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Myocardial fibrosis and inflammation by CMR predict cardiovascular outcome in people living with HIV
(2021)
Objectives_: The goal of this study was to examine prognostic relationships between cardiac imaging measures and cardiovascular outcome in people living with human immunodeficiency virus (HIV) (PLWH) on highly active antiretroviral therapy (HAART).
Background: PLWH have a higher prevalence of cardiovascular disease and heart failure (HF) compared with the noninfected population. The pathophysiological drivers of myocardial dysfunction and worse cardiovascular outcome in HIV remain poorly understood.
Methods: This prospective observational longitudinal study included consecutive PLWH on long-term HAART undergoing cardiac magnetic resonance (CMR) examination for assessment of myocardial volumes and function, T1 and T2 mapping, perfusion, and scar. Time-to-event analysis was performed from the index CMR examination to the first single event per patient. The primary endpoint was an adjudicated adverse cardiovascular event (cardiovascular mortality, nonfatal acute coronary syndrome, an appropriate device discharge, or a documented HF hospitalization).
Results: A total of 156 participants (62% male; age [median, interquartile range]: 50 years [42 to 57 years]) were included. During a median follow-up of 13 months (9 to 19 months), 24 events were observed (4 HF deaths, 1 sudden cardiac death, 2 nonfatal acute myocardial infarction, 1 appropriate device discharge, and 16 HF hospitalizations). Patients with events had higher native T1 (median [interquartile range]: 1,149 ms [1,115 to 1,163 ms] vs. 1,110 ms [1,075 to 1,138 ms]); native T2 (40 ms [38 to 41 ms] vs. 37 ms [36 to 39 ms]); left ventricular (LV) mass index (65 g/m2 [49 to 77 g/m2] vs. 57 g/m2 [49 to 64 g/m2]), and N-terminal pro–B-type natriuretic peptide (109 pg/l [25 to 337 pg/l] vs. 48 pg/l [23 to 82 pg/l]) (all p < 0.05). In multivariable analyses, native T1 was independently predictive of adverse events (chi-square test, 15.9; p < 0.001; native T1 [10 ms] hazard ratio [95% confidence interval]: 1.20 [1.08 to 1.33]; p = 0.001), followed by a model that also included LV mass (chi-square test, 17.1; p < 0.001). Traditional cardiovascular risk scores were not predictive of the adverse events.
Conclusions: Our findings reveal important prognostic associations of diffuse myocardial fibrosis and LV remodeling in PLWH. These results may support development of personalized approaches to screening and early intervention to reduce the burden of HF in PLWH (International T1 Multicenter Outcome Study; NCT03749343).
Co-design of a trustworthy AI system in healthcare: deep learning based skin lesion classifier
(2021)
This paper documents how an ethically aligned co-design methodology ensures trustworthiness in the early design phase of an artificial intelligence (AI) system component for healthcare. The system explains decisions made by deep learning networks analyzing images of skin lesions. The co-design of trustworthy AI developed here used a holistic approach rather than a static ethical checklist and required a multidisciplinary team of experts working with the AI designers and their managers. Ethical, legal, and technical issues potentially arising from the future use of the AI system were investigated. This paper is a first report on co-designing in the early design phase. Our results can also serve as guidance for other early-phase AI-similar tool developments.
Denervation-induced changes in excitatory synaptic strength were studied following entorhinal deafferentation of hippocampal granule cells in mature (≥3 weeks old) mouse organotypic entorhino-hippocampal slice cultures. Whole-cell patch-clamp recordings revealed an increase in excitatory synaptic strength in response to denervation during the first week after denervation. By the end of the second week synaptic strength had returned to baseline. Because these adaptations occurred in response to the loss of excitatory afferents, they appeared to be in line with a homeostatic adjustment of excitatory synaptic strength. To test whether denervation-induced changes in synaptic strength exploit similar mechanisms as homeostatic synaptic scaling following pharmacological activity blockade, we treated denervated cultures at 2 days post lesion for 2 days with tetrodotoxin. In these cultures, the effects of denervation and activity blockade were not additive, suggesting that similar mechanisms are involved. Finally, we investigated whether entorhinal denervation, which removes afferents from the distal dendrites of granule cells while leaving the associational afferents to the proximal dendrites of granule cells intact, results in a global or a local up-scaling of granule cell synapses. By using computational modeling and local electrical stimulations in Strontium (Sr2+)-containing bath solution, we found evidence for a lamina-specific increase in excitatory synaptic strength in the denervated outer molecular layer at 3–4 days post lesion. Taken together, our data show that entorhinal denervation results in homeostatic functional changes of excitatory postsynapses of denervated dentate granule cells in vitro.
Background: Treatment options for poorly differentiated (PDTC) and anaplastic (ATC) thyroid carcinoma are unsatisfactory and prognosis is generally poor. Lenvatinib (LEN), a multi-tyrosine kinase inhibitor targeting fibroblast growth factor receptors (FGFR) 1-4 is approved for advanced radioiodine refractory thyroid carcinoma, but response to single agent is poor in ATC. Recent reports of combining LEN with PD-1 inhibitor pembrolizumab (PEM) are promising. Materials and Methods: Primary ATC (n=93) and PDTC (n=47) tissue samples diagnosed 1997-2019 at five German tertiary care centers were assessed for PD-L1 expression by immunohistochemistry using Tumor Proportion Score (TPS). FGFR 1-4 mRNA was quantified in 31 ATC and 14 PDTC with RNAscope in-situ hybridization. Normal thyroid tissue (NT) and papillary thyroid carcinoma (PTC) served as controls. Disease specific survival (DSS) was the primary outcome variable. Results: PD-L1 TPS≥50% was observed in 42% of ATC and 26% of PDTC specimens. Mean PD-L1 expression was significantly higher in ATC (TPS 30%) than in PDTC (5%; p<0.01) and NT (0%, p<0.001). 53% of PDTC samples had PD-L1 expression ≤5%. FGFR mRNA expression was generally low in all samples but combined FGFR1-4 expression was significantly higher in PDTC and ATC compared to NT (each p<0.001). No impact of PD-L1 and FGFR 1-4 expression was observed on DSS. Conclusion: High tumoral expression of PD-L1 in a large proportion of ATCs and a subgroup of PDTCs provides a rationale for immune checkpoint inhibition. FGFR expression is low thyroid tumor cells. The clinically observed synergism of PEM with LEN may be caused by immune modulation.
The Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO) here presents its updated recommendations for the treatment of documented fungal infections. Invasive fungal infections are a main cause of morbidity and mortality in cancer patients undergoing intensive chemotherapy regimens. In recent years, new antifungal agents have been licensed, and agents already approved have been studied in new indications. The choice of the most appropriate antifungal treatment depends on the fungal species suspected or identified, the patient’s risk factors (e.g., length and depth of neutropenia), and the expected side effects. This guideline reviews the clinical studies that served as a basis for the following recommendations. All recommendations including the levels of evidence are summarized in tables to give the reader rapid access to the information.
Background. Transcatheter aortic valve implantation (TAVI) is currently recommended for patients with severe aortic stenosis at intermediate or high surgical risk. The decision process during TAVI evaluation includes a thorough benefit-risk assessment, and knowledge about long-term benefits and outcomes may improve patients’ expectation management. Objective. To evaluate patients’ perceived health status and self-reported long-term outcome more than 5 years after TAVI. Methods and Results. Demographic and procedure data were obtained from all patients treated with TAVI at our institution from 2006 to 2012. A cross-sectional survey was conducted on the patients alive, measuring health status, including the EQ-5D-5L questionnaire, and clinical outcomes. 103 patients (22.8%) were alive at a median follow-up period of 7 years (5.4–9.8). 99 (96%) of the 103 patients were included in the final analysis. The mean age at follow-up was 86.5 years ± 8.0 years, and 56.6% were female. Almost all patients (93.9%) described an improvement of their quality of life after receiving TAVI. At late follow-up, the mean utility index and EQ-VAS score were 0.80 ± 0.20 and 58.49 ± 11.49, respectively. Mobility was found to be the most frequently reported limitation (85.4%), while anxiety/depression was the least frequently reported limitation (19.8%). With respect to functional class, 64.7% were in New York Heart Association (NYHA) class III or IV, compared to 67.0% prior to TAVI (p = 0.51). Self-reported long-term outcomes revealed mainly low long-term complication rates. 74 total hospitalizations were reported after TAVI, and among those 43% for cardiovascular reasons. Within cardiovascular rehospitalizations, new pacemaker implantations were the most frequently reported (18.9%), followed by cardiac decompensation and coronary heart disease (15.6%). Conclusion. The majority of the patients described an improvement of health status after TAVI. More than five years after TAVI, the patients’ perceived health status was satisfactory, and the incidence of clinical events and hospitalizations was very low.
1. Recent research highlights the ecological importance of individual variation in behavioural predictability. Individuals may not only differ in their average expression of a behavioural trait (their behavioural type) and in their ability to adjust behaviour to changing environmental conditions (individual plasticity), but also in their variability around their average behaviour (predictability). However, quantifying behavioural predictability in the wild has been challenging due to limitations of acquiring sufficient repeated behavioural measures.
2. We here demonstrate how common biologging data can be used to detect individual variation in behavioural predictability in the wild and reveal the coexistence of highly predictable individuals along with unpredictable individuals within the same population.
3. We repeatedly quantified two behaviours—daily movement distance and diurnal activity—in 62 female brown bears Ursus arctos tracked across 187 monitoring years. We calculated behavioural predictability over the short term (50 consecutive monitoring days within 1 year) and long term (across monitoring years) as the residual intra-individual variability (rIIV) of behaviour around the behavioural reaction norm. We tested whether predictability varies systematically across average behavioural types and whether it is correlated across functionally distinct behaviours, that is, daily movement distance and amount of diurnal activity.
4. Brown bears showed individual variation in behavioural predictability from predictable to unpredictable individuals. For example, the standard deviation around the average daily movement distance within one monitoring year varied up to fivefold from 1.1 to 5.5 km across individuals. Individual predictability for both daily movement distance and diurnality was conserved across monitoring years. Individual predictability was correlated with behavioural type where individuals which were on average more diurnal and mobile were also more unpredictable in their behaviour. In contrast, more nocturnal individuals moved less and were more predictable in their behaviour. Finally, individual predictability in daily movement distance and diurnality was positively correlated, suggesting that individual predictability may be a quantitative trait in its own regard that could evolve and is underpinned by genetic variation.
5. Unpredictable individuals may cope better with stochastic events and unpredictability may hence be an adaptive behavioural response to increased predation risk.
Background: Cerebral O2 saturation (ScO2) reflects cerebral perfusion and can be measured noninvasively by near-infrared spectroscopy (NIRS). Objectives: In this pilot study, we describe the dynamics of ScO2 during TAVI in nonventilated patients and its impact on procedural outcome. Methods and Results: We measured ScO2 of both frontal lobes continuously by NIRS in 50 consecutive analgo-sedated patients undergoing transfemoral TAVI (female 58%, mean age 80.8 years). Compared to baseline ScO2 dropped significantly during RVP (59.3% vs. 53.9%, p < .01). Five minutes after RVP ScO2 values normalized (post RVP 62.6% vs. 53.9% during RVP, p < .01; pre 61.6% vs. post RVP 62.6%, p = .53). Patients with an intraprocedural pathological ScO2 decline of >20% (n = 13) had higher EuroSCORE II (3.42% vs. 5.7%, p = .020) and experienced more often delirium (24% vs. 62%, p = .015) and stroke (0% vs. 23%, p < .01) after TAVI. Multivariable logistic regression revealed higher age and large ScO2 drops as independent risk factors for delirium. Conclusions: During RVP ScO2 significantly declined compared to baseline. A ScO2 decline of >20% is associated with a higher incidence of delirium and stroke and a valid cut-off value to screen for these complications. NIRS measurement during TAVI procedure may be an easy to implement diagnostic tool to detect patients at high risks for cerebrovascular complications and delirium.
Cardiac rehabilitation (CR) is a multidisciplinary intervention including patient assessment and medical actions to promote stabilization, management of cardiovascular risk factors, vocational support, psychosocial management, physical activity counselling, and prescription of exercise training. Millions of people with cardiac implantable electronic devices live in Europe and their numbers are progressively increasing, therefore, large subsets of patients admitted in CR facilities have a cardiac implantable electronic device. Patients who are cardiac implantable electronic devices recipients are considered eligible for a CR programme. This is not only related to the underlying heart disease but also to specific issues, such as psychological adaptation to living with an implanted device and, in implantable cardioverter-defibrillator patients, the risk of arrhythmia, syncope, and sudden cardiac death. Therefore, these patients should receive special attention, as their needs may differ from other patients participating in CR. As evidence from studies of CR in patients with cardiac implantable electronic devices is sparse, detailed clinical practice guidelines are lacking. Here, we aim to provide practical recommendations for CR in cardiac implantable electronic devices recipients in order to increase CR implementation, efficacy, and safety in this subset of patients.
Preclinical studies have demonstrated that the endocannabinoid system (ECS) plays an important role in the protection against intestinal inflammation and colorectal cancer (CRC); however, human data are scarce. We determined members of the ECS and related components of the ‘endocannabinoidome’ in patients with inflammatory bowel disease (IBD) and CRC, and compared them to control subjects. Anandamide (AEA) and oleoylethanolamide (OEA) were increased in plasma of ulcerative colitis (UC) and Crohn’s disease (CD) patients while 2-arachidonoylglycerol (2-AG) was elevated in patients with CD, but not UC. 2-AG, but not AEA, PEA and OEA, was elevated in CRC patients. Lysophosphatidylinositol (LPI) 18:0 showed higher levels in patients with IBD than in control subjects whereas LPI 20:4 was elevated in both CRC and IBD. Gene expression in intestinal mucosal biopsies revealed different profiles in CD and UC. CD, but not UC patients, showed increased gene expression for the 2-AG synthesizing enzyme diacylglycerol lipase alpha. Transcripts of CNR1 and GPR119 were predominantly decreased in CD. Our data show altered plasma levels of endocannabinoids and endocannabinoid-like lipids in IBD and CRC and distinct transcript profiles in UC and CD. We also report alterations for less known components in intestinal inflammation, such as GPR119, OEA and LPI.
In the upcoming years, the internet of things (IoT)will enrich daily life. The combination of artificial intelligence(AI) and highly interoperable systems will bring context-sensitive multi-domain services to reality. This paper describesa concept for an AI-based smart living platform with open-HAB, a smart home middleware, and Web of Things (WoT) askey components of our approach. The platform concept con-siders different stakeholders, i.e. the housing industry, serviceproviders, and tenants. These activities are part of the Fore-Sight project, an AI-driven, context-sensitive smart living plat-form.
Der Artikel stellt aktuelle stilometrische Studien im Delta-Kontext vor. Diskutiert wird, warum die Verwendung des Kosinus-Abstands zu einer Verbesserung der Erfolgsquote führt; durch Experimente zur Vektornormalisierung gelingt es, die Funktionsweise von Delta besser zu verstehen. Anhand von mittelhochdeutschen Texten wird gezeigt, dass auch metrische Eigenschaften zur Autorschaftsattribution eingesetzt werden können. Zudem wird untersucht, inwieweit die mittelalterliche, nicht-normierte Schreibung die Erfolgsquote von Delta beeinflusst. Am Beispiel von arabisch-lateinischen Übersetzungen wird geprüft, inwieweit eine selektive Merkmalseliminierung dazu beitragen kann, das Übersetzersignal vom Genresignal zu isolieren.
