Search

Abstract Neutrophils (PMNs) are key players of innate immune responses through the release of cytoplasmic granule content and the formation of neutrophil extracellular traps (NETs). RNASET2 is an acidic ribonuclease, recently proposed as an alarmin signal associated with inflammatory responses. Here we show that, along the neutrophil maturation cascade, RNASET2 is expressed in segmented and mature PMNs. In human PMNs, RNASET2 colocalized with primary and tertiary granules and was found to be associated with NETs following PMA or Nigericin stimulation. Similarly, activation of PMNs by soluble immune complexes, a hallmark of several autoimmune diseases, also induced RNASET2-associated NETs. Genome-wide association studies recently identified RNASET2 among a cluster of genes associated with increased susceptibility to develop autoimmune diseases, including rheumatoid arthritis (RA). RNASET2 was found expressed by PMNs and macrophages infiltrating inflamed joints in a murine model of RA (K/BxN Serum-Transfer-Induced Arthritis, STIA), by immunostaining. Similar results were found in synovial biopsies of RA patients with active disease. In addition, we demonstrate that RNASET2 circulating levels correlated with the onset and the severity of disease in two mouse models of inflammatory arthritis, STIA and CIA (Collagen-Induced Arthritis) and in serum of RA patients. These results show that PMNs are an important source of RNASET2 and that its circulating levels are associated with RA development suggesting a role for RNASET2 in the pathogenesis of immune-mediated diseases.

Abstract A main goal in neuroscience is to understand the computations carried out by neural populations that give animals their cognitive skills. Neural network models allow to formulate explicit hypotheses regarding the algorithms instantiated in the dynamics of a neural population, its firing statistics, and the underlying connectivity. Neural networks can be defined by a small set of parameters, carefully chosen to procure specific capabilities, or by a large set of free parameters, fitted with optimization algorithms that minimize a given loss function. In this work we alternatively propose a method to make a detailed adjustment of the network dynamics and firing statistic to better answer questions that link dynamics, structure, and function. Our algorithm—termed generalised Firing-to-Parameter (gFTP)—provides a way to construct binary recurrent neural networks whose dynamics strictly follows a user pre-specified transition graph that details the transitions between population firing states triggered by stimulus presentations. Our main contribution is a procedure that detects when a transition graph is not realisable in terms of a neural network, and makes the necessary modifications in order to obtain a new transition graph that is realisable and preserves all the information encoded in the transitions of the original graph. With a realisable transition graph, gFTP assigns values to the network firing states associated with each node in the graph, and finds the synaptic weight matrices by solving a set of linear separation problems. We test gFTP performance by constructing networks with random dynamics, continuous attractor-like dynamics that encode position in 2-dimensional space, and discrete attractor dynamics. We then show how gFTP can be employed as a tool to explore the link between structure, function, and the algorithms instantiated in the network dynamics.

Abstract Stroke affects the interconnection between the nervous and immune systems, leading to a down-regulation of immunity called stroke-induced immunosuppression (SII). The primary aim of this study is to investigate SII role as a predictor of functional, neurological, and motor outcomes in the neurorehabilitation setting (NRB). We conducted a prospective observational study enrolling post-acute stroke patients hospitalized for neurorehabilitation. At NRB admission (T0) and discharge (T1), we assessed presence of SII (defined by a neutrophil-to-lymphocyte ratio ≥ 5) and we evaluated functional independence (Functional Independence Measure-FIM, Barthel Index-BI), motor performances (Tinetti Score, Hauser Ambulation Index) and neurological impairment (NIHSS). We enrolled 96 patients (45.8% females, 70.6 ± 13.9 years, 88.5% ischemic stroke). At T0, 15.6% of patients (15/96) had SII. When compared to immunocompetent patients (IC), the SII group was characterized by worse baseline functional independence, motor performances and neurological disability. The same was confirmed at T1 (FIM p = 0.012, BI p = 0.007, Tinetti p = 0.034, NIHSS p = 0.001). Neurological disability demonstrated a less pronounced improvement in SII (ΔNIHSS: SII: − 2.1 ± 2.3 vs. IC: − 3.1 ± 2.5, p = 0.035). SII group presented a higher percentage of infectious complications during the neurorehabilitation period (SII 80% vs. IC 25.9%; p = 0.001). SII may represent a negative prognostic factor in the neurorehabilitation setting. SII patients were characterized by poorer functional, motor, neurological performances and higher risk of infectious complications. ClinicaTrial registration: NCT05889169.

