Realized extreme quantile: A joint model for conditional quantiles and measures of volatility with EVT refinements

We propose a new framework exploiting realized measures of volatility to estimate and forecast extreme quantiles. Our realized extreme quantile (REQ) combines quantile regression with extreme value theory and uses a measurement equation that relates the realized measure to the latent conditional quantile. Model estimation is performed by quasi maximum likelihood, and a simulation experiment validates this estimator in finite samples. An extensive empirical analysis shows that high-frequency measures are particularly informative of the dynamic quantiles. Finally, an out-of-sample forecast analysis of quantile-based risk measures confirms the merit of the REQ

Autonomic dysfunction is associated with disease progression and survival in amyotrophic lateral sclerosis: a prospective longitudinal cohort study

Background: Among non-motor symptoms, autonomic disturbances have been described in amyotrophic lateral sclerosis (ALS) and reported as mild to moderate in up to 75% of patients. However, no study has systematically investigated autonomic symptoms as prognostic factors. Objectives: The main aim of this longitudinal study was to examine the association of autonomic dysfunction with disease progression and survival in ALS. Methods: We enrolled newly diagnosed ALS patients and a healthy control group (HC). Time from disease onset to disease milestone (King’s stage 4) and death were calculated to assess disease progression and survival. Autonomic symptoms were assessed by a dedicated questionnaire. Longitudinal evaluation of parasympathetic cardiovascular activity was performed by the heart rate variability (HRV). Multivariable Cox proportional hazards regression models on the risk of the disease milestone and death were used. A mixed-effect linear regression model was used to compare autonomic dysfunction with a HC group as well as its impairment over time. Results: A total of 102 patients and 41 HC were studied. ALS patients, compared with HC, complained of more autonomic symptoms, especially in bulbar onset patients. Autonomic symptoms occurred in 69 (68%) patients at diagnosis and progressed over time (post-6: p = 0.015 and post-12: p < 0.001). A higher autonomic symptom burden was an independent marker of faster development of King’s stage 4 (HR 1.05; 95% CI 1.00–1.11; p = 0.022); whereas, urinary complaints were independent factors of a shorter survival (HR 3.12; 95% CI 1.22–7.97; p = 0.018). Moreover, HRV in ALS patients was lower than in HC (p = 0.018) and further decreased over time (p = 0.003), implying a parasympathetic hypofunction that progressed over time. Conclusion: Autonomic symptoms occur in most of the ALS patients at diagnosis and progress over time, implying that autonomic dysfunction represents an intrinsic non-motor feature of the disease. A higher autonomic burden is a poor prognostic factor, associated with a more rapid development of disease milestones and shorter survival

Weekly chemotherapy in advanced prostatic cancer.

This randomised phase II study was performed in order to evaluate the effectiveness of a weekly chemotherapy regimen in advanced prostatic carcinoma patients (stage D2) refractory to hormonal therapy. Seventy-two cases were studied: they were randomised in a 2:1 ratio to receive either epirubicin (30 mg m-2 weekly) or doxorubicin (25 mg m-2 weekly); 48 patients received epirubicin and 24 received doxorubicin. After 12 courses of chemotherapy, the 45 evaluable patients in the epirubicin arm showed a response rate of 37.7% and the 21 evaluable patients in the doxorubicin arm showed a response rate of 33.3% (P = 0.51). Pain intensity, bone and prostatic tumour markers rapidly and significantly decreased in responders. An improvement in physical symptoms, functional conditions and in emotional well-being was observed in the majority of the treated patients. The histological analysis of bone metastases, performed before and after 12 courses of chemotherapy showed a significant reduction in neoplastic invasion and in new bone formation in responders. Cardiac performance worsened in five out of 45 patients and in ten out of 21 during the first 12 courses of epirubicin or doxorubicin respectively (P = 0.014). The median survival was 12.5 months in the epirubicin arm and 8.0 months in the doxorubicin arm (P = 0.042). Our data indicate that in advanced prostatic carcinoma, a weekly epirubicin regimen may give rapid palliative results, similar to that of doxorubicin, but with less side-effects

Monacha samsunensis (Pfeiffer, 1868): another Anatolian species introduced to Western Europe, where it is known as Monacha atacis Gittenberger & de Winter, 1985 (Gastropoda: Eupulmonata: Hygromiidae)

Populations of Monacha atacis from southern Occitania in France and of M. samsunensis from northern Anatolia in Turkey (Atakum/Samsun and Kastamonu) were investigated by an integrative approach based on morphological (shell and genitalia) and molecular (mitochondrial and nuclear gene sequences) features. Morphological examination revealed a complex pattern of variation within and between geographically separated populations, while molecular analysis showed strong similarity between the two species, confirming earlier suggestions that the species are conspecific. Pfeiffer’s name Helix samsunensis introduced in 1868 has priority over the name M. atacis given by Gittenberger &amp; de Winter in 1985. © 2022 The Author(s). Published by Informa UK Limited, trading as Taylor &amp; Francis Group

