One of the challenges in the healthcare sector is making accurate forecasts across insurance years for claims reserve. Healthcare claims present huge variability and heterogeneity influenced by ...random decisions of the courts and intrinsic characteristics of the damaged parties, which makes traditional methods for estimating reserves inadequate. We propose a new methodology to estimate claim reserves in the healthcare insurance system based on generalized linear models using the Overdispersed Poisson distribution function. In this context, we developed a method to estimate the parameters of the quasi-likelihood function using a Gauss–Newton algorithm optimized through a genetic algorithm. The genetic algorithm plays a crucial role in glimpsing the position of the global minimum to ensure a correct convergence of the Gauss–Newton method, where the choice of the initial guess is fundamental. This methodology is applied as a case study to the healthcare system of the Tuscany region. The results were validated by comparing them with state-of-the-art measurement of the confidence intervals of the Overdispersed Poisson distribution parameters with better outcomes. Hence, local healthcare authorities could use the proposed and improved methodology to allocate resources dedicated to healthcare and global management.
Different applications require different customizations of silicon photomultiplier (SiPM) technology. We present a review on the latest SiPM technologies developed at Fondazione Bruno Kessler (FBK, ...Trento), characterized by a peak detection efficiency in the near-UV and customized according to the needs of different applications. Original near-UV sensitive, high-density SiPMs (NUV-HD), optimized for Positron Emission Tomography (PET) application, feature peak photon detection efficiency (PDE) of 63% at 420 nm with a 35 um cell size and a dark count rate (DCR) of 100 kHz/mm². Correlated noise probability is around 25% at a PDE of 50% at 420 nm. It provides a coincidence resolving time (CRT) of 100 ps FWHM (full width at half maximum) in the detection of 511 keV photons, when used for the readout of LYSO(Ce) scintillator (Cerium-doped lutetium-yttrium oxyorthosilicate) and down to 75 ps FWHM with LSO(Ce:Ca) scintillator (Cerium and Calcium-doped lutetium oxyorthosilicate). Starting from this technology, we developed three variants, optimized according to different sets of specifications. NUV-HD⁻LowCT features a 60% reduction of direct crosstalk probability, for applications such as Cherenkov telescope array (CTA). NUV-HD⁻Cryo was optimized for cryogenic operation and for large photosensitive areas. The reference application, in this case, is the readout of liquid, noble-gases scintillators, such as liquid Argon. Measurements at 77 K showed a remarkably low value of the DCR of a few mHz/mm². Finally, vacuum-UV (VUV)-HD features an increased sensitivity to VUV light, aiming at direct detection of photons below 200 nm. PDE in excess of 20% at 175 nm was measured in liquid Xenon. In the paper, we discuss the specifications on the SiPM related to different types of applications, the SiPM design challenges and process optimizations, and the results from the experimental characterization of the different, NUV-sensitive technologies developed at FBK.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Five patients with acute myelogenous leukemia received hematopoietic stem-cell transplants from a haploidentical donor. They also received T cells from the donor. All five patients had a relapse, and ...at the time of relapse, genomic HLA typing of leukemic blasts could not detect the recipient's HLA haplotype that differed from the donor's. The loss of the haplotype was due to uniparental disomy. In vitro, the donor's T cells reacted against leukemic blasts obtained at the time of diagnosis, not against blasts obtained at relapse. The results indicate the presence of a mutation that allowed the leukemic cells to escape the immunosurveillance of the donor's T cells.
Five patients with acute myelogenous leukemia received hematopoietic stem-cell transplants from a haploidentical donor. They also received T cells from the donor. All five patients had a relapse, and at the time of relapse, genomic HLA typing of leukemic blasts could not detect the recipient's HLA haplotype that differed from the donor's.
Transplantation of hematopoietic stem cells from a haploidentical family donor who shares only one HLA haplotype with the recipient is a potentially curative option for patients with high-risk hematologic cancers who lack an HLA-matched donor.
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The major limitation of this strategy is the risk of severe graft-versus-host disease (GVHD), which can result from alloreactions mediated by donor T cells against the recipient's unshared HLA haplotype. Since the publication of studies on extensively T-cell–depleted grafts,
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a variety of strategies have been developed to prevent or control GVHD after transfer of haploidentical T cells.
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The feasibility and efficacy of . . .
