Dissolved noble gases and stable isotopes as tracers of preferential fluid flow along faults in the Lower Rhine Embayment, Germany

Groundwater in shallow unconsolidated sedimentary aquifers close to the Bornheim fault in the Lower Rhine Embayment (LRE), Germany, has relatively low δ2H and δ18O values in comparison to regional modern groundwater recharge, and 4He concentrations up to 1.7 × 10−4 cm3 (STP) g–1 ± 2.2 % which is approximately four orders of magnitude higher than expected due to solubility equilibrium with the atmosphere. Groundwater age dating based on estimated in situ production and terrigenic flux of helium provides a groundwater residence time of ∼107 years. Although fluid exchange between the deep basal aquifer system and the upper aquifer layers is generally impeded by confining clay layers and lignite, this study’s geochemical data suggest, for the first time, that deep circulating fluids penetrate shallow aquifers in the locality of fault zones, implying  that sub-vertical fluid flow occurs along faults in the LRE. However, large hydraulic-head gradients observed across many faults suggest that they act as barriers to lateral groundwater flow. Therefore, the geochemical data reported here also substantiate a conduit-barrier model of fault-zone hydrogeology in unconsolidated sedimentary deposits, as well as corroborating the concept that faults in unconsolidated aquifer systems can act as loci for hydraulic connectivity between deep and shallow aquifers. The implications of fluid flow along faults in sedimentary basins worldwide are far reaching and of particular concern for carbon capture and storage (CCS) programmes, impacts of deep shale gas recovery for shallow groundwater aquifers, and nuclear waste storage sites where fault zones could act as potential leakage pathways for hazardous fluids

Long-term parental distress after pediatric hematopoietic stem cell transplantation for nonmalignant diseases

Background: Survival rates have continued to increase for pediatric hematopoietic stem cell transplantation (HSCT) for nonmalignant diseases. Despite the crucial role of caregivers in this high-intensity treatment, knowledge about long-term parental impact is lacking. Procedure: This cross-sectional study assessed parental distress and everyday problems in parents of patients 2 years and older after pediatric HSCT for a nonmalignant disease using Distress Thermometer for Parents (DT-P), and compared outcomes to matched Dutch parents of healthy children and Dutch parents of children with a chronic condition (CC). Results: Median follow-up was 5.3 years (interquartile range [IQR]: 2.9–8.6). Underlying diseases were inborn errors of immunity (N = 30), hemoglobinopathies (N = 13), and bone marrow failure (N = 27). Mothers of pediatric HSCT recipients (N = 70) reported comparable overall distress levels to mothers of healthy children, but experienced more distress related to parenting problems, specifically managing their child's emotions, discussing disease consequences, and fostering independence. Fathers of HSCT recipients (N = 45) reported higher overall distress levels and had more emotional distress compared to fathers of healthy children. Conclusions: Overall, parental distress and everyday problems of parents of HSCT recipients are comparable to those of parents of children with CC. However, there is ongoing parental burden, both emotional and in parenting, long-term after HSCT compared to parents of healthy children, and the type of burden differs between mothers and fathers. These results indicate that individualized parental supportive care should not remain restricted to the acute hospitalization phase, but also be actively offered during long-term follow-up after pediatric HSCT.</p

Coronary artery calcification score in migraine patients

Epidemiological studies have shown an increased risk of cardiovascular events in migraineurs. The pathophysiological mechanisms of this observation remain largely unknown. Recent genetic and epidemiologic studies suggest, that atherosclerosis might be the overlapping pathophysiological mechanism in migraine and coronary heart disease. The aim of the present study was to evaluate if the increased cardiovascular risk in migraineurs is attributed to an increased coronary artery calcification. For this the coronary artery calcium score was assessed by computed tomography of the heart in 1.437 patients of which 337 were migraineurs. All patients had a similar cardiovascular risk profile, so that the risk for coronary calcifications could be considered similar between migraineurs and non-migraineurs. The results showed no significant differences in the amount of coronary calcifications in patients with or without migraine. This suggests that a more pronounced coronary artery calcification, as a surrogate marker of coronary atherosclerosis, does not underlie the increased cardiovascular risk in migraineurs. A distinct common pathophysiological mechanism in migraine and coronary heart disease such as endothelial dysfunction or vasospasm should be discussed instead. However, it has to be considered, that the coronary artery calcification score does not indicate the total risk of atherosclerotic changes in the coronary arteries

Health-related quality of life and functional impairment in acute vestibular disorders

