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The Canadian Multiple Sclerosis Working Group has updated its treatment optimization recommendations (TORs) on the optimal use of disease-modifying therapies for patients with all forms of multiple sclerosis (MS). Recommendations provide guidance on initiating effective treatment early in the course of disease, monitoring response to therapy, and modifying or switching therapies to optimize disease control. The current TORs also address the treatment of pediatric MS, progressive MS and the identification and treatment of aggressive forms of the disease. Newer therapies offer improved efficacy, but also have potential safety concerns that must be adequately balanced, notably when treatment sequencing is considered. There are added discussions regarding the management of pregnancy, the future potential of biomarkers and consideration as to when it may be prudent to stop therapy. These TORs are meant to be used and interpreted by all neurologists with a special interest in the management of MS.
Bipolar disorder (BPD) is a highly debilitating psychiatric disorder. The underlying molecular mechanisms of BPD remain largely unknown. Studies targeting postmortem brain tissues of BPD patients have identified very few consistently replicated differences in the expression levels of protein-coding RNAs across different areas of the brain. Since differential expression of the human genome produces a wide spectrum of protein-coding and noncoding RNAs, we hypothesized that major molecular deficits associated with BPD could reflect dysregulation of multiple classes of RNA. To test this hypothesis, we obtained postmortem human medial frontal gyrus tissue from BPD patients and healthy controls (n = 16). To survey the implication of both protein-coding and long non-coding RNAs (lncRNAs) in BPD, we then performed RNA sequencing, PCR validation and replication experiments adopting a case-control design. Thirty-six genes and fifteen lncRNA transcripts not previously implicated in BPD were detected as differentially expressed (FDR < 0.1). Functional analyses identified enrichments of angiogenesis, vascular system development and histone H3-K4 demethylation. In addition, we report extensive alternative splicing defects in the brains of BPD subjects compared to controls. Finally, we describe for the first time a large reservoir of circular RNAs (circRNAs) that populate the medial frontal gyrus and report significantly altered levels of two circular transcripts (cNEBL and cEPHA3) from the NEBL and EPHA3 loci in BPD. Our findings may not only contribute to gain insight into the pathophysiology of BPD but may be tested in the near future as potential biomarkers for diagnostics.
Disclosure of interest
The authors have not supplied their declaration of competing interest.
Clinically, OC-checkers often report staring compulsions and “lack of action completion” sensations, which have been linked to self-agency alterations. Belayachi and Van der Linden (2009) theoretically proposed that “abnormal” checkers self-agency could be due to an over-reliability on environmental cues and to a tendency to specify actions in a procedural and inflexible way, conceiving them as “low-level” agents. Currently, no studies have experimentally address this issue.
To investigate self-agency in OC-checkers subtype, measuring gaze agency (the ability to understand that we can cause events through our eye movements) and taking into account both agency beliefs and agency feelings.
13 OC-checkers and 13 healthy controls underwent two tasks. “Discovery” task, a completely novel task used to examine causal learning abilities. Subjects watched bouncing balls on a computer screen with the aim of discovering the cause of concurrently presented acoustical beeps. “Detection” task, a two-alternative forced choice task that required subjects to tell whether or not the beeps were generated by their own eye movements.
– lower performance scores and confidence ratings when they have to self-attribute the beep cause, but not eye behavioral differences, during discovery task;
– lower confidence ratings, but a level of accuracy similar to that of controls, during detection task.
Checkers do not show an altered self-agency per se, but what we have called a “doubtful” self-agency: indeed, we argue that agency beliefs alterations found during Discovery task can be due to pathological doubt, rather than to altered agency feelings.
Disclosure of interest
The authors have not supplied their declaration of competing interest.
Italy is prone to major earthquakes and has experienced several devastating earthquakes in the far and recent past. The objectives of this study were to assess the level of Italian households’ preparedness for earthquakes and to measure the public’s perception of the risk and its impact on preparedness behavior.
