Comparison of multi-state Markov models for cancer progression with different procedures for parameters estimation. An application to breast cancer

Background: the knowledge of sojourn time (the duration of the preclinical screen-detectable period) and screening test sensitivity is crucial for understanding the disease progression and the effectiveness of screening programmes. For this purpose a model of the natural history of the disease is needed. The aim of this work is to provide an illustration of the application of multistate Markov models for breast cancer progression to the data of the Florentine screening programme, in order to estimate the sojourn time and sensitivity for breast cancer screening. Methods: three different multi-state Markov models of increasing complexity were used with three different estimation procedures based on non-linear least squares, maximum likelihood, and on a Bayesian approach. All the models produced estimates for screening sensitivity and mean sojourn time. The data used in our application seem to lead to a non-identifiability problem, since the estimation procedures for both the Maximum Likelihood and Non-Linear Least Squares gave estimates that changed with the parameters’ initial values or difficultly converged. In order to take this problem into account we used the Bayesian Approach by incorporating prior information on all the parameters. Results: the mean sojourn time varied between 2-7 years and 3-5 years for women aged 50-59 and 60-69, respectively. When the model complexity was increased a higher variability in estimates was observed among the estimation procedures. The results of the screening sensitivity estimates were highly variable, both among estimation techniques and models - varying between 63% and 100%, and between 77% and 100% for women aged 50-59 and 60-69, respectively. Conclusions: results are in accord with the literature; those obtained through the Bayesian Approach seem to be more reliable.&nbsp

Brucella abortus Strain RB51 Vaccine: Immune Response after Calfhood Vaccination and Field Investigation in Italian Cattle Population

Immune response to Brucella abortus strain RB51 vaccine was measured in cattle vaccinated at calfhood. After an increase at day 6 post-vaccination (pv), the antibody level recorded in the 10 vaccinated animals remained constant for two months, and then progressively decreased. All vaccinated animals remained negative from day 162 pv to the end of the study (day 300 pv). Only at days 13 and 14 pv the RB51-CFT showed 100% sensitivity (credibility interval (CI) 76.2%–100%). The results indicate that the possibility to use RB51-CFT for the identification of cattle vaccinated at calfhood with RB51 is limited in time. A field investigation was carried out on 26,975 sera collected on regional basis from the Italian cattle population. The study outcomes indicate that in case of RB51-CFT positive results observed in officially Brucellosis-free (OBF) areas and, in any case, when an illegal use of RB51 vaccine is suspected, the use of the RB51-CFT alone is not sufficient to identify all the vaccinated animals. The design of a more sophisticated diagnostic protocol including an epidemiological investigation, the use of RB51-CFT, and the use of the skin test with RB51 as antigen is deemed more appropriate for the identification of RB51 vaccinated animals

Elevated miR-34a expression and altered transcriptional profile are associated with adverse electromechanical remodeling in the heart of male rats exposed to social stress.

This study investigated epigenetic risk factors that may contribute to stress-related cardiac disease in a rodent model. Experiment 1 was designed to evaluate the expression of microRNA-34a (miR-34a), a known modulator of both stress responses and cardiac pathophysiology, in the heart of male adult rats exposed to a single or repeated episodes of social defeat stress. Moreover, RNA sequencing was conducted to identify transcriptomic profile changes in the heart of repeatedly stressed rats. Experiment 2 was designed to assess cardiac electromechanical changes induced by repeated social defeat stress that may predispose rats to cardiac dysfunction. Results indicated a larger cardiac miR-34a expression after repeated social defeat stress compared to a control condition. This molecular modification was associated with increased vulnerability to pharmacologically induced arrhythmias and signs of systolic left ventricular dysfunction. Gene expression analysis identified clusters of differentially expressed genes in the heart of repeatedly stressed rats that are mainly associated with morphological and functional properties of the mitochondria and may be directly regulated by miR-34a. These results suggest the presence of an association between miR-34a overexpression and signs of adverse electromechanical remodeling in the heart of rats exposed to repeated social defeat stress, and point to compromised mitochondria efficiency as a potential mediator of this link. This rat model may provide a useful tool for investigating the causal relationship between miR-34a expression, mitochondrial (dys)function, and cardiac alterations under stressful conditions, which could have important implications in the context of stress-related cardiac disease

