Outcome of neuropsychiatric symptoms related to an antiretroviral drug following its substitution by nevirapine: the RELAX study

Objectives: The primary objective was to evaluate the improvement in neuropsychiatric symptoms attributed to an antiretroviral drug after that drug was substituted with nevirapine. The secondary objective was to evaluate the impact on patient adherence and quality of life. Methods: A prospective, observational study was carried out that included patients with HIV-1 plasma suppression for whom an antiretroviral drug was substituted with nevirapine because of central nervous system (CNS) side effects, a Pittsburgh Sleep Quality Index (PSQI) score > 5 or a Hospital Anxiety and Depression Scale (HADS) score ≥ 10, and who had not initiated psychoactive drug treatment during the prior 6 weeks. Evaluations were carried out at baseline and 1 and 3 months after the switch using the PSQI, HADS, Epworth Sleepiness Scale, Medical Outcomes Study-Short Form 30 items (MOS-SF-30) and Simplified Medication Adherence Questionnaire (SMAQ). Results: A total of 129 patients were included in the study. The drug substituted was mainly efavirenz (89.9%), and reasons for the switch included sleep disturbances (75.2%), anxiety (65.1%), depression (38.7%), attention disturbances (31%), and other reasons (31%), with a mean of 2.4 neuropsychiatric disturbances per patient. A statistically significant improvement was observed in all the tests evaluating neuropsychiatric symptoms and adherence at 1 and 3 months. The CD4 lymphocyte count remained stable (P = 0.096). Three (2.3%) patients had a detectable plasma HIV-1 RNA at the end of the study. Nine patients (6.9%) withdrew because of nevirapine-related toxicity (rash in seven patients and hypertransaminasaemia in two patients, none of which were > grade 2). Conclusions: The switch to nevirapine from a drug causing neuropsychiatric disturbances (primarily efavirenz) in subjects with virological suppression was effective in resolving those disturbances, with an improvement in all the parameters studied. This led to better adherence to treatment and quality of life, with no detrimental effect on their immunological and virological controlBoehringer Ingelheim Spai

Clinical and Immunologic Investigations in Patients With Stiff-Person Spectrum Disorder

Importance: Symptoms of stiff-person syndrome (SPS), stiff-limb syndrome (SLS), or progressive encephalomyelitis with rigidity, myoclonus, or other symptoms (SPS-plus) can occur with several autoantibodies, but the relative frequency of each antibody, syndrome specificity, and prognostic implications are unclear. Objective: To report the clinical and immunologic findings of a large cohort of patients with stiff-person spectrum disorder (SPSD), including SPS, SLS, and SPS-plus. Design, Setting, and Patients: This study retrospectively examined a case series (January 1, 1998, through December 31, 2014) of immunologic investigations performed in a neuroimmunology referral center. The study included 121 patients with clinical features of SPSD. Data analysis was performed from July 1, 2015, through November 1, 2015. Main Outcomes and Measures: Analysis of clinical-immunologic associations, including autoantibodies to 8 proteins expressed in inhibitory synapses. Results: The median age of the patients was 51 years (interquartile range, 40-61 years), and 75 (62.0%) were female. Fifty (41.3%) had SPS, 37 (30.6%) had SPS-plus, 24 (19.8%) had SLS, and 10 (8.3%) had SPS or SLS overlapping with ataxia, epilepsy, or encephalitis. Fifty-two patients (43.0%) had glutamic acid decarboxylase (GAD65) antibodies (2 with γ-aminobutyric acid-A [GABA-A] receptor antibodies), 24 (19.8%) had α1-subunit of the glycine receptor (GlyR) antibodies (2 with GAD65 antibodies), 5 (4.1%) had other antibodies, and 40 (33.1%) tested negative for antibodies. None had gephyrin or glycine transporter antibodies. Among the main immunologic groups (GAD65 antibodies, GlyR antibodies, and antibody negative), those with GAD65 antibodies were more likely to be female (45 [86.5%] of 52, 8 [36.4%] of 22, and 18 [45.0%] of 40, respectively; P < .001), have systemic autoimmunity (34 [65.4%] of 52, 7 [31.8%] of 22, and 13 [32.5%] of 40, respectively; P = .004), and have longer delays in being tested for antibodies (median, 3 vs 0.5 and 1 year; P < .001). Patients with GAD65 antibodies were more likely to develop SPS (27 [51.9%] of 52) or overlapping syndromes (8 [15.4%] of 52) than patients with GlyR antibodies (5 [22.7%] and 0 [0%] of 22, respectively), who more often developed SPS-plus (12 [54.5%] of 22 vs 7 [13.5%] in those with GAD65 antibodies); antibody-negative patients had an intermediate syndrome distribution. In multivariable analysis, symptom severity (P = .001) and immunologic group (P = .01) were independently associated with outcome. Compared with patients with GlyR antibodies, those with GAD65 antibodies (odds ratio, 11.1, 95% CI, 2.3-53.7; P = .003) had worse outcome. Patients without antibodies had similar outcome than patients with GlyR antibodies (odds ratio, 4.2, 95% CI, 0.9-20.0; P = .07). Conclusions and Relevance: In SPSD, symptom severity and presence and type of antibodies are predictors of outcome

