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We propose a general modular approach to support decision-makers' response in the early stages of a pandemic with resource expansion, motivated by the shortage of Covid-19-related intensive care units (ICU) capacity in 2020 in Italy. Our approach uses (1) a stochastic extension of an epidemic model for scenarios of projected infections, (2) a capacity load model to translate infections into scenarios of demand for the resources of interest, and (3) an optimization model to allocate this demand to the projected levels of resources based on different values of investment. We demonstrate this approach with the onset of the first and second Covid-19 waves in three Italian regions, using the data available at that time. For epidemic modeling, we used a parsimonious stochastic susceptible-infected-removed model with a robust estimation procedure based on bootstrap resampling, suitable for a noisy and data-limited environment. For capacity loading, we used a Cox queuing model to translate the projected infections into demand for ICU, using stochastic intensity to capture the variability of the patient arrival process. Finally, we used stochastic dynamic optimization to select the best policy (when and how much to expand) to minimize the expected number of patients denied ICU for any level of investment in capacity expansion and obtain an efficient frontier. The frontier allows a trade-off between investment in additional resources and the number of patients denied intensive care. Moreover, in the panic-driven early days of a pandemic, decision-makers can also obtain the time until which they can postpone action, potentially reducing investment costs without increasing the expected number of denied patients.

Adverse reactions, toxicity, and poor compliance from patients still represent major challenges for conventional chemotherapy treatments. Localized drug delivery would ideally improve therapeutic efficacy, minimizing the side effects. An MSU-type mesoporous silica-based nanodevice (FOL-MSN-BTZ), able to selectively deliver the antineoplastic drug bortezomib (BTZ) to folate receptor over-expressing multiple myeloma (FR+ MM) cells is described. The receptor-specific ligand, folic acid, grafted on the external surface of the nanosystem, allows tumor recognition and cell internalization, while BTZ, mainly linked to the pore internal surface through a covalent pH-sensitive bond, is released in an acidic tumor environment. A detailed investigation showed that only the fine balancing of different functionalities of the nanodevice around the external and internal surfaces of MSN particles shows the absence of toxicity towards healthy cells in vitro and negligible BTZ-release at physiological pH, which are suitable features for applicative purposes in the engineering of therapies. After complete characterization in vitro, an accurate suspendability assessment, which considered the sedimentation process that reduces the particle amount and, consequently, drug content in the suspensions, allowed the development of an injectable formulation of FOL-MSN-BTZ that showed higher antitumor efficacy and an overall tendency to lower toxicity in a MM mice model compared to the conventional bortezomib chemotherapy.

We propose a spatio-temporal analysis aiming at estimating the variation of gasoline and diesel consumption occurred in the Italian provinces as a consequence of the COVID-19 pandemic during 2020 and 2021. We employ generalized linear models and generalized additive models to predict business-as-usual per capita fuel consumption by means of socio-economic variables, such as demography, tourist stays, temperature and territorial characteristics. The province-specific impact of the restrictions is then estimated as the difference between the observed and model-predicted values. The spatio-temporal dynamics is introduced by means of appropriate spline basis functions allowing both spatial and time trend to be smooth surfaces. Moreover, we include a smooth spatio-temporal interaction that properly capture the seasonal characteristic of different areas. Our findings highlight that the national mobility restrictions imposed to fight the spread of COVID-19 in the first wave (March to May 2020) reduced gasoline and diesel consumption homogeneously nationwide, with some slight differences between northern and southern provinces. However, the second wave lockdown (Winter 2020–2021) determined heterogeneous impacts across Italian provinces. In particular, we highlight the existence of a divergence between North and South Italy in terms of reaction to the pandemic. Indeed, while southern provinces experienced the weakest and less variable reductions, the northern provinces recorded strong and persistent contractions of fuel consumption. Also, southern and tourism-devoted provinces recovered quickly and compact to the post-pandemic reopenings.