Abstract First-line selective internal radiation therapy (SIRT) showed promising outcomes in patients with uveal melanoma liver metastases (UMLM). Patient survival depends on liver’s disease control. SIRT planning is essential and little is known about dosimetry. We investigated whether 99mTc-MAA-SPECT/CT dosimetry could predict absorbed doses (AD) evaluated on 90Y-PET/CT and assess the dose–response relationship in UMLM patients treated with first-line SIRT. This IRB-approved, single-center, retrospective analysis (prospectively collected cohort) included 12 patients (median age 63y, range 43–82). Patients underwent MRI/CT, 18F-FDG-PET/CT before and 3–6 months post-SIRT, and 90Y-PET/CT immediately post-SIRT. Thirty-two target lesions were included. AD estimates in tumor and non-tumor liver were obtained from 99mTc-MAA-SPECT/CT and post-SIRT 90Y-PET/CT, and assessed with Lin’s concordance correlation coefficients (ρ c and C b), Pearson’s coefficient correlation (ρ), and Bland–Altman analyses (mean difference ± standard deviation; 95% limits-of-agreement (LOA)). Influence of tumor characteristics and microsphere type on AD was analyzed. Tumor response was assessed according to size-based, enhancement-based and metabolic response criteria. Mean target lesion AD was 349 Gy (range 46–1586 Gy). Concordance between 99mTc-MAA-SPECT/CT and 90Y-PET/CT tumor dosimetry improved upon dose correction for the recovery coefficient (RC) (ρ = 0.725, ρ c = 0.703, C b = 0.969) with good agreement (mean difference: − 4.93 ± 218.3 Gy, 95%LOA: − 432.8–422.9). Without RC correction, concordance was better for resin microspheres (ρ = 0.85, ρ c = 0.998, C b = 0.849) and agreement was very good between predictive 99mTc-MAA-SPECT/CT and 90Y-PET/CT dosimetry (mean difference: − 4.05 ± 55.9 Gy; 95%LOA: − 113.7–105.6). After RC correction, 99mTc-MAA-SPECT/CT dosimetry overestimated AD (− 70.9 ± 158.9 Gy; 95%LOA: − 382.3–240.6). For glass microspheres, concordance markedly improved with RC correction (ρ = 0.790, ρ c = 0.713, C b = 0.903 vs without correction: ρ = 0.395, ρ c = 0.244, C b = 0.617) and 99mTc-MAA-SPECT/CT dosimetry underestimated AD (148.9 ± 267.5 Gy; 95%LOA: − 375.4–673.2). For non-tumor liver, concordance was good between 99mTc-MAA-SPECT/CT and 90Y-PET/CT dosimetry (ρ = 0.942, ρ c = 0.852, C b = 0.904). 99mTc-MAA-SPECT/CT slightly overestimated liver AD for resin (3.4 ± 3.4 Gy) and glass (11.5 ± 13.9 Gy) microspheres. Tumor AD was not correlated with baseline or post-SIRT lesion characteristics and no dose–response threshold could be identified. 99mTc-MAA-SPECT/CT dosimetry provides good estimates of AD to tumor and non-tumor liver in UMLM patients treated with first-line SIRT.

Abstract Undocumented migrants represent a large part of the population in Countries of the European Union (EU) such as Italy. Their health burden is not fully understood and likely to be related mainly to chronic conditions. Information on their health needs and conditions may help to target public health interventions but is not found in national public health databases. We conducted a retrospective observational study of non-communicable disease (NCD) burden and management in undocumented migrants receiving medical care from Opera San Francesco, a non-governmental organization (NGO) in Milan, Italy. We analyzed the health records of 53,683 clients over a period of 10 years and collected data on demographics, diagnosis and pharmacological treatments prescribed. 17,292 (32.2%) of clients had one or more NCD diagnosis. The proportion of clients suffering from at least one NCD increased from 2011 to 2020. The risk of having an NCD was lower in men than women (RR = 0.88, 95% CI 0.86–0.89), increased with age (p for trend

Abstract Healthcare delivery reorganization during the COVID-19 emergency may have had a significant impact on access to care for older adults with chronic conditions. We investigated such impact among all adults with chronic conditions aged ≥ 65 years, identified through the electronic health databases of two local health agencies—ATS Brianza and ATS Bergamo—from the Lombardy region, Italy. We considered hospitalizations for 2020 compared to the average 2017–2019 and quantified differences using rate ratios (RRs). Overall, in 2017–2019 there were a mean of 374,855 older adults with ≥ 1 chronic condition per year in the two ATS and 405,371 in 2020. Hospitalizations significantly decreased from 84,624 (225.8/1000) in 2017–2019 to 78,345 (193.3/1000) in 2020 (RR 0.86). Declines were reported in individuals with many chronic conditions and for most Major Diagnostic Categories, except for diseases of the respiratory system. The strongest reductions were observed in hospitalizations for individuals with active tumours, particularly for surgical ones. Hospitalization rates increased in individuals with diabetes, likely due to COVID-19-related diseases. Although determinants of the decrease in demand and supply for care among chronic older adults are to be further explored, this raises awareness on their impacts on chronic patients’ health in the medium and long run.

