Cost-Effectiveness of Vaccination with the 20-Valent Pneumococcal Conjugate Vaccine in the Italian Adult Population

The availability of a new 20-valent pneumococcal conjugate vaccine (PCV) makes it appropriate to assess its cost-effectiveness. This was evaluated by adopting the Italian National Health Service perspective, using a cost consequences Markovian model. The expected effects of vaccination with 20-valent PCV were compared with the administration of 13-valent PCV and 15-valent PCV. Assuming a 100% vaccination of cohorts aged 65–74 years, in the (lifetime) comparison between 20-valent PCV and 13-valent PCV, the former is dominant (lower cost for a better health outcome). A reduction in disease events was estimated: −1208 deaths; −1171 cases of bacteraemia; −227 of meningitis; −9845 hospitalised all-cause nonbacteremic pneumonia cases (NBP) and −21,058 non-hospitalised. Overall, in the Italian population, a total gain of 6581.6 life years and of 4734.0 QALY was estimated. On the cost side, against an increase in vaccinations costs (EUR +40.568 million), other direct health costs are reduced by EUR 48.032 million, with a net saving of EUR +7.464 million. The comparison between 20-valent PCV and 15-valent PCV results in an Incremental Cost-Effectiveness Ratio (ICER) of EUR 66 per life year gained and EUR 91 per QALY gained. The sensitivity analyses confirm the robustness of the results. We can conclude that the switch to 20-valent PCV is a sustainable and efficient investment

A laser gyroscope system to detect the Gravito-Magnetic effect on Earth

Large scale square ring laser gyros with a length of four meters on each side are approaching a sensitivity of 1x10^-11 rad/s/sqrt(Hz). This is about the regime required to measure the gravitomagnetic effect (Lense Thirring) of the Earth. For an ensemble of linearly independent gyros each measurement signal depends upon the orientation of each single axis gyro with respect to the rotational axis of the Earth. Therefore at least 3 gyros are necessary to reconstruct the complete angular orientation of the apparatus. In general, the setup consists of several laser gyroscopes (we would prefer more than 3 for sufficient redundancy), rigidly referenced to each other. Adding more gyros for one plane of observation provides a cross-check against intra-system biases and furthermore has the advantage of improving the signal to noise ratio by the square root of the number of gyros. In this paper we analyze a system of two pairs of identical gyros (twins) with a slightly different orientation with respect to the Earth axis. The twin gyro configuration has several interesting properties. The relative angle can be controlled and provides a useful null measurement. A quadruple twin system could reach a 1% sensitivity after 3:2 years of data, provided each square ring has 6 m length on a side, the system is shot noise limited and there is no source for 1/f- noise.Comment: 9 pages, 6 figures. 2010 Honourable mention of the Gravity Research Foundation; to be published on J. Mod. Phys.

Accelerated partial breast irradiation using 3D conformal radiotherapy: Toxicity and cosmetic outcome

Purpose: The aim of this paper is to analyze the incidence of acute and late toxicity and cosmetic outcome in breast cancer patients submitted to breast conserving surgery and three-dimensional conformal radiotherapy (3D-CRT) to deliver accelerated partial breast irradiation (APBI). Methods and materials: 84 patients were treated with 3D-CRT for APBI. This technique was assessed in patients with low risk stage I breast cancer enrolled from September 2005 to July 2011. The prescribed dose was 34/38.5 Gy delivered in 10 fractions twice daily over 5 consecutive days. Four to five nocoplanar 6 MV beams were used. In all CT scans Gross Tumor Volume (GTV) was defined around the surgical clips. A 1.5 cm margin was added by defining a Clinical Target Volume (CTV). A margin of 1 cm was added to CTV to define the planning target volume (PTV). The doseevolume constraints were followed in accordance with the NSABP/RTOG protocol. Late toxicity was evaluated according to the RTOG grading schema. The cosmetic assessment was performed using the Harvard scale. Results: Median patient age was 66 years (range 51e87). Median follow-up was 36.5 months (range 13 e83). The overall incidence of acute skin toxicities was 46.4% for grade 1 and 1% for grade 2. The incidence of late toxicity was 16.7% for grade 1, 2.4% for grade 2 and 3.6% for grade 3. No grade 4 toxicity was observed. The most pronounced grade 2 late toxicity was telangiectasia, developed in three patients. Cosmetics results were excellent for 52%, good for 42%, fair for 5% and poor for 1% of the patients. There was no statistical correlation between toxicity rates and prescribed doses (p ¼ 0.33) or irradiated volume (p ¼ 0.45). Conclusions: APBI using 3D-CRT is technically feasible with very low acute and late toxicity. Long-term results are needed to assess its efficacy in reducing the incidence of breast relapse