The entorhino-dentate projection, i.e., the perforant pathway, terminates in a highly ordered and laminated fashion in the rodent dentate gyrus (DG): fibers arising from the medial entorhinal cortex (MEC) terminate in the middle molecular layer, whereas fibers arising from the lateral entorhinal cortex (LEC) terminate in the outer molecular layer of the DG. In rats and rabbits, a crossed entorhino-dentate projection exists, which originates from the entorhinal cortex (EC) and terminates in the contralateral DG. In contrast, in mice, such a crossed projection is reportedly absent. Using single and double mouse organotypic entorhino-hippocampal slice cultures, we studied the ipsi- and crossed entorhino-dentate projections. Viral tracing revealed that entorhino-dentate projections terminate with a high degree of lamina-specificity in single as well as in double cultures. Furthermore, in double cultures, entorhinal axons arising from one slice freely intermingled with entorhinal axons originating from the other slice. In single as well as in double cultures, entorhinal axons exhibited a correct topographical projection to the DG: medial entorhinal axons terminated in the middle and lateral entorhinal axons terminated in the outer molecular layer. Finally, entorhinal neurons were virally transduced with Channelrhodopsin2-YFP and stimulated with light, revealing functional connections between the EC and dentate granule cells. We conclude from our findings that entorhino-dentate projections form bilaterally in the mouse hippocampus in vitro and that the mouse DG provides a permissive environment for crossed entorhinal fibers.
During postnatal development hippocampal dentate granule cells (GCs) often extend dendrites from the basal pole of their cell bodies into the hilar region. These so-called hilar basal dendrites (hBD) usually regress with maturation. However, hBDs may persist in a subset of mature GCs under certain conditions (both physiological and pathological). The functional role of these hBD-GCs remains not well understood. Here, we have studied hBD-GCs in mature (≥18 days in vitro) mouse entorhino-hippocampal slice cultures under control conditions and have compared their basic functional properties (basic intrinsic and synaptic properties) and structural properties (dendritic arborisation and spine densities) to those of neighboring GCs without hBDs in the same set of cultures. Except for the presence of hBDs, we did not detect major differences between the two GC populations. Furthermore, paired recordings of neighboring GCs with and without hBDs did not reveal evidence for a heavy aberrant GC-to-GC connectivity. Taken together, our data suggest that in control cultures the presence of hBDs on GCs is neither sufficient to predict alterations in the basic functional and structural properties of these GCs nor indicative of a heavy GC-to-GC connectivity between neighboring GCs.
Olfactory self-assessments have been analyzed with often negative but also positive conclusions about their usefulness as a surrogate for sensory olfactory testing. Patients with nasal polyposis have been highlighted as a well-predisposed group for reliable self-assessment. In a prospective cohort of n = 156 nasal polyposis patients, olfactory threshold, odor discrimination, and odor identification were tested using the “Sniffin’ Sticks” test battery, along with self-assessments of olfactory acuity on a numerical rating scale with seven named items or on a 10-point scale with only the extremes named. Apparent highly significant correlations in the complete cohort proved to reflect the group differences in olfactory diagnoses of anosmia (n = 65), hyposmia (n = 74), and normosmia (n = 17), more than the true correlations of self-ratings with olfactory test results, which were mostly very weak. The olfactory self-ratings correlated with a quality of life score, however, only weakly. By contrast, olfactory self-ratings proved as informative in assigning the categorical olfactory diagnosis. Using an olfactory diagnostic instrument, which consists of a mapping rule of two numerical rating scales of one’s olfactory function to the olfactory functional diagnosis based on the “Sniffin’ Sticks” clinical test battery, the diagnoses of anosmia, hyposmia, or normosmia could be derived from the self-ratings at a satisfactorily balanced accuracy of about 80%. It remains to be seen whether this approach of translating self-assessments into olfactory diagnoses of anosmia, hyposmia, and normosmia can be generalized to other clinical cohorts in which olfaction plays a role.
Based on neurofeedback (NF) training as a neurocognitive treatment in attention-deficit/hyperactivity disorder (ADHD), we designed a randomized, controlled functional near-infrared spectroscopy (fNIRS) NF intervention embedded in an immersive virtual reality classroom in which participants learned to control overhead lighting with their dorsolateral prefrontal brain activation. We tested the efficacy of the intervention on healthy adults displaying high impulsivity as a sub-clinical population sharing common features with ADHD. Twenty participants, 10 in an experimental and 10 in a shoulder muscle-based electromyography control group, underwent eight training sessions across 2 weeks. Training was bookended by a pre- and post-test including go/no-go, n-back, and stop-signal tasks (SST). Results indicated a significant reduction in commission errors on the no-go task with a simultaneous increase in prefrontal oxygenated hemoglobin concentration for the experimental group, but not for the control group. Furthermore, the ability of the subjects to gain control over the feedback parameter correlated strongly with the reduction in commission errors for the experimental, but not for the control group, indicating the potential importance of learning feedback control in moderating behavioral outcomes. In addition, participants of the fNIRS group showed a reduction in reaction time variability on the SST. Results indicate a clear effect of our NF intervention in reducing impulsive behavior possibly via a strengthening of frontal lobe functioning. Virtual reality additions to conventional NF may be one way to improve the ecological validity and symptom-relevance of the training situation, hence positively affecting transfer of acquired skills to real life.
Clinical data on antifungal combination therapy are limited, in particular in the pediatric setting. We analyzed real-life data collected in two major pediatric cancer centers over a period of 4 years. Patients were identified in an observational study on children with acute leukemia and lymphoma or undergoing hematopoietic cell transplantation. Out of 438 patients, 19 patients received 21 episodes of antifungal combination therapy. Therapy was mostly started for sepsis (n = 5) or clinical deterioration with pulmonary infiltrates (n = 10), and less often for periorbital swelling with suspected mold infection (n = 2), clinical deterioration and new skin lesions, secondary antifungal prophylaxis, a persistently elevated galactomannan index, or as pre-emptive treatment (n = 1 each). Diagnostics revealed proven, probable, and possible invasive fungal disease in two, seven and four episodes, respectively. Most regimens included caspofungin (n = 19), and treatment was initiated as first line therapy in 10 episodes. The median duration was 13 days (4–46 days). Nine of the 13 patients with proven, probable, or possible invasive fungal disease survived, which was comparable to patients receiving antifungal monotherapy. Our analysis demonstrates that combination therapy has mainly been prescribed in selected immunocompromised patients with clinical deterioration due to suspected invasive fungal disease or those with sepsis, and is well tolerated. Future studies need to better characterize clinical settings in which patients may benefit from antifungal combination therapy.
Sleep disordered breathing (SDB) is a frequent comorbidity in cardiac disease patients. Nevertheless, the prevalence and relationship between SDB and severe primary mitral regurgitation (PMR) has not been well investigated to date. Methods: A cohort of 121 patients with significant PMR undergoing mitral valve surgery were prospectively enrolled and received a cardiorespiratory single night polygraphy screening using ApneaLink before surgery. Eighty-two of them underwent a follow-up examination including a follow-up single-night sleep study 3 months after surgery. Results: The mean age of patients was 65.3 ± 12.0 years. Sixty patients (49.6%) were female. The mean EuroSCORE II was 2.5 ± 2.4%. Initially, 91 (75.2%) patients presented with SDB, among whom 50.4% (46 patients, 38.0% of total cohort) were classified as moderate to severe. These patients tended to require significantly longer postoperative intensive care and mechanical ventilation. Among the 82 patients who completed follow-up exams, mitral valve surgery led to a significant reduction in relevant SDB (20.7%). The apnea-hypopnea index (from 11/h [4;18] to 4/h [3;14] (p = 0.04)), the oxygenation-desaturation index (from 8/h [3;18] to 5/h [3;12] (p = 0.008)) as well as the saturation time below 90% (from 32 min [13;86] to 18 min [5;36] (p = 0.005)), were all shown to be improved significantly. Conclusion: The prevalence of SDB is very high in patients with severe primary mitral regurgitation and may contribute to postoperative complications and prolonged intensive care. A significantly reduced but still high prevalence of SDB was observed 3 months after mitral valve surgery, highlighting the bidirectional relationship between SDB and heart failure.
On the robustness of the r-process in neutron-star mergers against variations of nuclear masses
(2016)
r-process calculations have been performed for matter ejected dynamically in neutron star mergers (NSM), such calculations are based on a complete set of trajectories from a three-dimensional relativistic smoothed particle hydrodynamic (SPH) simulation. Our calculations consider an extended nuclear reaction network, including spontaneous, β- and neutron-induced fission and adopting fission yield distributions from the ABLA code. In this contribution we have studied the sensitivity of the r-process abundances to nuclear masses by using diferent mass models for the calculation of neutron capture cross sections via the statistical model. Most of the trajectories, corresponding to 90% of the ejected mass, follow a relatively slow expansion allowing for all neutrons to be captured. The resulting abundances are very similar to each other and reproduce the general features of the observed r-process abundance (the second and third peaks, the rare-earth peak and the lead peak) for all mass models as they are mainly determined by the fission yields. We find distinct differences in the predictions of the mass models at and just above the third peak, which can be traced back to different predictions of neutron separation energies for r-process nuclei around neutron number N = 130.
A hallmark of several major neurological diseases is neuronal cell death. In addition to this primary pathology, secondary injury is seen in connected brain regions in which neurons not directly affected by the disease are denervated. These transneuronal effects on the network contribute considerably to the clinical symptoms. Since denervated neurons are viable, they are attractive targets for intervention. Therefore, we studied the role of Sphingosine-1-phosphate (S1P)-receptor signaling, the target of Fingolimod (FTY720), in denervation-induced dendritic atrophy. The entorhinal denervation in vitro model was used to assess dendritic changes of denervated mouse dentate granule cells. Live-cell microscopy of GFP-expressing granule cells in organotypic entorhino-hippocampal slice cultures was employed to follow individual dendritic segments for up to 6 weeks after deafferentation. A set of slice cultures was treated with FTY720 or the S1P-receptor (S1PR) antagonist VPC23019. Lesion-induced changes in S1P (mass spectrometry) and S1PR-mRNA levels (laser microdissection and qPCR) were determined. Denervation caused profound changes in dendritic stability. Dendritic elongation and retraction events were markedly increased, resulting in a net reduction of total dendritic length (TDL) during the first 2 weeks after denervation, followed by a gradual recovery in TDL. These changes were accompanied by an increase in S1P and S1PR1- and S1PR3-mRNA levels, and were not observed in slice cultures treated with FTY720 or VPC23019. We conclude that inhibition of S1PR signaling prevents dendritic destabilization and denervation-induced dendrite loss. These results suggest a novel neuroprotective effect for pharmaceuticals targeting neural S1PR pathways.
The HITRAP linear decelerator currently being set up at GSI will provide slow, few keV/u highly charged ions for atomic physics experiments. The expected beam intensity is up to 105 ions per shot. To optimize phase and amplitude of the RF systems intensity, bunch length and kinetic energy of the particles need to be monitored. The bunch length that we need to fit is about 2 ns, which is typically measured by capacitive pickups. However, they do not work for the low beam intensities that we face. We investigated the bunch length with a fast CVD diamond detector working in single particle counting mode. Averaging over 8 shots yields a clear, regular picture of the bunched beam. Energy measurements by capacitive pickups are limited by the presence of intense primary and partially decelerated beam and hence make tuning of the IH-structure impossible. The energy of the decelerated fraction of the beam behind the first deceleration cavity was determined to about 10 % accuracy with a permanent dipole magnet combined with a MCP. Better detector calibration should help reaching the required 1%. Design of the detectors as well as the results of the measurements will be presented.
Background: Preclinical studies demonstrate synergism between cancer immunotherapy and local radiation, enhancing anti-tumor effects and promoting immune responses. BI1361849 (CV9202) is an active cancer immunotherapeutic comprising protamine-formulated, sequence-optimized mRNA encoding six non-small cell lung cancer (NSCLC)-associated antigens (NY-ESO-1, MAGE-C1, MAGE-C2, survivin, 5T4, and MUC-1), intended to induce targeted immune responses.
Methods: We describe a phase Ib clinical trial evaluating treatment with BI1361849 combined with local radiation in 26 stage IV NSCLC patients with partial response (PR)/stable disease (SD) after standard first-line therapy. Patients were stratified into three strata (1: non-squamous NSCLC, no epidermal growth factor receptor (EGFR) mutation, PR/SD after ≥4 cycles of platinum- and pemetrexed-based treatment [n = 16]; 2: squamous NSCLC, PR/SD after ≥4 cycles of platinum-based and non-platinum compound treatment [n = 8]; 3: non-squamous NSCLC, EGFR mutation, PR/SD after ≥3 and ≤ 6 months EGFR-tyrosine kinase inhibitor (TKI) treatment [n = 2]). Patients received intradermal BI1361849, local radiation (4 × 5 Gy), then BI1361849 until disease progression. Strata 1 and 3 also had maintenance pemetrexed or continued EGFR-TKI therapy, respectively. The primary endpoint was evaluation of safety; secondary objectives included assessment of clinical efficacy (every 6 weeks during treatment) and of immune response (on Days 1 [baseline], 19 and 61).
Results: Study treatment was well tolerated; injection site reactions and flu-like symptoms were the most common BI1361849-related adverse events. Three patients had grade 3 BI1361849-related adverse events (fatigue, pyrexia); there was one grade 3 radiation-related event (dysphagia). In comparison to baseline, immunomonitoring revealed increased BI1361849 antigen-specific immune responses in the majority of patients (84%), whereby antigen-specific antibody levels were increased in 80% and functional T cells in 40% of patients, and involvement of multiple antigen specificities was evident in 52% of patients. One patient had a partial response in combination with pemetrexed maintenance, and 46.2% achieved stable disease as best overall response. Best overall response was SD in 57.7% for target lesions.
Conclusion: The results support further investigation of mRNA-based immunotherapy in NSCLC including combinations with immune checkpoint inhibitors.
Trial registration: ClinicalTrials.gov identifier: NCT01915524.
Background: The importance of the Notch signaling in the development of glomerular diseases has been recently described. Therefore we analyzed in podocytes the expression and activity of ADAM10, one important component of the Notch signaling complex. Methods: By Western blot, immunofluorescence and immunohistochemistry analysis we characterized the expression of ADAM10 in human podocytes, human urine and human renal tissue. Results: We present evidence, that differentiated human podocytes possessed increased amounts of mature ADAM10 and released elevated levels of L1 adhesion molecule, one well known substrate of ADAM10. By using specific siRNA and metalloproteinase inhibitors we demonstrate that ADAM10 is involved in the cleavage of L1 in human podocytes. Injury of podocytes enhanced the ADAM10 mediated cleavage of L1. In addition, we detected ADAM10 in urinary podocytes from patients with kidney diseases and in tissue sections of normal human kidney. Finally, we found elevated levels of ADAM10 in urinary vesicles of patients with glomerular kidney diseases. Conclusions: The activity of ADAM10 in human podocytes may play an important role in the development of glomerular kidney diseases.
