The FPGA-based Continious FFT Tune Measurement System for the LHC and its test at the CERN SPS

A base band tune (BBQ) measurement system has been developed at CERN. This system is based on a high-sensitivity direct-diode detection technique followed by a high resolution FFT algorithm implemented in an FPGA. The system allows acquisition of continuous real-time spectra with 32-bit resolution, while a digital frequency synthesiser (DFS) can provide an acquisition synchronised chirp excitation. All the implemented algorithms support dynamic reconfiguration of processing and excitation parameters. Results from both laboratory measurements and tests performed with beam at the CERN SPS are presented

On the Continuous Measurement of the LHC Beta-Function - Prototype Studies at the SPS

Until now, the continuous monitoring of the LHC lattice has been considered impractical due to tight constraints on the maximum allowed beam excitations and acquisition time usually required for betatron function measurements. As a further exploitation of the Base-Band-Tune (BBQ) detection principle, already widely used for tune diagnostics, a real-time beta-beat measurement prototype has been successfully tested at the CERN SPS and is based on the continuous measurement of the cell-to-cell betatron phase advance. Tests show that the phase resolution is better than a degree corresponding to a peak-to-peak beta-beat resolution of better than a percent. Due to the system’s high sensitivity, it required only micrometre-range excitation, making it compatible with nominal LHC operation. This contribution discusses results, measurement systematics and exploitation possibilities that may be used to improve the nominal LHC performance

Tune shift induced by nonlinear resistive wall wake field of flat collimator

We present formulae for the coherent and incoherent tune shifts due to the nonlinear resistive wall wake field for a single beam traveling between two parallel plates. In particular, we demonstrate that the nonlinear terms of the resistive-wall wake field become important if the gap between the plates is comparable to the transverse rms beam size. We also compare the theoretically predicted tune shift as a function of gap size with measurements for an LHC prototype graphite collimator in the CERN SPS and with simulations

Aperture Restriction Localisation in the LHC Arcs using an RF Mole and the LHC Beam Position Measurement System

Ensuring that the two 27km beam pipes of the LHC do not contain aperture restrictions is of utmost importance. Most of the ring is composed of continuous cryostats, so any intervention to remove aperture restrictions when the machine is at its operating temperature of 1.9K will require a substantial amount of time. On warming-up the first cooled sector, several of the sliding contacts which provide electrical continuity for the beam image current between successive sections of the vacuum chamber were found to have buckled into the beam pipe. This led to a search for a technique to verify the integrity of a complete LHC arc (~3km) before any subsequent cool-down. In this paper the successful results from using a polycarbonate ball fitted with a 40MHz RF transmitter are presented. Propulsion of the ball is achieved by sucking filtered air through the entire arc, while its progress is traced every 54m via the LHC beam position measurement system which is auto-triggered by the RF transmitter on passage of the ball. Reflectometry at frequencies in the 4-8 GHz range can cover the gaps between beam position monitors and could therefore be used to localise a ball blocked by an obstacle

Extracellular Matrix Proteomics Reveals Interplay of Aggrecan and Aggrecanases in Vascular Remodeling of Stented Coronary Arteries.

BACKGROUND: Extracellular matrix (ECM) remodeling contributes to in-stent restenosis and thrombosis. Despite its important clinical implications, little is known about ECM changes post-stent implantation. METHODS: Bare-metal and drug-eluting stents were implanted in pig coronary arteries with an overstretch under optical coherence tomography guidance. Stented segments were harvested 1, 3, 7, 14, and 28 days post-stenting for proteomics analysis of the media and neointima. RESULTS: A total of 151 ECM and ECM-associated proteins were identified by mass spectrometry. After stent implantation, proteins involved in regulating calcification were upregulated in the neointima of drug-eluting stents. The earliest changes in the media were proteins involved in inflammation and thrombosis, followed by changes in regulatory ECM proteins. By day 28, basement membrane proteins were reduced in drug-eluting stents in comparison with bare-metal stents. In contrast, the large aggregating proteoglycan aggrecan was increased. Aggrecanases of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family contribute to the catabolism of vascular proteoglycans. An increase in ADAMTS-specific aggrecan fragments was accompanied by a notable shift from ADAMTS1 and ADAMTS5 to ADAMTS4 gene expression after stent implantation. Immunostaining in human stented coronary arteries confirmed the presence of aggrecan and aggrecan fragments, in particular, at the contacts of the stent struts with the artery. Further investigation of aggrecan presence in the human vasculature revealed that aggrecan and aggrecan cleavage were more abundant in human arteries than in human veins. In addition, aggrecan synthesis was induced on grafting a vein into the arterial circulation, suggesting an important role for aggrecan in vascular plasticity. Finally, lack of ADAMTS-5 activity in mice resulted in an accumulation of aggrecan and a dilation of the thoracic aorta, confirming that aggrecanase activity regulates aggrecan abundance in the arterial wall and contributes to vascular remodeling. CONCLUSIONS: Significant differences were identified by proteomics in the ECM of coronary arteries after bare-metal and drug-eluting stent implantation, most notably an upregulation of aggrecan, a major ECM component of cartilaginous tissues that confers resistance to compression. The accumulation of aggrecan coincided with a shift in ADAMTS gene expression. This study provides the first evidence implicating aggrecan and aggrecanases in the vascular injury response after stenting

