Study of Faraday cups for fast ion beams provided by a LIS source

Faraday cups are widely utilized to characterize ion and electrons beams. Owing to the secondary electron emission (SEE) induced by the collision of beams with collectors, wrong measurements could emerge from these detectors. To overcome this problem a polarized grid is utilized in front the cup collector at a negative voltage with respect to the collector. Unfortunately, the high voltage connection of the Faraday cups is hard to obtain. Then, in this work we want to study the secondary emission on different Al ion collector designs having tilted surfaces with respect to beam axis. Tests were performed using ion beams accelerated by a power supply up to 40 kV. The results by the modified collector surfaces were compared to the ones performed with a simple flat collector. The results we obtained point out that the secondary electron emission enhanced on incident beam energy and on the angle with respect to the normal direction of the surface. The ratio of the SEE to angle value results constant for the accelerating voltage and the possibility to design an ion collector able to reset the SEE seems not to be reached

Internal alignment and position resolution of the silicon tracker of DAMPE determined with orbit data

The DArk Matter Particle Explorer (DAMPE) is a space-borne particle detector designed to probe electrons and gamma-rays in the few GeV to 10 TeV energy range, as well as cosmic-ray proton and nuclei components between 10 GeV and 100 TeV. The silicon-tungsten tracker-converter is a crucial component of DAMPE. It allows the direction of incoming photons converting into electron-positron pairs to be estimated, and the trajectory and charge (Z) of cosmic-ray particles to be identified. It consists of 768 silicon micro-strip sensors assembled in 6 double layers with a total active area of 6.6 m$^2$. Silicon planes are interleaved with three layers of tungsten plates, resulting in about one radiation length of material in the tracker. Internal alignment parameters of the tracker have been determined on orbit, with non-showering protons and helium nuclei. We describe the alignment procedure and present the position resolution and alignment stability measurements

DYNAMICS OF EXPANSION OF TYROSINE KINASE INHIBITOR-RESISTANT MUTANTS AS ASSESSED BY DEEP SEQUENCING OF THE BCR-ABL KINASE DOMAIN: IMPLICATIONS FOR ROUTINE MUTATION TESTING

Background: In Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL) patients (pts), efficacy of tyrosine kinase inhibitor (TKI)-based therapies is often compromised by selection of resistant mutations in the BCR-ABL kinase domain (KD). Currently, the gold standard for BCR-ABL KD mutation screen- ing is conventional Sanger sequencing (SS). However, more sensitive approaches are desirable to allow more timely and rational therapeutic intervention. Aims: A Deep sequencing (DS) strategy based on the Roche 454 next-generation sequencing technology was set up in order to: study the dynamics of expansion of different types of BCR-ABL KD mutations in Ph+ ALL patients developing resistance to TKI-based therapies; test the ability of DS to highlight emerging clones harboring TKI-resistant mutations. Methods: 29 Ph+ ALL pts who had developed resistance to TKI-based (imatinib, dasatinib, nilotinib) therapies were selected for this retrospective analysis. All the pts were known to have developed TKI-resistant BCR-ABL mutations on treatment, as assessed by SS. To reconstruct the dynamics of mutation emergence, longitudinal re-analysis of samples from relapse backwards (n=97; 1-3 months sampling interval) was performed on a Roche GS Junior instru- ment. DS runs were designed so as to enable high sensitivity mutation calling (minimum target sequence coverage 4,000 reads). However, to minimize the likelihood of false positive results, data were analyzed filtering out all variants with <1% abundance. Results: DS could successfully detect all the mutations (n=85) previously identified by SS (>15% abundance). In addition, DS revealed that both those samples that had been scored as apparently wild-type by SS and those samples already known to harbor mutations as assessed by SS might be carrying one or more ‘lower level’ mutations (<15% abundance). In the latter cases, clonal analysis showed complex textures with the same mutation alone and also in combination with other(s) (‘compound’ mutations) in distinct subclones. Some lower level mutations were silent or apparently irrelevant from a clinical standpoint (passenger mutations?). In more than half of the cases, however, known TKI-resistant variants could be recognized that corresponded either to ‘withdrawing’ mutants not (yet) entirely de-selected by the switch in TKI or to outgrowing mutations anticipating an imminent relapse. Lower level mutations were confirmed with independent methods (ASO-PCR, RFLP). Notably, in 16/29 (55%) pts with molecularly detectable disease but not yet evidence of cytogenetic or hematologic relapse, DS could identify emerging mutations 1 to 3 months before they became detectable by SS. In the remaining 13 pts, however, outgrowth of the TKI-resistant mutation (T315I=7, Y253H=2, E255K=2, E255V=1 and F317L=1) was so rapid that not even a strict monthly monitoring could have allowed to pick them up before they became dominant. Summary / Conclusion: Now that multiple options are available, BCR-ABL KD mutation monitoring is a precious tool to maximize the efficacy of TKI-based regimens as induction or salvage therapy of Ph+ ALL. DS proved as reliable as SS for the detection of mutations with >15% abundance. As a key advantage, DS added precious quantitative and qualitative information on the full repertoire of mutated populations, that SS underestimated in more than half of the samples analyzed. TKI-resistant mutations leading to patient relapse were not necessarily preexisting at diagnosis or at the time of switchover to another TKI, underlining the importance of regular monitoring of pts. Although the majority of mutations were found to arise and take over very rapidly, a monthly monitoring by our DS approach would have allowed to identify them earlier than SS actually did - and well in advance of clinical relapse - in half of the pts. DS technologies would enable higher sensitivity mutation calling: further studies are warranted to determine the optimal lower detection limit to aim to in order to exclude both transient mutant subclones that will never take over and sequencing errors

