Long-term management of natalizumab discontinuation in a large monocentric cohort of multiple sclerosis patients

Background Pivotal and post-marketing studies demonstrated the impressive efficacy and the good tolerability profile of natalizumab in Multiple Sclerosis patients. On the other hand long-term safety of natalizumab therapy is burdened by the risk of progressive multifocal leukoencephalopathy, especially in anti-JCV seropositive patients treated for more than two years. Some of these patients must stop the drug at the risk of disease reactivation. Objectives To evaluate the effects of natalizumab discontinuation in a monocentric cohort of multiple sclerosis patients followed for a mean time of 22.4 months. Methods One hundred and ten patients, who stopped therapy after at least 12 infusions, were followed with periodic clinical and magnetic resonance imaging evaluations. One hundred patients started either immunomodulant therapy (n=90) or fingolimod (n=10) while 10 remained without any drug. Results "Disease-activity free" patients were 25% at one year after discontinuation and annualized relapse rate significantly increased from 0.06 to 0.84 (p<0.0001). We found that the risk of reactivation peaked despite alternative treatments between the second and the eighth month after suspension, a so-called "high risk period". During this period the majority of patients showed a return to pre-natalizumab disease activity while 10% of patients presented a "rebound activity". A higher pre-natalizumab disease activity was correlated with an increased risk of reactivation (p=0.004). Conclusions Our data suggest that disease reactivation peaked during a "high risk period" between the second and the eighth month since stopping the drug. During this period no alternative treatments seemed to provide an adequate protection from disease reactivation. Though transient, this phase could be potentially dangerous, therefore we need to develop more effective strategies to deal with this challenge

Out-of-Hospital Cardiac Arrest in Patients With Psychiatric Disorders - Characteristics and Outcomes

Aims To investigate whether the recent improvements in pre-hospital cardiac arrest-management and survival following out-of-hospital cardiac arrest (OHCA) also apply to OHCA patients with psychiatric disorders. Methods We identified all adult Danish patients with OHCA of presumed cardiac cause, 2001–2015. Psychiatric disorders were defined by hospital diagnoses up to 10 years before OHCA and analyzed as one group as well as divided into five subgroups (schizophrenia-spectrum disorders, bipolar disorder, depression, substance-induced mental disorders, other psychiatric disorders). Association between psychiatric disorders and pre-hospital OHCA-characteristics and 30-day survival were assessed by multiple logistic regression. Results Of 27,523 OHCA-patients, 4772 (17.3%) had a psychiatric diagnosis. Patients with psychiatric disorders had lower odds of 30-day survival (0.37 95% confidence interval 0.32–0.43) compared with other OHCA-patients. Likewise, they had lower odds of witnessed status (0.75 CI 0.70–0.80), bystander cardiopulmonary resuscitation (CPR) (0.77 CI 0.72–0.83), shockable heart rhythm (0.37 95% CI, 0.33–0.40), and return of spontaneous circulation (ROSC) at hospital arrival (0.66 CI 0.59–0.72). Similar results were seen in all five psychiatric subgroups. The difference in 30-day survival between patients with and without psychiatric disorders increased in recent years: from 8.4% (CI 7.0–10.0%) in 2006 to 13.9% (CI 12.4–15.4%) in 2015 and from 7.0% (4.3–10.8%) in 2006 to 7.0% (CI 4.5–9.7%) in 2015, respectively. Conclusion Patients with psychiatric disorders have lower survival following OHCA compared to non-psychiatric patients and the gap between the two groups has widened over time

Transcriptomic analyses and leukocyte telomere length measurement in subjects exposed to severe recent stressful life events

Stressful life events occurring in adulthood have been found able to affect mood and behavior, thus increasing the vulnerability for several stress-related psychiatric disorders. However, although there is plenty of clinical data supporting an association between stressful life events in adulthood and an enhanced vulnerability for psychopathology, the underlying molecular mechanisms are still poorly investigated. Thus, in this study we performed peripheral/whole-genome transcriptomic analyses in blood samples obtained from 53 adult subjects characterized for recent stressful life events occurred within the previous 6 months. Transcriptomic data were analyzed using Partek Genomics Suite; pathway and network analyses were performed using Ingenuity Pathway Analysis and GeneMANIA Software. We found 207 genes significantly differentially expressed in adult subjects who reported recent stressful life experiences (n=21) compared with those without such experiences (n=32). Moreover, the same subjects exposed to such stressful experiences showed a reduction in leukocyte telomere length. A correlation analyses between telomere length and transcriptomic data indicated an association between the exposures to recent stressful life events and the modulation of several pathways, mainly involved in immune-inflammatory-related processes and oxidative stress, such as natural killer cell signaling, interleukin-1 (IL-1) signaling, MIF regulation of innate immunity and IL-6 signaling. Our data suggest an association between exposures to recent stressful life events in adulthood and alterations in the immune, inflammatory and oxidative stress pathways, which could be also involved in the negative effect of stressful life events on leukocyte telomere length. The modulation of these mechanisms may underlie the clinical association between the exposure to recent Stressful life events in adulthood and an enhanced vulnerability to develop psychiatric diseases in adulthood

