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With the advent of next-generation sequencing (NGS), monogenic forms of common variable immunodeficiency (CVID) have been increasingly described. Our study aimed to identify disease-causing variants in a Western Australian CVID cohort using a novel targeted NGS panel. Targeted amplicon NGS was performed on 22 unrelated subjects who met the formal European Society for Immunodeficiencies–Pan-American Group for Immunodeficiency diagnostic criteria for CVID and had at least one of the following additional criteria: disease onset at age <18 years, autoimmunity, low memory B lymphocytes, family history, and/or history of lymphoproliferation. Candidate variants were assessed by in silico predictions of deleteriousness, comparison to the literature, and classified according to the American College of Medical Genetics and Genomics–Association for Molecular Pathology criteria. All detected genetic variants were verified independently by an external laboratory, and additional functional studies were performed if required. Pathogenic or likely pathogenic variants were detected in 6 of 22 (27%) patients. Monoallelic variants of uncertain significance were also identified in a further 4 of 22 patients (18%). Pathogenic variants, likely pathogenic variants, or variants of uncertain significance were found in TNFRSF13B, TNFRSF13C, ICOS, AICDA, IL21R, NFKB2, and CD40LG, including novel variants and variants with unexpected inheritance pattern. Targeted amplicon NGS is an effective tool to identify monogenic disease-causing variants in CVID, and is comparable or superior to other NGS methods. Moreover, targeted amplicon NGS identified patients who may benefit from targeted therapeutic strategies and had important implications for family members.

The prognostic impact of diabetes mellitus (DM) on cardiovascular outcomes is well known. As a consequence of previous studies showing the high incidence of coronary artery disease (CAD) in diabetic patients and the relatively poor outcome compared to nondiabetic populations, DM is considered as CAD equivalent which means that diabetic patients are labeled as asymptomatic individuals at high cardiovascular risk. Lessons learned fromthe analysis of prognostic studies over the past decade have challenged this dogma and now support the idea that diabetic population is not uniformly distributed in the highest risk box. Detecting CAD in asymptomatic high risk individuals is controversial and, what ismore, in patients with diabetes is challenging, and that is why the reliability of traditional cardiac stress tests for detectingmyocardial ischemia is limited. Cardiac computed tomography angiography (CCTA) represents an emerging noninvasive technique able to explore the atherosclerotic involvement of the coronary arteries and, thus, to distinguish different risk categories tailoring this evaluation on each patient. The aim of the review is to provide a wide overview on the clinical meaning of CCTA in this field and to integrate the anatomical information with a reliable therapeutic approach.

The prognostic impact of diabetes mellitus (DM) on cardiovascular outcomes is well known. As a consequence of previous studies showing the high incidence of coronary artery disease (CAD) in diabetic patients and the relatively poor outcome compared to nondiabetic populations, DM is considered as CAD equivalent which means that diabetic patients are labeled as asymptomatic individuals at high cardiovascular risk. Lessons learned fromthe analysis of prognostic studies over the past decade have challenged this dogma and now support the idea that diabetic population is not uniformly distributed in the highest risk box. Detecting CAD in asymptomatic high risk individuals is controversial and, what ismore, in patients with diabetes is challenging, and that is why the reliability of traditional cardiac stress tests for detectingmyocardial ischemia is limited. Cardiac computed tomography angiography (CCTA) represents an emerging noninvasive technique able to explore the atherosclerotic involvement of the coronary arteries and, thus, to distinguish different risk categories tailoring this evaluation on each patient. The aim of the review is to provide a wide overview on the clinical meaning of CCTA in this field and to integrate the anatomical information with a reliable therapeutic approach.

Letter to the Editor

Fluid flows through rod bundles are observed in many nuclear applications, such as in the core of Gen IV liquid metal fast breeder nuclear reactors (LMFBR). One of the main features of this configuration is the appearance of flow fluctuations in the rod gaps due to the velocity difference in the sub-channels between the rods. On one side, these pulsations are beneficial as they enhance the heat exchange between the rods and the fluid. On the other side, the fluid pulsations might induce vibrations of the flexible fuel rods, a mechanism generally referred to as Flow Induced Vibrations (FIV). Over time, this might result in mechanical fatigue of the rods and rod fretting, which eventually can compromise their structural integrity. Within the SESAME framework, a joint work between Delft University of Technology (TU Delft), Ghent University (UGent), and NRG has been carried out with the aim of performing experimental measurements of FIV in a 7-rods bundle and validate numerical simulations against the obtained experimental data. The experiments performed by TU Delft consisted of a gravity-driven flow through a 7-rods, hexagonal bundle with a pitch-to-diameter ratio P/D=1.11. A section of 200 mm of the central rod was made out of silicone, of which 100 mm were flexible. Flow measurements have been carried out with Laser Doppler Anemometry (LDA) whereas a high-speed camera has measured the vibrations induced on the silicone rod. The numerical simulations made use of the Unsteady Reynolds-averaged Navier-Stokes equations (URANS) approach for the turbulence modelling, and of strongly coupled algorithms for the solution of the fluid-structure interaction (FSI) problems. The measured frequency of the flow pulsations, as well as the mean rod displacement and vibration frequency, have been used to carry out the benchmark., RST/Reactor Physics and Nuclear Materials