Allogeneic stem cell transplantation (allo-SCT) has become an important treatment modality for patients with high-risk acute myeloid leukemia (AML) and is also under investigation for soft tissue sarcomas. The therapeutic success is still limited by minimal residual disease (MRD) status ultimately leading to patients’ relapse. Adoptive donor lymphocyte infusions based on MRD status using IL-15-expanded cytokine-induced killer (CIK) cells may prevent relapse without causing graft-versus-host-disease (GvHD). To generate preclinical data we developed mouse models to study anti-leukemic- and anti-tumor-potential of CIK cells in vivo. Immunodeficient mice (NOD/SCID/IL-2Rγc−, NSG) were injected intravenously with human leukemic cell lines THP-1, SH-2 and with human rhabdomyosarcoma (RMS) cell lines RH41 and RH30 at minimal doses required for leukemia or tumor engraftment. Mice transplanted with THP-1 or RH41 cells were randomly assigned for analysis of CIK cell treatment. Organs of mice were analyzed by flow cytometry as well as quantitative polymerase chain reaction for engraftment of malignant cells and CIK cells. Potential of CIK cells to induce GvHD was determined by histological analysis. Tissues of the highest degree of THP-1 cell expansion included bone marrow followed by liver, lung, spleen, peripheral blood (PB), and brain. RH30 and RH41 engraftment mainly took place in liver and lung, but was also detectable in spleen and PB. In spite of delayed CIK cell expansion compared with malignant cells, CIK cells injected at equal amounts were sufficient for significant reduction of RH41 cells, whereas against fast-expanding THP-1 cells 250 times more CIK than THP-1 cells were needed to achieve comparable results. Our preclinical in vivo mouse models showed a reliable 100% engraftment of malignant cells which is essential for analysis of anti-cancer therapy. Furthermore our data demonstrated that IL-15-activated CIK cells have potent cytotoxic capacity against AML and RMS cells without causing GvHD.
Objectives: We explore the importance of SARS-CoV-2 sentinel surveillance testing in primary care during a regional COVID-19 outbreak in Austria.
Design: Prospective cohort study.
Setting: A single sentinel practice serving 22 829 people in the ski-resort of Schladming-Dachstein.
Participants: All 73 patients presenting with mild-to-moderate flu-like symptoms between 24 February and 03 April, 2020.
Intervention: Nasopharyngeal sampling to detect SARS-CoV-2 using real-time reverse transcriptase-quantitative PCR (RT-qPCR).
Outcome measures: We compared RT-qPCR at presentation with confirmed antibody status. We split the outbreak in two parts, by halving the period from the first to the last case, to characterise three cohorts of patients with confirmed infection: early acute (RT-qPCR reactive) in the first half; and late acute (reactive) and late convalescent (non-reactive) in the second half. For each cohort, we report the number of cases detected, the accuracy of RT-qPCR, the duration and variety of symptoms, and the number of viral clades present.
Results: Twenty-two patients were diagnosed with COVID-19 (eight early acute, seven late acute and seven late convalescent), 44 patients tested SARS-CoV-2 negative and 7 were excluded. The sensitivity of RT-qPCR was 100% among all acute cases, dropping to 68.1% when including convalescent. Test specificity was 100%. Mean duration of symptoms for each group were 2 days (range 1–4) among early acute, 4.4 days (1–7) among late acute and 8 days (2–12) among late convalescent. Confirmed infection was associated with loss of taste. Acute infection was associated with loss of taste, nausea/vomiting, breathlessness, sore throat and myalgia; but not anosmia, fever or cough. Transmission clusters of three viral clades (G, GR and L) were identified.
Conclusions: RT-qPCR testing in primary care can rapidly and accurately detect SARS-CoV-2 among people with flu-like illness in a heterogeneous viral outbreak. Targeted testing in primary care can support national sentinel surveillance of COVID-19.
Despite the progress to understand inflammatory reactions, mechanisms causing their resolution remain poorly understood. Prostanoids, especially prostaglandin E2 (PGE2), are well-characterized mediators of inflammation. PGE2 is produced in an inducible manner in macrophages (Mϕ) by microsomal PGE2-synthase-1 (mPGES-1), with the notion that it also conveys pro-resolving properties. We aimed to characterize the role of mPGES-1 during resolution of acute, zymosan-induced peritonitis. Experimentally, we applied the mPGES-1 inhibitor compound III (CIII) once the inflammatory response was established and confirmed its potent PGE2-blocking efficacy. mPGES-1 inhibition resulted in an incomplete removal of neutrophils and a concomitant increase in monocytes and Mϕ during the resolution process. The mRNA-seq analysis identified enhanced C-X3-C motif receptor 1 (CX3CR1) expression in resident and infiltrating Mϕ upon mPGES-1 inhibition. Besides elevated Cx3cr1 expression, its ligand CX3CL1 was enriched in the peritoneal lavage of the mice, produced by epithelial cells upon mPGES-1 inhibition. CX3CL1 not only increased adhesion and survival of Mϕ but its neutralization also completely reversed elevated inflammatory cell numbers, thereby normalizing the cellular, peritoneal composition during resolution. Our data suggest that mPGES-1-derived PGE2 contributes to the resolution of inflammation by preventing CX3CL1-mediated retention of activated myeloid cells at sites of injury.
hintergrund: Männer in Deutschland sterben früher als Frauen und nehmen weniger häufig Krebsvorsorgeuntersuchungen wahr.
Fragestellung: Ziel war die prospektive Evaluation einer „Movember-Gesundheitsinitiative“ am Universitätsklinikum Frankfurt (UKF) im November 2019.
Methoden: Im Rahmen der „Movember-Gesundheitsinitiative“ wurde allen männlichen Mitarbeitern des UKF ab dem 45. Lebensjahr und bei erstgradiger familiärer Vorbelastung eines Prostatakarzinoms ab dem 40. Lebensjahr im November 2019 gemäß S3-Leitlinien der Deutschen Gesellschaft für Urologie (DGU) eine Prostatakarzinom-Vorsorgeuntersuchung angeboten.
Ergebnisse: Insgesamt nahmen 14,4 % der Mitarbeiter teil. Eine familiäre Vorbelastung gaben insgesamt 14,0 % Teilnehmer an. Das mediane Alter betrug 54 Jahre. Der mediane PSA(prostataspezifisches Antigen)-Wert lag bei 0,9 ng/ml, der mediane PSA-Quotient bei 30 %. Bei 5 % (n = 6) zeigte sich ein suspekter Tastbefund in der DRU (digital-rektale Untersuchung). Nach Altersstratifizierung (≤ 50 vs. > 50 Lebensjahre) zeigten sich signifikante Unterschiede im medianen PSA-Wert (0,7 ng/ml vs. 1,0 ng/ml, p < 0,01) und der bereits zuvor durchgeführten urologischen Vorsorge (12,1 vs. 42,0 %, p < 0,01). Vier Teilnehmer (3,3 %) zeigten erhöhte Gesamt-PSA-Werte. Bei 32,2 % der Teilnehmer zeigte sich mindestens ein kontrollbedürftiger Befund. Insgesamt wurden 6 Prostatabiopsien durchgeführt. Hierbei zeigte sich in einem Fall ein intermediate-risk Prostatakarzinom (Gleason 3 + 4, pT3a, pPn1, pNx, R0).
Schlussfolgerungung: Im Rahmen der UKF-Movember-Gesundheitsinitiative 2019 konnten durch ein Vorsorgeangebot 121 Männer für eine Prostatakrebs-Vorsorge inklusive PSA-Testung gewonnen werden. Auffällige/kontrollbedürftige Befunde zeigten sich bei 32,2 %. Bei einem Mitarbeiter wurde ein therapiebedürftiges Prostatakarzinom entdeckt und therapiert.
An ever-increasing demand for novel antimicrobials to treat life-threatening infections caused by the global spread of multidrug-resistant bacterial pathogens stands in stark contrast to the current level of investment in their development, particularly in the fields of natural-product-derived and synthetic small molecules. New agents displaying innovative chemistry and modes of action are desperately needed worldwide to tackle the public health menace posed by antimicrobial resistance. Here, our consortium presents a strategic blueprint to substantially improve our ability to discover and develop new antibiotics. We propose both short-term and long-term solutions to overcome the most urgent limitations in the various sectors of research and funding, aiming to bridge the gap between academic, industrial and political stakeholders, and to unite interdisciplinary expertise in order to efficiently fuel the translational pipeline for the benefit of future generations.
Although the 12C(n,p)12B and 12C(n,d)11B reactions are of interest in several fields of basic and applied Nuclear Physics the present knowledge of these two cross-sections is far from being accurate and reliable, with both evaluations and data showing sizable discrepancies. As part of the challenging n_TOF program on (n,cp) nuclear reactions study, the energy differential cross-sections of the 12C(n,p)12B and 12C(n,d)11 B reactions have been measured at CERN from the reaction thresholds up to 30 MeV neutron energy. Both measurements have been recently performed at the long flight-path (185 m) experimental area of the n_TOF facility at CERN using a pure (99.95%) rigid graphite target and two silicon telescopes. In this paper an overview of the experiment is presented together with a few preliminary results.
Background: The potential anti-cancer effects of mammalian target of rapamycin (mTOR) inhibitors are being intensively studied. To date, however, few randomised clinical trials (RCT) have been performed to demonstrate anti-neoplastic effects in the pure oncology setting, and at present, no oncology endpoint-directed RCT has been reported in the high-malignancy risk population of immunosuppressed transplant recipients. Interestingly, since mTOR inhibitors have both immunosuppressive and anti-cancer effects, they have the potential to simultaneously protect against immunologic graft loss and tumour development. Therefore, we designed a prospective RCT to determine if the mTOR inhibitor sirolimus can improve hepatocellular carcinoma (HCC)-free patient survival in liver transplant (LT) recipients with a pre-transplant diagnosis of HCC. Methods: The study is an open-labelled, randomised, RCT comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing LT for HCC. Patients with a histologically confirmed HCC diagnosis are randomised into 2 groups within 4-6 weeks after LT; one arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol and the second arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol for the first 4-6 weeks, at which time sirolimus is initiated. A 3-year recruitment phase is planned with a 5-year follow-up, testing HCC-free survival as the primary endpoint. Our hypothesis is that sirolimus use in the second arm of the study will improve HCC-free survival. The study is a non-commercial investigator-initiated trial (IIT) sponsored by the University Hospital Regensburg and is endorsed by the European Liver and Intestine Transplant Association; 13 countries within Europe, Canada and Australia are participating. Discussion: If our hypothesis is correct that mTOR inhibition can reduce HCC tumour growth while simultaneously providing immunosuppression to protect the liver allograft from rejection, patients should experience less post-transplant problems with HCC recurrence, and therefore could expect a longer and better quality of life. A positive outcome will likely change the standard of posttransplant immunosuppressive care for LT patients with HCC. (trial registered at www.clinicaltrials.gov: NCT00355862) (EudraCT Number: 2005-005362-36)
This report provides a brief review of the 20th annual meeting of the German Language Branch of the Society of Environmental Toxicology and Chemistry (SETAC GLB) held from September 7th to 10th 2015 at ETH (Swiss Technical University) in Zurich, Switzerland. The event was chaired by Inge Werner, Director of the Swiss Centre for Applied Ecotoxicology (Ecotox Centre) Eawag-EPFL, and organized by a team from Ecotox Centre, Eawag, Federal Office of the Environment, Federal Office of Agriculture, and Mesocosm GmbH (Germany). Over 200 delegates from academia, public agencies and private industry of Germany, Switzerland and Austria attended and discussed the current state of science and its application presented in 75 talks and 83 posters. In addition, three invited keynote speakers provided new insights into scientific knowledge ‘brokering’, and—as it was the International Year of Soil—the important role of healthy soil ecosystems. Awards were presented to young scientists for best oral and poster presentations, and for best 2014 master and doctoral theses. Program and abstracts of the meeting (mostly in German) are provided as Additional file 1.
The German postgraduate degree program in ecotoxicology (SETAC GLB and GDCh) : a success story
(2016)
This article gives a comprehensive overview on the strategy, the development and the progress of the German postgraduate degree program in ecotoxicology (SETAC GLB and GDCh). The program soon prompted positive results: more than 10 years now the courses had an average enrolment rate of 90 %, and employment-seeking graduates from the first courses mostly succeeded in quickly finding employment relevant to their training. With over 450 students enrolled to date, the degree program contributes significantly to the field of Environmental Chemistry and Ecotoxicology.
Profiles of CFC-11 (CCl3F) and CFC-12 (CCl2F2) of the Michelson Interferometer for Passive Atmospheric Sounding (MIPAS) aboard the European satellite Envisat have been retrieved from versions MIPAS/4.61 to MIPAS/4.62 and MIPAS/5.02 to MIPAS/5.06 level-1b data using the scientific level-2 processor run by Karlsruhe Institute of Technology (KIT), Institute of Meteorology and Climate Research (IMK) and Consejo Superior de Investigaciones Científicas (CSIC), Instituto de Astrofísica de Andalucía (IAA). These profiles have been compared to measurements taken by the balloon-borne cryosampler, Mark IV (MkIV) and MIPAS-Balloon (MIPAS-B), the airborne MIPAS-STRatospheric aircraft (MIPAS-STR), the satellite-borne Atmospheric Chemistry Experiment Fourier transform spectrometer (ACE-FTS) and the High Resolution Dynamic Limb Sounder (HIRDLS), as well as the ground-based Halocarbon and other Atmospheric Trace Species (HATS) network for the reduced spectral resolution period (RR: January 2005–April 2012) of MIPAS. ACE-FTS, MkIV and HATS also provide measurements during the high spectral resolution period (full resolution, FR: July 2002–March 2004) and were used to validate MIPAS CFC-11 and CFC-12 products during that time, as well as profiles from the Improved Limb Atmospheric Spectrometer, ILAS-II. In general, we find that MIPAS shows slightly higher values for CFC-11 at the lower end of the profiles (below ∼ 15 km) and in a comparison of HATS ground-based data and MIPAS measurements at 3 km below the tropopause. Differences range from approximately 10 to 50 pptv ( ∼ 5–20 %) during the RR period. In general, differences are slightly smaller for the FR period. An indication of a slight high bias at the lower end of the profile exists for CFC-12 as well, but this bias is far less pronounced than for CFC-11 and is not as obvious in the relative differences between MIPAS and any of the comparison instruments. Differences at the lower end of the profile (below ∼ 15 km) and in the comparison of HATS and MIPAS measurements taken at 3 km below the tropopause mainly stay within 10–50 pptv (corresponding to ∼ 2–10 % for CFC-12) for the RR and the FR period. Between ∼ 15 and 30 km, most comparisons agree within 10–20 pptv (10–20 %), apart from ILAS-II, which shows large differences above ∼ 17 km. Overall, relative differences are usually smaller for CFC-12 than for CFC-11. For both species – CFC-11 and CFC-12 – we find that differences at the lower end of the profile tend to be larger at higher latitudes than in tropical and subtropical regions. In addition, MIPAS profiles have a maximum in their mixing ratio around the tropopause, which is most obvious in tropical mean profiles. Comparisons of the standard deviation in a quiescent atmosphere (polar summer) show that only the CFC-12 FR error budget can fully explain the observed variability, while for the other products (CFC-11 FR and RR and CFC-12 RR) only two-thirds to three-quarters can be explained. Investigations regarding the temporal stability show very small negative drifts in MIPAS CFC-11 measurements. These instrument drifts vary between ∼ 1 and 3 % decade−1. For CFC-12, the drifts are also negative and close to zero up to ∼ 30 km. Above that altitude, larger drifts of up to ∼ 50 % decade−1 appear which are negative up to ∼ 35 km and positive, but of a similar magnitude, above.