Measurement of the muon decay spectrum with the ICARUS liquid Argon TPC

Examples are given which prove the ICARUS detector quality through relevant physics measurements. We study the muon decay energy spectrum from a sample of stopping muon events acquired during the test run of the ICARUS T600 detector. This detector allows the spatial reconstruction of the events with fine granularity, hence, the precise measurement of the range and dE/dx of the muon with high sampling rate. This information is used to compute the calibration factors needed for the full calorimetric reconstruction of the events. The Michel rho parameter is then measured by comparison of the experimental and Monte Carlo simulated muon decay spectra, obtaining rho = 0.72 +/- 0.06(stat.) +/- 0.08(syst.). The energy resolution for electrons below ~50 MeV is finally extracted from the simulated sample, obtaining (Emeas-Emc)/Emc = 11%/sqrt(E[MeV]) + 2%.Comment: 16 pages, 8 figures, LaTex, A4. Some text and 1 figure added. Final version as accepted for publication in The European Physical Journal

De Novo Unbalanced Translocations in Prader-Willi and Angelman Syndrome Might Be the Reciprocal Product of inv dup(15)s

The 15q11-q13 region is characterized by high instability, caused by the presence of several paralogous segmental duplications. Although most mechanisms dealing with cryptic deletions and amplifications have been at least partly characterized, little is known about the rare translocations involving this region. We characterized at the molecular level five unbalanced translocations, including a jumping one, having most of 15q transposed to the end of another chromosome, whereas the der(15)(pter->q11-q13) was missing. Imbalances were associated either with Prader-Willi or Angelman syndrome. Array-CGH demonstrated the absence of any copy number changes in the recipient chromosome in three cases, while one carried a cryptic terminal deletion and another a large terminal deletion, already diagnosed by classical cytogenetics. We cloned the breakpoint junctions in two cases, whereas cloning was impaired by complex regional genomic architecture and mosaicism in the others. Our results strongly indicate that some of our translocations originated through a prezygotic/postzygotic two-hit mechanism starting with the formation of an acentric 15qter->q1::q1->qter representing the reciprocal product of the inv dup(15) supernumerary marker chromosome. An embryo with such an acentric chromosome plus a normal chromosome 15 inherited from the other parent could survive only if partial trisomy 15 rescue would occur through elimination of part of the acentric chromosome, stabilization of the remaining portion with telomere capture, and formation of a derivative chromosome. All these events likely do not happen concurrently in a single cell but are rather the result of successive stabilization attempts occurring in different cells of which only the fittest will finally survive. Accordingly, jumping translocations might represent successful rescue attempts in different cells rather than transfer of the same 15q portion to different chromosomes. We also hypothesize that neocentromerization of the original acentric chromosome during early embryogenesis may be required to avoid its loss before cell survival is finally assured

Guidelines for the use and interpretation of diagnostic methods in adult food allergy

Food allergy has an increasing prevalence in the general population and in Italy concerns 8 % of people with allergies. The spectrum of its clinical manifestations ranges from mild symptoms up to potentially fatal anaphylactic shock. A number of patients can be diagnosed easily by the use of first- and second-level procedures (history, skin tests and allergen specific IgE). Patients with complex presentation, such as multiple sensitizations and pollen-food syndromes, frequently require a third-level approach including molecular diagnostics, which enables the design of a component-resolved sensitization profile for each patient. The use of such techniques involves specialists' and experts' skills on the issue to appropriately meet the diagnostic and therapeutic needs of patients. Particularly, educational programs for allergists on the use and interpretation of molecular diagnostics are needed

A roadmap for amphibious drilling at the Campi Flegrei caldera: insights from a MagellanPlus workshop

Large calderas are among the Earth's major volcanic features. They are associated with large magma reservoirs and elevated geothermal gradients. Caldera-forming eruptions result from the withdrawal and collapse of the magma chambers and produce large-volume pyroclastic deposits and later-stage deformation related to post-caldera resurgence and volcanism. Unrest episodes are not always followed by an eruption; however, every eruption is preceded by unrest. The Campi Flegrei caldera (CFc), located along the eastern Tyrrhenian coastline in southern Italy, is close to the densely populated area of Naples. It is one of the most dangerous volcanoes on Earth and represents a key example of an active, resurgent caldera. It has been traditionally interpreted as a nested caldera formed by collapses during the 100–200 km3 Campanian Ignimbrite (CI) eruption at ∼39 ka and the 40 km3 eruption of the Neapolitan Yellow Tuff (NYT) at ∼15 ka. Recent studies have suggested that the CI may instead have been fed by a fissure eruption from the Campanian Plain, north of Campi Flegrei. A MagellanPlus workshop was held in Naples, Italy, on 25–28 February 2017 to explore the potential of the CFc as target for an amphibious drilling project within the International Ocean Discovery Program (IODP) and the International Continental Drilling Program (ICDP). It was agreed that Campi Flegrei is an ideal site to investigate the mechanisms of caldera formation and associated post-caldera dynamics and to analyze the still poorly understood interplay between hydrothermal and magmatic processes. A coordinated onshore–offshore drilling strategy has been developed to reconstruct the structure and evolution of Campi Flegrei and to investigate volcanic precursors by examining (a) the succession of volcanic and hydrothermal products and related processes, (b) the inner structure of the caldera resurgence, (c) the physical, chemical, and biological characteristics of the hydrothermal system and offshore sediments, and (d) the geological expression of the phreatic and hydromagmatic eruptions, hydrothermal degassing, sedimentary structures, and other records of these phenomena. The deployment of a multiparametric in situ monitoring system at depth will enable near-real-time tracking of changes in the magma reservoir and hydrothermal system