Letter to the Editor

Fluid flows through rod bundles are observed in many nuclear applications, such as in the core of Gen IV liquid metal fast breeder nuclear reactors (LMFBR). One of the main features of this configuration is the appearance of flow fluctuations in the rod gaps due to the velocity difference in the sub-channels between the rods. On one side, these pulsations are beneficial as they enhance the heat exchange between the rods and the fluid. On the other side, the fluid pulsations might induce vibrations of the flexible fuel rods, a mechanism generally referred to as Flow Induced Vibrations (FIV). Over time, this might result in mechanical fatigue of the rods and rod fretting, which eventually can compromise their structural integrity. Within the SESAME framework, a joint work between Delft University of Technology (TU Delft), Ghent University (UGent), and NRG has been carried out with the aim of performing experimental measurements of FIV in a 7-rods bundle and validate numerical simulations against the obtained experimental data. The experiments performed by TU Delft consisted of a gravity-driven flow through a 7-rods, hexagonal bundle with a pitch-to-diameter ratio P/D=1.11. A section of 200 mm of the central rod was made out of silicone, of which 100 mm were flexible. Flow measurements have been carried out with Laser Doppler Anemometry (LDA) whereas a high-speed camera has measured the vibrations induced on the silicone rod. The numerical simulations made use of the Unsteady Reynolds-averaged Navier-Stokes equations (URANS) approach for the turbulence modelling, and of strongly coupled algorithms for the solution of the fluid-structure interaction (FSI) problems. The measured frequency of the flow pulsations, as well as the mean rod displacement and vibration frequency, have been used to carry out the benchmark., RST/Reactor Physics and Nuclear Materials

Objectives: To assess the image quality and diagnostic accuracy of a noise-optimized virtual monoenergetic imaging (VMI+) algorithm compared with standard virtual monoenergetic imaging (VMI) and linearly-blended (M_0.6) reconstructions for the detection of hypervascular liver lesions in dual-energy CT (DECT). Methods: Thirty patients who underwent clinical liver MRI were prospectively enrolled. Within 60 days of MRI, arterial phase DECT images were acquired on a third-generation dual-source CT and reconstructed with M_0.6, VMI and VMI+ algorithms from 40 to 100 keV in 5-keV intervals. Liver parenchyma and lesion contrast-to-noise-ratios (CNR) were calculated. Two radiologists assessed image quality. Lesion sensitivity, specificity and area under the receiver operating characteristic curves (AUCs) were calculated for the three algorithms with MRI as the reference standard. Results: VMI+ datasets from 40 to 60 keV provided the highest liver parenchyma and lesion CNR (p ≤0.021); 50 keV VMI+ provided the highest subjective image quality (4.40±0.54), significantly higher compared to VMI and M_0.6 (all p <0.001), and the best diagnostic accuracy in < 1-cm diameter lesions (AUC=0.833 vs. 0.777 and 0.749, respectively; p ≤0.003). Conclusions: 50-keV VMI+ provides superior image quality and diagnostic accuracy for the detection of hypervascular liver lesions with a diameter < 1cm compared to VMI or M_0.6 reconstructions. Key Points: • Low-keV VMI+ are characterized by higher contrast resulting from maximum iodine attenuation. • VMI+ provides superior image quality compared with VMI or M_0.6. • 50-keV_VMI+ provides higher accuracy for the detection of hypervascular liver lesions < 1cm.