The ENVISAT validation programme for the atmospheric instruments MIPAS, SCIAMACHY and GOMOS is based on a number of balloon-borne, aircraft, satellite and ground-based correlative measurements. In particular the activities of validation scientists were coordinated by ESA within the ENVISAT Stratospheric Aircraft and Balloon Campaign or ESABC. As part of a series of similar papers on other species [this issue] and in parallel to the contribution of the individual validation teams, the present paper provides a synthesis of comparisons performed between MIPAS CH4 and N2O profiles produced by the current ESA operational software (Instrument Processing Facility version 4.61 or IPF v4.61, full resolution MIPAS data covering the period 9 July 2002 to 26 March 2004) and correlative measurements obtained from balloon and aircraft experiments as well as from satellite sensors or from ground-based instruments. In the middle stratosphere, no significant bias is observed between MIPAS and correlative measurements, and MIPAS is providing a very consistent and global picture of the distribution of CH4 and N2O in this region. In average, the MIPAS CH4 values show a small positive bias in the lower stratosphere of about 5%. A similar situation is observed for N2O with a positive bias of 4%. In the lower stratosphere/upper troposphere (UT/LS) the individual used MIPAS data version 4.61 still exhibits some unphysical oscillations in individual CH4 and N2O profiles caused by the processing algorithm (with almost no regularization). Taking these problems into account, the MIPAS CH4 and N2O profiles are behaving as expected from the internal error estimation of IPF v4.61 and the estimated errors of the correlative measurements.
The three-dimensional quantification of small scale processes in the upper troposphere and lower stratosphere is one of the challenges of current atmospheric research and requires the development of new measurement strategies. This work presents first results from the newly developed Gimballed Limb Observer for Radiance Imaging of the Atmosphere (GLORIA) obtained during the ESSenCe and TACTS/ESMVal aircraft campaigns. The focus of this work is on the so-called dynamics mode data characterized by a medium spectral and a very high spatial resolution. The retrieval strategy for the derivation of two- and three-dimensional constituent fields in the upper troposphere and lower stratosphere is presented. Uncertainties of the main retrieval targets (temperature, O3, HNO3 and CFC-12) and their spatial resolution are discussed. During ESSenCe, high resolution two-dimensional cross-sections have been obtained. Comparisons to collocated remote-sensing and in-situ data indicate a good agreement between the data sets. During TACTS/ESMVal a tomographic flight pattern to sense an intrusion of stratospheric air deep into the troposphere has been performed. This filament could be reconstructed with an unprecedented spatial resolution of better than 500 m vertically and 20 km × 20 km horizontally.
Estimates of the recovery time of stratospheric ozone heavily rely on the exact knowledge of the processes that lead to the decomposition of the relevant halogenated source gases. Crucial parameters in this context are Fractional Release Factors (FRFs) as well as stratospheric lifetimes and Ozone Depletion Potentials (ODPs). We here present data from the analysis of air samples collected between 2009 and 2011 on board research aircraft flying in the mid- and high latitudinal stratosphere and infer the above-mentioned parameters for ten major source gases:CFCl3 (CFC-11), CF2Cl2 (CFC-12), CF2ClCFCl2(CFC-113), CCl4 (carbon tetrachloride),CH3CCl3 (methyl chloroform), CHF2Cl (HCFC-22), CH3CFCl2 (HCFC-141b), CH3CF2Cl (HCFC-142b), CF2ClBr (H-1211), and CF3Br (H-1301). The inferred correlations of their FRFs with mean ages of air reveal less decomposition as compared to previous studies for most compounds. When using the calculated set of FRFs to infer equivalent stratospheric chlorine we find a reduction of more than 20% as compared to the values inferred in the most recent Scientific Assessment of Ozone Depletion by the World Meteorological Organisation (WMO, 2011). We also note that FRFs and their correlations with mean age are not generally time-independent as often assumed. The stratospheric lifetimes were calculated relative to that of CFC-11. Within our uncertainties the inferred ratios between lifetimes agree with those between stratospheric lifetimes from recent WMO reports except for CFC-11, CFC-12 and CH3CCl3. Finally we calculate lower ODPs than WMO for six out of ten compounds with changes most pronounced for the three HCFCs. Collectively these newly calculated values may have important implications for the severity and recovery time of stratospheric ozone loss.
Chlorine monoxide (ClO) plays a key role in stratospheric ozone loss processes at midlatitudes. We present two balloonborne in situ measurements of ClO conducted in northern hemisphere midlatitudes during the period of the maximum of total inorganic chlorine loading in the atmosphere. Both ClO measurements were conducted on board the TRIPLE balloon payload, launched in November 1996 in Le´on, Spain, and in May 1999 in Aire sur l’Adour, France. For both flights a ClO daylight and night time vertical profile could be derived over an altitude range of approximately 15–31 km. ClO mixing ratios are compared to model simulations performed with the photochemical box model version of the Chemical Lagrangian Model of the Stratosphere (CLaMS). Simulations along 24-h backward trajectories were performed to study the diurnal variation of ClO in the midlatitude lower stratosphere. Model simulations for the flight launched in Aire sur l’Adour 1999 show a good agreement with the ClO measurements. For the flight launched in Le´on 1996, a similar good agreement is found, except at around ~ 650 K potential temperature (~26km altitude). However, a tendency is found that for solar zenith angles greater than 86°–87° the simulated ClO mixing ratios substantially overestimate measured ClO by approximately a factor of 2.5 or more for both flights. Therefore we conclude that no indication can be deduced from the presented ClO measurements that substantial uncertainties exist in midlatitude chlorine chemistry of the stratosphere. An exception is the situation at solar zenith angles greater than 86°–87° where model simulations substantial overestimate ClO observations.
AirCore samplers have been increasingly used to capture vertical profiles of trace gases reaching from the ground up to about 30 km, in order to validate remote sens- ing instruments and to investigate transport processes in the stratosphere. When deployed to a weather balloon, accu- rately attributing the trace gas measurements to the sampling altitudes is nontrivial, especially in the stratosphere. In this paper we present the CO-spiking experiment, which can be deployed to any AirCore on any platform in order to evalu- ate different computational altitude attribution processes and to experimentally derive the vertical resolution of the profile by injecting small volumes of signal gas at predefined GPS altitudes during sampling. We performed two CO-spiking flights with an AirCore from the Goethe University Frankfurt (GUF) deployed to a weather balloon in Traînou, France, in June 2019. The altitude retrieval based on an instantaneous pressure equilibrium assumption slightly overestimates the sampling altitudes, especially at the top of the profiles. For these two flights our altitude attribution is accurate within 250 m below 20 km. Above 20 km the positive bias becomes larger and reaches up to 1.2 km at 27 km altitude. Differences in descent velocities are shown to have a major impact on the altitude attribution bias. We parameterize the time lag between the theoretically attributed altitude and the actual CO-spike release altitude for both flights together and use it to empirically correct our AirCore altitude retrieval. Regard- ing the corrected profiles, the altitude attribution is accurate within ±120 m throughout the profile. Further investigations are needed in order to test for the scope of validity of this correction parameter regarding different ambient conditions and maximum flight altitudes. We derive the vertical resolu- tion from the CO spikes of both flights and compare it to the modeled vertical resolution. The modeled vertical resolution is too optimistic compared to the experimentally derived res- olution throughout the profile, albeit agreeing within 220 m. All our findings derived from the two CO-spiking flights are strictly bound to the GUF AirCore dimensions. The newly introduced CO-spiking experiment can be used to test differ- ent combinations of AirCore configurations and platforms in future studies.
We conduct a field experiment with clients of a German universal bank to explore the impact of peer information on sustainable retail investments. Our results show that infor-mation about peers’ inclination towards sustainable investing raises the amount allocated to stock funds labeled sustainable, when communicated during a buying decision. This effect is primarily driven by participants initially underestimating peers’ propensity to invest sustainably. Further, treated individuals indicate an increased interest in addi-tional information on sustainable investments, primarily on risk and return expectations. However, when analyzing account-level portfolio holding data over time, we detect no spillover effects of peer information on later sustainable investment decisions.
The ENVISAT validation programme for the atmospheric instruments MIPAS, SCIAMACHY and GOMOS is based on a number of balloon-borne, aircraft, satellite and ground-based correlative measurements. In particular the activities of validation scientists were coordinated by ESA within the ENVISAT Stratospheric Aircraft and Balloon Campaign or ESABC. As part of a series of similar papers on other species [this issue] and in parallel to the contribution of the individual validation teams, the present paper provides a synthesis of comparisons performed between MIPAS CH4 and N2O profiles produced by the current ESA operational software (Instrument Processing Facility version 4.61 or IPF v4.61, full resolution MIPAS data covering the period 9 July 2002 to 26 March 2004) and correlative measurements obtained from balloon and aircraft experiments as well as from satellite sensors or from ground-based instruments. In the middle stratosphere, no significant bias is observed between MIPAS and correlative measurements, and MIPAS is providing a very consistent and global picture of the distribution of CH4 and N2O in this region. In average, the MIPAS CH4 values show a small positive bias in the lower stratosphere of about 5%. A similar situation is observed for N2O with a positive bias of 4%. In the lower stratosphere/upper troposphere (UT/LS) the individual used MIPAS data version 4.61 still exhibits some unphysical oscillations in individual CH4 and N2O profiles caused by the processing algorithm (with almost no regularization). Taking these problems into account, the MIPAS CH4 and N2O profiles are behaving as expected from the internal error estimation of IPF v4.61 and the estimated errors of the correlative measurements.
Estimates of the recovery time of stratospheric ozone heavily rely on the exact knowledge of the processes that lead to the decomposition of the relevant halogenated source gases. Crucial parameters in this context are fractional release factors (FRFs) as well as stratospheric lifetimes and ozone depletion potentials (ODPs). We here present data from the analysis of air samples collected between 2009 and 2011 on board research aircraft flying in the mid- and high-latitude stratosphere and infer the above-mentioned parameters for ten major source gases: CFCl3 (CFC-11), CF2Cl2 (CFC-12), CF2ClCFCl2 (CFC-113), CCl4 (carbon tetrachloride), CH3CCl3 (methyl chloroform), CHF2Cl (HCFC-22), CH3CFCl2 (HCFC-141b), CH3CF2Cl (HCFC-142b), CF2ClBr (H-1211), and CF3Br (H-1301). The inferred correlations of their FRFs with mean ages of air reveal less decomposition as compared to previous studies for most compounds. When using the calculated set of FRFs to infer equivalent stratospheric chlorine, we find a reduction of more than 20% as compared to the values inferred in the most recent Scientific Assessment of Ozone Depletion by the World Meteorological Organisation (WMO, 2011). We also note that FRFs and their correlations with mean age are not generally time-independent as often assumed. The stratospheric lifetimes were calculated relative to that of CFC-11. Within our uncertainties the ratios between stratospheric lifetimes inferred here agree with the values in recent WMO reports except for CFC-11, CFC-12 and CH3CCl3. Finally, we calculate lower ODPs than recommended by WMO for six out of ten compounds, with changes most pronounced for the three HCFCs. Collectively these newly calculated values may have important implications for the severity and recovery time of stratospheric ozone loss.
The three-dimensional quantification of small-scale processes in the upper troposphere and lower stratosphere is one of the challenges of current atmospheric research and requires the development of new measurement strategies. This work presents the first results from the newly developed Gimballed Limb Observer for Radiance Imaging of the Atmosphere (GLORIA) obtained during the ESSenCe (ESa Sounder Campaign) and TACTS/ESMVal (TACTS: Transport and composition in the upper troposphere/lowermost stratosphere, ESMVal: Earth System Model Validation) aircraft campaigns. The focus of this work is on the so-called dynamics-mode data characterized by a medium-spectral and a very-high-spatial resolution. The retrieval strategy for the derivation of two- and three-dimensional constituent fields in the upper troposphere and lower stratosphere is presented. Uncertainties of the main retrieval targets (temperature, O3, HNO3, and CFC-12) and their spatial resolution are discussed. During ESSenCe, high-resolution two-dimensional cross-sections have been obtained. Comparisons to collocated remote-sensing and in situ data indicate a good agreement between the data sets. During TACTS/ESMVal, a tomographic flight pattern to sense an intrusion of stratospheric air deep into the troposphere was performed. It was possible to reconstruct this filament at an unprecedented spatial resolution of better than 500 m vertically and 20 × 20 km horizontally.
Fractional release factors of long-lived halogenated organic compounds in the tropical stratosphere
(2010)
Fractional release factors (FRFs) of organic trace gases are time-independent quantities that influence the calculation of Global Warming Potentials and Ozone Depletion Potentials. We present the first set of vertically resolved FRFs for 15 long-lived halocarbons in the tropical stratosphere up to 34 km altitude. They were calculated from measurements on air samples collected on board balloons and a high altitude aircraft. We compare the derived dependencies of FRFs on the mean stratospheric transit times (the so-called mean ages of air) with similarly derived FRFs originating from measurements at higher latitudes and find significant differences. Moreover a comparison with averaged FRFs currently used by the World Meteorological Organisation revealed the limitations of these measures due to their observed vertical and latitudinal variability. The presented data set could be used to improve future ozone level and climate projections.
The first concerted multi-model intercomparison of halogenated very short-lived substances (VSLS) has been performed, within the framework of the ongoing Atmospheric Tracer Transport Model Intercomparison Project (TransCom). Eleven global models or model variants participated (nine chemical transport models and two chemistry–climate models) by simulating the major natural bromine VSLS, bromoform (CHBr3) and dibromomethane (CH2Br2), over a 20-year period (1993–2012). Except for three model simulations, all others were driven offline by (or nudged to) reanalysed meteorology. The overarching goal of TransCom-VSLS was to provide a reconciled model estimate of the stratospheric source gas injection (SGI) of bromine from these gases, to constrain the current measurement-derived range, and to investigate inter-model differences due to emissions and transport processes. Models ran with standardised idealised chemistry, to isolate differences due to transport, and we investigated the sensitivity of results to a range of VSLS emission inventories. Models were tested in their ability to reproduce the observed seasonal and spatial distribution of VSLS at the surface, using measurements from NOAA's long-term global monitoring network, and in the tropical troposphere, using recent aircraft measurements – including high-altitude observations from the NASA Global Hawk platform.
The models generally capture the observed seasonal cycle of surface CHBr3 and CH2Br2 well, with a strong model–measurement correlation (r ≥ 0.7) at most sites. In a given model, the absolute model–measurement agreement at the surface is highly sensitive to the choice of emissions. Large inter-model differences are apparent when using the same emission inventory, highlighting the challenges faced in evaluating such inventories at the global scale. Across the ensemble, most consistency is found within the tropics where most of the models (8 out of 11) achieve best agreement to surface CHBr3 observations using the lowest of the three CHBr3 emission inventories tested (similarly, 8 out of 11 models for CH2Br2). In general, the models reproduce observations of CHBr3 and CH2Br2 obtained in the tropical tropopause layer (TTL) at various locations throughout the Pacific well. Zonal variability in VSLS loading in the TTL is generally consistent among models, with CHBr3 (and to a lesser extent CH2Br2) most elevated over the tropical western Pacific during boreal winter. The models also indicate the Asian monsoon during boreal summer to be an important pathway for VSLS reaching the stratosphere, though the strength of this signal varies considerably among models.
We derive an ensemble climatological mean estimate of the stratospheric bromine SGI from CHBr3 and CH2Br2 of 2.0 (1.2–2.5) ppt, ∼ 57 % larger than the best estimate from the most recent World Meteorological Organization (WMO) Ozone Assessment Report. We find no evidence for a long-term, transport-driven trend in the stratospheric SGI of bromine over the simulation period. The transport-driven interannual variability in the annual mean bromine SGI is of the order of ±5 %, with SGI exhibiting a strong positive correlation with the El Niño–Southern Oscillation (ENSO) in the eastern Pacific. Overall, our results do not show systematic differences between models specific to the choice of reanalysis meteorology, rather clear differences are seen related to differences in the implementation of transport processes in the models.
