Abstract
A series of monolithic active pixel sensor prototypes (APTS chips) were manufactured in the TPSCo 65 nm CMOS imaging process in the framework of the CERN-EP R&D on monolithic sensors and the ...ALICE ITS3 upgrade project. Each APTS chip contains a 4 × 4 pixel matrix with fast analog outputs buffered to individual pads. To explore the process and sensor characteristics, various pixel pitches (10 µm–25 µm), geometries and reverse biasing schemes were included. Prototypes are fully functional with detailed sensor characterization ongoing. The design will be presented with some experimental results also correlating to some transistor measurements.
Abstract
Time-dependent energy spectra of galactic cosmic rays (GCRs) carry crucial information regarding their origin and propagation throughout the interstellar environment. When observed at the ...Earth, after traversing the interplanetary medium, such spectra are heavily affected by the solar wind and the embedded solar magnetic field permeating the inner sectors of the heliosphere. The activity of the Sun changes significantly over an 11 yr solar cycle—and so does the effect on cosmic particles; this translates into a phenomenon called solar modulation. Moreover, GCR spectra during different epochs of solar activity provide invaluable information for a complete understanding of the plethora of mechanisms taking place in various layers of the Sun’s atmosphere and how they evolve over time. The High-Energy Particle Detector (HEPD-01) has been continuously collecting data since 2018 August, during the quiet phase between solar cycles 24 and 25; the activity of the Sun is slowly but steadily rising and is expected to peak around 2025/2026. In this paper, we present the first spectra for ∼50–250 MeV galactic protons measured by the HEPD-01 instrument—placed on board the CSES-01 satellite—from 2018 August to 2022 March over a one-Carrington-rotation time basis. Such data are compared to the ones from other spaceborne experiments, present (e.g., EPHIN, Parker Solar Probe) and past (PAMELA), and to a state-of-the-art three-dimensional model describing the GCRs propagation through the heliosphere.
Purpose In cruciate retaining total knee arthroplasty, posterior cruciate ligament damage may occur during tibial cutting. A prospective randomized study was conducted to investigate whether a novel ...tibial cutting technique was more effective than the currently used techniques.
Materials and methods Patients undergoing cruciate retaining total knee arthroplasty were recruited in a prospective, randomized, controlled trial. In 25 patients (group 1) the tibial cut was performed using a double tibial cut technique; in 25 (group 2) and 25 (group 3) patients, the bone island and en bloc resection techniques were performed, respectively. Posterior cruciate ligament integrity and femoral rollback were assessed at the end of surgery. The Oxford Knee Score, WOMAC score and range of motion were assessed postoperatively.
Results Posterior cruciate ligament was completely preserved in 92% of patients in group 1 and in 64% in group 2 and 3, respectively (p = 0.03). The Oxford Knee Score and WOMAC scores did not differ between groups (p = 0.4). The mean knee flexion was 126.4°, 121.5° and 123.9° in groups 1, 2 and 3, respectively (p = 0.04). The femoral rollback at 120° flexion was 80.7%, 72.2% and 75.4% in groups 1, 2 and 3, respectively (p = 0.01).
Conclusions The double cut technique preserves the posterior cruciate ligament at significantly higher rates than the bone island or en bloc resection techniques. Better posterior cruciate ligament preservation may improve the femoral rollback and knee flexion.
Level of evidence Prospective randomized controlled trial, Level I.
BACKGROUND AND PURPOSE—Preventive strategies, together with demographic and socioeconomic changes, might have modified the worldwide distribution of ischemic stroke (IS) subtypes. We investigated ...those changes by means of a systematic review and meta-analysis.
METHODS—We evaluated all population- and hospital-based studies reporting the distribution of IS etiologic subtypes according to the TOAST criteria (Trial of ORG 10172 in Acute Stroke Treatment). Studies were identified by searching articles indexed on PubMed and Scopus from January 1, 1993, to June 30, 2017. Two independent investigators extracted data and checked them for accuracy. Proportions of each etiologic subtype were pooled according to a random effect meta-analytic model weighted by study size; temporal trends were assessed using a mixed-effect meta-regression model.