Italian households’ preparedness for earthquakes is insufficient and is influenced by different threat perception components that were assessed.
A cross-sectional study, using an online questionnaire, was conducted in early 2018. The sample included 1,093 responders from a diverse sociodemographic background. The primary outcome was the Preparedness Index (PI), a score indicating the number of preparedness actions complied-with out of 10.
The PI’s mean was 5.26 (SD = 2.17). The recommendation most complied-with was keeping a flashlight at home (87.7%) and the least was securing the kitchen cupboards (15.1%). The PI was positively correlated with a higher sense of preparedness (r = 0.426; P <.001). The PI was higher for responders residing in high-seismic-risk areas and those who experienced a major earthquake before. The predictors of PI were: gender, age, prior experience, sense of preparedness, searching for information, and threat intrusiveness (negatively).
The findings demonstrate a medium-level of preparedness; however, this might be circumstantial. Italians perceive major earthquakes to be unlikely, yet severe if and when they do occur. A validated tool in Italian now exists and can be used in future studies.
Bodas M, Giuliani F, Ripoll-Gallardo A, Caviglia M, Dell’Aringa MF, Linty M, Della Corte F, Ragazzoni L. Threat perception and public preparedness for earthquakes in Italy. Prehosp Disaster Med. 2019;34(2):114–124
In cosmic environments, polycyclic aromatic hydrocarbons (PAHs) strongly interact with vacuum ultraviolet (VUV) photons emitted by young stars. Trapped PAH cations ranging in size from 30 to 48 carbon atoms were irradiated by tunable synchrotron light (DESIRS beamline at SOLEIL). Their ionization and dissociation cross sections were determined and compared with TD-DFT computed photoabsorption cross sections. Evidence for radiative cooling is reported.
This article investigates the role, reception, and socio-cultural, political relevance of mondo movies in the context of late 1950s–early 1980s film and documentary. The mondo genre debuted with reportage films about sexuality in Europe and reached its pinnacle with Gualtiero Jacopetti’s assemblage films. The historical context in which this genre evolved, and white masculinity was rearticulated and positioned at the centre of the national imagined community, is mapped focusing both on gender and race constructions and on the gaze identifying, encoding and decoding the sensationalist presentation of postcolonial/ decolonising Otherness. A brief review of some of the author’s published work on 1962–1971 mondo movies introduces Cannibal Holocaust (1979) and director Ruggero Deodato’s controversial reflection on the white, capitalist, sexist, Western and neo-colonial anthropological gaze.
Objectives: The aim of the present study was to investigate “Proactive-Adjustment hypothesis” (PA) during the Stop Signal Task (SST). The PA is implied in the highly inconsistent literature, and it deals with the role of response inhibition (RI) in obsessive-compulsive disorder (OCD). This hypothesis assumed that participants would balance stopping and going by adjusting the response threshold (RT) in the go task. We verified whether the PA strategy was also implemented in our clinical group. Methods: To reach this goal, we analyzed SST performances in a group of 36 patients with OCD and 36 healthy controls (HCs). To identify different participants’ behaviors during the task, without preconceived notions regarding the diagnosis, we performed a cluster analysis. Furthermore, we analyzed the influence of drug therapy and we investigated whether the rule and reversal acquisition investigated with the Intra-Extra Dimensional Set Shift, differed in the two clusters. Results: We did not find any difference relative to the number of patients with OCD and HCs included in the two clusters. Furthermore, we found that only Not Proactive participants performed the task as fast as possible, while Proactive participants consistently slowed down their RTs and showed a lower number of Direction Errors, higher Stop Signal Delay, and worse cognitive flexibility. Conclusions: Our results show that among patients with OCD the use of PA is changeable and does not differ from HCs. This finding supports the idea that the RI heterogeneity concerning patients with OCD could be related to PA. (JINS, 2018, 24, 1–12)
The Italian 2013 election ended the period of bipolarism that characterized the so-called ‘Second Republic’, and paved the way for new parties such as the Five Star Movement. We investigate that election, which took place after the technocratic government led by Mario Monti, through the analytical lenses of the retrospective theory of economic voting applied at the provincial level. Local unemployment rates shape the electoral performances of those parties that were more supportive and sympathetic to the caretaker executive, thus confirming a distinction between incumbent and non-incumbent even in that critical and politically undecided election. We further contribute to the literature on retrospective voting by relaxing the locally untenable assumption of independence among the units. Making use of spatial regression models, we demonstrate the relevance of both the internal and contiguous economies, and their relative impact due to the different size of the provinces.