We hypothesized that HIV-specific CD8 T cell clonotypes can be stimulated by allogeneic HLA molecules. Multiple HIV-specific CD8 T cell clones were derived from 12 individuals with chronic HIV infection, specific for 13 different HIV Gag antigens and restricted to 7 different HLA molecules. The generated T cell clones were assayed for alloreactivity against a panel of single HLA class I expressing cell lines (SALs). HIV-specific T cells recognising at least one allogeneic HLA molecule could be identified from 7 of 12 patients tested. Allorecognition was associated with IFNγ cytokine production, CD137 upregulation and cytotoxicity, suggesting high avidity allo-stimulation. Allo-HLA recognition by HIV-specific T cells was specific to the HIV target peptide/HLA restriction and TCR TRBV usage of the T cells. HIV-specific T cells do crossreact against allogeneic HLA molecules in an epitope and TRBV specific manner. Therefore allo-HLA stimulation could be exploited to induce or augment HIV-specific T cell responses.

The paper describes an innovative visualization modality to present online contents and relationships of the web portal of the Interdipartimental Research Center Aspi – Historical Archive of Italian Psychology (Milano-Bicocca University). Established in 2005, Aspi is aimed to preserve, inventory, digitize and valorize psychologists and psychiatrists documents of the XIX and XX centuries. The web portal www.aspi.unimib.it offers direct access to documental sources with critical notes and historical and scientific contextualization cards to describe biographies and disciplinary evolution, interdisciplinary and institutional connections and personal relationships among protagonists. The portal is a performing research tool for historians and scholars, which enables a direct access to the archival sources. It also allows contributors to collaborate with the editorial committee by publishing their research results. A custom software directly access the open source DB CollectiveAccess to extract data and visualize them dynamically and interactively, according to three main criteria: people, places and time. In particular, gravitational graphs show relationships between individuals (e.g. scholar, professor, co-worker, relative), between people and locations where they worked. Timelines and maps show on the other hand birth/death places and birth/death dates, where institutions were located and when they were operating.

Il presente saggio ripercorre gli studi relativi alla psicologia del soldato svolti sul fronte della Grande guerra da padre Agostino Gemelli, nella triplice veste di cappellano, medico e direttore del Laboratorio psicofisiologico del Comando supremo dell’esercito. A livello sperimentale, con le ricerche psicofisiologiche sugli aviatori e quelle sull’udito, sul piano individuale con la determinazione di quella fisionomia psichica del combattente che ebbe ampia applicazione sul campo e grazie alle indagini di stampo antropologico e sociologico, come quelle relative al folklore di guerra, Gemelli contribuì a mettere in luce i numerosi risvolti applicativi della psicologia, tracciò con maggior precisione nuove linee di ricerca, rafforzando la crescente autonomia epistemologica e istituzionale della disciplina. La psicologia del soldato, rilevante sia sul piano militare sia su quello scientifico, alimentò e sostenne nella sua dimensione filosofica l’audace progetto di rinnovamento promosso all'interno della Chiesa cattolica dalla corrente neoscolastica, il cui fine ultimo consisteva nel ridefinire la sfera esistenziale dell’uomo moderno attraverso un nuovo percorso pedagogico e culturale

In questo studio si ripercorrono gli eventi legati alla celebrazione delle feste centenarie per la morte di Lazzaro Spallanzani: dalle fonti emerge un quadro storico importante e inedito che dimostra la validità del “metodo Spallanzani” per il progresso delle “scienze della mente” e in particolar modo della nascente psicologia sperimentale. Con l’inaugurazione dei nuovi laboratori del manicomio di Reggio Emilia, il giovane Giulio Cesare Ferrari raccoglieva la preziosa eredità di Spallanzani nel tentativo di dare forma concreta a un progresso non solo tecnologico ma anche etico e culturale.

Riassunto Con la pubblicazione e la traduzione di 12 lettere inedite, l’articolo contestualizza l’attività dello psicologo Giulio Cesare Ferrari (1867-1932) nel corso della Grande Guerra, mettendo in luce i suoi rapporti con i vertici militari e politici e con la co-munità scientifica nazionale e internazionale. La corrispondenza con i capi di stato maggiore Luigi Cadorna (1850-1928) e Armando Diaz (1861-1928), con il senato-re e ministro di grazia e giustizia Lodovico Mortara (1855-1937), con lo psicologo Agostino Gemelli (1878-1959), con lo psicopedagogista Edouard Claparède (1873-1940) e con diversi militari, fornisce significativi elementi per comprendere il ruo-lo e le potenzialità applicative che Ferrari attribuiva alla psicologia. Abstract With the publication and translation of 12 unreleased letters, the article con-textualizes the work of the psychologist Giulio Cesare Ferrari (1867-1932) during the Great War, and brings to light his relations with the political and military high-est authorities and the national and international scientific community. His corre-spondence with the Italian army chiefs of staff Luigi Cadorna (1850-1928) and Armando Diaz (1861-1928), with the senator and minister of justice Luigi Mortara (1855-1937), with the psychologist Agostino Gemelli (1878-1959), with the psy-chopedagogist Edouard Claparède (1873-1940) and with several soldiers provides important elements to let us understand the role and practical potential that Ferrari attributed to psychology.