Clinical and Immunologic Investigations in Patients With Stiff-Person Spectrum Disorder

Importance: Symptoms of stiff-person syndrome (SPS), stiff-limb syndrome (SLS), or progressive encephalomyelitis with rigidity, myoclonus, or other symptoms (SPS-plus) can occur with several autoantibodies, but the relative frequency of each antibody, syndrome specificity, and prognostic implications are unclear. Objective: To report the clinical and immunologic findings of a large cohort of patients with stiff-person spectrum disorder (SPSD), including SPS, SLS, and SPS-plus. Design, Setting, and Patients: This study retrospectively examined a case series (January 1, 1998, through December 31, 2014) of immunologic investigations performed in a neuroimmunology referral center. The study included 121 patients with clinical features of SPSD. Data analysis was performed from July 1, 2015, through November 1, 2015. Main Outcomes and Measures: Analysis of clinical-immunologic associations, including autoantibodies to 8 proteins expressed in inhibitory synapses. Results: The median age of the patients was 51 years (interquartile range, 40-61 years), and 75 (62.0%) were female. Fifty (41.3%) had SPS, 37 (30.6%) had SPS-plus, 24 (19.8%) had SLS, and 10 (8.3%) had SPS or SLS overlapping with ataxia, epilepsy, or encephalitis. Fifty-two patients (43.0%) had glutamic acid decarboxylase (GAD65) antibodies (2 with γ-aminobutyric acid-A [GABA-A] receptor antibodies), 24 (19.8%) had α1-subunit of the glycine receptor (GlyR) antibodies (2 with GAD65 antibodies), 5 (4.1%) had other antibodies, and 40 (33.1%) tested negative for antibodies. None had gephyrin or glycine transporter antibodies. Among the main immunologic groups (GAD65 antibodies, GlyR antibodies, and antibody negative), those with GAD65 antibodies were more likely to be female (45 [86.5%] of 52, 8 [36.4%] of 22, and 18 [45.0%] of 40, respectively; P < .001), have systemic autoimmunity (34 [65.4%] of 52, 7 [31.8%] of 22, and 13 [32.5%] of 40, respectively; P = .004), and have longer delays in being tested for antibodies (median, 3 vs 0.5 and 1 year; P < .001). Patients with GAD65 antibodies were more likely to develop SPS (27 [51.9%] of 52) or overlapping syndromes (8 [15.4%] of 52) than patients with GlyR antibodies (5 [22.7%] and 0 [0%] of 22, respectively), who more often developed SPS-plus (12 [54.5%] of 22 vs 7 [13.5%] in those with GAD65 antibodies); antibody-negative patients had an intermediate syndrome distribution. In multivariable analysis, symptom severity (P = .001) and immunologic group (P = .01) were independently associated with outcome. Compared with patients with GlyR antibodies, those with GAD65 antibodies (odds ratio, 11.1, 95% CI, 2.3-53.7; P = .003) had worse outcome. Patients without antibodies had similar outcome than patients with GlyR antibodies (odds ratio, 4.2, 95% CI, 0.9-20.0; P = .07). Conclusions and Relevance: In SPSD, symptom severity and presence and type of antibodies are predictors of outcome

