SIMCER was a 6‐mo, multicenter, open‐label trial. Selected de novo liver transplant recipients were randomized (week 4) to everolimus with low‐exposure tacrolimus discontinued by month 4 (n = 93) or ...to tacrolimus‐based therapy (n = 95), both with basiliximab induction and enteric‐coated mycophenolate sodium with or without steroids. The primary end point, change in estimated GFR (eGFR; MDRD formula) from randomization to week 24 after transplant, was superior with everolimus (mean eGFR change +1.1 vs. −13.3 mL/min per 1.73 m2 for everolimus vs. tacrolimus, respectively; difference 14.3 95% confidence interval 7.3–21.3; p < 0.001). Mean eGFR at week 24 was 95.8 versus 76.0 mL/min per 1.73 m2 for everolimus versus tacrolimus (p < 0.001). Treatment failure (treated biopsy‐proven acute rejection BPAR; rejection activity index score >3, graft loss, or death) from randomization to week 24 was similar (everolimus 10.0%, tacrolimus 4.3%; p = 0.134). BPAR was more frequent between randomization and month 6 with everolimus (10.0% vs. 2.2%; p = 0.026); the rate of treated BPAR was 8.9% versus 2.2% (p = 0.055). Sixteen everolimus‐treated patients (17.8%) and three tacrolimus‐treated patients (3.2%) discontinued the study drug because of adverse events. In conclusion, early introduction of everolimus at an adequate exposure level with gradual calcineurin inhibitor (CNI) withdrawal after liver transplantation, supported by induction therapy and mycophenolic acid, is associated with a significant renal benefit versus CNI‐based immunosuppression but more frequent BPAR.
This multicenter, open‐label trial of de novo liver transplant recipients randomized at week 4 to everolimus with low‐exposure tacrolimus discontinued by month 4, or to standard tacrolimus‐based therapy with both basiliximab induction and enteric‐coated mycophenolate sodium ± steroids, shows a significant renal benefit for the everolimus‐treated group versus the control arm but more frequent mild or moderate biopsy‐proven acute rejection.
Markers of epithelial‐mesenchymal transition (EMT) may identify patients at high risk of graft fibrogenesis who could benefit from early calcineurin inhibitor (CNI) withdrawal. In a randomized, ...open‐label, 12‐month trial, de novo kidney transplant patients received cyclosporine, enteric‐coated mycophenolate sodium (EC‐MPS) and steroids to month 3. Patients were stratified as EMT+ or EMT− based on month 3 biopsy, then randomized to start everolimus with half‐dose EC‐MPS (720 mg/day) and cyclosporine withdrawal (CNI‐free) or continue cyclosporine with standard EC‐MPS (CNI). The primary endpoint was progression of graft fibrosis (interstitial fibrosis/tubular atrophy IF/TA grade increase ≥1 between months 3–12) in EMT+ patients. 194 patients were randomized (96 CNI‐free, 98 CNI); 153 (69 CNI‐free, 84 CNI) were included in histological analyses. Fibrosis progression occurred in 46.2% (12/26) CNI‐free EMT+ patients versus 51.6% (16/31) CNI EMT+ patients (p = 0.68). Biopsy‐proven acute rejection (BPAR, including subclinical events) occurred in 25.0% and 5.1% of CNI‐free and CNI patients, respectively (p < 0.001). In conclusion, early CNI withdrawal with everolimus initiation does not prevent interstitial fibrosis. Using this CNI‐free protocol, in which everolimus exposure was relatively low and administered with half‐dose EC‐MPS, CNI‐free patients were overwhelmingly under‐immunosuppressed and experienced an increased risk of BPAR.
In a 12‐month trial of 194 de novo kidney transplant patients receiving cyclosporine, enteric‐coated mycophenolate sodium, and steroids, the cohort randomized at month three to start everolimus with halfdose EC‐MPS and no cyclosporine was underimmunosuppressed and did not experience a benefit in terms of the primary endpoint of the study, progression of graft fibrosis in patients positive for epithelial‐mesenchymal transition.
