Ecosystem services are increasingly being considered in decision-making with respect to mitigating future climate impacts. In this respect, there is a clear need to identify how nature-based ...solutions (NBS) can benefit specific ecosystem services, in particular within the complex spatial and temporal dynamics that characterize most river catchments. To capture these changes, ecosystem models require spatially explicit data that are often difficult to obtain for model development and validation. Citizen science allows for the participation of trained citizen volunteers in research or regulatory activities, resulting in increased data collection and increased participation of the general public in resource management. Despite the increasing experience in citizen science, these approaches have seldom been used in the modeling of provisioning ecosystem services. In the present study, we examined the temporal and spatial drivers in nutrient delivery in a major Italian river catchment and under different NBS scenarios. Information on climate, land use, soil and river conditions, as well as future climate scenarios, were used to explore future (2050) benefits of NBS on local and catchment scale nutrient loads and nutrient export. We estimate the benefits of a reduction in nitrogen and phosphorus export to the river and the receiving waters (Adriatic Sea) with respect to the costs associated with individual and combined NBS approaches related to river restoration and catchment reforestation.
Dissolved organic carbon (DOC) and particulate organic carbon (POC) play a fundamental role in biogeochemical cycles of freshwater ecosystems. However, the lack of readily available distributed ...models for carbon export has limited the effective management of organic carbon fluxes from soils, through river networks and to receiving marine waters. We develop a spatially semi-distributed mass balance modeling approach to estimate organic carbon flux at a sub-basin and basin scales, using commonly available data, to allow stakeholders to explore the impacts of alternative river basin management scenarios and climate change on riverine DOC and POC dynamics. Data requirements, related to hydrological, land-use, soil and precipitation characteristics are easily retrievable from international and national databases, making it appropriate for data-scarce basins. The model is built as an open-source plugin for QGIS and can be easily integrated with other basin scale decision support models on nutrient and sediment export.
We tested the model in Piave river basin, in northeast Italy. Results show that the model reproduces spatial and temporal changes in DOC and POC fluxes in relation to changes in precipitation, basin morphology and land use across different sub-basins. For example, the highest DOC export were associated with both urban and forest land use classes and during months of elevated precipitation. We used the model to evaluate alternative land use scenarios and the impact of climate on basin level carbon export to Mediterranean.
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•Riverine DOC and POC dynamics reflect sub-basin land use and climate conditions.•Semi-distributed mass balance models show spatial and temporal changes.•An open source QGIS plug-in allows for scenario analysis of alternative land uses.•Future climate scenarios show major reductions of riverine DOC and POC export.
Summary Background Metachromatic leukodystrophy (a deficiency of arylsulfatase A ARSA) is a fatal demyelinating lysosomal disease with no approved treatment. We aimed to assess the long-term outcomes ...in a cohort of patients with early-onset metachromatic leukodystrophy who underwent haemopoietic stem-cell gene therapy (HSC-GT). Methods This is an ad-hoc analysis of data from an ongoing, non-randomised, open-label, single-arm phase 1/2 trial, in which we enrolled patients with a molecular and biochemical diagnosis of metachromatic leukodystrophy (presymptomatic late-infantile or early-juvenile disease or early-symptomatic early-juvenile disease) at the Paediatric Clinical Research Unit, Ospedale San Raffaele, in Milan. Trial participants received HSC-GT, which consisted of the infusion of autologous HSCs transduced with a lentiviral vector encoding ARSA cDNA, after exposure-targeted busulfan conditioning. The primary endpoints of the trial are safety (toxicity, absence of engraftment failure or delayed haematological reconstitution, and safety of lentiviral vector-tranduced cell infusion) and