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

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 < 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 < 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

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

Thermal-Plume fibre Optic Tracking (T-POT) test for flow velocity measurement in groundwater boreholes

International audienceWe develop an approach for measuring in-well fluid velocities using point electrical heating combined with spatially and temporally continuous temperature monitoring using Distributed Temperature Sensing (DTS). The method uses a point heater to warm a discrete volume of water. The rate of advection of this plume, once the heating is stopped, equates to the average flow velocity in the well. We conducted Thermal-Plume fibre Optic Tracking (T-POT) tests in a borehole in a fractured rock aquifer with the heater at the same depth and multiple pumping rates. Tracking of the thermal plume peak allowed the spatially varying velocity to be estimated up to 50 m downstream from the heating point, depending on the pumping rate. The T-POT technique can be used to estimate the velocity throughout long intervals provided that thermal dilution due to inflows, dispersion, or cooling by conduction do not render the thermal pulse unresolvable with DTS. A complete flow log may be obtained by deploying the heater at multiple depths, or with multiple point heaters

Active-distributed temperature sensing to continuously quantify vertical flow in boreholes

We show how a distributed borehole flowmeter can be created from armored Fiber Optic cables with the Active-Distributed Temperature Sensing (A-DTS) method. The principle is that in a flowing fluid, the difference in temperature between a heated and unheated cable is a function of the fluid velocity. We outline the physical basis of the methodology and report on the deployment of a prototype A-DTS flowmeter in a fractured rock aquifer. With this design, an increase in flow velocity from 0.01 to 0.3 m s−1 elicited a 2.5°C cooling effect. It is envisaged that with further development this method will have applications where point measurements of borehole vertical flow do not fully capture combined spatiotemporal dynamics

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

Thermal-plume fibre optic tracking (T-POT) test for flow velocity measurement in groundwater boreholes

We develop an approach for measuring in-well fluid velocities using point electrical heating combined with spatially and temporally continuous temperature monitoring using distributed temperature sensing (DTS). The method uses a point heater to warm a discrete volume of water. The rate of advection of this plume, once the heating is stopped, equates to the average flow velocity in the well. We conducted thermal-plume fibre optic tracking (T-POT) tests in a borehole in a fractured rock aquifer with the heater at the same depth and multiple pumping rates. Tracking of the thermal plume peak allowed the spatially varying velocity to be estimated up to 50 m downstream from the heating point, depending on the pumping rate. The T-POT technique can be used to estimate the velocity throughout long intervals provided that thermal dilution due to inflows, dispersion, or cooling by conduction does not render the thermal pulse unresolvable with DTS. A complete flow log may be obtained by deploying the heater at multiple depths, or with multiple point heaters

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

Considering the biology of late recurrences in selecting patients for extended endocrine therapy in breast cancer

Extended endocrine therapy can reduce recurrences occurring more than 5 years after diagnosis (late recurrences) in estrogen receptor (ER)-positive breast cancer. Given the side effects of endocrine therapy, optimal patient selection for extended treatment is crucial. Enhanced understanding of late recurrence biology could optimize patient selection in this setting. We therefore summarized the current knowledge of late recurrence biology, clinical trials on extended endocrine therapy, and tools for predicting late recurrence and benefit from treatment extension. Extending 5 years of tamoxifen therapy with 5 years of tamoxifen or an aromatase inhibitor (AI) reduces late recurrence risk by 2-5%, but results of extending AI-based therapy are inconsistent. Although several clinicopathological parameters and multigene assays are prognostic for late recurrence, selection tools predicting benefit from extended endocrine therapy are sparse. Therefore, we additionally performed a pooled analysis using 2231 mRNA profiles of patients with ER-positive/human epidermal growth factor receptor 2 negative breast cancer. Gene Set Enrichment Analysis was applied on genes ranked according to their association with early and late recurrence risk. Higher expression of estrogen-responsive genes was associated with a high recurrence risk beyond 5 years after diagnosis when patients had received no systemic therapy. Although 5 years of endocrine therapy reduced this risk, this effect disappeared after treatment cessation. This suggests that late recurrences of tumors with high expression of estrogen-responsive genes are likely ER-driven. Long-term intervention in this pathway by means of extended endocrine therapy might reduce late recurrences in patients with tumors showing high expression of estrogen-responsive genes