50 litres TPC with sCMOS-based optical readout for the CYGNO project Mazzitelli, G.; Domingues, F. Amaro; Baracchini, E. ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
01/2023, Letnik:
1045
Journal Article
Recenzirano
The CYGNO project aims at realizing a one cubic meter gaseous Time Projection Chamber (TPC) equipped with Scientific CMOS (sCMOS) commercial cameras to optically readout Gas Electron Multiplier (GEM) ...to be operated at the underground of Gran Sasso National Laboratory (LNGS).
The purpose of the project is to study the technology needed for a large size gaseous TPC (30–100 m3) operated at atmospheric pressure for the directional search of low mass O(GeV) dark matter and low energy (eg solar) neutrinos astronomy. The roadmap of the project foresees the underground operation of a 50 litres TPC prototype, called LIME, the largest TPC realized with this technology, fully equipped with copper and water shielding. LIME is equivalent to about a 1/20 of the CYGNO demonstrator and aims to validate: The construction materials, the Monte Carlo simulations, the data reconstruction and the particle identification performances at low energy threshold. LIME is under installation at the LNGS and it is supposed to start data taking at the beginning of 2022. The detector description and installation will be presented, as well as the overground performance and limitations that require underground characterization.
The CYGNO/INITIUM experiment Amaro, F. D.; Baracchini, Elisabetta; Benussi, L. ...
SciPost physics proceedings,
07/2023
12
Journal Article
Recenzirano
Odprti dostop
The CYGNO project for the development of a high precision optical readout gaseous TPC for directional Dark Matter search and solar neutrino spectroscopy will be presented. It is to be hosted at ...Laboratori Nazionali del Gran Sasso. CYGNO peculiar features are the use of sCMOS cameras and PMTs coupled to GEMs amplification of a helium-based gas mixture at atmospheric pressure, in order to achieve 3D tracking with head tail capability and background rejection down to O(keV) energy, to boost sensitivity to low WIMP masses. The latest R&D results within the CYGNO project will be discussed along with the underground installation and operation of a 50 l prototype, soon to be followed by a O(1) m3 experiment demonstrator in 2024-2026. The latest results on the negative ion drift operation at atmospheric pressure within CYGNO optical readout approach will be illustrated, which is the aim of the ERC Consolidator Grant project INITIUM.
In a six-month, multicenter, open-label trial, de novo kidney transplant recipients at low immunological risk were randomized to steroid avoidance or steroid withdrawal with IL-2 receptor antibody ...(IL-2RA) induction, enteric-coated mycophenolate sodium (EC-MPS: 2160 mg/day to week 6, 1440 mg/day thereafter), and cyclosporine. Results from a 30-month observational follow-up study are presented. Of 166 patients who completed the core study on treatment, 131 entered the follow-up study (70 steroid avoidance, 61 steroid withdrawal). The primary efficacy endpoint of treatment failure (clinical biopsy-proven acute rejection (BPAR) graft loss, death, or loss to follow-up) occurred in 21.4% (95% CI 11.8–31.0%) of steroid avoidance patients and 16.4% (95% CI 7.1–25.7%) of steroid withdrawal patients by month 36 ( P = 0.46 ). BPAR had occurred in 20.0% and 11.5%, respectively ( P = 0.19 ). The incidence of adverse events with a suspected relation to steroids during months 6–36 was 22.9% versus 37.1% ( P = 0.062 ). By month 36, 32.4% and 51.7% of patients in the steroid avoidance and steroid withdrawal groups, respectively, were receiving oral steroids. In conclusion, IL-2RA induction with early intensified EC-MPS dosing and CNI therapy in de novo kidney transplant patients at low immunological risk may achieve similar three-year efficacy regardless of whether oral steroids are withheld for at least three months.