The Vinschgau Shear Zone (VSZ) is one of the largest and most significant shear zones developed under plastic conditions within the Austroalpine domain, juxtaposing the Ötztal and the Texel units to the Campo, Scharl and Sesvenna units during the building of the Eo-Alpine Orogen. The VSZ dominates the structural setting of a large portion of the central Austroalpine Late Cretaceous thrust stack. In order to fully assess the evolution of the VSZ, a multi-faceted approach based on detailed multiscale structural and petrochronological analyses has been carried out across representative transects of the shear zone in the Vinschgau Valley. The research has been performed with a view to characterizing kinematics, P-T conditions and timing of motion of the VSZ. Our fieldwork-based analyses suggest that the dip angle of mylonitic foliation increases from west to east with an E-W-trending stretching lineation which dips alternatively to the west and to the east, due to later folding related to the Cenozoic crustal shortening. The dominant top-to-W shear sense of the mylonites recognized in the field and confirmed by microstructural analyses led to exhumation of the upper Austroalpine nappes in the hanging wall of the shear zone; the Texel unit with Late Cretaceous eclogites and the Schneeberg and Ötztal units were all affected by Eo-Alpine amphibolite-facies metamorphism. Chemical and microstructural analyses suggest deformation temperatures of ca. 350-400C during shearing. Timing of deformation along the VSZ has been constrained for the first time through 40Ar/39Ar dating of syn-shearing micas, which reveal a Late Cretaceous age of the VSZ mylonites with ages ranging between 80 and 97Ma. A systematic younging age of deformation occurs towards the central part of the shear zone in the studied transects. Vorticity analysis shows a clear decrease in the simple shear component correlated to the younging of mica ages towards the core of the shear zone. This evolution is consis

BACKGROUND: Dysphagia is a common symptom during the trajectory of ALS, and it can significantly impact on the quality of life and prognosis of patients. Nowadays, no specific tool for the screening of dysphagia in ALS is validated, and the approach is heterogeneous across the Italian centres. OBJECTIVE: To validate the DYALS (dysphagia in amyotrophic lateral sclerosis) questionnaire, adapting the DYMUS (dysphagia in multiple sclerosis) questionnaire, for the assessment of dysphagia in ALS patients, in order to uniform the evaluations across the Italian ALS network. METHODS: We included 197 patients diagnosed with ALS following the El Escorial criteria, in sixteen Italian ALS centres between 1st December 2019 and 1st July 2020. For each patient, we collected clinical and demographic data and obtained ALSFRS-r score, ALSAQ-5 score, DYMUS score, and EAT-10 score. RESULTS: Across the 197 patients, the ratio M/F was 113/84, and the median age was 64 years (IQR 56-72.5). Bulbar patients were 20%, and spinal patients 80%. The median ALSFRSr total score of patients was 35 (IQR 28-39). DYALS score was statistically higher in bulbar ALS than in spinal ALS (median = 6, IQR 4.5-9 vs median = 1, IQR 0-5, z = 6.253, p < 0.0001). DYALS questionnaire showed a high internal consistency (Cronbach's alpha = 0.88). There was a statistically significant correlation between DYALS and EAT-10 (rho = 0.90, p < 0.0001). CONCLUSIONS: DYALS scale is reliable, manageable, and easily usable for the screening of dysphagia in ALS. It can be shared with all the Italian ALS centres in order to collect uniform data for therapeutic strategies and clinical trials.

