Using deceased-donor kidneys to initiate chains of living donor kidney paired donations: algorithms and experimentation

We design a flexible algorithm that exploits deceased donor kidneys to initiate chains of living donor kidney paired donations, combining deceased and living donor allocation mechanisms to improve the quantity and quality of kidney transplants. The advantages of this approach have been measured using retrospective data on the pool of donor/recipient incompatible and desensitized pairs at the Padua University Hospital, the largest center for living donor kidney transplants in Italy. The experiments show a remarkable improvement on the number of patients with incompatible donor who could be transplanted, a decrease in the number of desensitization procedures, and an increase in the number of UT patients (that is, patients unlikely to be transplanted for immunological reasons) in the waiting list who could receive an organ.Comment: To be published in AIES 201

Experimental and Numerical Analysis of Seismic Response of Unreinforced Masonry Cross Vaults

The present paper shows an experimental and numerical analysis to understand the seismic behaviour of unreinforced masonry cross vault. The experimental tests were performed on a 1:5 scale model of a cross vault made of 3D-printed blocks with dry joints. The seismic actions was experimentally simulated as a horizontal force proportional to the vault\u2019s mass by using a quasi-static tilt testing setup. The vault 3D collapse mechanism and its strength expressed in terms of collapse multiplier was investigated, also considering the direction of the seismic action with respect to the vault\u2019s base. The tests results were compared to those obtained from a numerical analysis using a rigid-block model based on 3D limit analysis. The model formulation allows to take into account both associative and non-associative behaviour. A sensitivity analysis on friction angle variation was also investigated to evaluate the accuracy and robustness of the model

Deceased donor-initiated Chains: first report of a successful deliberate case and its ethical implications

Background: The utilization of deceased donor kidneys to initiate chains of living donor kidney paired donation (KPD) has been proposed, although the potential gain of this practice needs to be quantified and the ethical implications must be addressed before starting its application. Methods: The gain of implementing deceased donor-initiated chains has been measured through a mathematical algorithm, using retrospective data on the pool of donor/recipient incompatible pairs at a single Center. Allocation rules of chain ending kidneys and characteristics/quality of the chain initiating kidney (CIK) are described. Results: the quantification of benefit analysis showed that with a pool of 69 kidneys from deceased donors and 16 pairs enrolled in the KPD program, over a period of 3 years it is possible to transplant 8/16 recipients (50%). Following the approval of the Bioethical Committee of the Veneto Region and the revision of the allocation policies by the Italian National Transplant Center, the first successful case has been performed. The waiting time of the recipient (male, 53 yo) after entering the program for the CIK with a kidney donor risk index (KDRI) equal to 0.61 and a kidney donor profile index (KDPI) of 3%, was 4 days. His willing donor (female, 53 yo) with a living kidney donor profile index (LKDPI) of 2, donated 2 days later to a chain ending recipient (male, 47 yo,) who had been on dialysis for 5 years. Conclusions: This is the first report of a deliberate deceased donor-initiated chain, which has been successfully performed. This has been made possible thanks to an extensive phase of evaluation of the ethical issues and allocation policy impact. This paper includes a preliminary efficacy assessment and the development a dedicated algorithm

Synthesis of built-in highly strained monolayer MoS2 using liquid precursor chemical vapor deposition

Strain engineering is an efficient tool to tune and tailor the electrical and optical properties of 2D materials. The built-in strain can be tuned during the synthesis process of a two dimensional semiconductor, as molybdenum disulfide, by employing different growth substrate with peculiar thermal properties. In this work we demonstrate that the built-in strain of MoS2 monolayers, grown on SiO2/Si substrate using liquid precursors chemical vapor deposition, is mainly dominated by the size of the monolayer. In fact, we identify a critical size equal to 20 um, from which the built-in strain increases drastically. The built-in strain is maximized for 60 um sized monolayer, leading to 1.2% tensile strain with a partial release of strain close to the monolayer triangular vertexes due to formation of nanocracks. These findings also imply that the standard method for evaluation of the number of layers based on the Raman modes separation becomes unreliable for monolayer with a lateral size above 20 um

