Ribonucleotide reductase regulatory subunit M2 drives glioblastoma TMZ resistance through modulation of dNTP production

During therapy, adaptations driven by cellular plasticity are partly responsible for driving the inevitable recurrence of glioblastoma (GBM). To investigate plasticity-induced adaptation during standard-of-care chemotherapy temozolomide (TMZ), we performed in vivo single-cell RNA sequencing in patient-derived xenograft (PDX) tumors of GBM before, during, and after therapy. Comparing single-cell transcriptomic patterns identified distinct cellular populations present during TMZ therapy. Of interest was the increased expression of ribonucleotide reductase regulatory subunit M2 (RRM2), which we found to regulate dGTP and dCTP production vital for DNA damage response during TMZ therapy. Furthermore, multidimensional modeling of spatially resolved transcriptomic and metabolomic analysis in patients’ tissues revealed strong correlations between RRM2 and dGTP. This supports our data that RRM2 regulates the demand for specific dNTPs during therapy. In addition, treatment with the RRM2 inhibitor 3-AP (Triapine) enhances the efficacy of TMZ therapy in PDX models. We present a previously unidentified understanding of chemoresistance through critical RRM2-mediated nucleotide production

Incidence of premature battery depletion in subcutaneous cardioverter-defibrillator patients: insights from a multicenter registry.

BACKGROUND The subcutaneous ICD established its role in the prevention of sudden cardiac death in recent years. The occurrence of premature battery depletion in a large subset of potentially affected devices has been a cause of concern. The incidence of premature battery depletion has not been studied systematically beyond manufacturer-reported data. METHODS Retrospective data and the most recent follow-up data on S-ICD devices from fourteen centers in Europe, the US, and Canada was studied. The incidence of generator removal or failure was reported to investigate the incidence of premature S-ICD battery depletion, defined as battery failure within 60 months or less. RESULTS Data from 1054 devices was analyzed. Premature battery depletion occurred in 3.5% of potentially affected devices over an observation period of 49 months. CONCLUSIONS The incidence of premature battery depletion of S-ICD potentially affected by a battery advisory was around 3.5% after 4 years in this study. Premature depletion occurred exclusively in devices under advisory. This is in line with the most recently published reports from the manufacturer. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT04767516

The assessment of circulating volume using inferior vena cava collapse index and carotid Doppler velocity time integral in healthy volunteers: a pilot study

International audienceBackground: Assessment of circulating volume and the requirement for fluid replacement are fundamental to resuscitation but remain largely empirical. Passive leg raise (PLR) may determine fluid responders while avoiding potential fluid overload. We hypothesised that inferior vena cava collapse index (IVCCI) and carotid artery blood flow would change predictably in response to PLR, potentially providing a non-invasive tool to assess circulating volume and identifying fluid responsive patients.Methods: We conducted a prospective proof of concept pilot study on fasted healthy volunteers. One operator measured IVC diameter during quiet respiration and sniff, and carotid artery flow. Stroke volume (SV) was also measured using suprasternal Doppler. Our primary endpoint was change in IVCCI after PLR. We also studied changes in IVCCI after “sniff”, and correlation between carotid artery flow and SV.Results: Passive leg raise was associated with significant reduction in the mean inferior vena cava collapsibility index from 0.24 to 0.17 (p < 0.01). Mean stroke volume increased from 56.0 to 69.2 mL (p < 0.01). There was no significant change in common carotid artery blood flow. Changes in physiology consequent upon passive leg raise normalised rapidly.Discussion: Passive leg raise is associated with a decrease of IVCCI and increase in stroke volume. However, the wide range of values observed suggests that factors other than circulating volume predominate in determining the proportion of collapse with respiration.Conclusion: In contrast to other studies, we did not find that carotid blood flow increased with passive leg raise. Rapid normalisation of post-PLR physiology may account for this

Tranexamic acid to reduce head injury death in people with traumatic brain injury: the CRASH-3 international RCT