An inherited immunoglobulin class-switch recombination deficiency associated with a defect in the INO80 chromatin remodeling complex

BACKGROUND: Immunoglobulin class-switch recombination defects (CSR-D) are rare primary immunodeficiencies characterized by impaired production of switched immunoglobulin isotypes and normal or elevated IgM levels. They are caused by impaired T:B cooperation or intrinsic B cell defects. However, many immunoglobulin CSR-Ds are still undefined at the molecular level. OBJECTIVE: This study's objective was to delineate new causes of immunoglobulin CSR-Ds and thus gain further insights into the process of immunoglobulin class-switch recombination (CSR). METHODS: Exome sequencing in 2 immunoglobulin CSR-D patients identified variations in the INO80 gene. Functional experiments were performed to assess the function of INO80 on immunoglobulin CSR. RESULTS: We identified recessive, nonsynonymous coding variations in the INO80 gene in 2 patients affected by defective immunoglobulin CSR. Expression of wild-type INO80 in patients' fibroblastic cells corrected their hypersensitivity to high doses of gamma-irradiation. In murine CH12-F3 cells, the INO80 complex accumulates at Salpha and Emu regions of the IgH locus, and downregulation of INO80 as well as its partners Reptin and Pontin impaired CSR. In addition, Reptin and Pontin were shown to interact with activation-induced cytidine deaminase. Finally, an abnormal separation of sister chromatids was observed upon INO80 downregulation in CH12-F3 cells, pinpointing its role in cohesin activity. CONCLUSION: INO80 deficiency appears to be associated with defective immunoglobulin CSR. We propose that the INO80 complex modulates cohesin function that may be required during immunoglobulin switch region synapsis

Measuring Gravito-magnetic Effects by Multi Ring-Laser Gyroscope

We propose an under-ground experiment to detect the general relativistic effects due to the curvature of space-time around the Earth (de Sitter effect) and to rotation of the planet (dragging of the inertial frames or Lense-Thirring effect). It is based on the comparison between the IERS value of the Earth rotation vector and corresponding measurements obtained by a tri-axial laser detector of rotation. The proposed detector consists of six large ring-lasers arranged along three orthogonal axes. In about two years of data taking, the 1% sensitivity required for the measurement of the Lense-Thirring drag can be reached with square rings of 6 $m$ side, assuming a shot noise limited sensitivity ($20 prad/s/\sqrt{Hz}$). The multi-gyros system, composed of rings whose planes are perpendicular to one or the other of three orthogonal axes, can be built in several ways. Here, we consider cubic and octahedron structures. The symmetries of the proposed configurations provide mathematical relations that can be used to study the stability of the scale factors, the relative orientations or the ring-laser planes, very important to get rid of systematics in long-term measurements, which are required in order to determine the relativistic effects.Comment: 24 pages, 26 Postscript figure

Immunofluorescent Detection of Two Thymidine Analogues (CldU and IdU) in Primary Tissue

