medtronic Guardian Connect System, and intermittent devices such as Freestyle Libre 2. Both approaches are invasive and can cause allergic reactions and dermatitis. As a result, many researchers propose non-invasive methods including optical coherence tomography, spectroscopy, and fluorescence. The growing accessibility leads to the usage of CGM devices in everyday life not only by patients with diabetes melitus. Conclusions: Advancements in diabetes technologies allow patients to maintain glucose homeostasis and improve their Quality of life. CGM devices are constantly being developed to be more accessible and easy to use, which may help adjust the training programs and diets for individual needs.

Physical activity is an effective therapy for preventing and treating cardiovascular diseases. However, studies show a curvilinear relationship between exercise and survival, with diminishing returns beyond optimal fitness levels. Extreme athletic training can harm some individuals, as long-term training in professional athletes can lead to Athlete's Heart Syndrome (AHS), characterized by structural heart changes and altered cardiac conduction due to high-intensity exercise. Intense exertion also increases the risk of sudden cardiac death by exacerbating underlying cardiac conditions. A step-by-step multimodality approach, starting with personal and family history, clinical evaluation, and 12-lead ECG, followed by further investigations like exercise testing, echocardiography, 24-hour ECG Holter monitoring, cardiac MRI, CT, nuclear scintigraphy, or genetic testing, is essential for differentiating between extreme physiological adaptations and cardiac pathology. In this process, cardiovascular imaging is crucial for identifying structural abnormalities in athletes within the grey zone between normal adaptations and early cardiovascular disease.

BackgroundThe “translational roadblock” between successful animal stroke studies and neutral clinical trials is usually attributed to conceptual weaknesses. However, we hypothesized that rodent studies cannot inform the human disease due to intrinsic pathophysiological differences between rodents and humans., i.e., differences in infarct evolution.MethodsTo verify our hypothesis, we employed a mixed study design and compared findings from meta-analyses of animal studies and a retrospective clinical cohort study. For animal data, we systematically searched pubmed to identify all rodent studies, in which stroke was induced by MCAO and at least two sequential MRI scans were performed for infarct volume assessment within the first two days. For clinical data, we included 107 consecutive stroke patients with large artery occlusion, who received MRI scans upon admission and one or two days later.ResultsOur preclinical meta-analyses included 50 studies with 676 animals. Untreated animals had a median post-reperfusion infarct volume growth of 74%. Neuroprotective treatments reduced this infarct volume growth to 23%. A retrospective clinical cohort study showed that stroke patients had a median infarct volume growth of only 2% after successful recanalization. Stroke patients with unsuccessful recanalization, by contrast, experienced a meaningful median infarct growth of 148%.ConclusionOur study shows that rodents have a significant post-reperfusion infarct growth, and that this post-reperfusion infarct growth is the target of neuroprotective treatments. Stroke patients with successful recanalization do not have such infarct growth and thus have no target for neuroprotection.

Abstract Aims To distinguish between the genuine cellular impact of the ischemic cascade by leukocytes and unspecific effects of edema and humoral components, two knock‐in mouse lines were utilized. Mouse lines Y731F and Y685F possess point mutations in VE‐cadherin, which lead to a selective inhibition of transendothelial leukocyte migration or impaired vascular permeability. Methods Ischemic stroke was induced by a model of middle cerebral artery occlusion. Analysis contained structural outcomes (infarct volume and extent of brain edema), functional outcomes (survival analysis, rotarod test, and neuroscore), and the extent and spatial distribution of leukocyte migration (heatmaps and fluorescence‐activated cell sorting (FACS) analysis). Results Inhibition of transendothelial leukocyte migration as in Y731F mice leads to smaller infarct volumes (52.33 ± 4719 vs. 70.43 ± 6483 mm3, p = .0252) and improved motor skills (rotarod test: 85.52 ± 13.24 s vs. 43.06 ± 15.32 s, p = .0285). An impaired vascular permeability as in Y685F mice showed no effect on structural or functional outcomes. Both VE‐cadherin mutations did not influence the total immune cell count or spatial distribution in ischemic brain parenchyma. Conclusion Selective inhibition of transendothelial leukocyte migration by VE‐cadherin mutation after ischemic stroke in a mouse model leads to smaller infarct volumes and improved motor skills.

