Distance measurement by delayed optical feedback in a ring laser

We numerically study the behavior of a semiconductor ring laser subject to bidirectional delayed optical feedback, when the isolated laser is in the quasi-unidirectional regime. The optical feedback, provided by two external refectors located in front of the ring output waveguides, can modify the laser regime produced by the cross-saturation between the clockwise and the counter-clockwise mode. Thus, the system exhibits new diferent regimes, most of which are asymmetric and bidirectional, with alternating dominant mode. Two of these regimes are of special interest in view of applications, because the laser switching period, between the clockwise and the counter-clockwise mode, is linearly related to the time of fight from the laser to one or both refectors. In these operating conditions, the laser is thus suitable to implement a telemeter. A convenient electrical output signal is obtained by a photodiode located behind one (partially refecting) fxed mirror, or by measuring the voltage drop across the laser junction. Simulations are performed by mathematical models based on rate-equations, assuming typical literature parameters for a 1 mW ring laser

A real world experience with fingolimod in active RRMS patients naïve to second-line agents: a 2 years, intention-to-treat, observational, single center study

Fingolimod is approved by EMA as a second-line treatment for relapsing-remitting multiple sclerosis (RRMS). Experience with fingolimod in real life is still limited. Aim of our study was to report data on fingolimod effectiveness in a real life cohort of Italian active RRMS patients, naive to second-line agents, followed for 2 years. Fingolimod was a part of the patients' regular treatment and is produced by Novartis. We included all consecutive RRMS patients starting fingolimod at our center according to EMA criteria before January 1st 2013. Exclusion criteria were a previous treatment with natalizumab or an immunosuppressant therapy in the previous 12 months. All patients were clinically evaluated quarterly, and performed brain MRI yearly. Definition of "no evidence of disease activity" (NEDA-3): no relapses, no brain MRI activity and no 6-months confirmed worsening in EDSS score. We included 38 RRMS patients, 35 switched from first-line injectable therapies. Six patients were also previously treated with immunosuppressants (5 mitoxantrone, 1 cyclophosphamide). At 24th month 34 patients continued fingolimod treatment. Main adverse events were infections (18 %), liver-enzymes elevation (8 %), and leukopenia (8 %). After 12 and 24 months 79 and 63 % of patients were relapses-free. Fingolimod significantly reduced ARR compared to the previous year (0.3 ± 0.6 vs 1.2 ± 0.5; p < 0.001). After 12 and 24 months 63 and 37 % of patients had NEDA-3. Previous use of immunosuppressants and an ARR ≥1 in the 2 years predicted disease activity. Fingolimod significantly reduce disease activity in active RRMS patients, with no severe/unexpected safety issues. Patients previously treated with immunosuppressants and with a higher ARR at baseline may respond less to fingolimod treatment

Impact of resistance mutations on virological efficacy of DTG-based maintenance two-drug regimens: an ARCA cohort study

Background: Two-drug regimens (2DR) are largely prescribed as maintenance therapy, nowadays mainly based on DTG. While many data have been reported about PI-based 2DR, the impact of resistance mutations and duration of virological suppression on DTG-based 2DR remains to be clarified. The aim of this study was to evaluate the impact of resistance mutations on virological outcome of DTG-based 2DR maintenance ART. Material and methods: Virologically suppressed patients (pts) switching to DTG+3TC or DTG+RPV with pre-baseline (time of switch=baseline, BL) resistance genotype (at least PR/RT) were selected from the ARCA database. Primary endpoint was virological failure (VF: an HIV-RNA, VL, &gt;200 cps/mL or 2 consecutive &gt;50 cps/mL). The probability of VF was estimated by Kaplan-Meier analysis. Resistance to 2DR was defined as occurrence of at least Stanford HIVdb (v.8.5) low-level resistance (LLR) to at least one drug included in the current 2DR, based on cumulative genotype. CD4 changes were assessed using Student’s t- test for paired samples. A secondary analysis comparing 2DR with DTG-based 3D regimens was also performed. Results: A total of 318 2DR pts were analysed: 260 (82%) switching to DTG+3TC, 58 (18%) to DTG+RPV; 68% were males, median age was 51 (44-56) years, 12 (6-23) years of HIV infection, 5 (3-8) years of virological suppression, nadir CD4 231 (121-329), 5 (3-9) previous ARV lines, 59% previously exposed to INSTI, 11% with resistance to current 2DR. The integrase sequence was available in 14% of patients, none harbouring resistance to DTG. 20 VF were observed, of whom 4 (3/17 VF in DTG+3TC, 1/3 in DTG+RPV) in patients with at least LLR at BL (M184V+K219Q; D67N+K70R+K219Q; D67N+K70R+T215Y+219Q; E138A), in a median FU of 1.3 years (IQR 0.6-2). The 2-year estimated probability of VF was 8.7% (95% CI 4.4;13); 8.6% (4.1;13.1) in those without resistance and 9.7% (-4.4;23.8) in those with resistance (Log rank: p=ns, figure 1). No factor was significantly associated with VF at multivariate analysis, but in pts with &lt;6 years of virological suppression, BL resistance was associated with a higher probability of VF (p=0.003). After 48 weeks, a statistically significant increase in CD4+ was detected (+56 cells/mmc, p&lt;0.001), independently from baseline resistance. The 2-year estimated probability of VF in the reference 3DR group (n=564) was not different from that for the 2DR group: 8.8% (5.9;11.7) in the whole case file and 9.7% (6.6;12.8) in the presence of baseline resistance. Longer time of virological suppression was the only factor associated with a lower risk of VF in the 3DR dataset. Conclusions: DTG-based 2DRs show high virological efficacy, even in the context of predicted incomplete activity, at least within a short-term follow-up. A longer duration of virological suppression seems to decrease the impact of resistance on virological outcome, however further studies are warranted to confirm this hypothesis and possibly define a clinically useful threshold