Accurate measurement of cell division is a fundamental challenge in experimental biology that becomes increasingly complex when slowly dividing cells are analyzed. Established methods to detect cell division include direct visualization by continuous microscopy in cell culture, dilution of vital dyes such as carboxyfluorescein di-aetate succinimidyl ester (CFSE), immuno-detection of mitogenic antigens such as ki67 or PCNA, and thymidine analogues. Thymidine analogues can be detected by a variety of methods including radio-detection for tritiated thymidine, immuno-detection for bromo-deoxyuridine (BrdU), chloro-deoxyuridine (CldU) and iodo-deoxyuridine (IdU), and chemical detection for ethinyl-deoxyuridine (EdU). We have derived a strategy to detect sequential incorporation of different thymidine analogues (CldU and IdU) into tissues of adult mice. Our method allows investigators to accurately quantify two successive rounds of cell division. By optimizing immunostaining protocols our approach can detect very low dose thymidine analogues administered via the drinking water, safe to administer to mice for prolonged periods of time. Consequently, our technique can be used to detect cell turnover in very long-lived tissues. Optimal immunofluoresent staining results can be achieved in multiple tissue types, including pancreas, skin, gut, liver, adrenal, testis, ovary, thyroid, lymph node, and brain. We have also applied this technique to identify oncogenic transformation within tissues. We have further applied this technique to determine if transit-amplifying cells contribute to growth or renewal of tissues. In this sense, sequential administration of thymidine analogues represents a novel approach for studying the origins and survival of cells involved in tissue homeostasis

Measuring gravito-magnetic effects by multi ring-laser gyroscope

We propose an under-ground experiment to detect the general relativistic effects due to the curvature of space-time around the Earth (de Sitter effect) and to the rotation of the planet (dragging of the inertial frames or Lense-Thirring effect). It is based on the comparison between the IERS value of the Earth rotation vector and corresponding measurements obtained by a tri-axial laser detector of rotation. The proposed detector consists of six large ring-lasers arranged along three orthogonal axes. In about two years of data taking, the 1% sensitivity required for the measurement of the Lense-Thirring drag can be reached with square rings of 6 m side, assuming a shot noise limited sensitivity (20prad/s/sqrt(Hz). The multi-gyros system, composed of rings whose planes are perpendicular to one or the other of three orthogonal axes, can be built in several ways. Here, we consider cubic and octahedral structures. It is shown that the symmetries of the proposed configurations provide mathematical relations that can be used to ensure the long term stability of the apparatus

Long-term (trophic) purinergic signalling: purinoceptors control cell proliferation, differentiation and death

The purinergic signalling system, which uses purines and pyrimidines as chemical transmitters, and purinoceptors as effectors, is deeply rooted in evolution and development and is a pivotal factor in cell communication. The ATP and its derivatives function as a 'danger signal' in the most primitive forms of life. Purinoceptors are extraordinarily widely distributed in all cell types and tissues and they are involved in the regulation of an even more extraordinary number of biological processes. In addition to fast purinergic signalling in neurotransmission, neuromodulation and secretion, there is long-term (trophic) purinergic signalling involving cell proliferation, differentiation, motility and death in the development and regeneration of most systems of the body. In this article, we focus on the latter in the immune/defence system, in stratified epithelia in visceral organs and skin, embryological development, bone formation and resorption, as well as in cancer. Cell Death and Disease (2010) 1, e9; doi:10.1038/cddis.2009.11; published online 14 January 201

Sensitivity Studies for Third-Generation Gravitational Wave Observatories

Advanced gravitational wave detectors, currently under construction, are expected to directly observe gravitational wave signals of astrophysical origin. The Einstein Telescope, a third-generation gravitational wave detector, has been proposed in order to fully open up the emerging field of gravitational wave astronomy. In this article we describe sensitivity models for the Einstein Telescope and investigate potential limits imposed by fundamental noise sources. A special focus is set on evaluating the frequency band below 10Hz where a complex mixture of seismic, gravity gradient, suspension thermal and radiation pressure noise dominates. We develop the most accurate sensitivity model, referred to as ET-D, for a third-generation detector so far, including the most relevant fundamental noise contributions.Comment: 13 pages, 7 picture