Although CSF analysis routinely enables the diagnosis of neurological diseases, it is mainly used for the gross distinction between infectious, autoimmune inflammatory, and degenerative disorders of the CNS. To investigate, whether a multi-dimensional cellular blood and CSF characterization can support the diagnosis of clinically similar neurological diseases, we analysed 546 patients with autoimmune neuroinflammatory, degenerative, or vascular conditions in a cross-sectional retrospective study. By combining feature selection with dimensionality reduction and machine learning approaches we identified pan-disease parameters that were altered across all autoimmune neuroinflammatory CNS diseases and differentiated them from other neurological conditions and inter-autoimmunity classifiers that subdifferentiate variants of CNS-directed autoimmunity. Pan-disease as well as diseases-specific changes formed a continuum, reflecting clinical disease evolution. A validation cohort of 231 independent patients confirmed that combining multiple parameters into composite scores can assist the classification of neurological patients. Overall, we showed that the integrated analysis of blood and CSF parameters improves the differential diagnosis of neurological diseases, thereby facilitating early treatment decisions.

AimsCardiomyopathy in Fabry disease (FD) is a major determinant of morbidity and mortality. This study investigates the effects of FD-specific treatment using enzyme replacement therapy (ERT) and chaperone therapy on left atrial (LA) function using two-dimensional speckle tracking echocardiography (2DSTE).Methods and resultsIn this prospective observational single-center study, 20 FD patients [10 (50%) females] treated with migalastat, 48 FD patients [24 (50%) females] treated with ERT (agalsidase-alfa and agalsidase-beta), and 30 untreated FD patients (all females) as controls were analyzed. The mean follow-up time ranged from 26 to 81 months. 2DSTE was performed for left ventricle strain, right ventricle strain, and LA strain (LAS). FD-specific treated patients presented with increased left ventricular mass index (LVMi) and higher frequency of left ventricular hypertrophy at baseline, whereas untreated control patients showed normal baseline values. FD-specific treated (including migalastat and ERT) patients showed stabilization of LAS over time (p > 0.05). LVMi was also stable in treated FD patients during observation (p > 0.05).ConclusionIn patients with FD, treated with either ERT or chaperone therapy, LAS values measured by echocardiographic speckle tracking were stable over time, pointing toward disease stabilization.

Abstract Background Breast cancer (BC) is the most common cancer type in women. The purpose of this study was to assess the eligibility criteria in recent clinical trials in BC, especially those that can limit the enrollment of older patients as well as those with comorbidities and poor performance status. Methods Data on clinical trials in BC were extracted from ClinicalTrials.gov. Co-primary outcomes were proportions of trials with different types of the eligibility criteria. Associations between trial characteristics and the presence of certain types of these criteria (binary variable) were determined with univariate and multivariate logistic regression. Results Our analysis included 522 trials of systemic anticancer treatments started between 2020 and 2022. Upper age limits, strict exclusion criteria pertaining to comorbidities, and those referring to inadequate performance status of the patient were used in 204 (39%), 404 (77%), and 360 (69%) trials, respectively. Overall, 493 trials (94%) had at least one of these criteria. The odds of the presence of each type of the exclusion criteria were significantly associated with investigational site location and trial phase. We also showed that the odds of the upper age limits and the exclusion criteria involving the performance status were significantly higher in the cohort of recent trials compared with cohort of 309 trials started between 2010 and 2012 (39% vs 19% and 69% vs 46%, respectively; p 0.05). Only three of recent trials (1%) enrolled solely patients aged 65 or 70 and older. Conclusions Many recent clinical trials in BC exclude large groups of patients, especially older adults, individuals with different comorbidities, and those with poor performance status. Careful modification of some of the eligibility criteria in these trials should be considered to allow investigators to assess the benefits and harms of investigational treatments in participants with characteristics typically encountered in clinical practice.