The first concerted multi-model intercomparison of halogenated very short-lived substances (VSLS) has been performed, within the framework of the ongoing Atmospheric Tracer Transport Model Intercomparison Project (TransCom). Eleven global models or model variants participated, simulating the major natural bromine VSLS, bromoform (CHBr3) and dibromomethane (CH2Br2), over a 20-year period (1993-2012). The overarching goal of TransCom-VSLS was to provide a reconciled model estimate of the stratospheric source gas injection (SGI) of bromine from these gases, to constrain the current measurement-derived range, and to investigate inter-model differences
due to emissions and transport processes. Models ran with standardised idealised chemistry, to isolate differences due to transport, and we investigated the sensitivity of results to a range of VSLS emission inventories. Models were tested in their ability to reproduce the observed seasonal and spatial distribution of VSLS at the surface, using measurements from NOAA’s long-term global monitoring network, and in the tropical troposphere, using recent aircraft measurements - including high altitude observations from the NASA Global Hawk platform.
The models generally capture the seasonal cycle of surface CHBr3 and CH2Br2 well, with a strong model measurement correlation (r ≥0.7) and a low sensitivity to the choice of emission inventory, at most sites. In a given model, the absolute model-measurement agreement is highly sensitive to the choice of emissions and inter-model differences are also apparent, even when using the same inventory, highlighting the challenges faced in evaluating such inventories at the global scale. Across the ensemble, most consistency is found within the tropics where most of the models (8 out of 11) achieve optimal agreement to surface CHBr3 observations using the lowest of the three CHBr3 emission inventories tested (similarly, 8 out of 11 models for CH2Br2). In general, the models are able to reproduce well observations of CHBr3 and CH2Br2 obtained in the tropical tropopause layer (TTL) at various locations throughout the Pacific. Zonal variability in VSLS loading in the TTL is generally consistent among models, with CHBr3 (and to a lesser extent CH2Br2) most elevated over the tropical West Pacific during boreal winter. The models also indicate the Asian Monsoon during boreal summer to be an important pathway for VSLS reaching the stratosphere, though the strength of this signal varies considerably among models.
We derive an ensemble climatological mean estimate of the stratospheric bromine SGI from CHBr3 and CH2Br2 of 2.0 (1.2-2.5) ppt, ∼57% larger than the best estimate from the most re- cent World Meteorological Organization (WMO) Ozone Assessment Report. We find no evidence for a long-term, transport-driven trend in the stratospheric SGI of bromine over the simulation period. However, transport-driven inter-annual variability in the annual mean bromine SGI is of the order of a ±5%, with SGI exhibiting a strong positive correlation with ENSO in the East Pacific
The isotopic composition of methane in the stratosphere : high-altitude balloon sample measurements
(2011)
The isotopic composition of stratospheric methane has been determined on a large suite of air samples from stratospheric balloon flights covering subtropical to polar latitudes and a time period of 16 yr. 154 samples were analyzed for δC and 119 samples for δD, increasing the previously published dataset for balloon borne samples by an order of magnitude, and more than doubling the total available stratospheric data (including aircraft samples) published to date. The samples also cover a large range in mixing ratio from tropospheric values near 1800 ppb down to only 250 ppb, and the strong isotope fractionation processes accordingly increase the isotopic composition up to δ13C=−14‰ and δD= +190‰, the largest enrichments observed for atmospheric CH4 so far. When analyzing and comparing kinetic isotope effects (KIEs) derived from single balloon profiles, it is necessary to take into account the residence time in the stratosphere in combination with the observed mixing ratio and isotope trends in the troposphere, and the range of isotope values covered by the individual profile. Temporal isotope trends can also be determined in the stratosphere and compare reasonably well with the tropospheric trends. The effects of chemical and dynamical processes on the isotopic composition of CH4 in the stratosphere are discussed in detail. Different ways to interpret the data in terms of the relative fractions of the three important sink mechanisms (reaction with OH, O(1D)) and Cl, respectively), and their limitations, are investigated. The classical approach of using global mean KIE values can be strongly biased when profiles with different minimum mixing ratios are compared. Approaches for more local KIE investigations are suggested. It is shown that any approach for a formal sink partitioning from the measured data severely underestimates the fraction removed by OH, which is likely due to the insensitivity of the measurements to the kinetic fractionation in the lower stratosphere. Attempts can be made to correct for the lower stratospheric sink bias, but full quantitative interpretation of the CH4 isotope data in terms of the three sink reactions requires a global model.
The isotopic composition of methane in the stratosphere : high-altitude balloon sample measurements
(2011)
The isotopic composition of stratospheric methane has been determined on a large suite of air samples from stratospheric balloon flights covering subtropical to polar latitudes and a time period of 16 yr. 154 samples were analyzed for δ13C and 119 samples for δD, increasing the previously published dataset for balloon borne samples by an order of magnitude, and more than doubling the total available stratospheric data (including aircraft samples) published to date. The samples also cover a large range in mixing ratio from tropospheric values near 1800 ppb down to only 250 ppb, and the strong isotope fractionation processes accordingly increase the isotopic composition up to δ13C = −14‰ and δD = +190‰, the largest enrichments observed for atmospheric CH4 so far. When analyzing and comparing kinetic isotope effects (KIEs) derived from single balloon profiles, it is necessary to take into account the residence time in the stratosphere in combination with the observed mixing ratio and isotope trends in the troposphere, and the range of isotope values covered by the individual profile. The isotopic composition of CH4 in the stratosphere is affected by both chemical and dynamical processes. This severely hampers interpretation of the data in terms of the relative fractions of the three important sink mechanisms (reaction with OH, O(1D) and Cl). It is shown that a formal sink partitioning using the measured data severely underestimates the fraction removed by OH, which is likely due to the insensitivity of the measurements to the kinetic fractionation in the lower stratosphere. Full quantitative interpretation of the CH4 isotope data in terms of the three sink reactions requires a global model.
An accelerating Brewer-Dobson circulation (BDC) is a robust signal of climate change in model predictions but has been questioned by trace gas observations. We analyze stratospheric mean age of air and the full age spectrum as measures for the BDC and its trend. Age of air is calculated with the Chemical Lagrangian Model of the Stratosphere (CLaMS) driven by ERA-Interim, JRA-55 and MERRA-2 reanalysis data to assess the robustness of the representation of the BDC in current generation meteorological reanalyses. We find that climatological mean age significantly depends on the reanalysis, with JRA-55 showing the youngest and MERRA-2 the oldest mean age. Consideration of the age spectrum indicates that the older age for MERRA-2 is related to a stronger spectrum tail, likely related to weaker tropical upwelling and stronger recirculation. Seasonality of stratospheric transport is robustly represented in reanalyses, with similar mean age variations and age spectrum peaks. Long-term changes over 1989–2015 turn out to be similar for the reanalyses with mainly decreasing mean age accompanied by a shift of the age spectrum peak towards shorter transit times, resembling the forced response in climate model simulations to increasing greenhouse gas concentrations. For the shorter periods 1989–2001 and 2002–2015 age of air changes are less robust. Only ERA-Interim shows the hemispheric dipole pattern in age changes during 2002–2015 as viewed by recent satellite observations. Consequently, the representation of decadal variability of the BDC in current generation reanalyses appears less robust and a major uncertainty of modelling the BDC.
Chlorine monoxide (ClO) plays a key role in stratospheric ozone loss processes at midlatitudes. We present two balloon-borne in situ measurements of ClO conducted in northern hemisphere midlatitudes during the period of the maximum of total inorganic chlorine loading in the atmosphere. Both ClO measurements were conducted on board the TRIPLE balloon payload, launched in November 1996 in León, Spain, and in May 1999 in Aire sur l'Adour, France. For both flights a ClO daylight and night-time vertical profile was derived over an altitude range of approximately 15-35 km. ClO mixing ratios are compared to model simulations performed with the photochemical box model version of the Chemical Lagrangian Model of the Stratosphere (CLaMS). Simulations along 24-hour backward trajectories were performed to study the diurnal variation of ClO in the midlatitude lower stratosphere. Model simulations for the flight launched in Aire sur l'Adour 1999 show an excellent agreement with the ClO measurements. For the flight launched in León 1996, an overall good agreement is found, whereas the flight is characterized by a more complex dynamical situation due to a possible mixture of vortex and non-vortex air. We note that for both flights at solar zenith angles greater than 86°-87° simulated ClO mixing ratios are higher than observed ClO mixing ratios. However, the present findings indicate that no substantial uncertainties exist in midlatitude chlorine chemistry of the stratosphere.
Fractional release factors of long-lived halogenated organic compounds in the tropical stratosphere
(2009)
Fractional release factors (FRFs) of organic trace gases are time-independent quantities that influence the calculation of Global Warming Potentials and Ozone Depletion Potentials. We present the first set of vertically resolved FRFs for 15 long-lived halo carbons in the tropical stratosphere up to 34 km altitude. They were calculated from measurements on air samples collected on board balloons and a high altitude aircraft. We compare the derived dependencies of FRFs on the mean stratospheric transit times (the so-called mean ages of air) with similarly derived FRFs originating from measurements at higher latitudes and find significant differences. Moreover a comparison with averaged FRFs currently used by the World Meteorological Organisation revealed the latter to be imprecise measures due to their observed vertical and latitudinal variability. The presented data set could thus be used to improve future ozone level and climate projections.
Creatinine and proteinuria are used to monitor kidney transplant patients. However, renal biopsies are needed to diagnose renal graft rejection. Here, we assessed whether the quantification of different urinary cells would allow non-invasive detection of rejection. Urinary cell numbers of CD4+ and CD8+ T cells, monocytes/macrophages, tubular epithelial cells (TEC), and podocalyxin(PDX)-positive cells were determined using flow cytometry and were compared to biopsy results. Urine samples of 63 renal transplant patients were analyzed. Patients with transplant rejection had higher amounts of urinary T cells than controls; however, patients who showed worsening graft function without rejection had similar numbers of T cells. T cells correlated with histological findings (interstitial inflammation p = 0.0005, r = 0.70; tubulitis p = 0.006, r = 0.58). Combining the amount of urinary T cells and TEC, or T cells and PDX+ cells, yielded a significant segregation of patients with rejection from patients without rejection (all p < 0.01, area under the curve 0.89–0.91). Urinary cell populations analyzed by flow cytometry have the potential to introduce new monitoring methods for kidney transplant patients. The combination of urinary T cells, TEC, and PDX-positive cells may allow non-invasive detection of transplant rejection.
The assembly of a specific polymeric ubiquitin chain on a target protein is a key event in the regulation of numerous cellular processes. Yet, the mechanisms that govern the selective synthesis of particular polyubiquitin signals remain enigmatic. The homologous ubiquitin-conjugating (E2) enzymes Ubc1 (budding yeast) and Ube2K (mammals) exclusively generate polyubiquitin linked through lysine 48 (K48). Uniquely among E2 enzymes, Ubc1 and Ube2K harbor a ubiquitin-binding UBA domain with unknown function. We found that this UBA domain preferentially interacts with ubiquitin chains linked through lysine 63 (K63). Based on structural modeling, in vitro ubiquitination experiments, and NMR studies, we propose that the UBA domain aligns Ubc1 with K63-linked polyubiquitin and facilitates the selective assembly of K48/K63-branched ubiquitin conjugates. Genetic and proteomics experiments link the activity of the UBA domain, and hence the formation of this unusual ubiquitin chain topology, to the maintenance of cellular proteostasis.
Wastewater-based epidemiology (WBE) has demonstrated its importance to support SARS-CoV-2 epidemiology complementing individual testing strategies. Due to their immune-evasive potential and the resulting significance for public health, close monitoring of SARS-CoV-2 variants of concern (VoC) is required to evaluate the regulation of early local countermeasures. In this study, we demonstrate a rapid workflow for wastewater-based early detection and monitoring of the newly emerging SARS-CoV-2 VoCs Omicron in the end of 2021 at the municipal wastewater treatment plant (WWTP) Emschermuendung (KLEM) in the Federal State of North-Rhine-Westphalia (NRW, Germany).
Initially, available primers detecting Omicron-related mutations were rapidly validated in a central laboratory. Subsequently, RT-qPCR analysis of purified SARS-CoV-2 RNA was performed in a decentral PCR laboratory in close proximity to KLEM. This decentralized approach enabled the early detection of K417N present in Omicron in samples collected on 8th December 2021 and the detection of further mutations (N501Y, Δ69/70) in subsequent biweekly sampling campaigns. The presence of Omicron in wastewater was confirmed by next generation sequencing (NGS) in a central laboratory with samples obtained on 14th December 2021. Moreover, the relative increase of the mutant fraction of Omicron was quantitatively monitored over time by dPCR in a central PCR laboratory starting on 12th December 2021 confirming Omicron as the dominant variant by the end of 2021.
In conclusions, WBE plays a crucial role in surveillance of SARS-CoV-2 variants and is suitable as an early warning system to identify variant emergence. In particular, the successive workflow using RT-qPCR, RT-dPCR and NGS demonstrates the strength of WBE as a versatile tool to monitor variant spreading.
Purpose: Surgery of KOOS IV vestibular schwannoma remains challenging regarding the balance of extent of tumor resection (EoR) and functional outcome. Our aim was to evaluate the outcome of surgical resection and define a cut-off value for safe resection with low risk for tumor regrowth of KOOS IV vestibular schwannoma.
Methods: All patients presenting at the authors’ institution between 2000 and 2019 with surgically treated KOOS IV vestibular schwannoma were included. Outcome measures included EoR, facial/hearing nerve function, surgical complications and progression of residual tumor during the median follow-up period of 28 months.
Results: In 58 patients, mean tumor volume was 17.1 ± 9.2 cm3, and mean EoR of 81.6 ± 16.8% could be achieved. Fifty-one patients were available for the follow-up analysis. Growth of residual tumor was observed in 11 patients (21.6%) followed by adjuvant treatment with stereotactic radiosurgery or repeat surgery in 15 patients (29.4%). Overall serviceable hearing preservation was achieved in 38 patients (74.5%) and good facial outcome at discharge was observed in 66.7% of patients, significantly increasing to 82.4% at follow-up. Independent predictors for residual tumor growth was EoR ≤ 87% (OR11.1) with a higher EoR being associated with a very low number of residual tumor progression amounting to 7.1% at follow-up (p=0.008).
Conclusions: Subtotal tumor resection is a good therapeutic concept in patients with KOOS IV vestibular schwannoma resulting in a high rate of good hearing and facial nerve function and a very low rate of subsequent tumor progression. The goal of surgery should be to achieve more than 87% of tumor resection to keep residual tumor progression low.
Improved integration of single cell transcriptome data demonstrated on heart failure in mice and men
(2023)
Biomedical research frequently uses murine models to study disease mechanisms. However, the translation of these findings to human disease remains a significant challenge. In order to improve the comparability of mouse and human data, we present a cross-species integration pipeline for single-cell transcriptomic assays.
The pipeline merges expression matrices and assigns clear orthologous relationships. Starting from Ensembl ortholog assignments, we allocated 82% of mouse genes to unique orthologs by using additional publicly available resources such as Uniprot, and NCBI databases. For genes with multiple matches, we employed the Needleman-Wunsch global alignment based on either amino acid or nucleotide sequence to identify the ortholog with the highest degree of similarity.
The workflow was tested for its functionality and efficiency by integrating scRNA-seq datasets from heart failure patients with the corresponding mouse model. We were able to assign unique human orthologs to up to 80% of the mouse genes, utilizing the known 17,492 orthologous pairs. Curiously, the integration process enabled the identification of both common and unique regulatory pathways between species in heart failure.
In conclusion, our pipeline streamlines the integration process, enhances gene nomenclature alignment and simplifies the translation of mouse models to human disease. We have made the OrthoIntegrate R-package accessible on GitHub (https://github.com/MarianoRuzJurado/OrthoIntegrate), which includes the assignment of ortholog definitions for human and mouse, as well as the pipeline for integrating single cells.