efficacy (improvement in Gross Motor Function Measure GMFM score relative to untreated historical controls, and ARSA activity, 24 months post-treatment) of HSC-GT. For this ad-hoc analysis, we assessed safety and efficacy outcomes in all patients who had received treatment and been followed up for at least 18 months post-treatment on June 1, 2015. This trial is registered with ClinicalTrials.gov , number NCT01560182. Findings Between April, 2010, and February, 2013, we had enrolled nine children with a diagnosis of early-onset disease (six had late-infantile disease, two had early-juvenile disease, and one had early-onset disease that could not be definitively classified). At the time of analysis all children had survived, with a median follow-up of 36 months (range 18–54). The most commonly reported adverse events were cytopenia (reported in all patients) and mucositis of different grades of severity (in five of nine patients grade 3 in four of five patients). No serious adverse events related to the medicinal product were reported. Stable, sustained engraftment of gene-corrected HSCs was observed (a median of 60·4% range 14·0–95·6 lentiviral vector-positive colony-forming cells across follow-up) and the engraftment level was stable during follow-up; engraftment determinants included the duration of absolute neutropenia and the vector copy number of the medicinal product. A progressive reconstitution of ARSA activity in circulating haemopoietic cells and in the cerebrospinal fluid was documented in all patients in association with a reduction of the storage material in peripheral nerve samples in six of seven patients. Eight patients, seven of whom received treatment when presymptomatic, had prevention of disease onset or halted disease progression as per clinical and instrumental assessment, compared with historical untreated control patients with early-onset disease. GMFM scores for six patients up to the last follow-up showed that gross motor performance was similar to that of normally developing children. The extent of benefit appeared to be influenced by the interval between HSC-GT and the expected time of disease onset. Treatment resulted in protection from CNS demyelination in eight patients and, in at least three patients, amelioration of peripheral nervous system abnormalities, with signs of remyelination at both sites. Interpretation Our ad-hoc findings provide preliminary evidence of safety and therapeutic benefit of HSC-GT in patients with early-onset metachromatic leukodystrophy who received treatment in the presymptomatic or very early-symptomatic stage. The results of this trial will be reported when all 20 patients have achieved 3 years of follow-up. Funding Italian Telethon Foundation and GlaxoSmithKline.
Abstract
Objective
During rheumatoid arthritis (RA), the angiogenic processes, occurring with pannus-formation, may be a therapeutic target. JAK/STAT-pathway may play a role and the aim of this work ...was to investigate the inhibiting role of a JAK-inhibitor, tofacitinib, on the angiogenic mechanisms occurring during RA.
Methods
After ethical approval, JAK-1, JAK-3, STAT-1, STAT-3 and VEGF expression was evaluated on RA-synovial-tissues. In vitro, endothelial cells (ECs), stimulated with 20 ng/ml of VEGF and/or 1 μM of tofacitinib, were assessed for tube formation, migration and proliferation, by Matrigel, Boyden chamber assay and ki67 gene-expression. In vivo, 32 mice received collagen (collagen-induced arthritis (CIA)) and 32 mice PBS (control). At day 19, CIA and controls mice were divided: 16 mice receiving vehicle and 16 mice receiving tofacitinib. At day 35, the arthritis score, the thickness of paw joints and the serum levels of VEGF and Ang-2 were evaluated.
Results
The expression of JAK-1, JAK-3, STAT-1, STAT-3 and VEGF in synovial tissue of RA-patients were significantly higher than healthy controls. In vitro, tofacitinib inhibited the ECs ability to form vessels, to proliferate and to migrate. In vivo, administration of tofacitinib prevented the increase of the arthritis score, the paw thickness, the synovial vessels and VEGF and Ang-2 serum-accumulation, when compared to CIA without tofacitinib.
Conclusions
We explored the anti-angiogenic role of tofacitinib, reporting its ability to inhibit in vitro the angiogenic mechanisms of ECs and in vivo the formation of new synovial vessels, occurring in CIA model. These findings suggest that the therapeutic effect of tofacitinib during RA may be also related to its anti-angiogenic activity.