Riassunto Con la pubblicazione e la traduzione di 12 lettere inedite, l’articolo contestualizza l’attività dello psicologo Giulio Cesare Ferrari (1867-1932) nel corso della Grande Guerra, mettendo in luce i suoi rapporti con i vertici militari e politici e con la co-munità scientifica nazionale e internazionale. La corrispondenza con i capi di stato maggiore Luigi Cadorna (1850-1928) e Armando Diaz (1861-1928), con il senato-re e ministro di grazia e giustizia Lodovico Mortara (1855-1937), con lo psicologo Agostino Gemelli (1878-1959), con lo psicopedagogista Edouard Claparède (1873-1940) e con diversi militari, fornisce significativi elementi per comprendere il ruo-lo e le potenzialità applicative che Ferrari attribuiva alla psicologia. Abstract With the publication and translation of 12 unreleased letters, the article con-textualizes the work of the psychologist Giulio Cesare Ferrari (1867-1932) during the Great War, and brings to light his relations with the political and military high-est authorities and the national and international scientific community. His corre-spondence with the Italian army chiefs of staff Luigi Cadorna (1850-1928) and Armando Diaz (1861-1928), with the senator and minister of justice Luigi Mortara (1855-1937), with the psychologist Agostino Gemelli (1878-1959), with the psy-chopedagogist Edouard Claparède (1873-1940) and with several soldiers provides important elements to let us understand the role and practical potential that Ferrari attributed to psychology.

Quando fu effettuata per la prima volta una fecondazione artificiale medica e quali furono le prime reazioni di fronte ad un intervento così rivoluzionario e secondo molti blasfemo? Partendo da questi interrogativi, ripercorrendo le teorie embriologiche settecentesche e gli esperimenti compiuti dai naturalisti europei, questo studio ricostruisce le dinamiche scientifiche e filosofiche che portarono alla realizzazione delle prime fecondazioni artificiali sul genere umano; in un dibattito sospeso fra mito, scienza, teologia e filosofia viene delineato il percorso culturale che ha permesso ai chirurghi settecenteschi di ideare e sviluppare un'operazione volta a sconfiggere la sterilità

The scientifijic debate which developed during the eighteenth century, proposed and difffused new theories on the generation not only within the scientifijic community. Microscopic investigation and various experimental campaigns fostered daring models attempting to unveil the natural phenomena from which life originates. Besides the famous scientifijic and philosophical works that marked the age, in the second part of the century two pamphlets appeared that well represent the importance of the querelle about embryological systems defijining the concept of generation as a voyage within the human body. Lucina sine concubitu and Juno abortans, respectively published in England and in Germany between 1750 and 1760, narrate the odd and imaginary adventures of two doctors who are trying to interrupt and modify the embryos’ journey towards the body of the mother.

No abstract available

NK cell receptors and HLA molecules are intimately involved in the immune response against viral infections. The killer immunoglobulin-like receptors (KIRs) on NK cells regulate responses via the recognition of particular HLA class I products on the surface of infected cells. At the genomic level, both genetic systems are highly polymorphic and have recognised haplotypes, which adds complexity to their interaction. Previously, we and others have shown the association of HLA class I with HIV progression. More recently, the Carrington group observed a synergistic effect involving the activating KIR3DS1 allele and HLA-B Bw4-80Ile on the progression to depletion of CD4+ T cells, suggestive of an interactive model in the immune response to HIV infection. To further investigate the relationship between the two genetic systems, we examined changes in viral load in 249 pre-treatment patients from the Western Australia HIV cohort. Genetic variants known to affect HIV progression were associated with changes in HIV-1 viral load. However, we could not show a significant association with KIR3DS1 nor the epistatic effect with Bw4-80Ile. When we examined only those patients with known seroconversion dates, we found that the KIR3DS1 allele was associated with rapid progression to depletion of CD4+ T cells (p=0.01). We did not have sufficient statistical power to determine the KIR3DS1 and Bw4-80Ile relationship, but suggest that other KIR genes may be involved. We suggest that further analyses of haplotypes in both genetic systems is needed to understand their complex interactions in driving NK cell responses to HIV and disease.