Wastewater-based SARS-CoV-2 epidemiology (WBE) has been established as an important tool to support individual testing strategies. The Omicron sub-variants BA.4/BA.5 have spread globally, displacing the preceding variants. Due to the severe transmissibility and immune escape potential of BA.4/BA.5, early monitoring was required to assess and implement countermeasures in time. In this study, we monitored the prevalence of SARS-CoV-2 BA.4/BA.5 at six municipal wastewater treatment plants (WWTPs) in the Federal State of North Rhine-Westphalia (NRW, Germany) in May and June 2022. Initially, L452R-specific primers/probes originally designed for SARS-CoV-2 Delta detection were validated using inactivated authentic viruses and evaluated for their suitability for detecting BA.4/BA.5. Subsequently, the assay was used for RT-qPCR analysis of RNA purified from wastewater obtained twice a week at six WWTPs. The occurrence of L452R carrying RNA was detected in early May 2022, and the presence of BA.4/BA.5 was confirmed by variant-specific single nucleotide polymorphism PCR (SNP-PCR) targeting E484A/F486V and NGS sequencing. Finally, the mutant fractions were quantitatively monitored by digital PCR, confirming BA.4/BA.5 as the majority variant by 5 June 2022. In conclusion, the successive workflow using RT-qPCR, variant-specific SNP-PCR, and RT-dPCR demonstrates the strength of WBE as a versatile tool to rapidly monitor variants spreading independently of individual test capacities.
Wastewater-based SARS-CoV-2 epidemiology (WBE) has been established as an important tool to support individual testing strategies. Omicron sub-variants BA.4/5 have spread globally displacing the predeceasing variants. Due to the severe transmissibility and immune escape potential of BA.4/5, early monitoring was required to asses and implement countermeasures in time.
In this study, we monitored the prevalence of SARS-CoV-2 BA.4/5 at six municipal wastewater treatment plants (WWTPs) in the Federal State of North-Rhine-Westphalia (NRW, Germany) in May and June 2022. Initially, L452R-specific primers/probes originally designed for SARS-CoV-2 Delta detection were validated using inactivated authentic viruses and evaluated for their suitability to detect BA.4/5. Subsequently, the assay was used for RT-qPCR analysis of RNA purified from wastewater obtained twice a week at six WWTPs. The occurrence of L452R carrying RNA was detected in early May 2022 and the presence of BA.4/5 was confirmed by variant-specific single nucleotide polymorphism PCR (SNP-PCR) targeting E484A/F486V. Finally, the mutant fractions were quantitatively monitored by digital PCR confirming BA.4/5 as the majority variant by 5th June 2022.
In conclusions, the successive workflow using RT-qPCR, variant-specific SNP-PCR, and RT-dPCR demonstrates the strength of WBE as a versatile tool to rapidly monitor variant spreading independent of individual test capacities.
The study of neutron-induced reactions is of high relevance in a wide variety of fields, ranging from stellar nucleosynthesis and fundamental nuclear physics to applications of nuclear technology. In nuclear energy, high accuracy neutron data are needed for the development of Generation IV fast reactors and accelerator driven systems, these last aimed specifically at nuclear waste incineration, as well as for research on innovative fuel cycles. In this context, a high luminosity Neutron Time Of Flight facility, n_TOF, is operating at CERN since more than a decade, with the aim of providing new, high accuracy and high resolution neutron cross-sections. Thanks to the features of the neutron beam, a rich experimental program relevant to nuclear technology has been carried out so far. The program will be further expanded in the near future, thanks in particular to a new high-flux experimental area, now under construction.
High precision measurement of the radiative capture cross section of 238U at the n_TOF CERN facility
(2017)
The importance of improving the accuracy on the capture cross-section of 238U has been addressed by the Nuclear Energy Agency, since its uncertainty significantly affects the uncertainties of key design parameters for both fast and thermal nuclear reactors. Within the 7th framework programme ANDES of the European Commission three different measurements have been carried out with the aim of providing the 238U(n,γ) cross-section with an accuracy which varies from 1 to 5%, depending on the energy range. Hereby the final results of the measurement performed at the n_TOF CERN facility in a wide energy range from 1 eV to 700 keV will be presented.
Neutron-induced fission cross sections of 238U and 235U are used as standards in the fast neutron region up to 200 MeV. A high accuracy of the standards is relevant to experimentally determine other neutron reaction cross sections. Therefore, the detection effciency should be corrected by using the angular distribution of the fission fragments (FFAD), which are barely known above 20 MeV. In addition, the angular distribution of the fragments produced in the fission of highly excited and deformed nuclei is an important observable to investigate the nuclear fission process.
In order to measure the FFAD of neutron-induced reactions, a fission detection setup based on parallel-plate avalanche counters (PPACs) has been developed and successfully used at the CERN-n_TOF facility. In this work, we present the preliminary results on the analysis of new 235U(n,f) and 238U(n,f) data in the extended energy range up to 200 MeV compared to the existing experimental data.
The n_TOF facility operates at CERN with the aim of addressing the request of high accuracy nuclear data for advanced nuclear energy systems as well as for nuclear astrophysics. Thanks to the features of the neutron beam, important results have been obtained on neutron induced fission and capture cross sections of U, Pu and minor actinides. Recently the construction of another beam line has started; the new line will be complementary to the first one, allowing to further extend the experimental program foreseen for next measurement campaigns.
The aim of this work is to provide a precise and accurate measurement of the 238U(n,γ) reaction cross section in the energy region from 1 eV to 700 keV. This reaction is of fundamental importance for the design calculations of nuclear reactors, governing the behavior of the reactor core. In particular, fast reactors, which are experiencing a growing interest for their ability to burn radioactive waste, operate in the high energy region of the neutron spectrum. In this energy region most recent evaluations disagree due to inconsistencies in the existing measurements of up to 15%. In addition, the assessment of nuclear data uncertainty performed for innovative reactor systems shows that the uncertainty in the radiative capture cross section of 238U should be further reduced to 1–3% in the energy region from 20 eV to 25 keV. To this purpose, addressed by the Nuclear Energy Agency as a priority nuclear data need, complementary experiments, one at the GELINA and two at the n_TOF facility, were proposed and carried out within the 7th Framework Project ANDES of the European Commission. The results of one of these 238U(n,γ) measurements performed at the n_TOF CERN facility are presented in this work. The γ-ray cascade following the radiative neutron capture has been detected exploiting a setup of two C6D6 liquid scintillators. Resonance parameters obtained from this work are on average in excellent agreement with the ones reported in evaluated libraries. In the unresolved resonance region, this work yields a cross section in agreement with evaluated libraries up to 80 keV, while for higher energies our results are significantly higher.
New results are presented of the 234U neutron-induced fission cross section, obtained with high accuracy in the resonance region by means of two methods using the 235U(n,f) as reference. The recent evaluation of the 235U(n,f) obtained with SAMMY by L. C. Leal et al. (these Proceedings), based on previous n_TOF data [1], has been used to calculate the 234U(n,f) cross section through the 234U/235U ratio, being here compared with the results obtained by using the n_TOF neutron flux.
The 236U isotope plays an important role in nuclear systems, both for future and currently operating ones. The actual knowledge of the capture reaction of this isotope is satisfactory in the thermal region, but it is considered insufficient for Fast Reactor and ADS applications. For this reason the 236U(n, γ) reaction cross-section has been measured for the first time in the whole energy region from thermal energy up to 1 MeV at the n_TOF facility with two different detection systems: an array of C6D6 detectors, employing the total energy deposited method, and a FX1 total absorption calorimeter (TAC), made of 40 BaF2 crystals. The two n_TOF data sets agree with each other within the statistical uncertainty in the Resolved Resonance Region up to 800 eV, while sizable differences (up to ≃ 20%) are found relative to the current evaluated data libraries. Moreover two new resonances have been found in the n_TOF data. In the Unresolved Resonance Region up to 200 keV, the n_TOF results show a reasonable agreement with previous measurements and evaluated data.
The radiative capture cross section of 238U is very important for the developing of new reactor technologies and the safety of existing ones. Here the preliminary results of the 238U(n,γ) cross section measurement performed at n_TOF with C6D6 scintillation detectors are presented, paying particular attention to data reduction and background subtraction.
An important experimental program on Nuclear Astrophysics is being carried out at the n_TOF since several years, in order to address the still open issues in stellar and primordial nucleosynthesis. Several neutron capture reactions relevant to s-process nucleosynthesis have been measured so far, some of which on important branching point radioisotopes. Furthermore, the construction of a second experimental area has recently opened the way to challenging measurements of (n, charged particle) reactions on isotopes of short half-life. The Nuclear Astrophysics program of the n_TOF Collaboration is here described, with emphasis on recent results relevant for stellar nucleosynthesis, stellar neutron sources and primordial nucleosynthesis.
The 33S(n,α)30Si cross section measurement, using 10B(n,α) as reference, at the n_TOF Experimental Area 2 (EAR2) facility at CERN is presented. Data from 0.01 eV to 100 keV are provided and, for the first time, the cross section is measured in the range from 0.01 eV to 10 keV. These data may be used for a future evaluation of the cross section because present evaluations exhibit large discrepancies. The 33S(n,α)30Si reaction is of interest in medical physics because of its possible use as a cooperative target to boron in Neutron Capture Therapy (NCT).
The spent fuel of current nuclear reactors contains fissile plutonium isotopes that can be combined with 238U to make mixed oxide (MOX) fuel. In this way the Pu from spent fuel is used in a new reactor cycle, contributing to the long-term sustainability of nuclear energy. The use of MOX fuels in thermal and fast reactors requires accurate capture and fission cross sections. For the particular case of 242Pu, the previous neutron capture cross section measurements were made in the 70's, providing an uncertainty of about 35% in the keV region. In this context, the Nuclear Energy Agency recommends in its “High Priority Request List” and its report WPEC-26 that the capture cross section of 242Pu should be measured with an accuracy of at least 7–12% in the neutron energy range between 500 eV and 500 keV. This work presents a brief description of the measurement performed at n_TOF-EAR1, the data reduction process and the first ToF capture measurement on this isotope in the last 40 years, providing preliminary individual resonance parameters beyond the current energy limits in the evaluations, as well as a preliminary set of average resonance parameters.
The Cosmological Lithium Problem refers to the large discrepancy between the abundance of primordial 7Li predicted by the standard theory of Big Bang Nucleosynthesis and the value inferred from the so-called “Spite plateau” in halo stars. A possible explanation for this longstanding puzzle in Nuclear Astrophysics is related to the incorrect estimation of the destruction rate of 7Be, which is responsible for the production of 95% of primordial Lithium. While charged-particle induced reactions have mostly been ruled out, data on the 7Be(n,α) and 7Be(n,p) reactions are scarce or completely missing, so that a large uncertainty still affects the abundance of 7Li predicted by the standard theory of Big Bang Nucleosynthesis. Both reactions have been measured at the n_TOF facility at CERN, providing for the first time data in a wide neutron energy range.
The CERN n_TOF neutron beam facility is characterized by a very high instantaneous neutron flux, excellent TOF resolution at the 185 m long flight path (EAR-1), low intrinsic background and coverage of a wide range of neutron energies, from thermal to a few GeV. These characteristics provide a unique possibility to perform high-accuracy measurements of neutron-induced reaction cross-sections and angular distributions of interest for fundamental and applied Nuclear Physics. Since 2001, the n_TOF Collaboration has collected a wealth of high quality nuclear data relevant for nuclear astrophysics, nuclear reactor technology, nuclear medicine, etc. The overall efficiency of the experimental program and the range of possible measurements has been expanded with the construction of a second experimental area (EAR-2), located 20 m on the vertical of the n_TOF spallation target. This upgrade, which benefits from a neutron flux 30 times higher than in EAR-1, provides a substantial extension in measurement capabilities, opening the possibility to collect data on neutron cross-section of isotopes with short half-lives or available in very small amounts. This contribution will outline the main characteristics of the n_TOF facility, with special emphasis on the new experimental area. In particular, we will discuss the innovative features of the EAR-2 neutron beam that make possible to perform very challenging measurements on short-lived radioisotopes or sub-mg samples, out of reach up to now at other neutron facilities around the world. Finally, the future perspectives of the facility will be presented.
The neutron capture cross section of several key unstable isotopes acting as branching points in the s-process are crucial for stellar nucleosynthesis studies, but they are very challenging to measure due to the difficult production of sufficient sample material, the high activity of the resulting samples, and the actual (n,γ) measurement, for which high neutron fluxes and effective background rejection capabilities are required. As part of a new program to measure some of these important branching points, radioactive targets of 147Pm and 171Tm have been produced by irradiation of stable isotopes at the ILL high flux reactor. Neutron capture on 146Nd and 170Er at the reactor was followed by beta decay and the resulting matrix was purified via radiochemical separation at PSI. The radioactive targets have been used for time-of-flight measurements at the CERN n_TOF facility using the 19 and 185 m beam lines during 2014 and 2015. The capture cascades were detected using a set of four C6D6 scintillators, allowing to observe the associated neutron capture resonances. The results presented in this work are the first ever determination of the resonance capture cross section of 147Pm and 171Tm. Activation experiments on the same 147Pm and 171Tm targets with a high-intensity 30 keV quasi-Maxwellian flux of neutrons will be performed using the SARAF accelerator and the Liquid-Lithium Target (LiLiT) in order to extract the corresponding Maxwellian Average Cross Section (MACS). The status of these experiments and preliminary results will be presented and discussed as well.
73Ge(n, γ ) cross sections were measured at the neutron time-of-flight facility n_TOF at CERN up to neutron energies of 300 keV, providing for the first time experimental data above 8 keV. Results indicate that the stellar cross section at kT = 30 keV is 1.5 to 1.7 times higher than most theoretical predictions. The new cross sections result in a substantial decrease of 73Ge produced in stars, which would explain the low isotopic abundance of 73Ge in the solar system.
he study of the resonant structures in neutron-nucleus cross-sections, and therefore of the compound-nucleus reaction mechanism, requires spectroscopic measurements to determine with high accuracy the energy of the neutron interacting with the material under study.
To this purpose, the neutron time-of-flight facility n_TOF has been operating since 2001 at CERN. Its characteristics, such as the high intensity instantaneous neutron flux, the wide energy range from thermal to few GeV, and the very good energy resolution, are perfectly suited to perform high-quality measurements of neutron-induced reaction cross sections. The precise and accurate knowledge of these cross sections plays a fundamental role in nuclear technologies, nuclear astrophysics and nuclear physics.
Two different measuring stations are available at the n_TOF facility, called EAR1 and EAR2, with different characteristics of intensity of the neutron flux and energy resolution. These experimental areas, combined with advanced detection systems lead to a great flexibility in performing challenging measurement of high precision and accuracy, and allow the investigation isotopes with very low cross sections, or available only in small quantities, or with very high specific activity.
The characteristics and performances of the two experimental areas of the n_TOF facility will be presented, together with the most important measurements performed to date and their physics case. In addition, the significant upcoming measurements will be introduced.
Neutron-induced reaction cross sections are important for a wide variety of research fields ranging from the study of nuclear level densities, nucleosynthesis to applications of nuclear technology like design, and criticality and safety assessment of existing and future nuclear reactors, radiation dosimetry, medical applications, nuclear waste transmutation, accelerator-driven systems and fuel cycle investigations. Simulations and calculations of nuclear technology applications largely rely on evaluated nuclear data libraries. The evaluations in these libraries are based both on experimental data and theoretical models. CERN’s neutron time-of-flight facility n_TOF has produced a considerable amount of experimental data since it has become fully operational with the start of its scientific measurement programme in 2001. While for a long period a single measurement station (EAR1) located at 185 m from the neutron production target was available, the construction of a second beam line at 20 m (EAR2) in 2014 has substantially increased the measurement capabilities of the facility. An outline of the experimental nuclear data activities at n_TOF will be presented.
