This open-label, randomized, phase 3 study compared melphalan at a dose of 200 mg per square meter of body-surface area plus autologous stem-cell transplantation with ...melphalan-prednisone-lenalidomide (MPR) and compared lenalidomide maintenance therapy with no maintenance therapy in patients with newly diagnosed multiple myeloma.
We randomly assigned 273 patients 65 years of age or younger to high-dose melphalan plus stem-cell transplantation or MPR consolidation therapy after induction, and 251 patients to lenalidomide maintenance therapy or no maintenance therapy. The primary end point was progression-free survival.
The median follow-up period was 51.2 months. Both progression-free and overall survival were significantly longer with high-dose melphalan plus stem-cell transplantation than with MPR (median progression-free survival, 43.0 months vs. 22.4 months; hazard ratio for progression or death, 0.44; 95% confidence interval CI, 0.32 to 0.61; P<0.001; and 4-year overall survival, 81.6% vs. 65.3%; hazard ratio for death, 0.55; 95% CI, 0.32 to 0.93; P=0.02). Median progression-free survival was significantly longer with lenalidomide maintenance than with no maintenance (41.9 months vs. 21.6 months; hazard ratio for progression or death, 0.47; 95% CI, 0.33 to 0.65; P<0.001), but 3-year overall survival was not significantly prolonged (88.0% vs. 79.2%; hazard ratio for death, 0.64; 95% CI, 0.36 to 1.15; P=0.14). Grade 3 or 4 neutropenia was significantly more frequent with high-dose melphalan than with MPR (94.3% vs. 51.5%), as were gastrointestinal adverse events (18.4% vs. 0%) and infections (16.3% vs. 0.8%); neutropenia and dermatologic toxic effects were more frequent with lenalidomide maintenance than with no maintenance (23.3% vs. 0% and 4.3% vs. 0%, respectively).
Consolidation therapy with high-dose melphalan plus stem-cell transplantation, as compared with MPR, significantly prolonged progression-free and overall survival among patients with multiple myeloma who were 65 years of age or younger. Lenalidomide maintenance, as compared with no maintenance, significantly prolonged progression-free survival. (Funded by Celgene; ClinicalTrials.gov number, NCT00551928.).
Polymerase chain reaction (PCR)-based minimal residual disease (MRD) analysis is a useful prognostic tool in multiple myeloma (MM), although its long-term impact still needs to be addressed. This ...report presents the updated results of the GIMEMA-VEL-03-096 trial. Thirty-nine MM patients receiving bortezomib-thalidomide-dexamethasone after autologous transplantation were monitored for MRD by both nested and real-time quantitative-PCR until relapse. Our data confirm the strong impact of MRD on survival: overall survival was 72% at 8 years median follow-up for patients in major MRD response versus 48% for those experiencing MRD persistence (P=0.041). In addition, MRD kinetics resulted predictive for relapse: indeed median remission duration was not reached for patients in major MRD response, 38 months for those experiencing MRD reappearance and 9 months for patients with MRD persistence (P<0.001). Moreover: (1) 26 patients achieving major MRD response (67%) benefit of excellent disease control (median TNT: 42 months); (2) MRD reappearance heralds relapse, with a TNT comparable to that of MRD persistence (9 versus 10 months, P=0.706); (3) the median lag between MRD reappearance and need for salvage treatment is 9 months. These results suggest the usefulness of a long-term MRD monitoring in MM patients and the need for maintenance or pre-emptive treatments ensuring durable responses.
An ambulatory monitoring system is developed for the estimation of spatio-temporal gait parameters. The inertial measurement unit embedded in the system is composed of one biaxial accelerometer and ...one rate gyroscope, and it reconstructs the sagittal trajectory of a sensed point on the instep of the foot. A gait phase segmentation procedure is devised to determine temporal gait parameters, including stride time and relative stance; the procedure allows to define the time intervals needed for carrying an efficient implementation of the strapdown integration, which allows to estimate stride length, walking speed, and incline. The measurement accuracy of walking speed and inclines assessments is evaluated by experiments carried on adult healthy subjects walking on a motorized treadmill. Root-mean-square errors less than 0.18 km/h (speed) and 1.52% (incline) are obtained for tested speeds and inclines varying in the intervals 3, 6 km/h and -5, +15%, respectively. Based on the results of these experiments, it is concluded that foot inertial sensing is a promising tool for the reliable identification of subsequent gait cycles and the accurate assessment of walking speed and incline.