Although unphysiological wall shear stress (WSS) has become the consensus hemodynamic mechanism for coronary atherosclerosis, the complex biomechanical stimulus affecting atherosclerosis evolution is ...still undetermined. This has motivated the interest on the contraction/expansion action exerted by WSS on the endothelium, obtained through the WSS topological skeleton analysis. This study tests the ability of this WSS feature, alone or combined with WSS magnitude, to predict coronary wall thickness (WT) longitudinal changes. Nine coronary arteries of hypercholesterolemic minipigs underwent imaging with local WT measurement at three time points: baseline (T1), after 5.6 ± 0.9 (T2), and 7.6 ± 2.5 (T3) months. Individualized computational hemodynamic simulations were performed at T1 and T2. The variability of the WSS contraction/expansion action along the cardiac cycle was quantified using the WSS topological shear variation index (
TSVI
). Alone or combined, high
TSVI
and low WSS significantly co-localized with high WT at the same time points and were significant predictors of thickening at later time points.
TSVI
and WSS magnitude values in a physiological range appeared to play an atheroprotective role. Both the variability of the WSS contraction/expansion action and WSS magnitude, accounting for different hemodynamic effects on the endothelium, (1) are linked to WT changes and (2) concur to identify WSS features leading to coronary atherosclerosis.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Thyroid cancer is the most common (~90%) type of endocrine-system tumor, accounting for 70% of the deaths from endocrine cancers. In the last years, the high-throughput genomics has been able to ...identify pathways/molecular targets involved in survival and tumor progression. Targeted therapy and immunotherapy individually have many limitations. Regarding the first one, although it greatly reduces the size of the cancer, clinical responses are generally transient and often lead to cancer relapse after initial treatment. For the second one, although it induces longer-lasting responses in cancer patients than targeted therapy, its response rate is lower. The individual limitations of these two different types of therapies can be overcome by combining them. Here, we discuss MAPK pathway inhibitors, i.e., BRAF and MEK inhibitors, combined with checkpoint inhibitors targeting PD-1, PD-L1, and CTLA-4. Several mutations make tumors resistant to treatments. Therefore, more studies are needed to investigate the patient's individual tumor mutation burden in order to overcome the problem of resistance to therapy and to develop new combination therapies.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) have a worse prognosis with respect to well differentiated TC, and the loss of the capability of up-taking
I is one of ...the main features characterizing aggressive TC. The knowledge of the genomic landscape of TC can help clinicians to discover the responsible alterations underlying more advance diseases and to address more tailored therapy. In fact, to date, the antiangiogenic multi-targeted kinase inhibitor (aaMKIs) sorafenib, lenvatinib, and cabozantinib, have been approved for the therapy of aggressive radioiodine (RAI)-resistant papillary TC (PTC) or follicular TC (FTC). Several other compounds, including immunotherapies, have been introduced and, in part, approved for the treatment of TC harboring specific mutations. For example, selpercatinib and pralsetinib inhibit mutant RET in medullary thyroid cancer but they can also block the RET fusion proteins-mediated signaling found in PTC. Entrectinib and larotrectinib, can be used in patients with progressive RAI-resistant TC harboring TRK fusion proteins. In addition FDA authorized the association of dabrafenib (BRAF
inhibitor) and trametinib (MEK inhibitor) for the treatment of BRAF
-mutated ATC. These drugs not only can limit the cancer spread, but in some circumstance they are able to induce the re-differentiation of aggressive tumors, which can be again submitted to new attempts of RAI therapy. In this review we explore the current knowledge on the genetic landscape of TC and its implication on the development of new precise therapeutic strategies.
The aim of the present paper is to establish feasibility and required power of a one-session psychological intervention devoted to increasing patient's self-efficacy and awareness in dealing with ...anxiety symptoms before major pancreatic cancer surgery.
Parallel assignment RCT. All consenting patients listed for pancreatic major surgery during day-hospital visits (T0) between June 2017-June 2018 were assigned randomly in blocks of ten to a psychological intervention vs usual care group to be held the day before surgery (T1). The psychological intervention provided the patient the opportunity to increase self-efficacy in dealing with anxiety by talking with a psychologist about personal concerns and learning mindfulness based techniques to cope with anxiety.
400 patients were randomized into the experimental vs. usual care group. 49 and 65, respectively, completed baseline and post-intervention measures. The dropout rate between day-hospital (T0) and pre-surgery intervention (T1) was high (74.5%) due to several management and organization pitfalls. The main outcome, perceived self-efficacy in managing anxiety, showed a significant increase in the intervention group compared to the control group (
< 0.001), and was related to a reduction in state anxiety (
< 0.001). The intervention group perceived also lower emotional pain (
= 0.03). A power analysis was performed to define the appropriate sample size in a definitive RCT.