NK cell receptors and HLA molecules are intimately involved in the immune response against viral infections. The killer immunoglobulin-like receptors (KIRs) on NK cells regulate NK cell responses via the recognition of their particular HLA class I ligands. At the genomic level, both genetic systems are polymorphic and have recognised haplotypes, which adds complexity to their interaction. Previously, we and others have shown the association of HLA class I with HIV progression. Recently, the Carrington group observed a synergistic effect involving the activating KIR3DS1 gene and HLA-B Bw4–80Ile on the rate of depletion of CD4+ T cells. To further investigate the relationship between the two genetic systems, we examined changes in viral load in 249 pre-treatment patients from the Western Australia HIV cohort. Genetic variants known to affect HIV progression including HLA-Bw4–80Ile but not KIR3DS1 were associated with differences in HIV-1 viral load set point. When we examined only those patients with known seroconversion dates, we found that the presence of the KIR3DS1 gene was associated with more rapid decline in the proportion of CD4+ T cells (p=0.01) but were unable to show a KIR3DS1 and Bw4–80Ile interaction. The presence of other KIR genes (viz KIR2DS2, KIR2DL2 and KIR2DS1), all found on KIR B group haplotypes, were also associated with a more rapid progression, whilst some KIR genes found the A haplotype with delayed progression We suggest that multiple KIR genes influence outcome in HIV infection. Further analyses of KIR haplotypes is needed to understand the complex interactions between KIR genes and their ligands in driving NK cell responses to HIV.

NK cell receptors and HLA molecules are intimately involved in the immune response against viral infections. The killer immunoglobulin-like receptors (KIRs) on NK cells regulate responses via the recognition of particular HLA class I products on the surface of infected cells. At the genomic level, both genetic systems are highly polymorphic and have recognised haplotypes, which adds complexity to their interaction. Previously, we and others have shown the association of HLA class I with HIV progression. More recently, the Carrington group observed a synergistic effect involving the activating KIR3DS1 allele and HLA-B Bw4-80Ile on the progression to depletion of CD4+ T cells, suggestive of an interactive model in the immune response to HIV infection. To further investigate the relationship between the two genetic systems, we examined changes in viral load in 249 pre-treatment patients from the Western Australia HIV cohort. Genetic variants known to affect HIV progression were associated with changes in HIV-1 viral load. However, we could not show a significant association with KIR3DS1 nor the epistatic effect with Bw4-80Ile. When we examined only those patients with known seroconversion dates, we found that the KIR3DS1 allele was associated with rapid progression to depletion of CD4+ T cells (p=0.01). We did not have sufficient statistical power to determine the KIR3DS1 and Bw4-80Ile relationship, but suggest that other KIR genes may be involved. We suggest that further analyses of haplotypes in both genetic systems is needed to understand their complex interactions in driving NK cell responses to HIV and disease.

NK cell receptors and HLA molecules are intimately involved in the immune response against viral infections. The killer immunoglobulin-like receptors (KIRs) on NK cells regulate NK cell responses via the recognition of their particular HLA class I ligands. At the genomic level, both genetic systems are polymorphic and have recognised haplotypes, which adds complexity to their interaction. Previously, we and others have shown the association of HLA class I with HIV progression. Recently, the Carrington group observed a synergistic effect involving the activating KIR3DS1 gene and HLA-B Bw4-80Ile on the rate of depletion of CD4+ T cells. To further investigate the relationship between the two genetic systems, we examined changes in viral load in 249 pre-treatment patients from the Western Australia HIV cohort. Genetic variants known to affect HIV progression including HLA-Bw4-80Ile but not KIR3DS1 were associated with differences in HIV-1 viral load set point. When we examined only those patients with known seroconversion dates, we found that the presence of the KIR3DS1 gene was associated with more rapid decline in the proportion of CD4+ T cells (p=0.01) but were unable to show a KIR3DS1 and Bw4-80Ile interaction. The presence of other KIR genes (viz KIR2DS2, KIR2DL2 and KIR2DS1), all found on KIR B group haplotypes, were also associated with a more rapid progression, whilst some KIR genes found the A haplotype with delayed progression We suggest that multiple KIR genes influence outcome in HIV infection. Further analyses of KIR haplotypes is needed to understand the complex interactions between KIR genes and their ligands in driving NK cell responses to HIV.