BACKGROUND AND PURPOSE Acute vestibular symptoms have a profound impact on patients' well-being. In this study, health-related quality of life (HRQoL) and functional impairment were investigated prospectively in patients with different peripheral and central vestibular disorders during the acute symptomatic stage to decipher the most relevant underlying factors. METHODS In all, 175 patients with acute vestibular disorders were categorized as central vestibular (CV, n~=~40), peripheral vestibular (PV, n~=~68) and episodic vestibular disorders (EV, n~=~67). All patients completed scores to quantify generic HRQoL (European Quality of Life Score Five Dimensions Five Levels, EQ-5D-5L) and disease-specific HRQoL (Dizziness Handicap Inventory, DHI). Vestibular-ocular motor signs were assessed by video-oculography, vestibular-spinal control by posturography and verticality perception by measurement of subjective visual vertical. RESULTS Patients with PV had a poorer HRQoL compared to patients with CV and EV (EQ-5D-5L/DHI: PV, 0.53~±~0.31/56.1~±~19.7; CV, 0.66~±~0.28/43.3~±~24.0; EV, 0.75~±~0.24/46.7~±~21.4). After adjusting for age, gender, cardiovascular risk factors and non-vestibular brainstem/cerebellar dysfunction patients with PV persisted to have poorer generic and disease-specific HRQoL (EQ-5D-5L -0.17, DHI +11.2) than patients with CV. Horizontal spontaneous nystagmus was a highly relevant factor for subgroup differences in EQ-5D-5L and DHI, whilst vertical spontaneous nystagmus, subjective visual vertical and sway path were not. EQ-5D-5L decreased significantly with more intense horizontal subjective visual vertical in CV (rho~=~-0.57) and PV (rho~=~-0.5) but not EV (rho~=~-0.13). CONCLUSIONS Patients with PV have the highest functional impairment of all patients with acute vestibular disorders. Vestibular-ocular motor disturbance in the yaw plane has more impact than vestibular-spinal or vestibular-perceptive asymmetry in the roll and pitch plane, suggesting that horizontal visual stability is the most critical for HRQoL

A novel pathogenic CACNA1A variant causing episodic ataxia type 2 (EA2) spectrum phenotype in four family members and a novel combined therapy

Objective!#!The safety and efficacy of surgical microvascular decompression (MVD) in elderly patients with trigeminal neuralgia (TN) is controversially discussed in the literature. A widespread reluctance to expose this cohort to major intracranial surgery persists. Our aim was to compare the efficacy and safety between older and younger patients with TN.!##!Methods!#!In this cross-sectional study, 139 MVD procedures (103 patients &amp;lt; 70 and 36 patients ≥ 70) were included. Surgical fitness was assessed by the American Society of Anesthesiology (ASA) grade. The pain-free interval was evaluated using Kaplan-Meier analysis only in patients with a recent follow-up visit. Independent risk factors for recurrence in patients with a minimum 12-month follow-up were determined.!##!Results!#!Patients ≥ 70 showed a significantly higher number of comorbidities. Pain intensity, affection of trigeminal branches and symptom duration was similar between groups. No significant difference in treatment associated complications and permanent neurological deficits was shown. There was no treatment-related mortality. A tendency towards a lower recurrence rate in patients &amp;lt; 70 did not reach statistical significance (17.6% vs. 28.6%, P = 0.274). Pain-free interval was not different between both cohorts (78.7 vs. 73.5 months, P = 0.391).!##!Conclusion!#!Despite a higher prevalence of comorbidities in elderly patients, complication rates and neurological deficits after MVD were comparable to younger patients. Rates of immediate and long-term pain relief compared favorably to previous studies and were similar between elderly and younger patients. These data endorse MVD as a safe and effective first-line surgical procedure for elderly patients with TN and neurovascular conflict on MRI

The value of using patient-reported outcomes for health screening during long-term follow-up after paediatric stem cell transplantation for nonmalignant diseases

Introduction: The assessment of using patient-reported outcomes (PROs) within comprehensive care follow-up programmes, specifically focused on health screening, remains largely unexplored. PROs were implemented in our late effects and comprehensive care programme after paediatric hematopoietic stem cell transplantation (HSCT) for nonmalignant diseases. The programme focuses solely on screening of physical and mental health and on discussing PROs during the consultation. Methods: The primary method of this study was semistructured interviews to explore the perspective of both patients and healthcare providers' (HCP) on the use of PROs, which were thematically analyzed. Additionally, an explorative quantitative approach with patient-reported experience measures (PREMS) was used, with a pretest–posttest design, to assess whether the use of PROs was accompanied by more patient-centred care. Results: From the patient-interviews (N = 15) four themes were extracted: use of PROs (1) help to discuss topics; (2) make the patients feel understood; (3) create a moment of self-reflection; and (4) make consultations more efficient. Pre- and postimplementation analysis of PREMs (N = 40) did not show significant differences in terms of patient-centeredness. Conclusion: Our results demonstrate the added value of integrating PROs for health screening purposes within the long-term follow-up programme after paediatric HSCT, as perceived by both patient and HCP. With the active use of PROs, patients are stimulated to consciously assess their health status. Patient Contribution: This study included patients as participants. Caregivers were approached if patients were below a certain age. Additionally, preliminary results were shared with all patients (including nonparticipants) during a patient conference day.</p

Transcriptional effects of copy number alterations in a large set of human cancers