Therapeutic potential of emerging NAD+-increasing strategies for cardiovascular diseases

Altres ajuts: Fundació La Marató de TV3 (303/C/2016)(201602.30.31)Cardiovascular diseases are the leading cause of death worldwide. Aging and/or metabolic stress directly impact the cardiovascular system. Over the last few years, the contributions of altered nicotinamide adenine dinucleotide (NAD+) metabolism to aging and other pathological conditions closely related to cardiovascular diseases have been intensively investigated. NAD+ bioavailability decreases with age and cardiometabolic conditions in several mammalian tissues. Compelling data suggest that declining tissue NAD+ is commonly related to mitochondrial dysfunction and might be considered as a therapeutic target. Thus, NAD+ replenishment by either genetic or natural dietary NAD+-increasing strategies has been recently demonstrated to be effective for improving the pathophysiology of cardiac and vascular health in different experimental models, as well as human health, to a lesser extent. Here, we review and discuss recent experimental evidence illustrating that increasing NAD+ bioavailability, particularly by the use of natural NAD+ precursors, may offer hope for new therapeutic strategies to prevent and treat cardiovascular diseases

Online Monitoring of the Osiris Reactor with the Nucifer Neutrino Detector

Originally designed as a new nuclear reactor monitoring device, the Nucifer detector has successfully detected its first neutrinos. We provide the second shortest baseline measurement of the reactor neutrino flux. The detection of electron antineutrinos emitted in the decay chains of the fission products, combined with reactor core simulations, provides an new tool to assess both the thermal power and the fissile content of the whole nuclear core and could be used by the Inter- national Agency for Atomic Energy (IAEA) to enhance the Safeguards of civil nuclear reactors. Deployed at only 7.2m away from the compact Osiris research reactor core (70MW) operating at the Saclay research centre of the French Alternative Energies and Atomic Energy Commission (CEA), the experiment also exhibits a well-suited configuration to search for a new short baseline oscillation. We report the first results of the Nucifer experiment, describing the performances of the 0.85m3 detector remotely operating at a shallow depth equivalent to 12m of water and under intense background radiation conditions. Based on 145 (106) days of data with reactor ON (OFF), leading to the detection of an estimated 40760 electron antineutrinos, the mean number of detected antineutrinos is 281 +- 7(stat) +- 18(syst) electron antineutrinos/day, in agreement with the prediction 277(23) electron antineutrinos/day. Due the the large background no conclusive results on the existence of light sterile neutrinos could be derived, however. As a first societal application we quantify how antineutrinos could be used for the Plutonium Management and Disposition Agreement.Comment: 22 pages, 16 figures - Version

Darunavir/cobicistat/emtricitabine/tenofovir alafenamide versus dolutegravir /abacavir/lamivudine in antiretroviral-naïve adults (SYMTRI): a multicenter randomized open-label study (PReEC/RIS-57)

D/C/F/TAF is the reference for combination therapy based on protease inhibitors but has not been compared with regimens containing integrase inhibitors as initial ART. We could not demonstrate D/C/F/TAF noninferiority relative to DTG/ABC/3TC, although both regimens were similarly well tolerated. Background Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) is the reference for combination therapy based on protease inhibitors due to its efficacy, tolerability, and convenience. Head-to-head randomized comparisons between D/C/F/TAF and combination therapy based on integrase inhibitors in antiretroviral-naive patients are lacking. Methods Adult (>18 years old) human immunodeficiency virus-infected antiretroviral-naive patients (HLA-B*5701 negative and hepatitis B virus negative), with viral load (VL) >= 500 c/mL, were centrally randomized to initiate D/C/F/TAF or dolutegravir/abacavir/lamivudine (DTG/3TC/ABC) after stratifying by VL and CD4 count. Clinical and analytical assessments were performed at weeks 0, 4, 12, 24, and 48. The primary endpoint was VL 100 000 copies/mL, and 13% had <200 CD4 cells/mu L. Median weight was 73 kg and median body mass index was 24 kg/m(2). At 48 weeks, 79% (D/C/F/TAF) versus 82% (DTG/3TC/ABC) had VL <50 c/mL (difference, -2.4%; 95% confidence interval [CI], -11.3 to 6.6). Eight percent versus four percent experienced virologic failure but no resistance-associated mutations emerged. Four percent versus six percent had drug discontinuation due to adverse events. In the per-protocol analysis, 94% versus 96% of patients had VL <50 c/mL (difference, -2%; 95% CI, -8.1 to 3.5). There were no differences in CD4 cell count or weight changes. Conclusions We could not demonstrate the noninferiority of D/C/F/TAF relative to DTG/ABC/3TC as initial antiretroviral therapy, although both regimens were similarly well tolerated