Safety and efficacy of ganaxolone in patients with CDKL5 deficiency disorder: results from the double-blind phase of a randomised, placebo-controlled, phase 3 trial

BACKGROUND: CDKL5 deficiency disorder (CDD) is a rare, X-linked, developmental and epileptic encephalopathy characterised by severe global developmental impairment and seizures that can begin in the first few months after birth and are often treatment refractory. Ganaxolone, an investigational neuroactive steroid, reduced seizure frequency in an open-label, phase 2 trial that included patients with CDD. We aimed to further assess the efficacy and safety of ganaxolone in patients with CDD-associated refractory epilepsy. METHODS: In the double-blind phase of this randomised, placebo-controlled, phase 3 trial, done at 39 outpatient clinics in eight countries (Australia, France, Israel, Italy, Poland, Russia, the UK, and the USA), patients were eligible if they were aged 2-21 years with a pathogenic or probably pathogenic CDKL5 variant and at least 16 major motor seizures (defined as bilateral tonic, generalised tonic-clonic, bilateral clonic, atonic, or focal to bilateral tonic-clonic) per 28 days in each 4-week period of an 8-week historical period. After a 6-week prospective baseline period, patients were randomly assigned (1:1) via an interactive web response system to receive either enteral adjunctive ganaxolone or matching enteral adjunctive placebo (maximum dose 63 mg/kg per day for patients weighing ≤28 kg or 1800 mg/day for patients weighing >28 kg) for 17 weeks. Patients, caregivers, investigators (including those analysing data), trial staff, and the sponsor (other than the investigational product manager) were masked to treatment allocation. The primary efficacy endpoint was percentage change in median 28-day major motor seizure frequency from the baseline period to the 17-week double-blind phase and was analysed (using a Wilcoxon-rank sum test) in all patients who received at least one dose of trial treatment and for whom baseline data were available. Safety (compared descriptively across groups) was analysed in all patients who received at least one dose of trial treatment. This study is registered with ClinicalTrials.gov, NCT03572933, and the open-label extension phase is ongoing. FINDINGS: Between June 25, 2018, and July 2, 2020, 114 patients were screened for eligibility, of whom 101 (median age 6 years [IQR 3 to 10]) were randomly assigned to receive either ganaxolone (n=50) or placebo (n=51). All patients received at least one dose of a study drug, but seizure frequency for one patient in the ganaxolone group was not recorded at baseline and so the primary endpoint was analysed in a population of 100 patients. There was a median percentage change in 28-day major motor seizure frequency of -30·7% (IQR -49·5 to -1·9) in the ganaxolone group and of -6·9% (-24·1 to 39·7) in the placebo group (p=0·0036). The Hodges-Lehmann estimate of median difference in responses to ganaxolone versus placebo was -27·1% (95% CI -47·9 to - 9·6). Treatment-emergent adverse events occurred in 43 (86%) of 50 patients in the ganaxolone group and in 45 (88%) of 51 patients in the placebo group. Somnolence, pyrexia, and upper respiratory tract infections occurred in at least 10% of patients in the ganaxolone group and more frequently than in the placebo group. Serious adverse events occurred in six (12%) patients in the ganaxolone group and in five (10%) patients in the placebo group. Two (4%) patients in the ganaxolone group and four (8%) patients in the placebo group discontinued the trial. There were no deaths in the double-blind phase. INTERPRETATION: Ganaxolone significantly reduced the frequency of CDD-associated seizures compared with placebo and was generally well tolerated. Results from what is, to our knowledge, the first controlled trial in CDD suggest a potential treatment benefit for ganaxolone. Long-term treatment is being assessed in the ongoing open-label extension phase of this trial. FUNDING: Marinus Pharmaceuticals