•VoA – DBS is effective on both dystonia and tremor.•VoA – DBS benefits are not impaired by tolerance or side effects.•The variable VoA-DBS outcome previously reported were not proven by VTA ...simulation.•Application of new consensus on tremor classification may improve patient selection.
Background and purpose
Reports on the safety and efficacy of intraventricularly administered (IVT) colistin for the treatment of Acinetobacter baumannii ventriculomeningitis in adults are limited and ...no comparative studies of IVT colistin versus intravenous (IV) therapy alone have been published. This study compared outcomes of patients with postneurosurgical ventriculomeningitis caused by extensively drug‐resistant A. baumannii treated with IV colistin or IV plus IVT colistin.
Methods
In an 11‐year period, information on 18 consecutive patients with extensively drug‐resistant A. baumannii ventriculomeningitis was collected. Infection was defined on the basis of (i) isolation of A. baumannii from the cerebrospinal fluid (CSF); (ii) laboratory evidence of CSF infection; (iii) signs/symptoms of central nervous system (CNS) infection. Patients were divided into group 1 (nine patients, IV colistin alone) and group 2 (nine patients, IV plus IVT colistin).
Results
Cerebrospinal fluid sterilization was documented for 12 of 18 patients (66.6%). The CSF sterilization rate was 33.3% in group 1 and 100% in group 2 (P = 0.009). The mean time to CSF sterilization was 21 days (range 8–48). Five patients died due to A. baumannii CNS infection (all in group 1), and five deaths were unrelated to A. baumannii ventriculomeningitis. Intensive care unit mean length of stay was shorter in group 2 (20.7 vs. 41.6 days, P = 0.046). Crude relative risk ratio of cumulative incidence of persistent CNS infection in group 1 versus group 2 was 13. No cases of chemical meningitis due to intrathecal colistin administration were encountered.
Conclusions
Intraventricular colistin administration is much more effective than IV therapy alone and does not seem to add further toxicity.
Background and purpose
For many years deep brain stimulation (DBS) devices relied only on voltage‐controlled stimulation (CV), but recently current‐controlled devices have been developed and approved ...for new implants as well as for replacement of CV devices after battery drain. Constant‐current (CC) stimulation has been demonstrated to be effective in new implanted parkinsonian and dystonic patients, but the effect of switching to CC therapy in patients chronically stimulated with CV implantable pulse generators (IPGs) has not been assessed. This report shows the results of a consecutive retrospective data collection performed at five Italian centers before and after replacement of constant‐voltage with constant‐current DBS devices, in order to verify the clinical efficacy and safety of this procedure.
Methods
Nineteen patients with Parkinson's disease or dystonic syndrome underwent DBS IPG CV/CC replacement. Clinical features and therapy satisfaction were assessed before surgery, 1 week after and 3 and 6 months after replacement. Programming settings and impedances were recorded before removing the CV device and when the CC IPGs were switched on.
Results
The clinical outcome of CC stimulation was similar to that obtained with CV devices and remained stable at 3 and 6 months of follow‐up. Impedance values recorded for CV and CC IPGs were similar. Ninety‐five percent of patients and physicians were satisfied with mixed implants. No adverse events occurred after IPG replacement.
Conclusion
Replacing CV with CC IPGs is a safe and effective procedure. Longer follow‐up is necessary to better clarify the impact of CC stimulation on clinical outcome after chronic stimulation in CV mode.
Large eddy simulations of pulverised coal combustion (PCC-LES) stabilised on a laboratory-scale piloted jet burner are carried out. The joint simulation effort of three research groups at Freiberg ...University (FG), Imperial College (IC) and Stuttgart University (ST) is presented, and the details of the comprehensive coal combustion models and their numerical implementation in three different computer programs are discussed. The (standard) coal sub-models and parameters used by the different groups are unified wherever possible. Differences amongst the groups are a different code basis and an Eulerian treatment of the coal particles by IC, while FG and ST use the Lagrangian framework for particle transport. The flow modelling is first validated for the corresponding non-reacting case and all LES calculations accurately capture the experimental trends. Velocity field statistics for the PCC case are in good accordance with the experimental evidence, but scalar statistics illustrate the complexity of coal combustion modelling. The results show notable differences amongst the groups that cannot only be attributed to the different treatment of the particle phase, and they highlight the difficulty to assess and interpret the quality of specific modelling approaches, and a need for further work by the research community. The present study is the first to compare three originally independent transient coal simulations and a step towards comprehensive PCC-LES.
