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Substrate channeling could be very useful for plant metabolic engineering; hence, we propose that functionalized supramolecular self-assembly scaffolds can act as enzymatic hubs able to perform reactions in close contiguity. Virus nanoparticles (VNPs) offer an opportunity in this context, and we present a functionalization strategy to display different enzymes on the outer surface of three different VNPs produced in plants. Tomato bushy stunt virus (TBSV) and Potato virus X (PVX) plant viruses were functionalized by the genetic fusion of the E-coil peptide coding sequence to their respective coat proteins genes, while the enzyme lichenase was tagged with the K-coil peptide. Immobilized E-coil VNPs were able to interact in vitro with the plant-produced functionalized lichenase, and catalysis was demonstrated by employing a lichenase assay. To prove this concept in planta, the Hepatitis B core (HBc) virus-like particles (VLPs) were similarly functionalized by genetic fusion with the E-coil sequence, while acyl-activating enzyme 1, olivetolic acid synthase, and olivetolic acid cyclase enzymes were tagged with the K-coil. The transient co-expression of the K-coil-enzymes together with E-coil-VLPs allowed the establishment of the heterologous cannabinoid precursor biosynthetic pathway. Noteworthy, a significantly higher yield of olivetolic acid glucoside was achieved when the scaffold E-coil-VLPs were employed.

Sonic hedgehog medulloblastoma (SHH-MB) accounts for 25–30% of all MBs, and conventional therapy results in severe long-term side effects. New targeted therapeutic approaches are urgently needed, drawing also on the fields of nanoparticles (NPs). Among these, plant viruses are very promising, and we previously demonstrated that tomato bushy stunt virus (TBSV), functionalized on the surface with CooP peptide, specifically targets MB cells. Here, we tested the hypothesis that TBSV-CooP can specifically deliver a conventional chemotherapeutic drug (i.e., doxorubicin, DOX) to MB in vivo. To this aim, a preclinical study was designed to verify, by histological and molecular methods, if multiple doses of DOX-TBSV-CooP were able to inhibit tumor progression of MB pre-neoplastic lesions, and if a single dose was able to modulate pro-apoptotic/anti-proliferative molecular signaling in full-blown MBs. Our results demonstrate that when DOX is encapsulated in TBSV-CooP, its effects on cell proliferation and cell death are similar to those obtained with a five-fold higher dose of non-encapsulated DOX, both in early and late MB stages. In conclusion, these results confirm that CooP-functionalized TBSV NPs are efficient carriers for the targeted delivery of therapeutics to brain tumors.

Homing peptides are widely used to improve the delivery of drugs, imaging agents, and nanoparticles (NPs) to their target sites. Plant virus-based particles represent an emerging class of structurally diverse nanocarriers that are biocompatible, biodegradable, safe, and cost-effective. Similar to synthetic NPs, these particles can be loaded with imaging agents and/or drugs and functionalized with affinity ligands for targeted delivery. Here we report the development of a peptide-guided Tomato Bushy Stunt Virus (TBSV)-based nanocarrier platform for affinity targeting with the C-terminal C-end rule (CendR) peptide, RPARPAR (RPAR). Flow cytometry and confocal microscopy demonstrated that the TBSV-RPAR NPs bind specifically to and internalize in cells positive for the peptide receptor neuropilin-1 (NRP-1). TBSV-RPAR particles loaded with a widely used anticancer anthracycline, doxorubicin, showed selective cytotoxicity on NRP-1-expressing cells. Following systemic administration in mice, RPAR functionalization conferred TBSV particles the ability to accumulate in the lung tissue. Collectively, these studies show the feasibility of the CendR-targeted TBSV platform for the precision delivery of payloads.