Abstract Only a few studies investigated changes in electronic cigarette (e-cigarette) and heated tobacco product (HTP) use during pandemic restrictions. We conducted a web-based cross-sectional study of a representative sample of 6,003 Italian adults during the strictest phase of the Covid-19 lockdown (April–May 2020). Participants were asked to report changes in e-cigarette and HTP use compared to before the pandemic. E-cigarette users increased from 8.1% to 9.1% and HTP users from 4.0% to 4.5%. Among e-cigarette non-users before lockdown, 1.8% started using e-cigarettes during lockdown. New users were more frequently younger (p for trend 0.001), men (odds ratio, OR 1.56; 95% confidence interval, CI: 1.03–2.34), cannabis users (OR 2.35; 95% CI: 1.33–4.13), gamblers (OR 3.34; 95% CI: 2.18–5.11) and individuals with anxiety symptoms (OR 1.58; 95% CI: 1.00–2.52). 1.0% of HTP non-users started using it during lockdown. New users were less frequently current than never cigarette smokers (OR 0.19; 95% CI: 0.06–0.61) and more frequently gamblers (OR 2.23; 95% CI: 1.22–4.07). E-cigarettes and HTPs played little role as smoking cessation tools for hardcore smokers but rather provided opportunities for young never smokers to engage in socially acceptable activities, perhaps reflecting the obstacles they faced in obtaining other addictive substances during confinement.

Abstract Globally, the burden of chronic wound infections is likely to increase due to the rising levels of bacterial resistance to antibiotics. In the United States of America alone, more than 6.5 million chronic wounds with evidence of bacterial infection are diagnosed every year. In addition, the polymicrobial environment in chronic wound infections has been observed from several studies as a risk factor for development of resistance to many antibiotics including the third generation cephalosporins currently used in Mbarara Regional Referral Hospital for treatment of chronic wound infections. Therefore the main objective of this study was to determine the prevalence of chronic wound isolates and their minimum inhibitory concentrations (MIC) against third generation cephalosporins. This study was a cross-sectional descriptive and analytical survey of bacterial isolates from chronic wound infection among 75 study participants admitted in the surgical ward of Mbarara Regional Referral Hospital (MRRH), a tertiary Hospital in Western Uganda. Standard laboratory bacterial culture and identification techniques as well as broth microdilution method were used to isolate, identify pathogens and test for MIC respectively. We found that 69/75 study participants had samples with bacterial growth and the most prevalent pathogens isolated were staphylococcus aureus (40.6%) and Klebsiella spp. (29%). Generally, most isolates were susceptible to cefoperazone + sulbactum 2 g (Sulcef) and ceftriaxone 1 g (Epicephin). The overall prevalence of isolates in chronic wound infection among patients admitted in the surgical ward of MRRH was 92% and the most prevalent isolates were Staphylococcus aureus, Klebsiella species and proteus species respectively. The observed MIC values were higher than the CLSI clinical breakpoint, implying a decreasing trend in susceptibility of chronic wound isolates to third generation cephalosporins.

Abstract Inflammation is a physiological process whose deregulation causes some diseases including cancer. Nuclear Factor kB (NF-kB) is a family of ubiquitous and inducible transcription factors, in which the p65/p50 heterodimer is the most abundant complex, that play critical roles mainly in inflammation. Glucocorticoid Receptor (GR) is a ligand-activated transcription factor and acts as an anti-inflammatory agent and immunosuppressant. Thus, NF-kB and GR are physiological antagonists in the inflammation process. Here we show that in mice and humans there is a spliced variant of p65, named p65 iso5, which binds the corticosteroid hormone dexamethasone amplifying the effect of the glucocorticoid receptor and is expressed in the liver of patients with hepatic cirrhosis and hepatocellular carcinoma (HCC). Furthermore, we have quantified the gene expression level of p65 and p65 iso5 in the PBMC of patients affected by SARS-CoV-2 disease. The results showed that in these patients the p65 and p65 iso5 mRNA levels are higher than in healthy subjects. The ability of p65 iso5 to bind dexamethasone and the regulation of the glucocorticoid (GC) response in the opposite way of the wild type improves our knowledge and understanding of the anti-inflammatory response and identifies it as a new therapeutic target to control inflammation and related diseases.