A detailed Large Eddy Simulation (LES) of pulverised coal combustion in a large-scale laboratory furnace is presented. To achieve a detailed representation of the flow, mixing and particle ...dispersion, a massively parallel LES was performed. Different phenomenological network models were applied and compared to each other in order to obtain the most adequate devolatilization kinetic data for the LES. An iterative procedure allowed to optimise the devolatilization kinetic data for the studied coal and operating conditions. The particle combustion history is studied by analysing particle instantaneous properties giving a perspective on coal combustion that currently is not available by other means than LES. Predicted major species and temperature were compared with measurements and a good agreement was obtained. The finely resolved near burner region revealed that the flame is stabilised very close to the burner. Furthermore, two distinct zones of CO2 production were found - one in the internal recirculation zone (IRZ) due to gaseous combustion, and one downstream of the vortex breakdown, due to intense char combustion. It was found that particle properties are inhomogeneous within the IRZ, whereas in the external recirculation zone (ERZ) and downstream of the vortex breakdown they were found to be homogeneous.
The objectives of this review are to: 1) appraise the methodological quality of clinical practice guidelines (CPGs) in juvenile idiopathic arthritis (JIA) providing pharmacological and/or ...non-pharmacological intervention recommendations, and 2) summarize the recommendations provided by the included CPGs and compare them where possible.
A systematic search was performed. Three trained appraisers independently evaluated the methodological quality of the CPGs using a validated and reliable instrument, the Appraisal of Guidelines in Research and Evaluation II. Six domains were considered: 1) score and purpose; 2) stakeholder involvement; 3) rigor of development; 4) clarity of presentation; 5) applicability; and 6) editorial independence. The domains consist of a total of 23 items each scored on a 7-point scale. High quality CPGs were identified if they had a domain score above 60% in rigor of development, and two other domains.
Of the three included CPGs, the Royal Australian College of General Practitioners (RACGP) and American College of Rheumatology (ACR) CPGs were considered to be of high quality, but the German Society for Pediatric Rheumatology was of lower quality. Domains one to four had high domain scores across the guidelines (mean (standard deviation)): 72.76 (13.80); 66.67 (9.81); 64.67 (7.77); and 87.00 (9.64), respectively. Lower scores were obtained for applicability (14.00 (5.57)) and editorial independence (43.44 (7.02)). Recommendations varied across CPGs due to differences in context, target audience (general practitioners, rheumatologists, and other multidisciplinary healthcare professionals) and patients' disease presentations. Despite this variability, progression of pharmacological treatment did not conflict between CPGs. Recommendations for non-pharmacological interventions were vague and the interventions considered varied between CPGs.
Overall, recommendations were based on a paucity of evidence and weak study designs. Further research is needed on interventions in JIA, as well as higher quality CPGs to facilitate implementation of the best evidence-based recommendations in clinical practice.
Purpose
The impact of SARS-CoV-2 pandemic on other pathogens is largely unknown. We aimed to compare the prevalence of vaccine-preventable invasive bacterial infections before and during the pandemic ...in Piedmont (Italy).
Methods
We defined the monthly incidence of
S. pneumoniae
,
H. influenzae
and
N. meningitides
-invasive diseases from January 2010 to June 2021. Then, we compared the mean monthly cases during the previous 5 years (2015–2019) and the monthly cases in 2020 or 2021.
Results
We found significant reductions for invasive pneumococcal diseases (IPDs) in adults and
H. influenzae
-invasive diseases in 2020 and 2021 in comparison to the previous years, but not for invasive meningococcal diseases and IPDs in children.
Conclusions
Further data are needed to confirm these findings and define possible post-pandemic evolutions in the epidemiology of vaccine-preventable invasive bacterial diseases.
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