Copy number alterations (CNAs) can promote tumor progression by altering gene expression levels. Due to transcriptional adaptive mechanisms, however, CNAs do not always translate proportionally into altered expression levels. By reanalyzing >34,000 gene expression profiles, we reveal the degree of transcriptional adaptation to CNAs in a genome-wide fashion, which strongly associate with distinct biological processes. We then develop a platform-independent method-transcriptional adaptation to CNA profiling (TACNA profiling)-that extracts the transcriptional effects of CNAs from gene expression profiles without requiring paired CNA profiles. By applying TACNA profiling to >28,000 patient-derived tumor samples we define the landscape of transcriptional effects of CNAs. The utility of this landscape is demonstrated by the identification of four genes that are predicted to be involved in tumor immune evasion when transcriptionally affected by CNAs. In conclusion, we provide a novel tool to gain insight into how CNAs drive tumor behavior via altered expression levels

Distributed temperature sensing as a down-hole tool in hydrogeology

Distributed Temperature Sensing (DTS) technology enables down-hole temperature monitoring to study hydrogeological processes at unprecedentedly high frequency and spatial resolution. DTS has been widely applied in passive mode in site investigations of groundwater flow, in-well flow, and subsurface thermal property estimation. However, recent years have seen the further development of the use of DTS in an active mode (A-DTS) for which heat sources are deployed. A suite of recent studies using A-DTS down-hole in hydrogeological investigations illustrate the wide range of different approaches and creativity in designing methodologies. The purpose of this review is to outline and discuss the various applications and limitations of DTS in down-hole investigations for hydrogeological conditions and aquifer geological properties. To this end, we first review examples where passive DTS has been used to study hydrogeology via down-hole applications. Secondly, we discuss and categorize current A-DTS borehole methods into three types. These are thermal advection tests, hybrid cable flow logging, and heat pulse tests. We explore the various options with regards to cable installation, heating approach, duration, and spatial extent in order to improve their applicability in a range of settings. These determine the extent to which each method is sensitive to thermal properties, vertical in well flow, or natural gradient flow. Our review confirms that the application of DTS has significant advantages over discrete point temperature measurements, particularly in deep wells, and highlights the potential for further method developments in conjunction with other emerging fiber optic based sensors such as Distributed Acoustic Sensing. This article is protected by copyright. All rights reserved

Cyclin E expression is associated with high levels of replication stress in triple-negative breast cancer

Replication stress entails the improper progression of DNA replication. In cancer cells, including breast cancer cells, an important cause of replication stress is oncogene activation. Importantly, tumors with high levels of replication stress may have different clinical behavior, and high levels of replication stress appear to be a vulnerability of cancer cells, which may be therapeutically targeted by novel molecularly targeted agents. Unfortunately, data on replication stress is largely based on experimental models. Further investigation of replication stress in clinical samples is required to optimally implement novel therapeutics. To uncover the relation between oncogene expression, replication stress, and clinical features of breast cancer subgroups, we immunohistochemically analyzed the expression of a panel of oncogenes (Cyclin E, c-Myc, and Cdc25A,) and markers of replication stress (phospho-Ser33-RPA32 and γ-H2AX) in breast tumor tissues prior to treatment (n = 384). Triple-negative breast cancers (TNBCs) exhibited the highest levels of phospho-Ser33-RPA32 (P < 0.001 for all tests) and γ-H2AX (P < 0.05 for all tests). Moreover, expression levels of Cyclin E (P < 0.001 for all tests) and c-Myc (P < 0.001 for all tests) were highest in TNBCs. Expression of Cyclin E positively correlated with phospho-RPA32 (Spearman correlation r = 0.37, P < 0.001) and γ-H2AX (Spearman correlation r = 0.63, P < 0.001). Combined, these data indicate that, among breast cancers, replication stress is predominantly observed in TNBCs, and is associated with expression levels of Cyclin E. These results indicate that Cyclin E overexpression may be used as a biomarker for patient selection in the clinical evaluation of drugs that target the DNA replication stress response

Comparison of observed and general circulation model derived continental subsurface heat flux in the Northern Hemisphere

Heat fluxes in the continental subsurface were estimated from general circulation model (GCM) simulations of the climate of the last millennium and compared to those obtained from subsurface geothermal data. Since GCMs have bottom boundary conditions (BBCs) that are less than 10 m deep and thus may be thermodynamically restricted in the continental subsurface, we used an idealized land surface model (LSM) with a very deep BBC to estimate the potential for realistic subsurface heat storage in the absence of bottom boundary constraints. Results indicate that there is good agreement between observed fluxes and GCM simulated fluxes for the 1780-1980 period when the GCM simulated temperatures are coupled to the LSM with deep BBC. These results emphasize the importance of placing a deep BBC in GCM soil components for the proper simulation of the overall continental heat budget. In addition, the agreement between the LSM surface fluxes and the borehole temperature reconstructed fluxes lends additional support to the overall quality of the GCM (ECHO-G) paleoclimatic simulations