Background Tranexamic acid safely reduces mortality in traumatic extracranial bleeding. Intracranial bleeding is common after traumatic brain injury and can cause brain herniation and death. We assessed the effects of tranexamic acid in traumatic brain injury patients. Objective To assess the effects of tranexamic acid on death, disability and vascular occlusive events in traumatic brain injury patients. We also assessed cost-effectiveness. Design Randomised trial and economic evaluation. Patients were assigned by selecting a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients, caregivers and those assessing outcomes were masked to allocation. All analyses were by intention to treat. We assessed the cost-effectiveness of tranexamic acid versus no treatment from a UK NHS perspective using the trial results and a Markov model. Setting 175 hospitals in 29 countries. Participants Adults with traumatic brain injury within 3 hours of injury with a Glasgow Coma Scale score of ≤ 12 or any intracranial bleeding on computerised tomography scan, and no major extracranial bleeding, were eligible. Intervention Tranexamic acid (loading dose 1 g over 10 minutes then infusion of 1 g over 8 hours) or matching placebo. Main outcome measures Head injury death in hospital within 28 days of injury in patients treated within 3 hours of injury. Secondary outcomes were early head injury deaths, all-cause and cause-specific mortality, disability, vascular occlusive events, seizures, complications and adverse events. Results Among patients treated within 3 hours of injury (n = 9127), the risk of head injury death was 18.5% in the tranexamic acid group versus 19.8% in the placebo group (855/4613 vs. 892/4514; risk ratio 0.94, 95% confidence interval 0.86 to 1.02). In a prespecified analysis excluding patients with a Glasgow Coma Scale score of 3 or bilateral unreactive pupils at baseline, the results were 12.5% in the tranexamic acid group versus 14.0% in the placebo group (485/3880 vs. 525/3757; risk ratio 0.89, 95% confidence interval 0.80 to 1.00). There was a reduction in the risk of head injury death with tranexamic acid in those with mild to moderate head injury (166/2846 vs. 207/2769; risk ratio 0.78, 95% confidence interval 0.64 to 0.95), but in those with severe head injury (689/1739 vs. 685/1710; risk ratio 0.99, 95% confidence interval 0.91 to 1.07) there was no apparent reduction (p-value for heterogeneity = 0.030). Early treatment was more effective in mild and moderate head injury (p = 0.005), but there was no obvious impact of time to treatment in cases of severe head injury (p = 0.73). The risk of disability, vascular occlusive events and seizures was similar in both groups. Tranexamic acid is highly cost-effective for mild and moderate traumatic brain injury (base case of £4288 per quality-adjusted life-year gained). Conclusion Early tranexamic acid treatment reduces head injury deaths. Treatment is cost-effective for patients with mild or moderate traumatic brain injury, or those with both pupils reactive. Future work Further trials should examine early tranexamic acid treatment in mild head injury. Research on alternative routes of administration is needed. Limitations Time to treatment may have been underestimated. Trial registration Current Controlled Trials ISRCTN15088122, ClinicalTrials.gov NCT01402882, EudraCT 2011-003669-14, Pan African Clinical Trial Registry PACTR20121000441277. Funding The project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 26. See the NIHR Journals Library website for further project information. In addition, funding was provided by JP Moulton Charitable Trust, Joint Global Health Trials (Medical Research Council, Department for International Development and the Wellcome Trust). This project was funded by the NIHR Global Health Trials programme

Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial

Background: Tranexamic acid reduces surgical bleeding and reduces death due to bleeding in patients with trauma. Meta-analyses of small trials show that tranexamic acid might decrease deaths from gastrointestinal bleeding. We aimed to assess the effects of tranexamic acid in patients with gastrointestinal bleeding. Methods: We did an international, multicentre, randomised, placebo-controlled trial in 164 hospitals in 15 countries. Patients were enrolled if the responsible clinician was uncertain whether to use tranexamic acid, were aged above the minimum age considered an adult in their country (either aged 16 years and older or aged 18 years and older), and had significant (defined as at risk of bleeding to death) upper or lower gastrointestinal bleeding. Patients were randomly assigned by selection of a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients received either a loading dose of 1 g tranexamic acid, which was added to 100 mL infusion bag of 0·9% sodium chloride and infused by slow intravenous injection over 10 min, followed by a maintenance dose of 3 g tranexamic acid added to 1 L of any isotonic intravenous solution and infused at 125 mg/h for 24 h, or placebo (sodium chloride 0·9%). Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcome was death due to bleeding within 5 days of randomisation; analysis excluded patients who received neither dose of the allocated treatment and those for whom outcome data on death were unavailable. This trial was registered with Current Controlled Trials, ISRCTN11225767, and ClinicalTrials.gov, NCT01658124. Findings: Between July 4, 2013, and June 21, 2019, we randomly allocated 12 009 patients to receive tranexamic acid (5994, 49·9%) or matching placebo (6015, 50·1%), of whom 11 952 (99·5%) received the first dose of the allocated treatment. Death due to bleeding within 5 days of randomisation occurred in 222 (4%) of 5956 patients in the tranexamic acid group and in 226 (4%) of 5981 patients in the placebo group (risk ratio [RR] 0·99, 95% CI 0·82–1·18). Arterial thromboembolic events (myocardial infarction or stroke) were similar in the tranexamic acid group and placebo group (42 [0·7%] of 5952 vs 46 [0·8%] of 5977; 0·92; 0·60 to 1·39). Venous thromboembolic events (deep vein thrombosis or pulmonary embolism) were higher in tranexamic acid group than in the placebo group (48 [0·8%] of 5952 vs 26 [0·4%] of 5977; RR 1·85; 95% CI 1·15 to 2·98). Interpretation: We found that tranexamic acid did not reduce death from gastrointestinal bleeding. On the basis of our results, tranexamic acid should not be used for the treatment of gastrointestinal bleeding outside the context of a randomised trial

System noise assessment of a tube-and-wing aircraft with geared turbofan engines

The Airbus A320neo family and the Bombardier CSeries can come equipped with a geared turbofan of increased bypass ratio. Such an engine concept promises reduced engine noise generation if compared to conventional turbofan engines with lower bypass ratios. As a result, the dominance of other noise sources on-board of an aircraft with geared turbofan engines are emphasized and will become more relevant. Consequently, to get an understanding of the modified noise source ranking due to the new engine concept, a noise assessment of the overall aircraft noise as received on the ground is essential, i.e., a so called system noise assessment. For this study a DLR & TU Braunschweig aircraft design synthesis process with integrated noise prediction capabilities is applied. An interface to process external input data allows the implementation of high-fidelity simulation results for the geared engine concept into the overall simulation process, i.e. including all required engine parameters for the noise prediction. The focus lies on the comparison of existing engine concepts and their impact on the overall vehicle design, flight performance, and ultimately the system noise. The noise assessment is not limited to the overall vehicle noise as received on the ground but moreover the dominance and ranking of all individual noise sources is discussed. A direct comparison and evaluation of the flight performance and the system noise of the different vehicle variants under consideration is presented. Among the vehicle variants, one aircraft is adapted to better match the engine concept. A geared turbofan engine concept will come with an inherent and advantageous implication on the overall aircraft performance, i.e., reduced specific fuel consumption. Since such beneficial characteristics are identified in the simulation results, the overall vehicle design is consequently adapted to fully exploit these characteristics. Furthermore, several known measures to reduce the airframe noise contribution are simulated on board of the vehicles under consideration. The system noise assessment will identify the impact of these technologies on the overall aircraft noise for each variant. Finally, the geared turbofan engine is also installed on board of an earlier low-noise aircraft concept featuring engine noise shielding. The impact of the new engine in combination with shielding effects is assessed. It is demonstrated that the influence of low-noise airframe measures in combination with geared turbofan aircraft concept are promising, especially on an airframe architecture dedicated to engine noise shielding

Aeroacoustics research in Europe: The CEAS-ASC report on 2017 highlights, Contribution: System noise assessment of a tube-and-wing aircraft with geared turbofan engines