SCORE underestimates cardiovascular risk (CVR) of HIV+ patients

The new European Guidelines of Dislipidemia Management of the European Societies of Cardiology and Arteriosclerosis consider HIV+ as patients at high risk of developing cardiovascular events and deaths. The objective of the study was to evaluate cardiovascular events and deaths in a series of HIV+ patients. Observational, cross-sectional study, including a cohort of HIV+ and HIV&#x2212; patients from 2008. CVR was calculated using the SCORE-CVR chart. Variation on lipid profile and incidence of cardiovascular events, cardiovascular death or death related to any cause were recorded. Data was analyzed using SPSS version 20.0 for MAC. 154 HIV+ and 155 HIV&#x2212; patients were included. Mean age: 44.8&#x00B1;9.5 vs 55.2&#x00B1;14.3 y and 69.5% vs 49% males respectively (p&#60;0.01). Mean time since HIV+ diagnosis was 11&#x00B1;6.2 y. Mean BMI and systolic blood pressure were lower in HIV+ (25.1&#x00B1;6.7 kg/m2 vs 28.7&#x00B1;5.1 kg/m2, (p&#60;0.01) and 119.6&#x00B1;19.4 vs 124.7&#x00B1;14.7 mmHg, (p=0.044; respectively)). A lower proportion of hypertense, diabetic and obese patients was observed in HIV+ (25.5% vs 6.5%; 20.6% vs 3.9% and 36.8% vs 12.3%) but a larger proportion of smokers (68.8% vs 29.7%) was observed (p&#60;0.01 in all cases). Mean cholesterol and LDLc were lower in HIV+ (191.2&#x00B1;41.4 vs 218.5&#x00B1;44.6 mg/dl and 109.5&#x00B1;33.9 vs 134.6&#x00B1;37.7 mg/dl; p&#60;0.01; respectively) but with a lower mean HDLc and higher TG (50.3&#x00B1;19 mg/dl vs 55.2&#x00B1;14.9 mg/dl; p=0.013 and 156.7&#x00B1;85.7 vs 135.8&#x00B1;66.2 mg/dl; p=0.017; respectively). There was no significant difference in mean CVR-SCORE (3.5&#x00B1;3.6% vs 4.4&#x00B1;3.8%; p=0.091). With this SCORE, 5.2&#x00B1;5.3 and 6.7&#x00B1;5.8 cardiovascular events or deaths should be expected in HIV+ and HIV&#x2212; respectively at 10 y. Four years later cholesterol, LDLc, HDLc, TG in HIV+ and HIV&#x2212; patients did not vary compared with those obtained 4 y before. 5 events and 1 death were seen at 4 y follow-up in HIV+, and in HIV&#x2212; patients. The incidence of events in HIV+ patients is similar to the expected according to their SCORE at 10 y. We could suppose that once the 10 y follow-up is reached, this incidence would be higher. On the other side, in HIV&#x2212; at 4 y just 3 events ocurred, far from the 6.7 events expected. There were no significant differences between lipid profiles in any of the cohorts. Lipid profile with low HDLc and high TG is persistent in HIV+ patients at 4 y follow-up. Understimation of CVR in HIV+ patients by SCORE charts could be present as soon as 4 y after the first assesment. This supports the stratification of HIV+ patients as high-risk patients in new guidelines