BackgroundBehavioral dyscontrol occurs commonly in the general population and in United States service members and Veterans (SM/V). This condition merits special attention in SM/V, particularly in the aftermath of deployments. Military deployments frequently give rise to posttraumatic stress disorder (PTSD) and deployment-related mild TBI traumatic brain injury (TBI), potentially leading to manifestations of behavioral dyscontrol.ObjectiveExamine associations among PTSD symptom severity, deployment-related mild traumatic brain injury, and behavioral dyscontrol among SM/V.DesignSecondary cross-sectional data analysis from the Long-Term Impact of Military-Relevant Brain Injury Consortium – Chronic Effects of Neurotrauma Consortium prospective longitudinal study among SM/V (N = 1,808).MethodsUnivariable and multivariable linear regression models assessed the association and interaction effects between PTSD symptom severity, as assessed by the PTSD Checklist for the Diagnostic and Statistical Manual, 5th edition (PCL-5), and deployment-related mild TBI on behavioral dyscontrol, adjusting for demographics, pain, social support, resilience, and general self-efficacy.ResultsAmong the 1,808 individuals in our sample, PTSD symptom severity (B = 0.23, 95% CI: 0.22, 0.25, p 22.96.ConclusionResults indicated an association between PTSD symptom severity, deployment-related mild TBI, and behavioral dyscontrol among SM/V. Notably, the effect of deployment-related mild TBI was pronounced for individuals with lower PTSD symptom severity. Higher social support scores were associated with lower dyscontrol, emphasizing the potential for social support to be a protective factor. General self-efficacy was also associated with reduced behavioral dyscontrol.

BackgroundWhile emerging evidence supports a link between traumatic brain injury (TBI) and progressive cognitive dysfunction in Veterans, there is insufficient information on the impact of cannabis use disorder (CUD) on long-term cognitive disorders. This study aimed to examine the incidences of cognitive disorders in Veterans with TBI and CUD and to evaluate their relationship.MethodsThis retrospective cohort study used the US Department of Veterans Affairs and Department of Defense administrative data from the Long-term Impact of Military-Relevant Brain Injury Consortium-Chronic Effects of Neurotrauma Consortium Phenotype study. Diagnoses suggesting cognitive disorders after a TBI index date were identified using inpatient and outpatient data from 2003 to 2022. We compared the differential cognitive disorders incidence in Veterans who had the following: (1) no CUD or TBI (control group), (2) CUD only, (3) TBI only, and (4) comorbid CUD+TBI. Kaplan-Meier analyses were used to estimate the overall cognitive disorders incidence in the above study groups. The crude and adjusted Cox proportional hazards models were used to estimate crude and adjusted hazard ratios (HRs) for cognitive disorders.ResultsA total of 1,560,556 Veterans [82.32% male, median (IQR) age at the time of TBI, 34.51 (11.29) years, and 61.35% white] were evaluated. The cognitive disorder incidence rates were estimated as 0.68 (95% CI, 0.62, 0.75) for CUD only and 1.03 (95% CI, 1.00, 1.06) for TBI only per 10,000 person-months of observations, with the highest estimated cognitive disorder incidence observed in participants with both TBI and CUD [1.83 (95% CI, 1.72, 1.95)]. Relative to the control group, the highest hazard of cognitive disorders was observed in Veterans with CUD+TBI [hazard ratio (HR), 3.26; 95% CI, 2.91, 3.65], followed by those with TBI only (2.32; 95 CI%, 2.13, 2.53) and with CUD (1.79; 95 CI%, 1.60, 2.00). Of note, in the CUD only subgroup, we also observed the highest risk of an early onset cognitive disorder other than Alzheimer's disease and Frontotemporal dementia.DiscussionThe results of this analysis suggest that individuals with comorbid TBI and CUD may be at increased risk for early onset cognitive disorders, including dementia.