RESULTS—Sixty-five studies including patients from 1993 to 2015 were finally included. Overall, ISs were attributed to cardioembolism (22%; 95% confidence interval CI, 20–23); large artery atherosclerosis (23%; 95% CI, 21–25); small artery occlusion (22%; 95% CI, 21–24); other determined cause (3%; 95% CI, 3–3); and undetermined cause (26%; 95% CI, 24–28). Cardioembolism was the leading IS etiologic subtype in whites (28%; 95% CI, 26–29) and large artery atherosclerosis in Asians (33%; 95% CI, 31–36). Meta-regression showed an increasing temporal trend for cardioembolism in whites (2.4% annually, P=0.008) and large artery atherosclerosis in Asians (5.7% annually, P<0.001), and a decrease for small artery occlusion in whites (−4.7% annually, P=0.001); there was considerable heterogeneity across all the analyses.
CONCLUSIONS—According to our systematic review and meta-analysis, cardioembolism in whites and large artery atherosclerosis in Asians are the leading causes of IS. The heterogeneous distribution of etiologic subtypes of IS may depend on the demographic and socioeconomic characteristics of the different populations. More extensive protocols should be adopted to reduce the persistently relevant proportion of undetermined cause IS.
Rationale
Previous work suggests that GET 73, a novel compound with putative activity on the metabotropic glutamate receptor subtype 5 (mGluR5), may represent a novel pharmacological treatment for ...alcohol use disorder (AUD).
Objective
In this study, we investigated the safety, tolerability, pharmacokinetics, and biobehavioral effects of GET 73, when co-administered with alcohol, in individuals with alcohol dependence (AD).
Methods
This was an inpatient, cross-over, randomized, double-blind, placebo-controlled, human laboratory study with non-treatment-seeking, alcohol-dependent individuals. The study used a within-subject design, with two counterbalanced stages, during which participants received GET 73 and then placebo, or vice versa. During each stage, participants underwent an alcohol interaction session and, on a separate day, an alcohol cue reactivity, followed by an alcohol self-administration session.
Results
Safety outcomes of GET 73 were excellent with no serious adverse events, nor adverse events of severe grade. The co-administration of alcohol and GET 73 did not affect the pharmacokinetics of GET 73 or alcohol. GET 73, compared to placebo, did not affect the alcohol-related stimulation effects, but increased the subjective sedative effects of alcohol. GET 73 did not affect alcohol cue–induced craving, or alcohol self-administration in the laboratory.
Conclusions
The study confirms the safety and tolerability of GET 73 when co-administered with alcohol. Although, under this experimental condition, we did not detect an effect on alcohol craving and consumption in the laboratory, additional studies should be conducted administering GET 73 for an extended period in an outpatient setting.
Fracture-related infections (FRI) pose a difficult management problem, as they require numerous surgical interventions and extended antibiotic treatments, especially when a multidrug-resistant ...organism is involved, with a paucity of available literature that provides guidance.
A 42 year-old male presents an open diaphyseal tibia and fibula fracture, complicated by soft tissue necrosis and infections caused by extensively drug-resistant Acinetobacter baumannii (XDR-Ab). Initially treated with a damage control external fixator, the patient underwent multiple surgical procedures, including radical debridement, negative pressure wound therapy, external fixator revisions and reconstructive surgery using a latissimus dorsi free flap. The emergence of colistin resistance in the Acinetobacter baumannii strain led to the compassionate use of cefiderocol, finally achieving clinical cure.
This case report is one of the firsts that highlights the potential efficacy of cefiderocol in treating challenging bone and joint infections sustained by XDR-Ab. The successful outcome also emphasizes the importance of a comprehensive, multidisciplinary approach in achieving favorable results in complex FRI.
Microglial cells play a key role in protecting the central nervous system from pathogens and toxic compounds and are involved in the pathogenesis of different neurodegenerative diseases. Cadmium is a ...widespread toxic heavy metal, released into the environment at a rate of 30,000 tons/year by anthropogenic activities; it is easily uptaken by the human body through diet and cigarette smoke, as well as by occupational exposure. Once inside the body, cadmium enters the cells and substitutes to zinc and other divalent cations altering many biological functions. Its extremely long half-life makes it a serious health threat. Recent data suggest a role for heavy metals in many neurodegenerative diseases; however, the role of cadmium is still to be elucidated. In this work we report the investigation of cadmium toxicity towards murine BV2 microglial cells, a widely used model for the study of neurodegeneration. Results show that increasing cadmium concentrations increase oxidative stress, a proposed mechanism of neurodegeneration, but also that BV2 cells can keep oxidative stress under control by increasing glutathione reduction. Moreover, cadmium induces alterations of cell morphology and metabolism leading to mitochondrial impairment, without switching the cells to Warburg effect. Finally cadmium induces the release of proinflammatory cytokines, but does not markedly switch BV2 cells to M1 phenotype.