What is the role of the placebo effect for pain relief in neurorehabilitation? Clinical implications from the Italian consensus conference on pain in neurorehabilitation

Background: It is increasingly acknowledged that the outcomes of medical treatments are influenced by the context of the clinical encounter through the mechanisms of the placebo effect. The phenomenon of placebo analgesia might be exploited to maximize the efficacy of neurorehabilitation treatments. Since its intensity varies across neurological disorders, the Italian Consensus Conference on Pain in Neurorehabilitation (ICCP) summarized the studies on this field to provide guidance on its use. Methods: A review of the existing reviews and meta-analyses was performed to assess the magnitude of the placebo effect in disorders that may undergo neurorehabilitation treatment. The search was performed on Pubmed using placebo, pain, and the names of neurological disorders as keywords. Methodological quality was assessed using a pre-existing checklist. Data about the magnitude of the placebo effect were extracted from the included reviews and were commented in a narrative form. Results: 11 articles were included in this review. Placebo treatments showed weak effects in central neuropathic pain (pain reduction from 0.44 to 0.66 on a 0-10 scale) and moderate effects in postherpetic neuralgia (1.16), in diabetic peripheral neuropathy (1.45), and in pain associated to HIV (1.82). Moderate effects were also found on pain due to fibromyalgia and migraine; only weak short-term effects were found in complex regional pain syndrome. Confounding variables might have influenced these results. Clinical implications: These estimates should be interpreted with caution, but underscore that the placebo effect can be exploited in neurorehabilitation programs. It is not necessary to conceal its use from the patient. Knowledge of placebo mechanisms can be used to shape the doctor-patient relationship, to reduce the use of analgesic drugs and to train the patient to become an active agent of the therapy

Serum Albumin Is Inversely Associated With Portal Vein Thrombosis in Cirrhosis

We analyzed whether serum albumin is independently associated with portal vein thrombosis (PVT) in liver cirrhosis (LC) and if a biologic plausibility exists. This study was divided into three parts. In part 1 (retrospective analysis), 753 consecutive patients with LC with ultrasound-detected PVT were retrospectively analyzed. In part 2, 112 patients with LC and 56 matched controls were entered in the cross-sectional study. In part 3, 5 patients with cirrhosis were entered in the in vivo study and 4 healthy subjects (HSs) were entered in the in vitro study to explore if albumin may affect platelet activation by modulating oxidative stress. In the 753 patients with LC, the prevalence of PVT was 16.7%; logistic analysis showed that only age (odds ratio [OR], 1.024; P = 0.012) and serum albumin (OR, -0.422; P = 0.0001) significantly predicted patients with PVT. Analyzing the 112 patients with LC and controls, soluble clusters of differentiation (CD)40-ligand (P = 0.0238), soluble Nox2-derived peptide (sNox2-dp; P < 0.0001), and urinary excretion of isoprostanes (P = 0.0078) were higher in patients with LC. In LC, albumin was correlated with sCD4OL (Spearman's rank correlation coefficient [r(s)], -0.33; P < 0.001), sNox2-dp (r(s), -0.57; P < 0.0001), and urinary excretion of isoprostanes (r(s), -0.48; P < 0.0001) levels. The in vivo study showed a progressive decrease in platelet aggregation, sNox2-dp, and urinary 8-iso prostaglandin F2 alpha-III formation 2 hours and 3 days after albumin infusion. Finally, platelet aggregation, sNox2-dp, and isoprostane formation significantly decreased in platelets from HSs incubated with scalar concentrations of albumin. Conclusion: Low serum albumin in LC is associated with PVT, suggesting that albumin could be a modulator of the hemostatic system through interference with mechanisms regulating platelet activation