BackgroundStudies have demonstrated that individuals diagnosed with traumatic brain injury (TBI) frequently use medical and recreational cannabis to treat persistent symptoms of TBI, such as chronic pain and sleep disturbances, which can lead to cannabis use disorder (CUD). We aimed to determine the Veterans Health Administration (VHA) healthcare utilization and costs associated with CUD and dementia diagnosis in veterans with TBI.MethodsThis observational study used administrative datasets from the population of post-9/11 veterans from the Long-term Impact of Military-Relevant Brain Injury Consortium-Chronic Effects of Neurotrauma Consortium and the VA Data Warehouse. We compared the differential VHA costs among the following cohorts of veterans: (1) No dementia diagnosis and No CUD group, (2) Dementia diagnosis only (Dementia only), (3) CUD only, and (4) comorbid dementia diagnosis and CUD (Dementia and CUD). Generalized estimating equations and negative binomial regression models were used to estimate total annual costs (inflation-adjusted) and the incidence rate of healthcare utilization, respectively, by dementia diagnosis and CUD status.ResultsData from 387,770 veterans with TBI (88.4% men; median [interquartile range (IQR)] age at the time of TBI: 30 [14] years; 63.5% white) were followed from 2000 to 2020. Overall, we observed a trend of gradually increasing healthcare costs 5 years after TBI onset. Interestingly, in this cohort of veterans within 5 years of TBI, we observed substantial healthcare costs in the Dementia only group (peak = $46,808) that were not observed in the CUD and dementia group. Relative to those without either condition, the annual total VHA costs were $3,368 higher in the CUD only group, while no significant differences were observed in the Dementia only and Dementia and CUD groups.DiscussionThe findings suggest that those in the Dementia only group might be getting their healthcare needs met more quickly and within 5 years of TBI diagnosis, whereas veterans in the Dementia and CUD group are not receiving early care, resulting in higher long-term healthcare costs. Further investigations should examine what impact the timing of dementia and CUD diagnoses have on specific categories of inpatient and outpatient care in VA and community care facilities.

Most cell therapy trials failed to show an improvement in global left ventricular (LV) function measures after myocardial infarction (MI). Myocardial segments are heterogeneously impacted by MI. Global LV function indices are not able to detect the small treatment effects on segmental myocardial function which may have prognostic implications for cardiac events. We aimed to test the efficacy of allogeneic cardiosphere-derived cells (CDCs) for improving regional myocardial function and contractility. In this exploratory analysis of a randomised clinical trial, 142 patients with post-MI with LVEF

Abstract Introduction Motor impairments are the objectively most striking sequelae after stroke, but non-motor consequences represent a high burden for stroke survivors as well. Depression is reported in one third of patients, the fatigue prevalence ranges from 23 to 75% due to heterogenous definitions and assessments. Cognitive impairment is found in one third of stroke patients 3–12 months after stroke and the risk for dementia is doubled by the event. Aerobic exercise has been shown to reduce depressive symptoms, counteract fatigue, and improve cognitive functions in non-stroke patients. Furthermore, exercise is known to strengthen the immune system. It is unknown, though, if aerobic exercise can counteract poststroke depression, fatigue, poststroke dementia and poststroke immunosuppression. Therefore, we aim to analyse the effect of aerobic exercise on functional recovery, cognition, emotional well-being, and the immune system. Reorganization of topological networks of the brain shall be visualized by diffusion MRI fibre tracking. Methods Adults with mild to moderate stroke impairment (initial NIHSS or NIHSS determined at the moment of maximal deterioration 1–18) are recruited within two weeks of stroke onset. Study participants must be able to walk independently without risk of falling. All patients are equipped with wearable devices (smartwatches) measuring the heart rate and daily step count. The optimal heart rate zone is determined by lactate ergometry at baseline. Patients are randomized to the control or the intervention group, the latter performing a heart rate-controlled walking training on own initiative 5 times a week for 45 min. All patients receive medical care and stroke rehabilitation to the usual standard of care. The following assessments are conducted at baseline and after 90 days: Fugl Meyer-assessment for the upper and lower extremity, 6 min-walk test, neuropsychological assessment (cognition: MoCA, SDMT; fatigue and depression: FSMC, HADS-D, participation: WHODAS 2.0 12-items), blood testing (i.e. immune profiling to obtain insights into phenotype and functional features of distinct immune-cell subsets) and cranial magnetic resonance imaging (MRI) with grid-sampled diffusion weighted imaging, white matter fibre tracking and MR spectroscopy. Perspective This study investigates the effect of smartwatch-controlled aerobic exercise on functional recovery, cognition, emotional well-being, the immune system, and neuronal network reorganization in stroke patients. Trial registration ClinicalTrials.gov NCT Number: NCT05690165. First posted19 January 2023. Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT05690165

