Study of the bolometers thermal response for the search of rare events

Large-mass bolometers are calorimeters working at low temperatures widely used in particle physics experiments to search for rare events. These devices are able to detect particles energies from few keV up to several MeV, but their response function is not linear and depends on the operating temperature. This study was performed with the bolometers of the CUORE experiment. In a previous work the non-linearities were attributed to the thermistor and to its biasing circuit and an algorithm was derived to obtain a linear response. In this work an improvement of the algorithm is proposed and the possibility of developing a more complete model of the response function, which accounts for the electrothermal feedback induced by the thermistor, is evaluated

A method to characterize the statistical extremes in marine biogeochemistry: the case of the Mediterranean chlorophyll

Biogeochemical extreme events are analysed for the special case of the surface chlorophyll in the Mediterranean open sea. The extremes are defined statistically as values over the 99th percentile threshold that are connected in space and time. A multidecadal simulation with daily output (1979-2012) was run to collect the statistics needed to carry out the study. The online coupled hydrodynamic-biogeochemical (MITgcm-BFM) model has a spatial resolution of 1/12\ub0, with 75 vertical levels. The model was corroborated with available observations and other validated models. To account for the heterogeneity of the chlorophyll features and dynamics across the Mediterranean area, the definition of the extremes as peaks over the threshold was initially applied at each grid point and then refined to include in one extreme event all the points near in space with extremes at the same time. The macro-events were then characterized by a set of indexes, related to their spatio-temporal localisation, shape and impact on the local marine ecosystem due to their supply of high and/or anomalous biomass production. Following, the macro-events occurred in the Mediterranean area in the winter-spring months of the 1994-2012 period were described and classified using the introduced set of indexes. Overall, the macro-events occurred in each year during the winter months, especially in the northern part of the Mediterranean Sea. They have a wide spectrum of possible shapes, mainly corresponding to a duration shorter than 20 days and a radius contained within the larger Mediterranean mesoscale (200 km). The most persistent macro-events (uniformity index higher than 60%) are relatively small and short within the total spectrum, with an inverse proportionality between area and duration. The most severe macro-events (mean severity higher than 1.1 kgChl/km2/day in the first meter of depth) have intermediate area and duration; generally they are not very persistent, but sometimes they are very anomalous (anomaly higher than 15%). The most anomalous macro-events have typically medium or long duration (up to 84 days) and they can be also very large (up to the whole sub-basin scale), but not very persistent. In agreement with literature, no significant trends are observed in the macro-events indexes on the basin-scale. Some subdomains were analysed in detail: the North Western Mediterranean Sea (NWM), the Ionian Sea (ION), the South Adriatic Sea (ADS) and the Levantine Sea (LEV). The decreasing eastward gradient of the mean severity across the subdomains reflects the well known gradients of the mean surface chlorophyll. More than 70% of the macro-events of chlorophyll occurred in NWM and ADS are classified as events of high severity and high anomaly with respect to the medians of the distributions of the mean severity and anomaly on the whole domain. Overall, the most severe macro-events are in NWM. ADS is the subdomain with the most persistent macro-events, possibly ascribed to the spatial constraints of the topography and of the circulation structure. In ION and LEV more than the 50% of macro-events show low values of both indexes, even if hot spots of macro-events heavily affecting the ecosystem can be observed in the North Ionian Sea, close to the southern coasts of Sicily and in the Rhodes Gyre regions. Focusing on some representative examples of macro-events further investigated, we observed that the model is able to reproduce the main features of timing and location of the chlorophyll patterns observed by remote sensing and that the physical forcing anomalies with respect to climatology appear to play the major role as trigger of the macro-events. Finally, the selected macro-events are characterized by phytoplankton subgroups (BFM parametrization of picophytoplankton, flagellates, diatoms, large phytoplankton) that evolve in space and time in different ways in the subdomains

A method to characterize the statistical extremes in marine biogeochemistry: the case of the Mediterranean chlorophyll