Sumac, Rhus coriaria L., is a Mediterranean plant showing several useful properties, such as antioxidant and neuroprotective effects. Currently, there is no evidence about its possible neuroprotective action in Parkinson’s disease (PD). We hypothesized that sumac could modulate mitochondrial functionality in fibroblasts of familial early-onset PD patients showing PARK2 mutations. Sumac extract volatile profile, polyphenolic content and antioxidant activity have been previously characterized. We evaluated ROS and ATP levels on sumac-treated patients’ and healthy control fibroblasts. In PD fibroblasts, all treatments were effective in reducing H2O2 levels, while patients’ ATP content was modulated differently, probably due to the varying mutations in the PARK2 gene found in individual patients which are also involved in different mitochondrial phenotypes. We also investigated the effect of sumac extract on THP-1-differentiated macrophages, which show different embryogenic origin with respect to fibroblasts. In THP-1 macrophages, sumac treatment determined a reduction in H2O2 levels and an increase in the mitochondrial ATP content in M1, assuming that sumac could polarize the M1 to M2 phenotype, as demonstrated with other food-derived compounds rich in polyphenols. In conclusion, Rhus coriaria L. extracts could represent a potential nutraceutical approach to PD.

Verticillium wilt (caused by Verticillium dahliae Kleb.) is an important disease affecting olive (Olea europaea L.) production. Effective control of this disease relies on integrated management strategies. In vitro antifungal activity of two hydroxytyrosol (HTyr) enriched extracts (HTE1 and HTE2) obtained from olive mill waste products (OMWP) was assessed against V. dahliae. Inhibitory effects of pure HTyr as a standard, and HTE1 and HTE2 at different concentrations, were evaluated on mycelium growth and conidium germination of V. dahliae. Chemical characterization of HTE1 and HTE2 allowed identification and quantification of HTyr as the main constituent in both extracts along with other low molecular weight phenols. HTE1 showed a higher inhibitory activity in both growth and conidium germination of V. dahliae. At the tested concentrations, low antifungal effects of HTyr were observed. After 3 d, 1 mg mL-1 of HTE1 gave greater inhibition of mycelium growth than HTE2 or HTyr. After 24 h, HTE1 gave 55% inhibition of conidium germination, and HTyr and HTE2 both gave 37% inhibition. This study has demonstrated that phenolic compounds derived from OMWP have antifungal activity against V. dahliae, indicating the potential of these compounds for eco-friendly control of Verticillium wilt.

The COVID-19 pandemic forced healthcare services organization to adjust to mutating healthcare needs. Not exhaustive data are available on the consequences of this on non-COVID-19 patients. The aim of this study was to assess the impact of the pandemic on non-COVID-19 patients living in a one-million inhabitants' area in Northern Italy (Bologna Metropolitan Area-BMA), analyzing time trends of Emergency Department (ED) visits, hospitalizations and mortality. We conducted a retrospective observational study using data extracted from BMA healthcare informative systems. Weekly trends of ED visits, hospitalizations, in- and out-of-hospital, all-cause and cause-specific mortality between December 1st, 2019 to May 31st, 2020, were compared with those of the same period of the previous year. Non-COVID-19 ED visits and hospitalizations showed a stable trend until the first Italian case of COVID-19 has been recorded, on February 19th, 2020, when they dropped simultaneously. The reduction of ED visits was observed in all age groups and across all severity and diagnosis groups. In the lockdown period a significant increase was found in overall out-of-hospital mortality (43.2%) and cause-specific out-of-hospital mortality related to neoplasms (76.7%), endocrine, nutritional and metabolic (79.5%) as well as cardiovascular (32.7%) diseases. The pandemic caused a sudden drop of ED visits and hospitalizations of non-COVID-19 patients during the lockdown period, and a concurrent increase in out-of-hospital mortality mainly driven by deaths for neoplasms, cardiovascular and endocrine diseases. As recurrencies of the COVID-19 pandemic are underway, the scenario described in this study might be useful to understand both the population reaction and the healthcare system response at the early phases of the pandemic in terms of reduced demand of care and systems capability in intercepting it.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has killed more than 37,000 people in Italy and has caused widespread socioeconomic disruption. Urgent measures are needed to contain and control the virus, particularly diagnostic kits for detection and surveillance, therapeutics to reduce mortality among the severely affected, and vaccines to protect the remaining population. Here we discuss the potential role of plant molecular farming in the rapid and scalable supply of protein antigens as reagents and vaccine candidates, antibodies for virus detection and passive immunotherapy, other therapeutic proteins, and virus-like particles as novel vaccine platforms. We calculate the amount of infrastructure and production capacity needed to deal with predictable subsequent waves of COVID-19 in Italy by pooling expertise in plant molecular farming, epidemiology and the Italian health system. We calculate the investment required in molecular farming infrastructure that would enable us to capitalize on this technology, and provide a roadmap for the development of diagnostic reagents and biopharmaceuticals using molecular farming in plants to complement production methods based on the cultivation of microbes and mammalian cells.