Summary: Background: Genomic characterisation has led to an improved understanding of adult melanoma. However, the aetiology of melanoma in children is still unclear and identifying the correct diagnosis and therapeutic strategies remains challenging. Methods: Exome sequencing of matched tumour-normal pairs from 26 paediatric patients was performed to study the mutational spectrum of melanomas. The cohort was grouped into different categories: spitzoid melanoma (SM), conventional melanoma (CM), and other melanomas (OT). Findings: In all patients with CM (n = 10) germline variants associated with melanoma were found in low to moderate melanoma risk genes: in 8 patients MC1R variants, in 2 patients variants in MITF, PTEN and BRCA2. Somatic BRAF mutations were detected in 60% of CMs, homozygous deletions of CDKN2A in 20%, TERTp mutations in 30%. In the SM group (n = 12), 5 patients carried at least one MC1R variant; somatic BRAF mutations were detected in 8.3%, fusions in 25% of the cases. No SM showed a homozygous CDKN2A deletion nor a TERTp mutation. In 81.8% of the CM/SM cases the UV damage signatures SBS7 and/or DBS1 were detected. The patient with melanoma arising in giant congenital nevus (CNM) demonstrated the characteristic NRAS Q61K mutation. Interpretation: UV-radiation and MC1R germline variants are risk factors in the development of conventional and spitzoid paediatric melanomas. Paediatric CMs share genomic similarities with adult CMs while the SMs differ genetically from the CM group. Consistent genetic characterization of all paediatric melanomas will potentially lead to better subtype differentiation, treatment, and prevention in the future. Funding: Found in Acknowledgement.

Approximately 70% of relapsing-remitting multiple sclerosis (RRMS) patients will develop secondary progressive multiple sclerosis (SPMS) within 10–15 years. This progression is characterized by a gradual decline in neurological functionality and increasing limitations of daily activities. Growing evidence suggests that both inflammation and neurodegeneration are associated with various pathological processes throughout the development of MS; therefore, to delay disease progression, it is critical to initiate disease-modifying therapy as soon as it is diagnosed. Currently, a diagnosis of SPMS requires a retrospective assessment of physical disability exacerbation, usually over the previous 6–12 months, which results in a delay of up to 3 years. Hence, there is a need to identify reliable and objective biomarkers for predicting and defining SPMS conversion. This review presents current knowledge of such biomarkers in the context of neurodegeneration associated with MS, and SPMS conversion.

BACKGROUND: Alzheimers disease (AD) pathology precedes symptoms and its detection can identify at-risk individuals who may benefit from early treatment. Since the retinal nerve fiber layer (RNFL) is depleted in established AD, we tested whether its thickness can predict whether cognitively healthy (CH) individuals have a normal or pathological cerebrospinal fluid (CSF) Aß42 (A) and tau (T) ratio. METHODS: As part of an ongoing longitudinal study, we enrolled CH individuals, excluding those with cognitive impairment and significant ocular pathology. We classified the CH group into two sub-groups, normal (CH-NAT, n = 16) or pathological (CH-PAT, n = 27), using a logistic regression model from the CSF AT ratio that identified >85% of patients with a clinically probable AD diagnosis. Spectral-domain optical coherence tomography (OCT) was acquired for RNFL, ganglion cell-inner plexiform layer (GC-IPL), and macular thickness. Group differences were tested using mixed model repeated measures and a classification model derived using multiple logistic regression. RESULTS: Mean age (± standard deviation) in the CH-PAT group (n = 27; 75.2 ± 8.4 years) was similar (p = 0.50) to the CH-NAT group (n = 16; 74.1 ± 7.9 years). Mean RNFL (standard error) was thinner in the CH-PAT group by 9.8 (2.7) μm; p < 0.001. RNFL thickness classified CH-NAT vs. CH-PAT with 87% sensitivity and 56.3% specificity. CONCLUSIONS: Our retinal data predict which individuals have CSF biomarkers of AD pathology before cognitive deficits are detectable with 87% sensitivity. Such results from easy-to-acquire, objective and non-invasive measurements of the RNFL merit further study of OCT technology to monitor or screen for early AD pathology.

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Abstract Heterotopic heart transplantation (HHT) is an alternative to the orthotopic technique in selected patients with terminal heart failure. We report the case of the longest survival after HHT, with an uneventful follow‐up for over three decades after transplantation. At the age of 25 years, endomyocardial fibrosis following myocarditis rendered the patient's native heart unable to maintain the body's needs. An allograft provided a second chance at life. The HHT technique was favoured due to severe pulmonary hypertension. The patient had an uneventful follow‐up since then. The scarcity of donors and the revolutionary advances in the mechanical circulatory device field restricted the utilization of the HHT technique, but it has the potential to provide an excellent prognosis with a good quality of life.