A small slug from a tropical greenhouse reveals a new rathouisiid lineage with triaulic tritrematic genitalia (Gastropoda: Systellommatophora)

A small slug found in the tropical greenhouse of the Science Museum (MUSE) of Trento (Italy) turned out to be a species of the little-known systellommatophoran family Rathouisiidae. We undertook detailed comparative anatomical and molecular studies using specimens of the MUSE slug, Rathouisia sinensis, and sequences of other systellommatophoran species deposited in GenBank to conduct a systematic and phylogenetic assessment. Analysis of the genitalia of the MUSE slug and R. sinensis revealed an unusual triaulic tritrematic structure: two separate female ducts – one for egg release (oviduct), the other for intake of allosperm (vagina) – and a separate male duct for autosperm release. Analysis of the nucleotide sequences of several mitochondrial (COI, 16S rDNA) and nuclear (18S rDNA, ITS2 flanked by 5.8S and 28S rDNA fragments, H3) gene fragments supported assignation of the MUSE slug to Rathouisiidae, but also its distinction from the other rathouisiid genera Atopos, Granulilimax, Rathouisia and an undescribed genus from the Ryukyu Islands (Japan). Therefore, we decided to describe the MUSE slug as a new species in a new genus: Barkeriella museensis gen. et sp. nov. The species is certainly an alien introduced into the tropical greenhouse of MUSE, but its origin is unknown and calls for further investigation. © 2022 The Linnean Society of London

Mycobacterium tuberculosis virulence: insights and impact on vaccine development

The existing TB vaccine, the attenuated Mycobacterium bovis strain BCG, is effective in protecting infants from severe forms of the disease, while its efficacy in protecting adults from pulmonary TB is poor. In the last two decades, a renewed interest in TB resulted in the development of several candidate vaccines that are now entering clinical trials. However, most of these vaccines are based on a common rationale and aim to induce a strong T-cell response against Mycobacterium tuberculosis. Recent advancements in the understanding of M. tuberculosis virulence determinants and associated pathogenic strategies are opening a new and broader view of the complex interaction between this remarkable pathogen and the human host, providing insights at molecular level that could lead to a new rationale for the design of novel antitubercular vaccines. A vaccination strategy that simultaneously targets different steps in TB pathogenesis may result in improved protection and reduced TB transmission

Targeting lipid rafts as a strategy against coronavirus

Lipid rafts are functional membrane microdomains containing sphingolipids, including gangliosides, and cholesterol. These regions are characterized by highly ordered and tightly packed lipid molecules. Several studies revealed that lipid rafts are involved in life cycle of different viruses, including coronaviruses. Among these recently emerged the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The main receptor for SARS-CoV-2 is represented by the angiotensin-converting enzyme-2 (ACE-2), although it also binds to sialic acids linked to host cell surface gangliosides. A new type of ganglioside-binding domain within the N-terminal portion of the SARS-CoV-2 spike protein was identified. Lipid rafts provide a suitable platform able to concentrate ACE-2 receptor on host cell membranes where they may interact with the spike protein on viral envelope. This review is focused on selective targeting lipid rafts components as a strategy against coronavirus. Indeed, cholesterol-binding agents, including statins or methyl-β-cyclodextrin (MβCD), can affect cholesterol, causing disruption of lipid rafts, consequently impairing coronavirus adhesion and binding. Moreover, these compounds can block downstream key molecules in virus infectivity, reducing the levels of proinflammatory molecules [tumor necrosis factor alpha (TNF-α), interleukin (IL)-6], and/or affecting the autophagic process involved in both viral replication and clearance. Furthermore, cyclodextrins can assemble into complexes with various drugs to form host–guest inclusions and may be used as pharmaceutical excipients of antiviral compounds, such as lopinavir and remdesivir, by improving bioavailability and solubility. In conclusion, the role of lipid rafts-affecting drugs in the process of coronavirus entry into the host cells prompts to introduce a new potential task in the pharmacological approach against coronavirus

Advances in the Pathophysiology of Thrombosis in Antiphospholipid Syndrome. Molecular Mechanisms and Signaling through Lipid Rafts

The pathological features of antiphospholipid syndrome (APS) are related to the activity of circulating antiphospholipid antibodies (aPLs) associated with vascular thrombosis and obstetric complications. Indeed, aPLs are not only disease markers, but also play a determining pathogenetic role in APS and exert their effects through the activation of cells and coagulation factors and inflammatory mediators for the materialization of the thromboinflammatory pathogenetic mechanism. Cellular activation in APS necessarily involves the interaction of aPLs with target receptors on the cell membrane, capable of triggering the signal transduction pathway(s). This interaction occurs at specific microdomains of the cell plasma membrane called lipid rafts. In this review, we focus on the key role of lipid rafts as signaling platforms in the pathogenesis of APS, and propose this pathogenetic step as a strategic target of new therapies in order to improve classical anti-thrombotic approaches with "new " immunomodulatory drugs