Cardiac Structural and Functional Consequences of Amyloid Deposition by Cardiac Magnetic Resonance and Echocardiography and Their Prognostic Roles

OBJECTIVES: This cross-sectional study aimed to describe the functional and structural cardiac abnormalities that occur across a spectrum of cardiac amyloidosis burden and to identify the strongest cardiac functional and structural prognostic predictors in amyloidosis using cardiac magnetic resonance (CMR) and echocardiography. BACKGROUND: Cardiac involvement in light chain and transthyretin amyloidosis is the main driver of prognosis and influences treatment strategies. Numerous measures of cardiac structure and function are assessed by multiple imaging modalities in amyloidosis. METHODS: Three hundred twenty-two subjects (311 systemic amyloidosis and 11 transthyretin gene mutation carriers) underwent comprehensive CMR and transthoracic echocardiography. The probabilities of 11 commonly measured structural and functional cardiac parameters being abnormal with increasing cardiac amyloidosis burden were evaluated. Cardiac amyloidosis burden was quantified using CMR-derived extracellular volume. The prognostic capacities of these parameters to predict death in amyloidosis were assessed using Cox proportional hazards models. RESULTS: Left ventricular mass and mitral annular plane systolic excursion by CMR along with strain and E/e' by echocardiography have high probabilities of being abnormal at low cardiac amyloid burden. Reductions in biventricular ejection fractions and elevations in biatrial areas occur at high burdens of infiltration. The probabilities of indexed stroke volume, myocardial contraction fraction, and tricuspid annular plane systolic excursion (TAPSE) being abnormal occur more gradually with increasing extracellular volume. Ninety patients (28%) died during a median follow-up of 22 months (interquartile range: 10 to 38 months). Univariable analysis showed that all imaging markers studied significantly predicted outcome. Multivariable analysis showed that TAPSE (hazard ratio: 1.46; 95% confidence interval: 1.16 to 1.85; p < 0.01) and indexed stroke volume (hazard ratio: 1.24; 95% confidence interval: 1.04 to 1.48; p < 0.05) by CMR were the only independent predictors of mortality. CONCLUSIONS: Specific functional and structural abnormalities characterize different burdens of cardiac amyloid deposition. In a multimodality imaging assessment of a large cohort of amyloidosis patients, CMR-derived TAPSE and indexed stroke volume are the strongest prognostic cardiac functional markers

The still under-investigated role of cognitive deficits in PML diagnosis.

Background Despite cognitive deficits frequently represent the first clinical manifestations of Progressive Multifocal Leukoencephalopathy (PML) in Natalizumab-treated MS patients, the importance of cognitive deficits in PML diagnosis is still under-investigated. The aim of the current study is to investigate the cognitive deficits at PML diagnosis in a group of Italian patients with PML. Methods Thirty-four PML patients were included in the study. The demographic and clinical data, the lesion load and localization, and the longitudinal clinical course was compared between patients with (n = 13) and without (n = 15) cognitive deficit upon PML suspicion (the remaining six patients were asymptomatic). Clinical presentation of cognitive symptoms was described in detail. Result After symptoms detection, the time to diagnosis resulted to be shorter for patients presenting with cognitive than for patients with non cognitive onset (p = 0.03). Within patients with cognitive onset, six patients were presenting with language and/or reading difficulties (46.15%); five patients with memory difficulties (38.4%); three patients with apraxia (23.1%); two patients with disorientation (15.3%); two patients with neglect (15.3%); one patients with object agnosia (7.7%), one patient with perseveration (7.7%) and one patient with dementia (7.7%). Frontal lesions were less frequent (p = 0.03), whereas temporal lesions were slightly more frequent (p = 0.06) in patients with cognitive deficits. The longitudinal PML course seemed to be more severe in cognitive than in non cognitive patients (F = 2.73, p = 0.03), but differences disappeared (F = 1.24, p = 0.29) when balancing for the incidence of immune reconstitution syndrome and for other treatments for PML (steroids, plasma exchange (PLEX) and other therapies (Mefloquine, Mirtazapine, Maraviroc). Conclusion Cognitive deficits at PML onset manifest with symptoms which are absolutely rare in MS. Their appearance in MS patients should strongly suggest PML. Clinicians should be sensitive to the importance of formal neuropsychological evaluation, with particular focus on executive function, which are not easily detected without a formal assessment

Comparison of anticoagulation quality between acenocoumarol and warfarin in patients with mechanical prosthetic heart valves: Insights from the nationwide PLECTRUM study