Abstract Ceragenins (CSAs) are synthetic, lipid-based molecules that display activities of natural antimicrobial peptides. Previous studies demonstrated their high in vitro activity against pathogens causing urinary tract infections (UTIs), but their efficiency in vivo was not explored to date. In this study, we aimed to investigate the bactericidal efficiency of ceragenins against E. coli (Xen14 and clinical UPEC strains) isolates both in vitro and in vivo, as well to explore CSA-13 biodistribution and ability to modulate nanomechanical alterations of infected tissues using animal model of UTI. CSA-44, CSA-131 and particularly CSA-13 displayed potent bactericidal effect against tested E. coli strains, and this effect was mediated by induction of oxidative stress. Biodistribution studies indicated that CSA-13 accumulates in kidneys and liver and is eliminated with urine and bile acid. We also observed that ceragenin CSA-13 reverses infection-induced alterations in mechanical properties of mouse bladders tissue, which confirms the preventive role of CSA-13 against bacteria-induced tissue damage and potentially promote the restoration of microenvironment with biophysical features unfavorable for bacterial growth and spreading. These data justify the further work on employment of CSA-13 in the treatment of urinary tract infections.

BackgroundVeterans with a history of traumatic brain injury (TBI) and/or posttraumatic stress disorder (PTSD) may be at increased risk of suicide attempts and other forms of intentional self-harm as compared to veterans without TBI or PTSD. ObjectiveUsing administrative data from the US Veterans Health Administration (VHA), we studied associations between TBI and PTSD diagnoses, and subsequent diagnoses of intentional self-harm among US veterans who used VHA health care between 2008 and 2017. MethodsAll veterans with encounters or hospitalizations for intentional self-harm were assigned “index dates” corresponding to the date of the first related visit; among those without intentional self-harm, we randomly selected a date from among the veteran’s health care encounters to match the distribution of case index dates over the 10-year period. We then examined the prevalence of TBI and PTSD diagnoses within the 5-year period prior to veterans’ index dates. TBI, PTSD, and intentional self-harm were identified using International Classification of Diseases diagnosis and external cause of injury codes from inpatient and outpatient VHA encounters. We stratified analyses by veterans’ average yearly VHA utilization in the 5-year period before their index date (low, medium, or high). Variations in prevalence and odds of intentional self-harm diagnoses were compared by veterans’ prior TBI and PTSD diagnosis status (TBI only, PTSD only, and comorbid TBI/PTSD) for each VHA utilization stratum. Multivariable models adjusted for age, sex, race, ethnicity, marital status, Department of Veterans Affairs service-connection status, and Charlson Comorbidity Index scores. ResultsAbout 6.7 million veterans with at least two VHA visits in the 5-year period before their index dates were included in the analyses; 86,644 had at least one intentional self-harm diagnosis during the study period. During the periods prior to veterans’ index dates, 93,866 were diagnosed with TBI only; 892,420 with PTSD only; and 102,549 with comorbid TBI/PTSD. Across all three VHA utilization strata, the prevalence of intentional self-harm diagnoses was higher among veterans diagnosed with TBI, PTSD, or TBI/PTSD than among veterans with neither diagnosis. The observed difference was most pronounced among veterans in the high VHA utilization stratum. The prevalence of intentional self-harm was six times higher among those with comorbid TBI/PTSD (6778/58,295, 11.63%) than among veterans with neither TBI nor PTSD (21,979/1,144,991, 1.92%). Adjusted odds ratios suggested that, after accounting for potential confounders, veterans with TBI, PTSD, or comorbid TBI/PTSD had higher odds of self-harm compared to veterans without these diagnoses. Among veterans with high VHA utilization, those with comorbid TBI/PTSD were 4.26 (95% CI 4.15-4.38) times more likely to receive diagnoses for intentional self-harm than veterans with neither diagnosis. This pattern was similar for veterans with low and medium VHA utilization. ConclusionsVeterans with TBI and/or PTSD diagnoses, compared to those with neither diagnosis, were substantially more likely to be subsequently diagnosed with intentional self-harm between 2008 and 2017. These associations were most pronounced among veterans who used VHA health care most frequently. These findings suggest a need for suicide prevention efforts targeted at veterans with these diagnoses.