Work on thermal pools at Poggetti Vecchi in Grosseto, Italy, exposed an up to 3-meter-thick succession of seven sedimentary units. Unit 2 in the lower portion of the succession contained vertebrate bones, mostly of the straight-tusked elephant, Palaeoloxodon antiquus, commingled with stone, bone, and wooden tools. Thermal carbonates overlying Unit 2 are radiometrically dated to the latter part of the middle Pleistocene. This time span indicates that early Neanderthals produced the human artifacts from Poggetti Vecchi. The elephant bones belong to seven individuals of different ages. Sedimentary facies analysis and paleoecological evidence suggest a narrow lacustrine-palustrine embayment affected by water-level fluctuations and, at times, by hydrothermal water. Cyclic lake-level variations were predominantly forced by the rapid climatic fluctuations that occurred at Marine Isotope Stage (MIS) 6–7 transition and throughout the MIS 6. Possibly an abrupt, intense, and protracted cold episode during the onset of MIS 6 led to the sudden death of the elephants, which formed an unexpected food resource for the humans of the area. The Poggetti Vecchi site adds new information on the behavioral plasticity and food procurement strategies that early Neanderthals were able to develop in Italy during the middle to the late Pleistocene transition.
In the framework of the Sardinia Radio Telescope (SRT) Early Science Program, we obtained single-dish high-resolution imaging of the Supernova Remnants IC443 and W44 at 7 GHz. By coupling them with SRT 1.5 GHz maps, we provided spatially-resolved spectral measurements that are highlighting a spread in spectral slope distribution. The observed features range from flat or slightly inverted spectra corresponding to bright radio limbs and filaments, to relatively steep spectra in fainter radio regions. Different theoretical possibilities explaining the above challenging findings are discussed. In particular, we exclude that the observed region-dependent wide spread in spectral slope distribution could be related to absorption processes. Our high-frequency results can be directly related to distinct electron populations in the SNRs including secondary hadronic electrons and resulting from different shocks conditions and/or undergoing different cooling processes. Integrated fluxes associated with the whole SNRs obtained by SRT in comparison with previous results in the literature support the evidence for a slight spectral steepening above 1 GHz for both sources, which could be related to primary electrons or more likely secondary hadronic electrons cut-offs.
We present single-dish imaging of the well-known Supernova Remnants (SNRs) IC443 and W44 at 1.5 GHz and 7 GHz with the recently commissioned 64-m diameter Sardinia Radio Telescope (SRT). Our images were obtained through on-the-fly mapping techniques, providing antenna beam oversampling, automatic baseline subtraction and radio-frequency interference removal. It results in high-quality maps of the SNRs at 7 GHz, which are usually lacking and not easily achievable through interferometry at this frequency due to the very large SNR structures. SRT continuum maps of our targets are consistent with VLA maps carried out at lower frequencies (at 324 MHz and 1.4 GHz), providing a view of the complex filamentary morphology. New estimates of the total flux density are given within 3% and 5% error at 1.5 GHz and 7 GHz respectively, in addition to flux measurements in different regions of the SNRs.