Item does not contain fulltext, Objective: Levels of chitotriosidase (CHIT1) are increased in the cerebrospinal fluid (CSF) of amyotrophic lateral sclerosis (ALS) patients reflecting microglial activation. Here, we determine the diagnostic and prognostic potential of CHIT1 for early symptomatic ALS. Methods: Overall, 275 patients from 8 European neurological centers were examined. We included ALS with <6 and >6 months from symptom onset, other motoneuron diseases (oMND), ALS mimics (DCon) and non-neurodegenerative controls (Con). CSF CHIT1 levels were analyzed for diagnostic power and association with progression and survival in comparison to the benchmark neurofilament. The 24-bp duplication polymorphism of CHIT1 was analyzed in a subset of patients (N = 65). Results: Homozygous CHIT1 duplication mutation carriers (9%) invariably had undetectable CSF CHIT1 levels, while heterozygous carriers had similar levels as patients with wildtype CHIT1 (p = 0.414). In both early and late symptomatic ALS CHIT1 levels was increased, did not correlate with patients' progression rates, and was higher in patients diagnosed with higher diagnostic certainty. Neurofilament levels correlated with CHIT1 levels and prevailed over CHIT1 regarding diagnostic performance. Both CHIT1 and neurofilaments were identified as independent predictors of survival in late but not early symptomatic ALS. Evidence is provided that CHIT1 predicts progression in El Escorial diagnostic category in the group of ALS cases with a short duration. Conclusions: CSF CHIT1 level may have additional value in the prognostication of ALS patients with a short history of symptoms classified in diagnostic categories of lower clinical certainty. To fully interpret apparently low CHIT1 levels knowledge of CHIT1 genotype is needed.

BACKGROUND AND AIMS: Despite concerns that liver transplant (LT) recipients may be at increased risk of unfavorable outcomes from COVID-19 due the high prevalence of co-morbidities, immunosuppression and ageing, a detailed analysis of their effects in large studies is lacking.METHODS: Data from adult LT recipients with laboratory confirmed SARS-CoV2 infection were collected across Europe. All consecutive patients with symptoms were included in the analysis.RESULTS: Between March 1st and June 27th2020, data from 243 adult symptomatic cases from 36 centers and 9 countries were collected. Thirty-nine (16%) were managed as outpatients while 204 (84%) required hospitalization including admission to the ICU (39/204, 19.1%). Forty-nine (20.2%) patients died after a median of 13.5 (10-23) days, respiratory failure was the major cause. After multivariable Cox regression analysis, age >70 (HR, 4.16; 95% CI, 1.78-9.73) had a negative effect and tacrolimus (TAC) use (HR, 0.55; 95% CI, 0.31-0.99) had a positive independent effect on survival. The role of co-morbidities was strongly influenced by the dominant effect of age where comorbidities increased with the increasing age of the recipients. In a second model excluding age, both diabetes (HR, 1.95; 95% CI, 1.06-3.58) and chronic kidney disease (HR, 1.97; 95% CI, 1.05-3.67) emerged as associated with death CONCLUSIONS: Twenty-five per cent of patients requiring hospitalization for Covid-19 died, the risk being higher in patients older than 70 and with medical co-morbidities, such as impaired renal function and diabetes. Conversely, the use of TAC was associated with a better survival thus encouraging clinicians to keep TAC at the usual dose.

Backgrounds & Aims: Treating patients with decompensated cirrhosis with direct-acting antiviral (DAA) therapy while on the waiting list for liver transplantation results in substantial improvement of liver function allowing 1 in 4 patients to be removed from the waiting list or delisted, as reported in a previous study promoted by the European Liver and Intestine Transplant Association (ELITA). The aim of this study was to report on clinical outcomes of delisted patients, including mortality risk, hepatocellular carcinoma development and clinical decompensation requiring relisting. Methods: One hundred and forty-two HCV-positive patients on the liver transplant waiting list for decompensated cirrhosis, negative for hepatocellular carcinoma, between February 2014 and June 2015 were treated with DAA therapy and were prospectively followed up. Results: Forty-four patients (30.9%) were delisted following clinical improvement. This percentage was higher than in the original study because of a number of patients being delisted long after starting DAAs. The median Child-Pugh and MELD score of delisted patients was 5.5 and 9 respectively. Four patients were relisted, because of HCC diagnosis in 1 case and 3 patients developed ascites. One further patient died (2.4%) because of rapidly progressing hepatocellular carcinoma twenty-two months after delisting. Of the 70 patients who received a liver graft, 9 died (13%). Conclusions: Antiviral therapy allows for a long-term improvement of liver function and the delisting of one-third of treated patients with risk of liver-related complications after delisting being very low.