Naxitamab Activity in Neuroblastoma Cells Is Enhanced by Nanofenretinide and Nanospermidine

Neuroblastoma cells highly express the disialoganglioside GD2, a tumor-associated carbohydrate antigen, which is also expressed in neurons, skin melanocytes, and peripheral nerve fibers. Immunotherapy with monoclonal anti-GD2 antibodies has a proven efficacy in clinical trials and is included in the standard treatment for children with high-risk neuroblastoma. However, the strong neuro-toxicity associated with anti-GD2 antibodies administration has hindered, until now, the possibility for dose-escalation and protracted use, thus restraining their therapeutic potential. Strategies to increase the efficacy of anti-GD2 antibodies are actively sought, with the aim to enable chronic treatments that could eradicate minimal residual disease and subsequent relapses, often occurring after treatment. Here, we report that Nanofenretinide and Nanospermidine improved the expression of GD2 in neuroblastoma cells (CHP-134) and provided different effects in combination with the anti-GD2 antibody naxitamab. In particular, Nanofenretinide significantly increased the cytotoxic effect of naxitamab while Nanospermidine inhibited cell motility at extents proportional to naxitamab concentration. In neuroblastoma cells characterized by a low and heterogeneous basal expression of GD2, such as SH-SY5Y, which may represent the cell heterogeneity in tumors after chemotherapy, both Nanofenretinide and Nanospermidine increased GD2 expression in approximately 50% of cells, thus shifting the tumor population towards improved sensitivity to anti-GD2 antibodies

A likely association between low mannan-binding lectin level and brain fog onset in long COVID patients

: Brain fog can be described as a constellation of new-onset neuropsychiatric sequelae in the post-acute phase of COVID-19 (long COVID). The symptoms include inattention, short-term memory loss, and reduced mental acuity, which may undermine cognition, concentration, and sleep. This cognitive impairment, persisting for weeks or months after the acute phase of SARS-CoV-2 infection, can significantly impact on daily activities and the quality of life. An important role for the complement system (C) in the pathogenesis of COVID-19 has emerged since the beginning of pandemic outbreak. A number of pathophysiological characteristics including microangiopathy and myocarditis have been attributed to dysregulated C activation due to SARS-CoV-2 infection. Mannan-binding lectin (MBL), the first recognition subcomponent of the C lectin pathway, has been shown to bind to glycosylated SARS-CoV-2 spike protein, genetic variants of MBL2 are suggested to have an association with severe COVID-19 manifestations requiring hospitalization. In the present study, we evaluated MBL activity (lectin pathway activation) and levels in the sera of a cohort of COVID-19 patients, presenting brain fog or only hyposmia/hypogeusia as persistent symptoms, and compared them with healthy volunteers. We found significantly lower levels of MBL and lectin pathway activity in the sera of patients experiencing brain fog as compared to recovered COVID-19 patients without brain fog. Our data indicate that long COVID-associated brain fog can be listed among the variegate manifestations of increased susceptibility to infections and diseases contributed by MBL deficiency

Immune activation, immune senescence and levels of Epstein Barr Virus in kidney transplant patients: Impact of mTOR inhibitors

Abstract Post-transplant lymphoproliferative disorders (PTLD) represent a severe complication in transplanted patients and Epstein-Barr Virus (EBV) is the main driver. Besides immunodepression, immune activation/chronic inflammation play an important role in both virus reactivation and expansion of EBV-positive B cells. The aim of this study was to assess the impact of immunosuppressive strategies on factors involved in the PTLD's pathogenesis. 124 kidney transplanted patients were enrolled in this study: 71 were treated with mycophenolic acid (MPA) and 53 treated with mTOR inhibitor (mTORi), both in combination with different doses of calcineurin inhibitor. At the time of the transplant (T0), profile of inflammation/immune activation and immune senescence didn't differ between the two groups, but after one year of treatment (T1) markers were significantly higher in MPA-treated patients; their immunosenescence process was supported by the greater erosion of telomeres despite their younger age. Percentages of activated B cells and levels of EBV-DNA significantly increased in MPA-treated patients, and at T1 were significantly higher in MPA- than in mTORi-treated patients. Overall, these findings indicate that mTOR inhibitors constrain the inflammation/immune activation and senescence status, thus reducing the expansion of EBV-infected B cells and the risk of virus-associated PTLD in kidney transplant recipients

Neurodegeneration: can metabolites from Eremurus persicus help?