Payment by result agreements have been quite widely used in Italy to provide access for high costs oncologic drugs and minimize uncertainties of real life benefits (1). The aim of this analysis was to overview the Roche experience in terms of Payment by Result (Pbr) in oncology and investigate the relation between timing for the evaluation of treatment failures and observed Time to Off Treatment (TTOT) from Phase III clinical trials (2).
A retrospective analysis of the Roche payment by results schemes in place in Italy was conducted. For each drug included in the analysis it was collected: (i) the negotiated timing to assess the treatment failure for payment by result, (ii) the median time to off treatment curve observed in clinical trials for the experimental drug, (iii) the median time to off treatment observed in clinical trials for the control arm. The mean ratios between timing to assess the treatment failure for payment by result and the time to off treatment observed for the experimental drug or the median time to off treatment observed in the control arm were calculated to identify potential correlations. High level of correlation was expected if ratio was close to 1 (±.2).
Roche products or different indications of the same product were identified as candidates for the analysis from 2008 to 2016. The timing for the evaluation of treatment failures for Pbr varies between 2 and 9 months, depending on the type of tumor and line of therapy. The mean Time to Payment By Result (TTPbr) / Control arm Time To Off Treatment (cTTOT) ratio was 1.16 (±.37) while the mean Time to Payment By Result (TTPbr) / Experimental arm Time To Off Treatment (eTTOT) ratio was .71 (±.13). Data analysis according to different time periods shows that the mean TTPbr/cTTOT and TTPbr/eTTOT for drugs negotiated from 2008 to 2015 were respectively 1.07 and 1.39 whereas for drugs negotiated in 2016 were respectively and .63 and 1.
Good level of correlation between TTPbr and cTTOT was found. This finding is in line with the methodology used by Italian Medicines Agency so far, leveraging the cTTOT as the most appropriate proxy to assess any incremental effect of a new drug compared to the previous Standard of Care. The analysis over time of TTPbr shows that in the first years of payment by result negotiation TTPbr is more correlated to the cTTOT whereas in the last years is moving closer to the experimental one.
In a budget constrained environment characterized by an increasing number of high-cost medicines, manufacturers need to demonstrate that their drugs can provide value-for-money. In this complex environment Managed Entry Agreements (MEAs) have been developed with the aim of sharing the risk between the National Health Service (NHS) and manufacturers (1). The objective of this analysis was to identify a correlation between Anatomical Therapeutic Chemical Classification (ATC) and different type of agreements assigned taking into consideration the distribution of Italian Medicines Agency registries by ATC and by kind of agreement negotiated (financial or performance based) (2).
This analysis takes into account all drugs under monitoring AIFA registries in place in Italy from 2006. For each registry included in the analysis it was collected the status of the registry (active, closed or incoming), the disease area that the registry covers and the monitored drugs with or without an associated Managed Entry Agreements. Considering the high weight of oncology drugs, a sub-analysis was done to investigate registries distribution for each specific form of cancer.
The majority of drugs monitored are under a registry with no associated risk sharing agreement according to AIFA (60 percent). For what concerned monitored drugs with an associated agreement, performance-based agreement is the most diffused type of MEA. In terms of therapeutic area involved in the monitoring registries activity, oncology was the most common area. Financial based agreements characterize principally medicines used for Leukemia and Hepatitis C, whereas drugs administrated for Melanoma, Breast and Ovarian Cancer and Ophthalmology diseases follow performance based agreements.
MEAs represent a way to guarantee a sustainable access for innovative medicines. It is proven that oncology products are most likely to have a MEA since they represent some of the most expensive drugs launched in recent years. From this study appear a correlation between the therapeutic disease area of the monitored drugs and MEA assigned by AIFA which is influenced also by other factors like budget impact, risk-benefit ratio and the presence of appropriate endpoints to evaluate the treatment response.