ObjectiveAutosomal dominant optic atrophy (ADOA) starts in early childhood with loss of visual acuity and color vision deficits. OPA1 mutations are responsible for the majority of cases, but in a portion of patients with a clinical diagnosis of ADOA, the cause remains unknown. This study aimed to identify novel ADOA-associated genes and explore their causality.MethodsLinkage analysis and sequencing were performed in multigeneration families and unrelated patients to identify disease-causing variants. Functional consequences were investigated in silico and confirmed experimentally using the zebrafish model.ResultsWe defined a new ADOA locus on 7q33-q35 and identified 3 different missense variants in SSBP1 (NM_001256510.1; c.113G>A [p.(Arg38Gln)], c.320G>A [p.(Arg107Gln)] and c.422G>A [p.(Ser141Asn)]) in affected individuals from 2 families and 2 singletons with ADOA and variable retinal degeneration. The mutated arginine residues are part of a basic patch that is essential for single-strand DNA binding. The loss of a positive charge at these positions is very likely to lower the affinity of SSBP1 for single-strand DNA. Antisense-mediated knockdown of endogenous ssbp1 messenger RNA (mRNA) in zebrafish resulted in compromised differentiation of retinal ganglion cells. A similar effect was achieved when mutated mRNAs were administered. These findings point toward an essential role of ssbp1 in retinal development and the dominant-negative nature of the identified human variants, which is consistent with the segregation pattern observed in 2 multigeneration families studied.InterpretationSSBP1 is an essential protein for mitochondrial DNA replication and maintenance. Our data have established pathogenic variants in SSBP1 as a cause of ADOA and variable retinal degeneration. ANN NEUROL 2019;86:368-383.

ObjectiveTo assess the feasibility, safety, and efficacy of intracoronary allogeneic cardiosphere-derived cells (CAP-1002) in patients with Duchenne muscular dystrophy (DMD).MethodsThe Halt Cardiomyopathy Progression (HOPE)-Duchenne trial is a phase I/II, randomized, controlled, open-label trial (NCT02485938). Patients with DMD >12 years old, with substantial myocardial fibrosis, were randomized (1:1) to usual care (control) or global intracoronary infusion of CAP-1002 (75 million cells). Participants were enrolled at 3 US medical centers between January and August 2016 and followed for 12 months. An independent Data and Safety Monitoring Board provided safety oversight. Cardiac function and structure were assessed by MRI, and analyzed by a blinded core laboratory. Skeletal muscle function was assessed by performance of the upper limb (PUL).ResultsTwenty-five eligible patients (mean age 17.8 years; 68% wheelchair-dependent) were randomized to CAP-1002 (n = 13) or control (n = 12). Incidence of treatment-emergent adverse events was similar between groups. Compared to baseline, MRI at 12 months revealed significant scar size reduction and improvement in inferior wall systolic thickening in CAP-1002 but not control patients. Mid-distal PUL improved at 12 months in 8 of 9 lower functioning CAP-1002 patients, and no controls (p = 0.007).ConclusionsIntracoronary CAP-1002 in DMD appears safe and demonstrates signals of efficacy on both cardiac and upper limb function for up to 12 months. Thus, future clinical research on CAP-1002 treatment of DMD cardiac and skeletal myopathies is warranted.Classification of evidenceThis phase I/II study provides Class II evidence that for patients with DMD, intracoronary CAP-1002 is feasible and appears safe and potentially effective.