Olive oil production is associated with the generation of oil production waste products (OPWPs) rich in water-soluble polyphenols that represent serious environmental problems. Yet OPWPs can offer new opportunities by exploiting their bioactive properties. In this study, we chemically characterized OPWPs polyphenolic extracts and investigated their biological activities in normal and colorectal cancer cells. Hydroxytyrosol (HTyr), the major constituent of these extracts, was used as the control. We show that both HTyr and the extracts affect cell viability by inducing apoptosis and cell cycle arrest. They downregulate inflammation by impairing NF-κB phosphorylation and expression of responsive cytokine genes, as TNF-α and IL-8, at both mRNA and protein levels, and prevent any further increase elicited by external challenges. Mechanistically, HTyr and the extracts activate PPARγ while hampering pro-inflammatory genes expression, acting as a specific agonist, likely through a trans-repression process. Altogether, OPWPs polyphenolic extracts show stronger effects than HTyr, conceivably due to additive or synergistic effects of all polyphenols contained. They display anti-inflammatory properties and these results may pave the way for improving OPWPs extraction and enrichment methods to reduce the environmental impact and support their use to ameliorate the inflammation associated with diseases and tumors.

Rhus coriaria L. (Anacardiaceae), commonly known as sumac, has been used since ancient times for many different applications, and nowadays is used mostly as a spice obtained from its in the Mediterranean and the Middle ground fruits and employed for flavoring and garnishing food, predominantly Eastern regions. Traditionally, sumac has been also used in popular medicine for the treatment of many ailments including hemorrhoids, wound healing, diarrhea, ulcers, and eye inflammation. Sumac drupes are indeed rich in various classes of phytochemicals including organic acids, flavonoids, tannins, and others, which are responsible of their powerful antioxidant capacity, from which treatment of many common diseases such as cardiovascular disease, diabetes, and cancer could benefit. In this work we evaluated the influence of fruit ripeness, conservation, and processing. To this aim, a phytochemical characterization of six different samples of Rhus coriaria L. was carried out. Specifically, headspace solid-phase micro extraction gas chromatography coupled to mass spectrometry and comprehensive two-dimensional liquid chromatography coupled to photodiode array and mass spectrometry detection, were employed. A total of 263 volatile compounds, including terpene hydrocarbons, acids, and aldehydes, as well as 83 polyphenolic compounds, mainly gallic acid derivatives, were positively identified. All samples showed a significant antioxidant activity by means of oxygen radical absorbance capacity, in line with their polyphenolic content and composition. Such findings set a solid ground to support the utilization of this plant as an attractive target for novel nutraceutical approaches and for drug discovery.