The Italian Medicines Agency Registry represents a tool that could be a precious source of information regarding the mean treatment duration of a drug in a real world context. Monitoring registries are applied at the national level after market authorization and are designed not only to apply the Managed Entry Agreements (MEAs) but also to collect Real World Data on drugs safety, effectiveness and real life utilization. The purpose of this analysis was to compare the treatment duration from clinical trials and the mean treatment duration calculated using data from monitoring registries (1).
For each drug included in the analysis it was collected the treatment duration from Time To Off Treatment curves for the experimental drug (eTTOT) from Phase III clinical trials and the mean treatment duration data calculated by using the number of cycles (converted in months of treatment) of all treated patients extracted from AIFA registries (TTAR). The mean ratios between the Time of Treatment of Italian Medicines Agency and Experimental arm time to off treatment were calculated to identify potential correlations. High level of correlation was expected if Time to Payment By Result /Time To Off Treatment ratio was close to 1 (±.2).
Six Roche products or different indications of the same product were identified as candidates for the analysis from 2013 to 2016. The mean TTAR/eTTOT ratio observed in patients treated from 2013 to 2016 was .97 (±.10), meaning that the mean treatment duration calculated from AIFA Registries is strongly comparable with the treatment duration observed in clinical trials. In one case the TTAR is even more major than eTTOT.
A high level of correlation between TTAR and eTTOT was found. Additional analyses considering different cohorts of patients over time could be useful to have a more precise estimate of real world drug utilization. Even though RCTs remain the gold standard for demonstrating clinical efficacy in restricted trial setting, Real World Evidence from AIFA registries can contribute to the evidence base needed for healthcare decisions.
This paper introduces deep neural network (DNN)–hidden Markov model (HMM)-based methods to tackle speech recognition in heterogeneous groups of speakers including children. We target three speaker groups consisting of children, adult males and adult females. Two different kind of approaches are introduced here: approaches based on DNN adaptation and approaches relying on vocal-tract length normalisation (VTLN). First, the recent approach that consists in adapting a general DNN to domain/language specific data is extended to target age/gender groups in the context of DNN–HMM. Then, VTLN is investigated by training a DNN–HMM system by using either mel frequency cepstral coefficients normalised with standard VTLN or mel frequency cepstral coefficients derived acoustic features combined with the posterior probabilities of the VTLN warping factors. In this later, novel, approach the posterior probabilities of the warping factors are obtained with a separate DNN and the decoding can be operated in a single pass when the VTLN approach requires two decoding passes. Finally, the different approaches presented here are combined to take advantage of their complementarity. The combination of several approaches is shown to improve the baseline phone error rate performance by thirty per cent to thirty-five per cent relative and the baseline word error rate performance by about ten per cent relative.
Gem minerals at Lava Plains, northeast Queensland, offer further insights into mantle-crustal gemformation under young basalt fields. Combined mineralogy, U-Pb age determination, oxygen isotope and petrological data on megacrysts and meta-aluminosilicate xenoliths establish a geochemical evolution in sapphire, zircon formation between 5 to 2 Ma. Sapphire megacrysts with magmatic signatures (Fe/Mg ∼100–1000, Ga/Mg 3–18) grew with ∼3 Ma micro-zircons of both mantle (δ18O 4.5–5.6%) and crustal (δ18O 9.5–10.1‰) affinities. Zircon megacrysts (3±1 Ma) show mantle and crustal characteristics, but most grew at crustal temperatures (600–800°C). Xenolith studies suggest hydrous silicate melts and fluids initiated from amphibolized mantle infiltrated into kyanite+sapphire granulitic crust (800°C, 0.7 GPa). This metasomatized the sapphire (Fe/Mg ∼50–120, Ga/Mg ∼3–11), left relict metastable sillimanite-corundum-quartz and produced minerals enriched in high field strength, large ion lithophile and rare earth elements. The gem suite suggests a syenitic parentage before its basaltic transport. Geographical trace-element typing of the sapphire megacrysts against other eastern Australian sapphires suggests a phonolitic involvement.