The vertebral column, with the centra as its iteratively arranged building blocks, represents the anatomical key feature of the vertebrate phylum. In contrast to amniotes, where vertebrae are formed from chondrocytes and osteoblasts deriving from the segmentally organized neural crest or paraxial sclerotome, teleost vertebral column development is initiated by chordoblasts of the primarily unsegmented axial notochord, while sclerotomal cells only contribute to later steps of vertebrae formation. Yet, for both mammalian and teleostean model systems, unrestricted signaling by Bone Morphogenetic Proteins (BMPs) or retinoic acid (RA) has been reported to cause fusions of vertebral elements, while the interplay of the two signaling processes and their exact cellular targets remain largely unknown. Here, we address this interplay in zebrafish, identifying BMPs as potent and indispensable factors that, as formerly shown for RA, directly signal to notochord epithelial cells/chordoblasts to promote entpd5a expression and thereby metameric notochord sheath mineralization. In contrast to RA, however, which promotes sheath mineralization at the expense of further collagen secretion and sheath formation, BMP defines an earlier transitory stage of chordoblasts, characterized by sustained matrix production/col2a1 expression and concomitant matrix mineralization/entpd5a expression. BMP-RA epistasis analyses further indicate that RA can only affect chordoblasts and their further progression to merely mineralizing cells after they have received BMP signals to enter the transitory col2a1/entpd5a double-positive stage. This way, both signals ensure consecutively for proper mineralization of the notochord sheath within segmented sections along its anteroposterior axis. Our work sheds further light onto the molecular mechanisms that orchestrate early steps of vertebral column segmentation in teleosts. Similarities and differences to BMP’s working mechanisms during mammalian vertebral column formation and the pathomechanisms underlying human bone diseases such as Fibrodysplasia Ossificans Progressiva (FOP) caused by constitutively active BMP signaling are discussed.

IntroductionMansonella species are filarial parasites that infect humans worldwide. Although these infections are common, knowledge of the pathology and diversity of the causative species is limited. Furthermore, the lack of sequencing data for Mansonella species, shows that their research is neglected. Apart from Mansonella perstans, a potential new species called Mansonella sp “DEUX” has been identified in Gabon, which is prevalent at high frequencies. We aimed to further determine if Mansonella sp “DEUX” is a genotype of M. perstans, or if these are two sympatric species.MethodsWe screened individuals in the area of Fougamou, Gabon for Mansonella mono-infections and generated de novo assemblies from the respective samples. For evolutionary analysis, a phylogenetic tree was reconstructed, and the differences and divergence times are presented. In addition, mitogenomes were generated and phylogenies based on 12S rDNA and cox1 were created.ResultsWe successfully generated whole genomes for M. perstans and Mansonella sp “DEUX”. Phylogenetic analysis based on annotated protein sequences, support the hypothesis of two distinct species. The inferred evolutionary analysis suggested, that M. perstans and Mansonella sp “DEUX” separated around 778,000 years ago. Analysis based on mitochondrial marker genes support our hypothesis of two sympatric human Mansonella species.DiscussionThe results presented indicate that Mansonella sp “DEUX” is a new Mansonella species. These findings reflect the neglect of this research topic. And the availability of whole genome data will allow further investigations of these species

Abstract Background During parturition, animals exhibit variation in hormone levels, homeostasis disturbance and dysfunction of the immune system as a result of stress. Glutathione S-transferase (GST) is responsible for the occurrence of oxidative stress in the cells. Cortisol is known as the stress hormone, but it is also involved in the metabolism of proteins, carbohydrates and metabolism processes led by adipose tissue. The aim of the this study was to determine how the levels of GST and cortisol change depending on the parity. Additionally, the influence of lambing on the microbiological composition of the digestive system and placenta in Olkuska sheep was investigated. Methods Eighteen ewes were selected for the experiment - primiparas (n = 9) and multiparas (n = 9), they were kept in the same environmental conditions, had the same diet and did not show any disease symptoms. Fecal samples were collected individually from each ewe (n = 18) and then bacterial DNA isolation was made, then qPCR analysis for Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria phyla and Lactobacillaceae family bacteria levels was performed. These samples were also used to analyze cortisol levels by ELISA test. In addition, placenta fragments were collected during delivery, and then the GST level from the tissue was tested. Results The analysis of the results showed a higher level of cortisol in primiparous sheep than in multiparous ones, as in the case of glutathione transferase. There were differences between both studied groups in the microbiological composition of the digestive system. In primiparous sheep, the levels of the tested microorganisms were significantly lower than in multiparous ones. A similar relationship occurred in the study of the placental microbiome. Conclusion The results show that sheep microbiome, cortisol and GST levels are different in primiparas and multiparas. The study conducted may constitute an introduction to further analyzes that would help positively affect the welfare and homeostasis of the female organism.