Short review of DLR and TU Braunschweig application of a simulation process for aircraft design synthesis with integrated noise prediction capabilities. An existing process is upgraded in order to process external data from high-fidelity computation and measurements. Dedicated engine simulation data for a GTF engine and experimental findings for selected high-lift systems are incorporated into the study. Aircraft performance, e.g., direct operating costs, can now directly be compared to the predicted ground noise levels for different aircraft/engine combinations under consideration. The geared turbofan engine has been simulated on board of conventional tube-and-wing aircraft as well as on board of dedicated low-noise vehicles. It is demonstrated, that the combination of noise shielding and the geared turbofan concept is most effective. The most promising low-noise vehicle of the study is equipped with GTF engines that are shielded by the fuselage and the main wing. Consequently, the influence of the airframe noise sources is increased for this vehicle and any modification in order to reduce the airframe noise becomes especially effective. Application of low-noise airframe technologies to this vehicle reduce the overall aircraft noise as received on the ground

Short-term neurocognitive and symptomatic outcomes following mild traumatic brain injury: A prospective multi-centre observational cohort study.

OBJECTIVE: To determine the short-term cognitive and symptomatic outcome following mild traumatic brain injury. METHODS: Setting: Emergency Departments of two UK tertiary referral hospitals. PARTICIPANTS: Adult patients presenting to the Emergency Departments of the Royal London Hospital and Salford Royal Hospital with suspected traumatic brain injury within 24 hours and Glasgow Coma Score > 8. A non-TBI comparison group included adult patients with no head or neck injury. DESIGN: Prospective multi-centre cohort study. MAIN MEASURES: The Standardized Assessment of Concussion (SAC), the Concussion Symptom Inventory (CSI) and total number of symptoms, measured at baseline and 72 hours. RESULTS: This study enrolled 189 patients with and 51 patients without TBI. Patients with TBI had marked cognitive impairment which persisted at 72 hours (SAC score at baseline = 25 [23-27] vs 72 hours = 25 [22-27]; p = 0.1). Patients with TBI had persistent high symptom severity, although this had decreased at 72 hours (CSI score at baseline = 9 [4-22] vs 72 hours = 5 [1-19], p = 0.002). A similar pattern was observed with the total number of symptoms (baseline = 4 [2-8] vs 72 hours = 0 [0-4]; p < 0.001). Patients with TBI had worse neurocognitive function, higher overall symptom severity and higher total number of symptoms compared with patients without TBI. Patients without TBI' neurocognitive function and symptom severity remained constant, but the number of symptoms reduced between baseline and 72 hours. CONCLUSION: There is a cognitive deficit and symptom burden in patients with mild TBI presenting to the Emergency Department which persists at 72 hours

Short-term neurocognitive and symptomatic outcomes following mild traumatic brain injury: A prospective multi-centre observational cohort study

Objective: To determine the short-term cognitive and symptomatic outcome following mild traumatic brain injury. Methods: Setting: Emergency Departments of two UK tertiary referral hospitals. Participants: Adult patients presenting to the Emergency Departments of the Royal London Hospital and Salford Royal Hospital with suspected traumatic brain injury within 24 hours and Glasgow Coma Score > 8. A non-TBI comparison group included adult patients with no head or neck injury. Design: Prospective multi-centre cohort study. Main measures: The Standardized Assessment of Concussion (SAC), the Concussion Symptom Inventory (CSI) and total number of symptoms, measured at baseline and 72 hours. Results: This study enrolled 189 patients with and 51 patients without TBI. Patients with TBI had marked cognitive impairment which persisted at 72 hours (SAC score at baseline = 25 [23–27] vs 72 hours = 25 [22–27]; p = 0.1). Patients with TBI had persistent high symptom severity, although this had decreased at 72 hours (CSI score at baseline = 9 [4–22] vs 72 hours = 5 [1–19], p = 0.002). A similar pattern was observed with the total number of symptoms (baseline = 4 [2–8] vs 72 hours = 0 [0–4]; p Conclusion: There is a cognitive deficit and symptom burden in patients with mild TBI presenting to the Emergency Department which persists at 72 hours.</p