Biogeochemical extreme events are analysed for the special case of the surface chlorophyll in the Mediterranean open sea. The extremes are defined statistically as values over the 99th percentile threshold that are connected in space and time. A multidecadal simulation with daily output (1979-2012) was run to collect the statistics needed to carry out the study. The online coupled hydrodynamic-biogeochemical (MITgcm-BFM) model has a spatial resolution of 1/12\ub0, with 75 vertical levels. The model was corroborated with available observations and other validated models. To account for the heterogeneity of the chlorophyll features and dynamics across the Mediterranean area, the definition of the extremes as peaks over the threshold was initially applied at each grid point and then refined to include in one extreme event all the points near in space with extremes at the same time. The macro-events were then characterized by a set of indexes, related to their spatio-temporal localisation, shape and impact on the local marine ecosystem due to their supply of high and/or anomalous biomass production. Following, the macro-events occurred in the Mediterranean area in the winter-spring months of the 1994-2012 period were described and classified using the introduced set of indexes. Overall, the macro-events occurred in each year during the winter months, especially in the northern part of the Mediterranean Sea. They have a wide spectrum of possible shapes, mainly corresponding to a duration shorter than 20 days and a radius contained within the larger Mediterranean mesoscale (200 km). The most persistent macro-events (uniformity index higher than 60%) are relatively small and short within the total spectrum, with an inverse proportionality between area and duration. The most severe macro-events (mean severity higher than 1.1 kgChl/km2/day in the first meter of depth) have intermediate area and duration; generally they are not very persistent, but sometimes they are very anomalous (anomaly higher than 15%). The most anomalous macro-events have typically medium or long duration (up to 84 days) and they can be also very large (up to the whole sub-basin scale), but not very persistent. In agreement with literature, no significant trends are observed in the macro-events indexes on the basin-scale. Some subdomains were analysed in detail: the North Western Mediterranean Sea (NWM), the Ionian Sea (ION), the South Adriatic Sea (ADS) and the Levantine Sea (LEV). The decreasing eastward gradient of the mean severity across the subdomains reflects the well known gradients of the mean surface chlorophyll. More than 70% of the macro-events of chlorophyll occurred in NWM and ADS are classified as events of high severity and high anomaly with respect to the medians of the distributions of the mean severity and anomaly on the whole domain. Overall, the most severe macro-events are in NWM. ADS is the subdomain with the most persistent macro-events, possibly ascribed to the spatial constraints of the topography and of the circulation structure. In ION and LEV more than the 50% of macro-events show low values of both indexes, even if hot spots of macro-events heavily affecting the ecosystem can be observed in the North Ionian Sea, close to the southern coasts of Sicily and in the Rhodes Gyre regions. Focusing on some representative examples of macro-events further investigated, we observed that the model is able to reproduce the main features of timing and location of the chlorophyll patterns observed by remote sensing and that the physical forcing anomalies with respect to climatology appear to play the major role as trigger of the macro-events. Finally, the selected macro-events are characterized by phytoplankton subgroups (BFM parametrization of picophytoplankton, flagellates, diatoms, large phytoplankton) that evolve in space and time in different ways in the subdomains

Switch to maraviroc with darunavir/r, both QD, in patients with suppressed HIV-1 was well tolerated but virologically inferior to standard antiretroviral therapy: 48-Week results of a randomized trial

Objectives Primary study outcome was absence of treatment failure (virological failure, VF, or treatment interruption) per protocol at week 48. Methods Patients on 3-drug ART with stable HIV-1 RNA <50 copies/mL and CCR5-tropic virus were randomized 1:1 to maraviroc with darunavir/ritonavir qd (study arm) or continue current ART (continuation arm).Results In June 2015, 115 patients were evaluable for the primary outcome (56 study, 59 continuation arm). The study was discontinued due to excess of VF in the study arm (7 cases, 12.5%, vs 0 in the continuation arm, p = 0.005). The proportion free of treatment failure was 73.2% in the study and 59.3% in the continuation arm. Two participants in the study and 10 in the continuation arm discontinued therapy due to adverse events (p = 0.030). At VF, no emergent drug resistance was detected. Co-receptor tropism switched to non-R5 in one patient. Patients with VF reported lower adherence and had lower plasma drug levels. Femoral bone mineral density was significantly improved in the study arm. Conclusion Switching to maraviroc with darunavir/ritonavir qd in virologically suppressed patients was associated with improved tolerability but was virologically inferior to 3-drug therap

The Regional Earth System Model RegCM‐ES: Evaluation of the Mediterranean Climate and Marine Biogeochemistry

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TELERETINOGRAPHY INTO DIABETES INTEGRATED CARE: AN ITALIAN EXPERIENCE

Integrated care allows information exchange among health professionals. In diabetes, a better control of outcomes and a reduction of the need for hospital admission were noticed worldwide. Teleretinography, performed in Diabetology Units (DUs), graded by a remote ophthalmologist, and forwarded to general practitioners (GPs), can cost-effectively identify retinal microangiopathy. In our DU, participating in a national diabetes integrated care program (IGEA), in a ten-month period teleretinography was performed in 362 new patients not having undergone fundus examination in the last year or more. Retinal imaging allowed discovering stages of diabetic retinopathy (DR) to be referred to the hospital setting, and a series of comorbidities. The suggested care path and follow-up were rapidly forwarded to GPs for all patients, thus improving their adherence to guidelines. These advantages and other important ones, such as reducing fundus examinations in ophthalmic settings and conveying information into the patient\u27s Electronic Health Record, make teleretinography worth becoming part of the integrated care process in diabetic patients.   