Abstract Serotonin (5-HT) is a key neuromodulator of medial prefrontal cortex (mPFC) functions. Pharmacological manipulation of systemic 5-HT bioavailability alters the electrical activity of mPFC neurons. However, 5-HT modulation at the population level is not well characterized. In the present study, we made single neuron extracellular recordings in the mPFC of rats performing an operant conditioning task, and analyzed the effect of systemic administration of fluoxetine (a selective serotonin reuptake inhibitor) on the information encoded in the firing activity of the neural population. Chronic (longer than 15 days), but not acute (less than 15 days), fluoxetine administration reduced the firing rate of mPFC neurons. Moreover, fluoxetine treatment enhanced pairwise entropy but diminished noise correlation and redundancy in the information encoded, thus showing how mPFC differentially encodes information as a function of 5-HT bioavailability. Information about the occurrence of the reward-predictive stimulus was maximized during reward consumption, around 3 to 4 s after the presentation of the cue, and it was higher under chronic fluoxetine treatment. However, the encoded information was less robust to noise corruption when compared to control conditions.

Abstract The effect of the phosphorus (P) and glyphosate interactions on the growth and nutrition of Arabica coffee cultivars (Coffea arabica), as well as on the control of Ipomoea grandifolia and Urochloa decumbens, was evaluated. Catuaí-Amarelo/IAC-62 and Catuaí-Vermelho/IAC-144 cultivars did not show glyphosate poisoning, regardless of the soil P content. However, glyphosate reduced the growth of Catuaí-Vermelho/IAC-144. In addition, the soil P content influenced the height, leaf area and dry matter of Catuaí-Amarelo/IAC-62, and the absorption of P and Ca in both cultivars. On the other hand, glyphosate efficiently controlled U. decumbens but not I. grandifolia. Glyphosate effectiveness on I. grandifolia decreased as the soil P content increased. In addition, the soil P content and the glyphosate influenced the P content in I. grandifolia and U. decumbens plants. The soil P content influenced the growth and absorption of other nutrients by coffee plants as well as glyphosate effectiveness on weed control.

Abstract Neural network models are an invaluable tool to understand brain function since they allow us to connect the cellular and circuit levels with behaviour. Neural networks usually comprise a huge number of parameters, which must be chosen carefully such that networks reproduce anatomical, behavioural, and neurophysiological data. These parameters are usually fitted with off-the-shelf optimization algorithms that iteratively change network parameters and simulate the network to evaluate its performance and improve fitting. Here we propose to invert the fitting process by proceeding from the network dynamics towards network parameters. Firing state transitions are chosen according to the transition graph associated with the solution of a task. Then, a system of linear equations is constructed from the network firing states and membrane potentials, in a way that guarantees the consistency of the system. This allows us to uncouple the dynamical features of the model, like its neurons firing rate and correlation, from the structural features, and the task-solving algorithm implemented by the network. We employed our method to probe the structure–function relationship in a sequence memory task. The networks obtained showed connectivity and firing statistics that recapitulated experimental observations. We argue that the proposed method is a complementary and needed alternative to the way neural networks are constructed to model brain function.

Abstract We monitored the burden of cancer in Italy and its trends over the last three decades, providing estimates of cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years (DALYs), for cancer overall and 30 cancer sites using data from the Global Burden of Disease study 2017. An overview of mortality trends between 1990 and 2017 was also provided. In 2017, there were 254,336 new cancer cases in men and 214,994 in women, corresponding to an age-standardized incidence rate (ASIR) of 438 and 330/100,000, respectively. Between 1990 and 2017, incident cancer cases, and, to a lesser extent, ASIRs significantly increased overall and for almost all cancer sites, but ASIRs significantly declined for lung and other tobacco-related neoplasms. In 2017, there were 101,659 cancer deaths in men (age-standardized death rate, ASDR, 158.5/100,000) and 78,918 in women (ASDR 93.9/100,000). Cancer deaths significantly increased between 1990 and 2017 (+ 18%), but ASDR significantly decreased (− 28%). Deaths significantly increased for many cancer sites, but decreased for stomach, esophageal, laryngeal, Hodgkin lymphoma, and testicular cancer. ASDRs significantly decreased for most neoplasms, with the main exceptions of cancer of the pancreas and uterus, and multiple myeloma. In 2017, cancer caused 3,204,000 DALYs. Between 1990 and 2017, DALYs and age-standardized DALY rates significantly declined (-3.4% and -33%, respectively). Age-standardized mortality rates in Italy showed favorable patterns over the last few decades. However, the absolute number of cancer cases and, to a lower extent, of cancer deaths increased likely due to the progressive ageing of the population, this calling for a continuous effort in cancer prevention, early diagnosis, and treatment.