Beneath the complexity in retaining patients along their trajectory in pancreatic surgery department, when they had the opportunity to follow a brief psychological intervention, most of them adhered, showing a significant reduction in preoperative emotional distress and less emotional pain perception after surgery. Even if results need caution because of the high attrition rate, we can infer that our psychological intervention has the potential to be proposed in surgical setting, being short, easy to learn and applicable to a wide range of patients.
The trial was registered on ClinicalTrials.gov (identifier: NCT03408002). The full protocol is available from the last author.
•The neurophysiological correlates of religious coping to psychological stress have been investigated by means of qEEG.•Religious coping was positively associated with theta power in right frontal ...and temporal areas.•The results contribute to increase the knowledge on the neurophysiological concomitants of religious coping to stress.•Religious coping was positively associated with other adaptive coping strategies.
Religious coping to psychological stress has been linked to positive outcomes on both physical and mental health, but no studies have explored its neurophysiological correlates. Ninety-six participants (43 men and 53 women, mean age: 22.30 ± 2.48 years) were enrolled in the present study; they underwent an evaluation of coping with the brief version of the Coping Orientation to Problems Experienced (brief-COPE) scale and performed an eyes-closed resting state electroencephalographic (EEG) recording. EEG analyses were conducted with the exact Low-Resolution Electromagnetic Tomography software (eLORETA). Positive correlations between religious coping and EEG activity were observed in the theta frequency band in the right hemisphere, specifically in the superior temporal, inferior frontal, and middle temporal gyri. Religious coping scores were significantly positively associated with active coping and positive reframing coping strategies, with the latter not being significantly associated with EEG data. Taken together our results contribute to increase the knowledge on the neurophysiological concomitants of religious coping to stress.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Some infectious agents contributing to lymphomagenesis have been considered targets for new therapeutic strategies. Chlamydia psittaci DNA has been detected in 80% of ocular adnexal lymphomas. The ...present pilot study was carried out to assess whether C psittaci-eradicating antibiotic therapy is associated with tumor regression in ocular adnexal lymphomas.
Nine patients with C psittaci-positive marginal-zone B-cell lymphoma of the ocular adnexa at diagnosis or relapse were treated with doxycycline 100 mg, bid orally, for 3 weeks. The presence of C psittaci DNA in peripheral-blood mononuclear cells (PBMCs) was also assessed before and after treatment in seven patients. Objective lymphoma regression was assessed 1, 3, and 6 months after therapy conclusion and every 6 months during follow-up.
All patients completed antibiotic therapy with excellent tolerability. At 1 month from doxycycline assumption, chlamydial DNA was no longer detectable in PBMCs of all four positive patients. Objective response was complete in two patients, partial response (> 50%) was observed in two patients, and minimal response (< 50%) was observed in three patients. Duration of response in the seven responders was 12+, 29+, 31+, 8+, 7+, 2+, and 1+ months, respectively.
C psittaci-eradicating antibiotic therapy with doxycycline is followed by objective response in patients with ocular adnexal lymphoma, even after multiple relapses of the disease. A confirmatory, large, phase II trial is warranted to confirm whether this fast, cheap, and well-tolerated therapy could replace other more aggressive strategies as first-line treatment against ocular adnexal lymphomas.
Despite the important advancements in the stent technology for the treatment of diseased coronary arteries, major complications still affect the postoperative long-term outcome. The stent-induced ...flow disturbances, and especially the altered wall shear stress (WSS) profile at the strut level, play an important role in the pathophysiological mechanisms leading to stent thrombosis (ST) and in-stent restenosis (ISR). In this context, the analysis of the WSS topological skeleton is gaining more and more interest by extending the current understanding of the association between local hemodynamics and vascular diseases. This study aims to analyze the impact that a deployed coronary stent has on the WSS topological skeleton. Computational fluid dynamics (CFD) simulations were performed in three stented human coronary artery geometries reconstructed from clinical images. The selected cases presented stents with different designs (i.e., two contemporary drug-eluting stents and one bioresorbable scaffold) and included regions with stent malapposition or overlapping. A recently proposed Eulerian-based approach was applied to analyze the WSS topological skeleton features. The results highlighted that the presence of single or multiple stents within a coronary artery markedly impacts the WSS topological skeleton. In particular, repetitive patterns of WSS divergence were observed at the luminal surface, highlighting a WSS contraction action exerted proximal to the stent struts and a WSS expansion action distal to the stent struts. This WSS action pattern was independent from the stent design. In conclusion, these findings could contribute to a deeper understanding of the hemodynamics-driven processes underlying ST and ISR.
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