Comparable gut mucosal breakdown and microbial translocation in severe COVID-19 with and without HIV infection

In this study, we explored the link between gut impairment and severe COVID-19 in people with HIV (PWH). We compared PWH with COVID-19 to HIV-uninfected individuals hospitalized for the same condition. Despite more severe clinical symptoms in PWH, we did not observe significant differences in gut barrier dysfunction markers between the two groups. Our findings suggest a link between SARS-CoV-2 pneumonia and gut damage, independent of HIV status, warranting further investigation into its role in COVID-19 severity

Reprogramming normal cells into tumour precursors requires ECM stiffness and oncogene-mediated changes of cell mechanical properties

Defining the interplay between the genetic events and microenvironmental contexts necessary to initiate tumorigenesis in normal cells is a central endeavour in cancer biology. We found that receptor tyrosine kinase (RTK)–Ras oncogenes reprogram normal, freshly explanted primary mouse and human cells into tumour precursors, in a process requiring increased force transmission between oncogene-expressing cells and their surrounding extracellular matrix. Microenvironments approximating the normal softness of healthy tissues, or blunting cellular mechanotransduction, prevent oncogene-mediated cell reprogramming and tumour emergence. However, RTK–Ras oncogenes empower a disproportional cellular response to the mechanical properties of the cell’s environment, such that when cells experience even subtle supra-physiological extracellular-matrix rigidity they are converted into tumour-initiating cells. These regulations rely on YAP/TAZ mechanotransduction, and YAP/TAZ target genes account for a large fraction of the transcriptional responses downstream of oncogenic signalling. This work lays the groundwork for exploiting oncogenic mechanosignalling as a vulnerability at the onset of tumorigenesis, including tumour prevention strategies

Point-of-care fresh CAR T cells for pediatric or young adult BCP-ALL that is relapsed/refractory or in very-high-risk first relapse

: The point-of-care, automated manufacturing of CAR T cells can reduce the waiting window and increase the therapy accessibility to patients with relapsed/refractory (r/r) BCP-ALL as compared to commercially available drug products (DP). We conducted a phase I/II trial (NCT04787263) on the use of 2nd generation (4.1BB), CD19-CAR T cells, for the treatment of BCP-ALL patients with either 1st relapse and very high-risk (VHR) characteristics or >2nd relapse and rapidly progressing disease preventing access to the commercial DP. CAR-T cells were manufactured with a 12-day process using CliniMACS Prodigy®, from a fresh apheresis and infused fresh. Three dose levels were tested in the phase I, namely 1.0, 2.0 and 3.0×106 CAR+T cells/kg. Nineteen pts were enrolled, 13/19 (68%) in first VHR relapse. The designed dose was always successfully produced. No dose-limiting toxicities were observed in the phase I. Grade 1-2 cytokine release syndrome was observed in 13/19 (68%) patients. Grade 1-2 immune effector cell-associated neurotoxicity syndrome occurred in 2 patients and resolved spontaneously. All patients achieved bone marrow complete remission with negative minimal residual disease. Eight pts (42%) received hematopoietic stem cell transplantation (HSCT) consolidation. Overall, CR was maintained in 13/19 patients (68%), 7 of them having received HSCT. Importantly, all patients but one treated with 3.0x106 CAR+T cells/kg maintain CR. The 3y-EFS and OS of the whole cohort are 68% and 83%, respectively. Our data suggest that the point-of-care, manufacturing of autologous, anti-CD19 CAR T cells can successfully treat patients with BCP-ALL including those with 1st relapse and VHR characteristics. (NCT04787263)

Improvement of ALT decay kinetics by all-oral HCV treatment: Role of NS5A inhibitors and differences with IFN-based regimens

Background: Intracellular HCV-RNA reduction is a proposed mechanism of action of direct-acting antivirals (DAAs), alternative to hepatocytes elimination by pegylated-interferon plus ribavirin (PR). We modeled ALT and HCV-RNA kinetics in cirrhotic patients treated with currently-used all-DAA combinations to evaluate their mode of action and cytotoxicity compared with telaprevir (TVR)+PR. Study design: Mathematical modeling of ALT and HCV-RNA kinetics was performed in 111 HCV-1 cirrhotic patients, 81 treated with all-DAA regimens and 30 with TVR+PR. Kinetic-models and Cox-analysis were used to assess determinants of ALT-decay and normalization. Results: HCV-RNA kinetics was biphasic, reflecting a mean effectiveness in blocking viral production >99.8%. The first-phase of viral-decline was faster in patients receiving NS5A-inhibitors compared to TVR+PR or sofosbuvir+simeprevir (p<0.001), reflecting higher efficacy in blocking assembly/secretion. The second-phase, noted \u3b4 and attributed to infected-cell loss, was faster in patients receiving TVR+PR or sofosbuvir+simeprevir compared to NS5A-inhibitors (0.27 vs 0.21 d-1, respectively, p = 0.0012). In contrast the rate of ALT-normalization, noted \u3bb, was slower in patients receiving TVR+PR or sofosbuvir+simeprevir compared to NS5A-inhibitors (0.17 vs 0.27 d-1, respectively, p<0.001). There was no significant association between the second-phase of viral-decline and ALT normalization rate and, for a given level of viral reduction, ALT-normalization was more profound in patients receiving DAA, and NS5A in particular, than TVR+PR. Conclusions: Our data support a process of HCV-clearance by all-DAA regimens potentiated by NS5A-inhibitor, and less relying upon hepatocyte death than IFN-containing regimens. This may underline a process of "cell-cure" by DAAs, leading to a fast improvement of liver homeostasis