The characterization of the adaptive immune response to COVID-19 vaccination in individuals who recovered from SARS-CoV- 2 infection may define current and future clinical practice. To determine the ...effect of the 2-dose BNT162b2 mRNA COVID-19 vaccination schedule in individuals who recovered from COVID-19 (COVID- 19-recovered subjects) compared with naive subjects, we evaluated SARS-CoV-2 Spike-specific T and B cell responses, as well as specific IgA, IgG, IgM, and neutralizing antibodies titers in 22 individuals who received the BNT162b2 mRNA COVID-19 vaccine, 11 of whom had a previous history of SARS-CoV-2 infection. Evaluations were performed before vaccination and then weekly until 7 days after second injection. Data obtained clearly showed that one vaccine dose is sufficient to increase both cellular and humoral immune response in COVID-19-recovered subjects without any additional improvement after the second dose. On the contrary, the second dose proved mandatory in naive subjects to further enhance the immune response. These findings were further confirmed at the serological level in a larger cohort of naive (n = 68) and COVID-19-recovered (n = 29) subjects, tested up to 50 days after vaccination. These results question whether a second vaccine injection in COVID-19-recovered subjects is required, and indicate that millions of vaccine doses may be redirected to naive individuals, thus shortening the time to reach herd immunity.
A series of chemical and biochemical parameters of edible hemp resources (seeds, oil, and flour) from the monoecious EU registered hemp genotype Fedora, was determined, including fatty acid profile, ...phytosterol composition, total phenolics, antioxidant activity, macro- and micro-elements. The fatty acid ω-3/ω-6 approached the nutritionally optimal 3/1 ratio. β-sitosterol and other phytosterols sterols dominated the unsaponifiable fraction. Hemp seeds, flour, and oil contained 767 ± 41, 744 ± 29, and 21 ± 5 mg GAE kg
total polyphenols, respectively. The antioxidant potential of Fedora flour and seeds, evaluated through the DPPH (2,2-Diphenyl-1-picrylhydrazyl) assay, was higher than that of oil. K and Mg were the most abundant macro-elements, particularly in flour, while the concentration of trace elements was Fe > Cu > Ni > Mn. The presence of an array of bioactive compound candidate Fedora products as health-promoting food matrices. The ATR-FTIR spectra of hemp-derived products indicated the proximate composition of macro-nutrients.
All-trans-retinoic acid (ATRA) has greatly modified the prognosis of acute promyelocytic leukemia; however, the role of maintenance in patients in molecular complete remission after consolidation ...treatment is still debated. From July 1993 to May 2000, 807 genetically proven newly diagnosed acute promyelocytic leukemia patients received ATRA plus idarubicin as induction, followed by 3 intensive consolidation courses. Thereafter, patients reverse-transcribed polymerase chain reaction–negative for the PML-RARA fusion gene were randomized into 4 arms: oral 6-mercaptopurine and intramuscular methotrexate (arm 1); ATRA alone (arm 2); 3 months of arm1 alternating to 15 days of arm 2 (arm 3); and no further therapy (arm 4). Starting from February 1997, randomization was limited to ATRA-containing arms only (arms 2 and 3). Complete remission was achieved in 761 of 807 (94.3%) patients, and 681 completed the consolidation program. Of these, 664 (97.5%) were evaluated for the PML-RARA fusion gene, and 586 of 646 (90.7%) who tested reverse-transcribed polymerase chain reaction–negative were randomized to maintenance. The event-free survival estimate at 12 years was 68.9% (95% confidence interval, 66.4%-71.4%), and no differences in disease-free survival at 12 years were observed among the maintenance arms.
Background
International guidelines suggest hepatitis C virus (HCV) eradication by direct‐acting antivirals (DAAs) after first‐line immunochemotherapy (I‐CT) in patients with HCV‐positive diffuse ...large B‐cell lymphoma (DLBCL), although limited experiences substantiate this recommendation. Moreover, only a few data concerning concurrent administration of DAAs with I‐CT have been reported.
Subjects, Materials, and Methods
We analyzed hematological and virological outcome and survival of 47 consecutive patients with HCV‐positive DLBCL treated at 23 Italian and French centers with DAAs either concurrently (concurrent cohort ConC: n = 9) or subsequently (sequential cohort SeqC: n = 38) to first‐line I‐CT (mainly rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone R‐CHOP‐like).