The accurate knowledge of the neutron-induced fission cross-sections of actinides and other isotopes involved in the nuclear fuel cycle is essential for the design of advanced nuclear systems, such as Generation-IV nuclear reactors. Such experimental data can also provide the necessary feedback for the adjustment of nuclear model parameters used in the evaluation process, resulting in the further development of nuclear fission models. In the present work, the 240Pu(n,f) cross-section was measured at CERN's n_TOF facility relative to the well-known 235U(n,f) cross section, over a wide range of neutron energies, from meV to almost MeV, using the time-of-flight technique and a set-up based on Micromegas detectors. This measurement was the first experiment to be performed at n_TOF's new experimental area (EAR-2), which offers a significantly higher neutron flux compared to the already existing experimental area (EAR-1). Preliminary results as well as the experimental procedure, including a description of the facility and the data handling and analysis, are presented.
We have measured the radiative neutron-capture cross section and the total neutron-induced cross section of one of the most important isotopes for the s process, the 25Mg. The measurements have been carried out at the neutron time-of-flight facilities n_TOF at CERN (Switzerland) and GELINA installed at the EC-JRC-IRMM (Belgium). The cross sections as a function of neutron energy have been measured up to approximately 300 keV, covering the energy region of interest to the s process. The data analysis is ongoing and preliminary results show the potential relevance for the s process.
Background: To determine the correlation between urine loss in PAD-test after catheter removal, and early urinary continence (UC) in RP treated patients. Methods: Urine loss was measured by using a standardized, validated PAD-test within 24 h after removal of the transurethral catheter, and was grouped as a loss of <1, 1–10, 11–50, and >50 g of urine, respectively. Early UC (median: 3 months) was defined as the usage of no or one safety-pad. Uni- and multivariable logistic regression models tested the correlation between PAD-test results and early UC. Covariates consisted of age, BMI, nerve-sparing approach, prostate volume, and extraprostatic extension of tumor. Results: From 01/2018 to 03/2021, 100 patients undergoing RP with data available for a PAD-test and early UC were retrospectively identified. Ultimately, 24%, 47%, 15%, and 14% of patients had a loss of urine <1 g, 1–10 g, 11–50 g, and >50 g in PAD-test, respectively. Additionally, 59% of patients reported to be continent. In multivariable logistic regression models, urine loss in PAD-test predicted early UC (OR: 0.21 vs. 0.09 vs. 0.03; for urine loss 1–10 g vs. 11–50 g vs. >50 g, Ref: <1 g; all p < 0.05). Conclusions: Urine loss after catheter removal strongly correlated with early continence as well as a severity in urinary incontinence.
Background: We aimed to determine the concordance between the radiologic stage (rT), using multiparametric magnetic resonance imaging (mpMRI), and pathologic stage (pT) in patients with high-risk prostate cancer and its influence on nerve-sparing surgery compared to the use of the intraoperative frozen section technique (IFST). Methods: The concordance between rT and pT and the rates of nerve-sparing surgery and positive surgical margin were assessed for patients with high-risk prostate cancer who underwent radical prostatectomy. Results: The concordance between the rT and pT stages was shown in 66.4% (n = 77) of patients with clinical high-risk prostate cancer. The detection of patients with extraprostatic disease (≥pT3) by preoperative mpMRI showed a sensitivity, negative predictive value and accuracy of 65.1%, 51.7% and 67.5%. In addition to the suspicion of extraprostatic disease in mpMRI (≥rT3), 84.5% (n = 56) of patients with ≥rT3 underwent primary nerve-sparing surgery with IFST, resulting in 94.7% (n = 54) of men with at least unilateral nerve-sparing surgery after secondary resection with a positive surgical margin rate related to an IFST of 1.8% (n = 1). Conclusion: Patients with rT3 should not be immediately excluded from nerve-sparing surgery, as by using IFST some of these patients can safely undergo nerve-sparing surgery.
Above 1 MeV of incident neutron energy the fission fragment angular distribution (FFAD) has generally a strong anisotropic behavior due to the combination of the incident orbital momentum and the intrinsic spin of the fissioning nucleus. This effect has to be taken into account for the efficiency estimation of devices used for fission cross section measurements. In addition it bears information on the spin deposition mechanism and on the structure of transitional states. We designed and constructed a detection device, based on Parallel Plate Avalanche Counters (PPAC), for measuring the fission fragment angular distributions of several isotopes, in particular 232Th. The measurement has been performed at n_TOF at CERN taking advantage of the very broad energy spectrum of the neutron beam. Fission events were recognized by back to back detection in coincidence in two position-sensitive detectors surrounding the targets. The detection efficiency, depending mostly on the stopping of fission fragments in backings and electrodes, has been computed with a Geant4 simulation and validated by the comparison to the measured case of 235U below 3 keV where the emission is isotropic. In the case of 232Th, the result is in good agreement with previous data below 10 MeV, with a good reproduction of the structures associated to vibrational states and the opening of second chance fission. In the 14 MeV region our data are much more accurate than previous ones which are broadly scattered.
The 14N(n,p)14C reaction is of interest in neutron capture therapy, where nitrogen-related dose is the main component due to low-energy neutrons, and in astrophysics, where 14N acts as a neutron poison in the s-process. Several discrepancies remain between the existing data obtained in partial energy ranges: thermal energy, keV region and resonance region. Purpose: Measuring the 14N(n,p)14C cross section from thermal to the resonance region in a single measurement for the first time, including characterization of the first resonances, and providing calculations of Maxwellian averaged cross sections (MACS). Method: Time-of-flight technique. Experimental Area 2 (EAR-2) of the neutron time-of-flight (n_TOF) facility at CERN. 10B(n,α)7Li and 235U(n,f) reactions as references. Two detection systems running simultaneously, one on-beam and another off-beam. Description of the resonances with the R-matrix code sammy. Results: The cross section has been measured from sub-thermal energy to 800 keV resolving the two first resonances (at 492.7 and 644 keV). A thermal cross-section (1.809±0.045 b) lower than the two most recent measurements by slightly more than one standard deviation, but in line with the ENDF/B-VIII.0 and JEFF-3.3 evaluations has been obtained. A 1/v energy dependence of the cross section has been confirmed up to tens of keV neutron energy. The low energy tail of the first resonance at 492.7 keV is lower than suggested by evaluated values, while the overall resonance strength agrees with evaluations. Conclusions: Our measurement has allowed to determine the 14N(n,p) cross-section over a wide energy range for the first time. We have obtained cross-sections with high accuracy (2.5 %) from sub-thermal energy to 800 keV and used these data to calculate the MACS for kT = 5 to kT = 100 keV.
Inflammatory diseases including psoriasis are associated with metabolic and cardiovascular comorbidities, including obesity and metabolic syndrome. Obesity is associated with greater psoriasis disease severity and reduced response to treatment. Therefore, targeting metabolic comorbidities could improve patients’ health status and psoriasis-specific outcomes. METABOLyx is a randomized controlled trial evaluating the combination of a lifestyle intervention program with secukinumab treatment in psoriasis. Here, the rationale, methodology and baseline patient characteristics of METABOLyx are presented. A total of 768 patients with concomitant moderate to severe plaque psoriasis and metabolic syndrome were randomized to secukinumab 300 mg, or secukinumab 300 mg plus a tailored lifestyle intervention program, over 24 weeks. A substudy of immunologic and metabolic biomarkers is ongoing. The primary endpoint of METABOLyx is PASI90 response at week 24. Other endpoints include patient-reported outcomes and safety. METABOLyx represents the first large scale clinical trial of an immunomodulatory biologic in combination with a standardized lifestyle intervention.
A high proportion of patients with breast cancer develop bone metastases, yet data on routine treatment with bone-targeted agents (BTA) are rare. We report real-life outcome data of patients with breast cancer metastasised to the bone treated by office-based oncologists in Germany.
The ongoing, prospective, multicentre, population-based cohort study Tumour Registry Breast Cancer (TMK) was started in 2007 in 140 centres across Germany.
This interim analysis of 1094 patients with bone metastases revealed differences among the tumour subtypes: at start of first-line therapy, 36% of the patients with hormone receptor (HR)-positive and only 20% of the patients with HR-negative tumours presented with bone-only metastasis. The majority of patients with bone metastases (89%, n = 976) received BTA therapy. In 2014–2015, 37% of the patients received the bisphosphonate zoledronic acid and 36% the antibody denosumab. Median duration of BTA therapy was 20 months (interquartile range 31.5 months), starting a median of 3 weeks after diagnosis of bone metastases, and ending a median of 7 weeks before death. The median overall survival (OS) also varied among the types of metastasis at start of first-line therapy ranging from 54 months (95% confidence interval [CI] 37.6–70.8), 38 months (95% CI 29.4–44.2) to 28 months (95% CI 24.2–31.0) for patients with bone-only metastases, non-visceral with or without bone metastases and visceral with or without bone metastases respectively.
We show that choice and duration of BTA therapies are in conformity with guidelines applicable in Germany. To our knowledge, this is the first presentation of data on incidence, metastatic pattern, treatment and survival of patients with bone metastases in routine practice.
In this paper we present evidence that the observed increase in tropical upwelling after the year 2000 may be attributed to a change in the Brewer-Dobson circulation pattern. For this purpose, we use the concept of transit times derived from residual circulation trajectories and different in-situ measurements of ozone and nitrous dioxide. Observations from the Canadian midlatitude ozone profile record, probability density functions of in-situ N2O observations and a shift of the N2O-O3 correlation slopes, taken together, indicate that the increased upwelling in the tropics after the year 2000 appears to have triggered an intensification of tracer transport from the tropics into the extratropics in the lower stratosphere below about 500 K. This finding is corroborated by the fact that transit times along the shallow branch of the residual circulation into the LMS have decreased for the same time period (1993–2003). On a longer time scale (1979–2009), the transit time of the shallow residual circulation branch show a steady decrease of about −1 month/decade over the last 30 years, while the transit times of the deep branch remain unchanged. This highlights the fact that a change in the upwelling across the tropical tropopause is not a direct indicator for changes of the whole Brewer-Dobson circulation.
In this paper we present evidence that the observed increase in tropical upwelling after the year 2000 may be attributed to a change in the Brewer-Dobson circulation pattern. For this purpose, we use the concept of transit times derived from residual circulation trajectories and different in-situ measurements of ozone and nitrous dioxide. Observations from the Canadian midlatitude ozone profile record, probability density functions of in-situ N2O observations and a shift of the N2O-O3 correlation slopes, taken together, indicate that the increased upwelling in the tropics after the year 2000 appears to have triggered an intensification of tracer transport from the tropics into the extratropics in the lower stratosphere below about 500 K. This finding is corroborated by the fact that transit times along the shallow branch of the residual circulation into the LMS have decreased for the same time period (1993–2003). On a longer time scale (1979–2009), the transit time of the shallow residual circulation branch show a steady decrease of about −1 month/decade over the last 30 yr, while the transit times of the deep branch remain unchanged. This highlights that changes in the upwelling across the tropical tropopause are not sufficient as an indicator for changes in the entire Brewer-Dobson circulation.
Profiles of CFC-11 (CCl3F) and CFC-12 (CCl2F2) of the Michelson Interferometer for Passive Atmospheric Sounding (MIPAS) aboard the European satellite Envisat have been retrieved from versions MIPAS/4.61 to MIPAS/4.62 and MIPAS/5.02 to MIPAS/5.06 level-1b data using the scientific level-2 processor run by Karlsruhe Institute of Technology (KIT), Institute of Meteorology and Climate Research (IMK) and Consejo Superior de Investigaciones Científicas (CSIC), Instituto de Astrofísica de Andalucía (IAA). These profiles have been compared to measurements taken by the balloon-borne cryosampler, Mark IV (MkIV) and MIPAS-Balloon (MIPAS-B), the airborne MIPAS-STRatospheric aircraft (MIPAS-STR), the satellite-borne Atmospheric Chemistry Experiment Fourier transform spectrometer (ACE-FTS) and the High Resolution Dynamic Limb Sounder (HIRDLS), as well as the ground-based Halocarbon and other Atmospheric Trace Species (HATS) network for the reduced spectral resolution period (RR: January 2005–April 2012) of MIPAS. ACE-FTS, MkIV and HATS also provide measurements during the high spectral resolution period (full resolution, FR: July 2002–March 2004) and were used to validate MIPAS CFC-11 and CFC-12 products during that time, as well as profiles from the Improved Limb Atmospheric Spectrometer, ILAS-II. In general, we find that MIPAS shows slightly higher values for CFC-11 at the lower end of the profiles (below ∼ 15 km) and in a comparison of HATS ground-based data and MIPAS measurements at 3 km below the tropopause. Differences range from approximately 10 to 50 pptv ( ∼ 5–20 %) during the RR period. In general, differences are slightly smaller for the FR period. An indication of a slight high bias at the lower end of the profile exists for CFC-12 as well, but this bias is far less pronounced than for CFC-11 and is not as obvious in the relative differences between MIPAS and any of the comparison instruments. Differences at the lower end of the profile (below ∼ 15 km) and in the comparison of HATS and MIPAS measurements taken at 3 km below the tropopause mainly stay within 10–50 pptv (corresponding to ∼ 2–10 % for CFC-12) for the RR and the FR period. Between ∼ 15 and 30 km, most comparisons agree within 10–20 pptv (10–20 %), apart from ILAS-II, which shows large differences above ∼ 17 km. Overall, relative differences are usually smaller for CFC-12 than for CFC-11. For both species – CFC-11 and CFC-12 – we find that differences at the lower end of the profile tend to be larger at higher latitudes than in tropical and subtropical regions. In addition, MIPAS profiles have a maximum in their mixing ratio around the tropopause, which is most obvious in tropical mean profiles. Comparisons of the standard deviation in a quiescent atmosphere (polar summer) show that only the CFC-12 FR error budget can fully explain the observed variability, while for the other products (CFC-11 FR and RR and CFC-12 RR) only two-thirds to three-quarters can be explained. Investigations regarding the temporal stability show very small negative drifts in MIPAS CFC-11 measurements. These instrument drifts vary between ∼ 1 and 3 % decade−1. For CFC-12, the drifts are also negative and close to zero up to ∼ 30 km. Above that altitude, larger drifts of up to ∼ 50 % decade−1 appear which are negative up to ∼ 35 km and positive, but of a similar magnitude, above.
Background: Due to the difficulties in the definite diagnosis, data on brain imaging in pediatric patients with central nervous system (CNS)-invasive mold infection (IMD) are scarce. Our aim was to describe brain imaging abnormalities seen in immunocompromised children with CNS-IMD, and to analyze retrospectively whether specific imaging findings and sequences have a prognostic value. Methods: In a retrospective study of 19 pediatric patients with proven or probable CNS-IMD, magnetic resonance imaging (MRI)-findings were described and analyzed. The results were correlated with outcome, namely death, severe sequelae, or no neurological sequelae. Results: 11 children and 8 adolescents (11/8 with proven/probable CNS-IMD) were included. Seven of the patients died and 12/19 children survived (63%): seven without major neurological sequelae and five with major neurological sequelae. Multifocal ring enhancement and diffusion restriction were the most common brain MRI changes. Diffusion restriction was mostly seen at the core of the lesion. No patient with disease limited to one lobe died. Perivascular microbleeding seen on susceptibility weighted imaging (SWI) and/or gradient-echo/T2* images, as well as infarction, were associated with poor prognosis. Conclusions: The presence of infarction was related to poor outcome. As early microbleeding seems to be associated with poor prognosis, we suggest including SWI in routine diagnostic evaluation of immunocompromised children with suspected CNS-IMD.