Clinical Relevance of Liver Involvement in the Clinical Course of Systemic Sclerosis

Liver involvement in systemic sclerosis (SSc) is rare. We evaluated the prevalence of liver fibrosis and hepatic autoimmunity in SSc patients in a retrospective observational cohort (97 SSc or mixed connective tissue disease with sclerodermic manifestations patients undergoing transient elastography, evaluating liver stiffness (LS) and controlled attenuation parameter (CAP), due to clinical indications along with biochemistry assessments and major antibodies associated to liver autoimmunity). Among them, 11 had LS ≥ 7.5 kPa and 5 showed an LS compatible with cirrhosis (LS ≥ 12.5 kPa). Predictors of LS ≥ 7.5 fibrosis were alcohol consumption (>14 or >7 alcoholic units/week for men and women, respectively), waist circumference (>102 or >88 cm for men and women, respectively), elevated alkaline phosphatase, and anti-La and anti-mitochondrial antibody (AMA) positivity. Six patients had CAP values compatible with severe steatosis (≥280 dB/m). Waist circumference, body mass index and diabetes mellitus were significant predictors of steatosis. Out of 97 patients, 19 were positive for AMA, 4 for anti-Sp100, 1 for anti-Gp210 and 7 were diagnosed with primary biliary cholangitis. Among SSc patients, hepatic fibrosis biomarkers and AMA prevalence are relatively high, suggesting the opportunity of performing a transient elastography and a screening for hepatic autoimmunity at diagnosis and/or during disease progression

Classification performance for covid patient prognosis from automatic ai segmentation—a single-center study