Results
Median age was 61 years, 89% of patients had stage III/IV, and 25% presented evidence of cirrhosis. Genotype was 1 in 56% and 2 in 34% of cases. Overall, 46 of 47 patients obtained complete response to I‐CT. All patients received appropriate DAAs according to genotype, mainly sofosbuvir‐based regimens (n = 45). Overall, 45 patients (96%) achieved sustained virological response, 8 of 9 in ConC and 37 of 38 in SeqC. DAAs were well tolerated, with only 11 patients experiencing grade 1–2 adverse events. Twenty‐three patients experienced hepatic toxicity (grade 3–4 in seven) following I‐CT in SeqC, compared to only one patient in ConC. At a median follow‐up of 2.8 years, two patients died (2‐year overall survival, 97.4%) and three progressed (2‐year progression‐free survival, 93.1%).
Conclusion
Excellent outcome of this cohort of HCV‐positive DLBCL suggests benefit of HCV eradication by DAAs either after or during I‐CT. Moreover, concurrent DAAs and R‐CHOP administration appeared feasible, effective, and ideally preferable to deferred administration of DAAs for the prevention of hepatic toxicity.
Implications for Practice
Hepatitis C virus (HCV)‐associated diffuse large B‐cell lymphomas (DLBCLs) represent a great therapeutic challenge, especially in terms of hepatic toxicity during immune‐chemotherapy (I‐CT) and long‐term hepatic complications. The advent of highly effective and toxicity‐free direct‐acting antivirals (DAAs) created an exciting opportunity to easily eradicate HCV shortly after or in concomitance with first‐line immunochemotherapy (usually R‐CHOP). This retrospective international study reports the real‐life use of the combination of these two therapeutic modalities either in the concurrent or sequential approach (DAAs after I‐CT) in 47 patients. The favorable reported results on long‐term outcome seem to support the eradication of HCV with DAAs in all patients with HCV‐positive DLBCL. Moreover, the results from the concurrent approach were effective and safe and displayed an advantage in preventing hepatic toxicity during I‐CT.
Epidemiological studies have established that hepatitis C virus (HCV) is associated with diffuse large B‐cell lymphoma (DLBCL). This article reports on patients with HCV‐positive DLBCL treated with direct‐acting antivirals either concurrently or subsequently to a curative‐intent first‐line immunochemotherapy.
Cholangiocarcinoma (CCA) is the second most common primary liver cancer, characterized by a poor prognosis and resistance to chemotherapeutics. The progressive increase in CCA incidence and mortality ...registered worldwide in the last two decades and the need to clarify various aspects of clinical management have prompted the Italian Association for the Study of the Liver (AISF) to commission the drafting of dedicated guidelines in collaboration with a group of Italian scientific societies. These guidelines have been formulated in accordance with the Italian National Institute of Health indications and developed by following the GRADE method and related advancements.
BACKGROUNDImmunization against SARS-CoV-2, the causative agent of COVID-19, occurs via natural infection or vaccination. However, it is currently unknown how long infection- or vaccination-induced ...immunological memory will last.METHODSWe performed a longitudinal evaluation of immunological memory to SARS-CoV-2 up to 1 year after infection and following mRNA vaccination in naive individuals and individuals recovered from COVID-19 infection.RESULTSWe found that memory cells are still detectable 8 months after vaccination, while antibody levels decline significantly, especially in naive individuals. We also found that a booster injection is efficacious in reactivating immunological memory to spike protein in naive individuals, whereas it was ineffective in previously SARS-CoV-2-infected individuals. Finally, we observed a similar kinetics of decay of humoral and cellular immunity to SARS-CoV-2 up to 1 year following natural infection in a cohort of unvaccinated individuals.CONCLUSIONShort-term persistence of humoral immunity, together with the reduced neutralization capacity versus the currently prevailing SARS-CoV-2 variants, may account for reinfections and breakthrough infections. Long-lived memory B and CD4+ T cells may protect from severe disease development. In naive individuals, a booster dose restored optimal anti-spike immunity, whereas the needs for vaccinated individuals who have recovered from COVID-19 have yet to be defined.FUNDINGThis study was supported by funds to the Department of Experimental and Clinical Medicine, University of Florence (Project Excellence Departments 2018-2022), the University of Florence (project RICTD2122), the Italian Ministry of Health (COVID-2020-12371849), and the region of Tuscany (TagSARS CoV 2).
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