Vitamin K antagonists are indicated for the thromboprophylaxis in patients with mechanical prosthetic heart valves (MPHV). However, it is unclear whether some differences between acenocoumarol and warfarin in terms of anticoagulation quality do exist. We included 2111 MPHV patients included in the nationwide PLECTRUM registry. We evaluated anticoagulation quality by the time in therapeutic range (TiTR). Factors associated with acenocoumarol use and with low TiTR were investigated by multivariable logistic regression analysis. Mean age was 56.8 ± 12.3 years; 44.6% of patients were women and 395 patients were on acenocoumarol. A multivariable logistic regression analysis showed that patients on acenocoumarol had more comorbidities (i.e., ≥3, odds ratio (OR) 1.443, 95% confidence interval (CI) 1.081-1.927, p = 0.013). The mean TiTR was lower in the acenocoumarol than in the warfarin group (56.1 ± 19.2% vs. 61.6 ± 19.4%, p &lt; 0.001). A higher prevalence of TiTR (&lt;60%, &lt;65%, or &lt;70%) was found in acenocoumarol users than in warfarin ones (p &lt; 0.001 for all comparisons). Acenocoumarol use was associated with low TiTR regardless of the cutoff used at multivariable analysis. A lower TiTR on acenocoumarol was found in all subgroups of patients analyzed according to sex, hypertension, diabetes, age, valve site, atrial fibrillation, and INR range. In conclusion, anticoagulation quality was consistently lower in MPHV patients on acenocoumarol compared to those on warfarin

Extra-Visual Functional and Structural Connection Abnormalities in Leber's Hereditary Optic Neuropathy

We assessed abnormalities within the principal brain resting state networks (RSNs) in patients with Leber's hereditary optic neuropathy (LHON) to define whether functional abnormalities in this disease are limited to the visual system or, conversely, tend to be more diffuse. We also defined the structural substrates of fMRI changes using a connectivity-based analysis of diffusion tensor (DT) MRI data. Neuro-ophthalmologic assessment, DT MRI and RS fMRI data were acquired from 13 LHON patients and 13 healthy controls. RS fMRI data were analyzed using independent component analysis and SPM5. A DT MRI connectivity-based parcellation analysis was performed using the primary visual and auditory cortices, bilaterally, as seed regions. Compared to controls, LHON patients had a significant increase of RS fluctuations in the primary visual and auditory cortices, bilaterally. They also showed decreased RS fluctuations in the right lateral occipital cortex and right temporal occipital fusiform cortex. Abnormalities of RS fluctuations were correlated significantly with retinal damage and disease duration. The DT MRI connectivity-based parcellation identified a higher number of clusters in the right auditory cortex in LHON vs. controls. Differences of cluster-centroid profiles were found between the two groups for all the four seeds analyzed. For three of these areas, a correspondence was found between abnormalities of functional and structural connectivities. These results suggest that functional and structural abnormalities extend beyond the visual network in LHON patients. Such abnormalities also involve the auditory network, thus corroborating the notion of a cross-modal plasticity between these sensory modalities in patients with severe visual deficits

First overview on the 4th Annex I Habitats Report in Italy: methods, criticality, results and future prospects

Like all the other EU/28 countries, in 2019 Italy developed the 4th Italian Report ex-Art. 17 on the conservation status of the Habitats of Annex I to the 92/43/EEC Directive. Institutional referent of the process, on behalf of the Ministry for Environment, Land and Sea Protection (MATTM), was the Italian Institute for Environmental Protection and Research (ISPRA) with the scientific support of the Italian Botanical Society (SBI). A huge working group composed of thematic and territorial experts was formed with the task to collect, analyse, validate the data resulting from Annex I Habitat monitoring in Italy for the period 2013-2018, whose collection is in charge to the regional administrations. Data on 124 types of terrestrial and inland water Habitats present in Italy have been processed in order to assess their overall conservation status in the Biogeographic Regions of occurrence. The carried out activity led to the compilation of 278 assessment sheets. The work included a critical analysis of the data and a broad scientific confrontation aimed at finding methodologically robust solutions to fill the gaps. The work was structured so as to guarantee the traceability of the information and to allow the collection of "gray" literature and scientific articles, phytosociological surveys and unpublished material of the specialists, composing a substantial pool of data useful for starting a long-term process to support the next reporting cycles. Cartographic outcomes, associated databases and additional data used for the assessments will be available online on the ISPRA Portal as soon as the validation process by the European Commission will be completed. A freely accessible online archive of phytosociological surveys representative of the various Annex I Habitats in Italy is being set up within the national "VegItaly" database, managed by the Italian Society of Vegetation Science, by way of a dedicated archive named "HAB_IT". Such a long-term vision, oriented to the storage and enhancement of knowledge, represents an important innovative aspect and a significant progress towards the construction of an effective monitoring system for the conservation of Annex I Habitats in Italy