Abstract Fast, accurate and reliable methods to quantify the amount of myelin still lack, both in humans and experimental models. The overall objective of the present study was to demonstrate that sphingomyelin (SM) in the cerebrospinal fluid (CSF) of patients affected by demyelinating neuropathies is a myelin biomarker. We found that SM levels mirror both peripheral myelination during development and small myelin rearrangements in experimental models. As in acquired demyelinating peripheral neuropathies myelin breakdown occurs, SM amount in the CSF of these patients might detect the myelin loss. Indeed, quantification of SM in 262 neurological patients showed a significant increase in patients with peripheral demyelination (p = 3.81 * 10 − 8) compared to subjects affected by non-demyelinating disorders. Interestingly, SM alone was able to distinguish demyelinating from axonal neuropathies and differs from the principal CSF indexes, confirming the novelty of this potential CSF index. In conclusion, SM is a specific and sensitive biomarker to monitor myelin pathology in the CSF of peripheral neuropathies. Most importantly, SM assay is simple, fast, inexpensive, and promising to be used in clinical practice and drug development.

First-line selective internal radiation therapy (SIRT) showed promising outcomes in patients with uveal melanoma liver metastases (UMLM). Patient survival depends on liver's disease control. SIRT planning is essential and little is known about dosimetry. We investigated whether 99mTc-MAA-SPECT/CT dosimetry could predict absorbed doses (AD) evaluated on 90Y-PET/CT and assess the dose–response relationship in UMLM patients treated with first-line SIRT. This IRB-approved, single-center, retrospective analysis (prospectively collected cohort) included 12 patients (median age 63y, range 43–82). Patients underwent MRI/CT, 18F-FDG-PET/CT before and 3–6 months post-SIRT, and 90Y-PET/CT immediately post-SIRT. Thirty-two target lesions were included. AD estimates in tumor and non-tumor liver were obtained from 99mTc-MAA-SPECT/CT and post-SIRT 90Y-PET/CT, and assessed with Lin's concordance correlation coefficients (ρc and Cb), Pearson's coefficient correlation (ρ), and Bland–Altman analyses (mean difference ± standard deviation; 95% limits-of-agreement (LOA)). Influence of tumor characteristics and microsphere type on AD was analyzed. Tumor response was assessed according to size-based, enhancement-based and metabolic response criteria. Mean target lesion AD was 349 Gy (range 46–1586 Gy). Concordance between 99mTc-MAA-SPECT/CT and 90Y-PET/CT tumor dosimetry improved upon dose correction for the recovery coefficient (RC) (ρ = 0.725, ρc = 0.703, Cb = 0.969) with good agreement (mean difference: − 4.93 ± 218.3 Gy, 95%LOA: − 432.8–422.9). Without RC correction, concordance was better for resin microspheres (ρ = 0.85, ρc = 0.998, Cb = 0.849) and agreement was very good between predictive 99mTc-MAA-SPECT/CT and 90Y-PET/CT dosimetry (mean difference: − 4.05 ± 55.9 Gy; 95%LOA: − 113.7–105.6). After RC correction, 99mTc-MAA-SPECT/CT dosimetry overestimated AD (− 70.9 ± 158.9 Gy; 95%LOA: − 382.3–240.6). For glass microspheres, concordance markedly improved with RC correction (ρ = 0.790, ρc = 0.713, Cb = 0.903 vs without correction: ρ = 0.395, ρc = 0.244, Cb = 0.617) and 99mTc-MAA-SPECT/CT dosimetry underestimated AD (148.9 ± 267.5 Gy; 95%LOA: − 375.4–673.2). For non-tumor liver, concordance was good between 99mTc-MAA-SPECT/CT and 90Y-PET/CT dosimetry (ρ = 0.942, ρc = 0.852, Cb = 0.904). 99mTc-MAA-SPECT/CT slightly overestimated liver AD for resin (3.4 ± 3.4 Gy) and glass (11.5 ± 13.9 Gy) microspheres. Tumor AD was not correlated with baseline or post-SIRT lesion characteristics and no dose–response threshold could be identified. 99mTc-MAA-SPECT/CT dosimetry provides good estimates of AD to tumor and non-tumor liver in UMLM patients treated with first-line SIRT. [ABSTRACT FROM AUTHOR]