Human laboratory studies have contributed extensively in the research and development of novel medications to treat alcohol use disorder (AUD). Alcohol tolerance may represent one additional variable ...that can be utilized to expand the understanding of the AUD wide phenotypic profile and provide support to the medication development process. Tolerance is characterized as an individual's subjective response to alcohol and has been recognized as a predictor of AUD progression. Tolerance can be evaluated both by self-reported response (e.g. assessments) and objective measurements (e.g. motor impairment); as such, it represents an exploitable variable in the field of alcohol research.
This Narrative Review focuses on the use of alcohol tolerance, specifically within alcohol laboratory studies, for medication development. It seeks to identify a research gap and a research opportunity in clinical studies to evaluate biobehavioral responses captured in order to develop medications to treat AUD.
Alcohol tolerance may provide additional information on the safety and tolerability of medications to treat AUD, in particular, when novel medications are co-administered with alcohol within the AUD population.
As such, alcohol tolerance represents an additional outcome that may be included in randomized clinical trial (RCT) protocols designed for developing AUD pharmacotherapies.
One of the major limits of chemotherapy is depending on the ability of the cancer cells to elude and adapt to different drugs. Recently, we demonstrated how the activation of the M2 muscarinic ...receptor could impair neuroblastoma cell proliferation. In the present paper, we investigate the possible effects mediated by the preferential M2 receptor agonist arecaidine propargyl ester (APE) on drug resistance in two neuroblastoma cell lines, SK-N-BE and SK-N-BE(2C), a sub-clone presenting drug resistance. In both cell lines, we compare the expression of the M2 receptor and the effects mediated by the M2 agonist APE on cell cycle, demonstrating a decreased percentage of cells in S phase and an accumulation of SK-N-BE cells in G1 phase, while the APE treatment of SK-N-BE(2C) cells induced a block in G2/M phase. The withdrawal of the M2 agonist from the medium shows that only the SK-N-BE(2C) cells are able to rescue cell proliferation. Further, we demonstrate that the co-treatment of low doses of APE with doxorubicin or cisplatin significantly counteracts cell proliferation when compared with the single treatment. Analysis of the expression of ATP-binding cassette (ABC) efflux pumps demonstrates the ability of the M2 agonist to downregulate their expression and that this negative modulation may be dependent on N-MYC decreased expression induced by the M2 agonist. Our data demonstrate that the combined effect of low doses of conventional drugs and the M2 agonist may represent a new promising therapeutic approach in neuroblastoma treatment, in light of its significant impact on drug resistance and the possible reduction in the side effects caused by high doses of chemotherapy drugs.
To define electrocardiographic features of complete left bundle branch block (LBBB) and right bundle branch block (RBBB), and the use of R-peak time (RPT) to identify interventricular dyssynchrony in ...dogs with BBB.
Twelve-lead ECG tracings of 20 dogs with RBBB, 20 with LBBB, and 60 healthy dogs were retrospectively analyzed and RPT was measured in precordial leads. Interventricular dyssynchrony index (IDI) was than calculated.
In RBBB, mean electrical axis (MEA) was −111° −120/−100°, V1RPT was significantly longer (61 ms 55–72 ms) than left precordial leads RPT (V2:25 ms 22–30 ms; V3:25 ms 22–29 ms; V4:24 ms 21–29 ms; V5:25 ms 22–29 ms; V6:25 ms 22–29 ms) and when compared to normal dogs (P < 0.001). In LBBB, MEA was 76° 70/81°, RPT in left precordial leads was significantly longer (V2:49 ms 34–58 ms; V3:49 ms 43–57 ms; V4:52 ms 45–62 ms; V5:53 ms 45–63 ms; V6:55 ms 45–63 ms) than V1RPT (17 ms 15–20 ms) and when compared to normal dogs (P < 0.001). V1RPT > 28 ms and V5RPT > 36 ms were found to predict the presence of RBBB and LBBB with a sensitivity of 100% and 96.7%, and a specificity of 96.7% and 99.5%, respectively. The IDI was 23% 16–29% in normal dogs and significantly greater in dogs with RBBB (33% 30–38%; P < 0.001) and LBBB (32% 23–41%; P = 0.006).
This study defines ECG features and RPT in dogs with BBB. Electrical interventricular dyssynchrony can be defined using IDI in dogs with BBB.
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