The number of patients affected by neurodegenerative diseases is increasing worldwide, and no effective treatments have been developed yet. Although precision medicine could represent a powerful tool, it remains a challenge due to the high variability among patients. To identify molecules acting with innovative mechanisms of action, we performed a computational investigation using SAFAN technology, focusing specifically on HuD. This target belongs to the human embryonic lethal abnormal visual-like (ELAV) proteins and plays a key role in neuronal plasticity and differentiation. The results highlighted that the molecule able to bind the selected target was (R)-aloesaponol-III-8-methyl ether [(R)-ASME], a metabolite extracted from Eremurus persicus. Notably, this molecule is a TNF-alpha inhibitor, a cytokine involved in neuroinflammation. To obtain a suitable amount of (R)-ASME to confirm its activity on HuD, we optimized the extraction procedure. Together with ASME, another related metabolite, germichrysone, was isolated. Both ASME and germichrysone underwent biological investigation, but only ASME confirmed its ability to bind HuD. Given the multifactorial nature of neurodegenerative diseases, we decided to investigate ASME as a proteasome activator, being molecules endowed with this kind of activity potentially able to counteract aggregations of dysregulated proteins. ASME was able to activate the considered target both in enzymatic and cellular assays. Therefore, ASME may be considered a promising hit in the fight against neurodegenerative diseases

Colorectal Cancer Stage at Diagnosis Before vs During the COVID-19 Pandemic in Italy

IMPORTANCE Delays in screening programs and the reluctance of patients to seek medical attention because of the outbreak of SARS-CoV-2 could be associated with the risk of more advanced colorectal cancers at diagnosis. OBJECTIVE To evaluate whether the SARS-CoV-2 pandemic was associated with more advanced oncologic stage and change in clinical presentation for patients with colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS This retrospective, multicenter cohort study included all 17 938 adult patients who underwent surgery for colorectal cancer from March 1, 2020, to December 31, 2021 (pandemic period), and from January 1, 2018, to February 29, 2020 (prepandemic period), in 81 participating centers in Italy, including tertiary centers and community hospitals. Follow-up was 30 days from surgery. EXPOSURES Any type of surgical procedure for colorectal cancer, including explorative surgery, palliative procedures, and atypical or segmental resections. MAIN OUTCOMES AND MEASURES The primary outcome was advanced stage of colorectal cancer at diagnosis. Secondary outcomes were distant metastasis, T4 stage, aggressive biology (defined as cancer with at least 1 of the following characteristics: signet ring cells, mucinous tumor, budding, lymphovascular invasion, perineural invasion, and lymphangitis), stenotic lesion, emergency surgery, and palliative surgery. The independent association between the pandemic period and the outcomes was assessed using multivariate random-effects logistic regression, with hospital as the cluster variable. RESULTS A total of 17 938 patients (10 007 men [55.8%]; mean [SD] age, 70.6 [12.2] years) underwent surgery for colorectal cancer: 7796 (43.5%) during the pandemic period and 10 142 (56.5%) during the prepandemic period. Logistic regression indicated that the pandemic period was significantly associated with an increased rate of advanced-stage colorectal cancer (odds ratio [OR], 1.07; 95%CI, 1.01-1.13; P = .03), aggressive biology (OR, 1.32; 95%CI, 1.15-1.53; P < .001), and stenotic lesions (OR, 1.15; 95%CI, 1.01-1.31; P = .03). CONCLUSIONS AND RELEVANCE This cohort study suggests a significant association between the SARS-CoV-2 pandemic and the risk of a more advanced oncologic stage at diagnosis among patients undergoing surgery for colorectal cancer and might indicate a potential reduction of survival for these patients