Clinical activity after fingolimod cessation: Disease reactivation or rebound?

Background and purpose: There is debate as to whether the apparent rebound after fingolimod discontinuation is related to the discontinuation itself or whether it is due to the natural course of highly active multiple sclerosis (MS). Our aim was to survey the prevalence of severe reactivation and rebound after discontinuation of fingolimod in a cohort of Italian patients with MS. Methods: Patients with relapsing-remitting MS who were treated with fingolimod for at least 6 months and who stopped treatment for reasons that were unrelated to inefficacy were included in the analysis. Results: A total of 100 patients who had discontinued fingolimod were included in the study. Fourteen patients (14%) had a relapse within 3 months after fingolimod discontinuation, and an additional 12 (12%) had a relapse within 6 months. According to this study's criteria, 10 patients (10%) had a severe reactivation. Amongst these patients, five (5%) had a reactivation that was considered to be a rebound. Conclusions: The present study showed that more than 26% of patients are at risk of having a relapse within 6 months after fingolimod discontinuation. Nevertheless, the risk of severe reactivations and rebound is lower than has been previously described

Association of Genetic Markers with CSF Oligoclonal Bands in Multiple Sclerosis Patients

Objective:to explore the association between genetic markers and Oligoclonal Bands (OCB) in the Cerebro Spinal Fluid (CSF) of Italian Multiple Sclerosis patients.Methods:We genotyped 1115 Italian patients for HLA-DRB1*15 and HLA-A*02. In a subset of 925 patients we tested association with 52 non-HLA SNPs associated with MS susceptibility and we calculated a weighted Genetic Risk Score. Finally, we performed a Genome Wide Association Study (GWAS) with OCB status on a subset of 562 patients. The best associated SNPs of the Italian GWAS were replicated in silico in Scandinavian and Belgian populations, and meta-analyzed.Results:HLA-DRB1*15 is associated with OCB+: p = 0.03, Odds Ratio (OR) = 1.6, 95% Confidence Limits (CL) = 1.1-2.4. None of the 52 non-HLA MS susceptibility loci was associated with OCB, except one SNP (rs2546890) near IL12B gene (OR: 1.45; 1.09-1.92). The weighted Genetic Risk Score mean was significantly (p = 0.0008) higher in OCB+ (7.668) than in OCB- (7.412) patients. After meta-analysis on the three datasets (Italian, Scandinavian and Belgian) for the best associated signals resulted from the Italian GWAS, the strongest signal was a SNP (rs9320598) on chromosome 6q (p = 9.4×10-7) outside the HLA region (65 Mb).Discussion:genetic factors predispose to the development of OCB

Guidelines for the labelling of leucocytes with 99mTc-HMPAO

We describe here a protocol for labelling autologous white blood cells with 99mTc-HMPAO based on previously published consensus papers and guidelines. This protocol includes quality control and safety procedures and is in accordance with current European Union regulations and International Atomic Energy Agency recommendations