Invasive mold disease (IMD) of the central nervous system (CNS) is a severe infectious complication in immunocompromised patients, but early microbiological diagnosis is difficult. As data on the value of biomarkers in the CNS are scarce, in particular in children, we retrospectively analyzed the performance of galactomannan (GM) and PCR assays in CNS samples of 15 children with proven and probable CNS IMD and of 32 immunocompromised children without fungal infection. Galactomannan in the cerebrospinal fluid (CSF) was assessed in nine of the 15 pediatric patients and was positive in five of them. Polymerase chain reaction (PCR) was performed in eight of the 15 patients and detected nucleic acids from molds in six patients. Galactomannan and PCR in CNS samples were the only positive microbiologic parameter in the CNS in three and two patients, respectively. In four patients, PCR specified the pathogen detected in microscopy. Galactomannan and PCR results remained negative in the CSF of all immunocompromised children without evidence for CNS IMD. Our data suggest that GM and PCR in CNS specimens are valuable additional tools in diagnosing CNS IMD and should be included in the work up of all pediatric patients with suspected mold disease of the CNS.
Objectives: Current knowledge on infections caused by Scedosporium spp. and Lomentospora prolificans in children is scarce. We therefore aim to provide an overview of risk groups, clinical manifestation and treatment strategies of these infections.
Methods: Pediatric patients (age ≤18 years) with proven/probable Scedosporium spp. or L. prolificans infection were identified in PubMed and the FungiScope® registry. Data on diagnosis, treatment and outcome were collected.
Results: Fifty-five children (median age 9 years [IQR: 5–14]) with invasive Scedosporium spp. (n = 33) or L. prolificans (n = 22) infection were identified between 1990 and 2019. Malignancy, trauma and near drowning were the most common risk factors. Infections were frequently disseminated. Most patients received systemic antifungal therapy, mainly voriconazole and amphotericin B, plus surgical treatment.
Overall, day 42 mortality was 31%, higher for L. prolificans (50%) compared to Scedosporium spp. (18%). L. prolificans infection was associated with a shorter median survival time compared to Scedosporium spp. (6 days [IQR: 3–28] versus 61 days [IQR: 16–148]). Treatment for malignancy and severe disseminated infection were associated with particularly poor outcome (HR 8.33 [95% CI 1.35–51.40] and HR 6.12 [95% CI 1.52–24.66], respectively). Voriconazole use at any time and surgery for antifungal treatment were associated with improved clinical outcome (HR 0.33 [95% CI 0.11–0.99] and HR 0.09 [95% CI 0.02–0.40], respectively).
Conclusions: Scedosporium spp. and L. prolificans infections in children are associated with high mortality despite comprehensive antifungal therapy. Voriconazole usage and surgical intervention are associated with successful outcome.
Objective: We aimed to estimate the incidence of cerebral sinus and venous thrombosis (CVT) within 1 month from first dose administration and the frequency of vaccine-induced immune thrombotic thrombocytopenia (VITT) as the underlying mechanism after vaccination with BNT162b2, ChAdOx1, and mRNA-1273, in Germany. Methods: A web-based questionnaire was e-mailed to all departments of neurology. We requested a report of cases of CVT occurring within 1 month of a COVID-19 vaccination. Other cerebral events could also be reported. Incidence rates of CVT were calculated by using official statistics of 9 German states. Results: A total of 45 CVT cases were reported. In addition, 9 primary ischemic strokes, 4 primary intracerebral hemorrhages, and 4 other neurological events were recorded. Of the CVT patients, 35 (77.8%) were female, and 36 (80.0%) were younger than 60 years. Fifty-three events were observed after vaccination with ChAdOx1 (85.5%), 9 after BNT162b2 (14.5%) vaccination, and none after mRNA-1273 vaccination. After 7,126,434 first vaccine doses, the incidence rate of CVT within 1 month from first dose administration was 0.55 (95% confidence interval [CI] = 0.38–0.78) per 100,000 person-months (which corresponds to a risk of CVT within the first 31 days of 0.55 per 100,000 individuals) for all vaccines and 1.52 (95% CI = 1.00–2.21) for ChAdOx1 (after 2,320,535 ChAdOx1 first doses). The adjusted incidence rate ratio was 9.68 (95% CI = 3.46–34.98) for ChAdOx1 compared to mRNA-based vaccines and 3.14 (95% CI = 1.22–10.65) for females compared to non-females. In 26 of 45 patients with CVT (57.8%), VITT was graded highly probable. Interpretation: Given an incidence of 0.02 to 0.15 per 100,000 person-months for CVT in the general population, these findings point toward a higher risk for CVT after ChAdOx1 vaccination, especially for women.
INDIVIDUAL INVESTORS ARE REPEATEDLY FOUND TO UNDERPERFORM RELATIVE TO A MARKET INDEX. BESIDES EXCESSIVE TRADING, LITTLE IS KNOWN WHEN RETAIL INVESTORS COLLECTIVELY LOSE. THIS ARTICLE SHOWS THAT TRADING IN SHORT-SELLING CONSTRAINED, VOLATILE STOCKS AROUND EARNINGS ANNOUNCEMENTS IS COSTLY TO INDIVIDUAL INVESTORS. THE EFFECT IS PARTICULARLY PRONOUNCED FOR LESS SOPHISTICATED INVESTORS.
Background: Brodalumab is a fully human monoclonal immunoglobulin IgG2 antibody that binds to the human IL-17 receptor subunit A and by that inhibits the biologic action of IL-17A, IL-17F, IL-17C and IL-17E. Therapy with fumaric acid esters (FAE) is a well established and widely used first-line systemic treatment for subjects with moderate-to-severe plaque psoriasis. Objectives: To compare brodalumab to FAE in terms of clinical efficacy, patient-reported outcomes and safety in subjects with moderate-to-severe plaque psoriasis who were naïve to systemic treatment. Methods: Eligible subjects were randomized 1 : 1 to 210 mg brodalumab injections or oral FAE according to product label in this 24-week, open-label, assessor-blinded, multi-centre, head-to-head phase 4 trial. The primary endpoints were having PASI75 and having sPGA score of 0 or 1 (sPGA 0/1). Subjects with missing values for the primary endpoints were considered non-responders. Results: A total of 210 subjects were randomized. 91/105 subjects completed brodalumab treatment and 58/105 subjects completed FAE treatment. At Week 24, significantly more subjects in the brodalumab group compared to the FAE group had PASI75 (81.0% vs. 38.1%, P < 0.001) and sPGA 0/1 (64.8% vs. 20.0%, P < 0.001). In the brodalumab group, the median time to both PASI75 and to PASI90 was significantly shorter than in the FAE group (4.1 weeks vs. 16.4 weeks, and 7.4 weeks vs. 24.4 weeks, respectively, P < 0.0001 for both). The rate of adverse events was lower in subjects treated with brodalumab compared to subjects treated with FAE (616.4 vs. 1195.8 events per 100 exposure years). No new safety signals were detected for brodalumab. Conclusions: Brodalumab was associated with rapid and significant improvements in signs and symptoms of moderate-to-severe plaque psoriasis, with a superior efficacy profile to what was observed with FAE in systemic-naïve subjects over 24 weeks.
Novel therapies for lung cancer are being explored nowadays with local therapies being the tip of the arrow. Intratumoral chemotherapy administration and local microwave ablation have been investigated in several studies. It has been previously proposed that lipiodol has the ability to modify the microenvironment matrix. In our current study we investigated this theory in BALBC mice. In total 160 BALBC mice were divided in eight groups: a) control, b) cisplatin, c) microwave, d) microwave and lipiodol, e) cisplatin and lipiodol, f) microwave and cisplatin, g) lipiodol and h) lipiodol, cisplatin and microwave. Lewis lung carcinoma cell lines (106) were injected into the right back leg of each mouse. After the 8th day, when the tumor volume was about 100mm3 the therapy application was initiated, once per week for four weeks. Magnetic resonance imaging was performed for each tumor when a mouse died or when sacrificed if they were still alive by the end of the experiment (8-Canal multifunctional spool; NORAS MRI products, Gmbh, Germany). Imaging and survival revealed efficient tumor apoptosis for the groups b,c,d,e and f. However; severe toxicity was observed in group h and no follow up was available for this group after the second week of therapy administration. Lipiodol in its current form does assist in a more efficient way the distribution of cisplatin, as the microwave apoptotic effect. Future modification of lipiodol might provide a more efficient method of therapy enhancement. Combination of drug and microwave ablation is possible and has an efficient apoptotic effect.
The Tarim River Basin, located in Xinjiang, NW China, is the largest endorheic river basin of China and one of the largest in whole Central Asia. Due to the extremely arid climate with an annual precipitation of less than 100 mm, the water supply along the Aksu and Tarim River solely depends on river water. This applies for anthropogenic activities (e.g. agriculture) as well as for the natural ecosystems so that both compete for water. The on-going increase of water consumption by agriculture and other human activities in this region has been enhancing the competition for water between human needs and nature. Against this background, 11 German and 6 Chinese universities and research institutes formed the consortium SuMaRiO (www.sumario.de), which aims at gaining a holistic picture of the availability of water resources in the Tarim River Basin and the impacts on anthropogenic activities and natural ecosystems caused by the water distribution within the Tarim River Basin. The discharge of the Aksu River, which is the major tributary to the Tarim, has been increasing over the past 6 decades due to enhanced glacier melt. Alone from 1989 to 2011, the area under agriculture more than doubled. Thereby, cotton became the major crop and there was a shift from small-scale farming to large-scale intensive farming. The major natural ecosystems along the Aksu and Tarim River are riparian ecosystems: Riparian (Tugai) forests, shrub vegetation, reed beds, and other grassland. Within the SuMaRiO Cluster the focus was laid on the Tugai forests, with Populus euphratica as dominant tree, because the most productive and species-rich natural ecosystems can be found among those forests. On sites with groundwater distance of less than 7.5 m the annual increments correlated with river runoffs of the previous year. But, the further downstream along the Tarim River, the more the natural river dynamics ceased, which impacts on the recruitment of Populus euphratica. Household surveys revealed that there is a considerable willingness to pay for conservation of those riparian forests with the mitigation of dust and sandstorms considered as the most important ecosystem service. This interdisciplinary project will result in a decision support tool (DST), build on the participation of regional stakeholders and models based on results and field experiments. This DST finally shall assist stakeholders in balancing the water competition acknowledging the major external effects of any water allocation.
Based on accumulating evidence of a role of lipid signaling in many physiological and pathophysiological processes including psychiatric diseases, the present data driven analysis was designed to gather information needed to develop a prospective biomarker, using a targeted lipidomics approach covering different lipid mediators. Using unsupervised methods of data structure detection, implemented as hierarchal clustering, emergent self-organizing maps of neuronal networks, and principal component analysis, a cluster structure was found in the input data space comprising plasma concentrations of d = 35 different lipid-markers of various classes acquired in n = 94 subjects with the clinical diagnoses depression, bipolar disorder, ADHD, dementia, or in healthy controls. The structure separated patients with dementia from the other clinical groups, indicating that dementia is associated with a distinct lipid mediator plasma concentrations pattern possibly providing a basis for a future biomarker. This hypothesis was subsequently assessed using supervised machine-learning methods, implemented as random forests or principal component analysis followed by computed ABC analysis used for feature selection, and as random forests, k-nearest neighbors, support vector machines, multilayer perceptron, and naïve Bayesian classifiers to estimate whether the selected lipid mediators provide sufficient information that the diagnosis of dementia can be established at a higher accuracy than by guessing. This succeeded using a set of d = 7 markers comprising GluCerC16:0, Cer24:0, Cer20:0, Cer16:0, Cer24:1, C16 sphinganine, and LacCerC16:0, at an accuracy of 77%. By contrast, using random lipid markers reduced the diagnostic accuracy to values of 65% or less, whereas training the algorithms with randomly permuted data was followed by complete failure to diagnose dementia, emphasizing that the selected lipid mediators were display a particular pattern in this disease possibly qualifying as biomarkers.
OBJECTIVE: There is scarce research on the effects of mindfulness in individual therapy. As many practitioners integrate mindfulness exercises into individual therapy, empirical evidence is of high clinical relevance.
METHOD: We investigated the effects of a session-introducing intervention with mindfulness elements (SIIME) in a randomized, controlled design. The effects of SIIME on therapeutic alliance and symptomatic outcome were compared with progressive muscle relaxation (PMR) and treatment-as-usual (TAU) control conditions. The sample comprised 162 patients with anxiety and depression.
RESULTS: Multilevel modeling revealed a significant symptom reduction and significant increase of alliance over the course of therapy. There were no significant time-condition interactions on outcome and alliance, indicating the comparable efficiency of all three treatment conditions.
CONCLUSIONS: We found no advantage of SIIME versus PMR and TAU. Add-on mindfulness might not improve individual therapy related to alliance and outcome.
Background: There are several ways to conduct a job task analysis in medical work environments including pencil-paper observations, interviews and questionnaires. However these methods implicate bias problems such as high inter-individual deviations and risks of misjudgement. Computer-based observation helps to reduce these problems. The aim of this paper is to give an overview of the development process of a computer-based job task analysis instrument for real-time observations to quantify the job tasks performed by physicians working in different medical settings. In addition reliability and validity data of this instrument will be demonstrated.
Methods: This instrument was developed in consequential steps. First, lists comprising tasks performed by physicians in different care settings were classified. Afterwards content validity of task lists was proved. After establishing the final task categories, computer software was programmed and implemented in a mobile personal computer. At least inter-observer reliability was evaluated. Two trained observers recorded simultaneously tasks of the same physician.
Results: Content validity of the task lists was confirmed by observations and experienced specialists of each medical area. Development process of the job task analysis instrument was completed successfully. Simultaneous records showed adequate interrater reliability.
Conclusion: Initial results of this analysis supported the validity and reliability of this developed method for assessing physicians' working routines as well as organizational context factors. Based on results using this method, possible improvements for health professionals' work organisation can be identified.
Survival according to BRAF-V600 tumor mutations : an analysis of 437 patients with primary melanoma
(2014)
The prognostic impact of BRAF-V600 tumor mutations in stage I/II melanoma patients has not yet been analyzed in detail. We investigated primary tumors of 437 patients diagnosed between 1989 and 2006 by Sanger sequencing. Mutations were detected in 38.7% of patients and were associated with age, histological subtype as well as mitotic rate. The mutational rate was 36.7% in patients with disease-free course and 51.7% in those with subsequent distant metastasis (p = 0.031). No difference in overall survival (p = 0.119) but a trend for worse distant-metastasis-free survival (p = 0.061) was observed in BRAF mutant compared to BRAF wild-type patients. Independent prognostic factors for overall survival were tumor thickness, mitotic rate and ulceration. An interesting significant prognostic impact was observed in patients with tumor thickness of 1 mm or less, with the mutation present in 6 of 7 patients dying from melanoma. In conclusion, no significant survival differences were found according to BRAF-V600 tumor mutations in patients with primary melanoma but an increasing impact of the mutational status was observed in the subgroup of patients with tumor thickness of 1 mm or less. A potential role of the mutational status as a prognostic factor especially in this subgroup needs to be investigated in larger studies.
The decay behavior of low-lying dipole states in 140Ce was investigated exploiting the γ3-setup at the HIγS facility using quasi-monochromatic photon beams. Branching ratios of individual excited states as well as average branching ratios to low-lying states have been extracted using γ – γ coincidence measurements. The comparison of the average branching ratios to QPM calculations shows a remarkable agreement between experiment and theory in the energy range from 5.0 to 8.5 MeV.