Summary Introduction New-onset diabetes mellitus (NODM) has important implications for long-term outcome following liver transplantation. Aim To evaluate the impact of conversion from tacrolimus to ...cyclosporine in liver transplant patients presenting NODM. Method In a 12-month pilot study, 39 liver transplant patients with NODM were converted from tacrolimus to cyclosporine. Most patients (59%) were receiving antidiabetic therapy (18% insulin, 41% oral) and all patients had received dietary advice prior to the study. Results At month 12, NODM had significantly resolved (FBG < 7 mmol/L without treatment) in 36% of patients (95% CI 20.8–51.0%). In the 16 patients not receiving antidiabetic drugs at baseline, mean FBG decreased from 8.1 mmol/L to 6.6 mmol/L ( P = 0.008) and mean HbA1c decreased from 6.4 to 6.0% ( P = 0.05). Steroids were stopped rapidly in the nine patients receiving steroids at inclusion but NODM resolution was observed in only one of these nine patients. No significant factors were identified that could have affected NODM resolution. There were three episodes of biopsy-proven acute rejection (7.7%), no graft losses and one death. Overall, cyclosporine tolerance was good with no significant change in creatinine clearance at month 12. Total cholesterol increased from 4.6 mmol/L to 5.1 mmol/L ( P < 0.001). Conclusions These results suggest that liver transplant patients with NODM may benefit from conversion to cyclosporine from tacrolimus through improved glucose metabolism. Confirmation in a prospective, randomized comparative study is required.
CYGNO is an international collaboration with the aim of operating a ▪ optical time projection chamber (TPC) for directional Dark Matter (DM) searches and solar neutrino spectroscopy, to be deployed ...at the Laboratori Nazionali del Gran Sasso (LNGS). A ▪/▪ (60/40) mixture is used, along with a triple Gas Electron Multiplier (GEM) cascade to amplify the ionisation signal. The scintillation produced in the electron avalanches is read out using a scientific complementary metal–oxide–semiconductor (sCMOS) camera. This solution has proven to provide very high sensitivity to interactions in the few ▪ energy range. The inclusion of a hydrogen-based gas will offer an even lighter target, resulting in a more efficient energy transfer in a DM particle collision, and consequently, a lower detection threshold. Additionally, longer track lengths of light nuclear recoils are easier to detect with a clearer direction. However, the addition of such gas will contribute to quenching the scintillation, jeopardizing the TPC performance. In this work, we demonstrate the feasibility of adding 1% to 5% isobutane to the ▪/▪ (60/40) mixture by measuring the respective absolute scintillation yield output. The overall scintillation produced in the charge avalanches is not drastically suppressed by quenching due to the isobutane addition. The presence of Penning transfer from excited He atoms to isobutane molecules increases the number of electrons in the avalanches, partially compensating for the loss of scintillation due to quenching. For the highest applied GEM voltage, the total number of photons produced in the avalanche per ▪ deposited in the absorption region presents a decrease of only a factor of about three, from 2.30(20)×104 to 8.2(4)×103▪, as the isobutane content increases from 0 to 5%. The quantification of the visible component of the scintillation shows that isobutane quenches both visible and ultraviolet (UV) photons emitted by ▪/▪.
The CYGNO project aims to study rare events, as low-mass (few GeV) Dark Matter (DM) particle or solar neutrino interactions, exploiting the approach of the optical readout of the scintillation light ...produced in the amplification in a multiple Gas Electron Multiplier (GEM) structure, of the primary ionization originated in large volume Time Projection Chamber (TPCs).
The volume is filled with an He:CF4 gas mixture at atmospheric pressure. The 3D topology, and therefore direction of the recoils, is reconstructed thanks to the combined use of high-granularity, high sensitivity sCMOS cameras, for the precise tracking of the projection of the recoils on the GEM plane, and of fast light sensors in order to obtain the coordinate perpendicular to the camera plane.
To conclude the R&D phase, the 50 L prototype, called Long Imaging ModulE (LIME), was moved underground at the Laboratori Nazionali del Gran Sasso (LNGS) in order to study the performance of the CYGNO experimental approach in a low background environment and to assess the contributions to the background from different sources, also comparing with Monte Carlo simulations.
Stability studies and the effects of environmental condition on the light yield will be discussed, focusing on the effect of humidity on the detector response and stability amount and rate of self-sustaining micro-discharges. This is a crucial step towards the development of a large demonstrator.
•A TPC filled with a gas mixture based on light atoms as target.•The combined usage of PMTs and sCMOS camera enables the 3D tracks reconstruction.•Studies on the effects of environmental condition on the light yield.
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