Background: COVID assessment can be performed using the recently developed individual risk score (prediction of severe respiratory failure in hospitalized patients with SARS-COV2 infection, PREDI-CO score) based on High Resolution Computed Tomography. In this study, we evaluated the possibility of automatizing this estimation using semi-supervised AI-based Radiomics, leveraging the possibility of performing non-supervised segmentation of ground-glass areas. Methods: We collected 92 from patients treated in the IRCCS Sant’Orsola-Malpighi Policlinic and public databases; each lung was segmented using a pre-trained AI method; ground-glass opacity was identified using a novel, non-supervised approach; radiomic measurements were collected and used to predict clinically relevant scores, with particular focus on mortality and the PREDI-CO score. We compared the prediction obtained through different machine learning approaches. Results: All the methods obtained a well-balanced accuracy (70%) on the PREDI-CO score but did not obtain satisfying results on other clinical characteristics due to unbalance between the classes. Conclusions: Semi-supervised segmentation, implemented using a combination of non-supervised segmentation and feature extraction, seems to be a viable approach for patient stratification and could be leveraged to train more complex models. This would be useful in a high-demand situation similar to the current pandemic to support gold-standard segmentation for AI training

Serum Total Tryptase Level Confirms Itself as a More Reliable Marker of Mast Cells Burden in Mast Cell Leukaemia (Aleukaemic Variant)

Mast cell leukemia (MCL) is a very rare form of systemic mastocytosis (SM) with a short median survival of 6 months. We describe a case of a 65-year-old woman with aleukaemic variant of MCL with a very high serum total tryptase level of 2255 μg/L at diagnosis, which occurred following an episode of hypotensive shock. She fulfilled the diagnostic criteria of SM, with a bone marrow smear infiltration of 50–60% of atypical mast cells (MCs). She tested negative for the KIT D816V mutation, without any sign of organ damage (no B- or C-findings) and only few mediator-related symptoms. She was treated with antihistamine alone and then with imatinib for the appearance of anemia. She maintained stable tryptase level and a very indolent clinical course for twenty-two months; then, she suddenly progressed to acute MCL with a serum tryptase level up to 12960 μg/L. The patient died due to haemorrhagic diathesis twenty-four months after diagnosis. This clinical case maybe represents an example of the chronic form of mast cell leukemia, described as unpredictable disease, in which the serum total tryptase level has confirmed itself as a reliable marker of mast cells burden regardless of the presence of other signs or symptoms

Unraveling the complexity of tyrosine kinase inhibitor-resistant populations by ultra-deep sequencing of the BCR-ABL kinase domain

In chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia, tyrosine kinase inhibitor (TKI) therapy may select for drug-resistant BCR-ABL mutants. We used an ultra-deep sequencing (UDS) approach to resolve qualitatively and quantitatively the complexity of mutated populations surviving TKIs and to investigate their clonal structure and evolution over time in relation to therapeutic intervention. To this purpose, we performed a longitudinal analysis of 106 samples from 33 patients who had received sequential treatment with multiple TKIs and had experienced sequential relapses accompanied by selection of 1 or more TKI-resistant mutations. We found that conventional Sanger sequencing had misclassified or underestimated BCR-ABL mutation status in 55% of the samples, where mutations with 1% to 15% abundance were detected. A complex clonal texture was uncovered by clonal analysis of samples harboring multiple mutations and up to 13 different mutated populations were identified. The landscape of these mutated populations was found to be highly dynamic. The high degree of complexity uncovered by UDS indicates that conventional Sanger sequencing might be an inadequate tool to assess BCR-ABL kinase domain mutation status, which currently represents an important component of the therapeutic decision algorithms. Further evaluation of the clinical usefulness of UDS-based approaches is warranted

Italian multicenter study on infection hazards during dental practice: Control of environmental microbial contamination in public dental surgeries

Background. The present study assessed microbial contamination in Italian dental surgeries. Methods. An evaluation of water, air and surface microbial contamination in 102 dental units was carried out in eight Italian cities. Results. The findings showed water microbial contamination in all the dental surgeries; the proportion of water samples with microbial levels above those recommended decreased during working. With regard to Legionella spp., the proportion of positive samples was 33.3%. During work activity, the index of microbial air contamination (IMA) increased. The level of microbial accumulation on examined surfaces did not change over time. Conclusion. These findings confirm that some Italian dental surgeries show high biocontamination, as in other European Countries, which highlights the risk of occupational exposure and the need to apply effective measures to reduce microbial loads