Medulloblastoma (MB) is a primary central nervous system tumor affecting mainly young children. New strategies of drug delivery are urgent to treat MB and, in particular, the SHH-dependent subtype—the most common in infants—in whom radiotherapy is precluded due to the severe neurological side effects. Plant virus nanoparticles (NPs) represent an innovative solution for this challenge. Tomato bushy stunt virus (TBSV) was functionally characterized as a carrier for drug targeted delivery to a murine model of Shh-MB. The TBSV NPs surface was genetically engineered with peptides for brain cancer cell targeting, and the modified particles were produced on a large scale using Nicotiana benthamiana plants. Tests on primary cultures of Shh-MB cells allowed us to define the most efficient peptides able to induce specific uptake of TBSV. Immunofluorescence and molecular dynamics simulations supported the hypothesis that the specific targeting of the NPs was mediated by the interaction of the peptides with their natural partners and reinforced by the presentation in association with the virus. In vitro experiments demonstrated that the delivery of Doxorubicin through the chimeric TBSV allowed reducing the dose of the chemotherapeutic agent necessary to induce a significant decrease in tumor cells viability. Moreover, the systemic administration of TBSV NPs in MB symptomatic mice, independently of sex, confirmed the ability of the virus to reach the tumor in a specific manner. A significant advantage in the recognition of the target appeared when TBSV NPs were functionalized with the CooP peptide. Overall, these results open new perspectives for the use of TBSV as a vehicle for the targeted delivery of chemotherapeutics to MB in order to reduce early and late toxicity.

Oxidative stability of food is one of the most important parameters affecting integrity and consequently nutritional properties of dietary constituents. Antioxidants are widely used to avoid deterioration during transformation, packaging, and storage of food. In this paper, novel poly (vinyl alcohol) (PVA)-based films were prepared by solvent casting method adding an hydroxytyrosol-enriched extract (HTyrE) or an oleuropein-enriched extract (OleE) in different percentages (5, 10 and 20% w/w) and a combination of both at 5% w/w. Both extracts were obtained from olive oil wastes and by-products using a sustainable process based on membrane technologies. Qualitative and quantitative analysis of each sample carried out by high performance liquid chromatography (HPLC) and nuclear resonance magnetic spectroscopy (NMR) proved that the main components were hydroxytyrosol (HTyr) and oleuropein (Ole), respectively, two well-known antioxidant bioactive compounds found in Olea europaea L. All novel formulations were characterized investigating their morphological, optical and antioxidant properties. The promising performances suggest a potential use in active food packaging to preserve oxidative-sensitive food products. Moreover, this research represents a valuable example of reuse and valorization of agro-industrial wastes and by-products according to the circular economy model.

Hyponatremia is common in cirrhosis. It mostly occurs in an advanced stage of the disease and is associated with complications and increased mortality. Either hypovolemic or, more commonly, hypervolemic hyponatremia can be seen in cirrhosis. Impaired renal sodium handling due to renal hypoperfusion and increased arginine-vasopressin secretion secondary to reduced effective volemia due to peripheral arterial vasodilation represent the main mechanisms leading to dilutional hyponatremia in this setting. Patients with cirrhosis usually develop slowly progressing hyponatremia. In different clinical contexts, it is associated with neurological manifestations due to increased brain water content, where the intensity is often magnified by concomitant hyperammonemia leading to hepatic encephalopathy. Severe hyponatremia requiring hypertonic saline infusion is rare in cirrhosis. The management of asymptomatic or mildly symptomatic hyponatremia mainly rely on the identification and treatment of precipitating factors. However, sustained resolution of hyponatremia is often difficult to achieve. V2 receptor blockade by Vaptans is certainly effective, but their long-term safety, especially when associated to diuretics given to control ascites, has not been established as yet. As in other conditions, a rapid correction of long-standing hyponatremia can lead to irreversible brain damage. The liver transplant setting represents a condition at high risk for the occurrence of such complications.

Liver involvement in patients with sickle cell anemia/trait includes a wide range of alterations, from mild liver function test abnormalities to cirrhosis and acute liver failure. Approximately 15–30% of patients with sickle cell anemia present cirrhosis at autopsy. The pathogenesis of cirrhosis is usually related to chronic hepatitis B or C infection or to iron overload resulting from the many transfusions received by these patients in their lifetime. Thus, cirrhosis has been described almost exclusively in patients with sickle cell anemia, while only mild liver abnormalities have been associated with the sickle cell trait. In the present case study, we describe a young Mediterranean man carrying a sickle cell trait (Hb Sβ+ thalassemia) who developed liver cirrhosis being negative for hepatitis C and B viruses or for other causes of cirrhosis and not receiving chronic blood transfusions.

Mushroom poisoning is a relatively rare cause of acute liver failure (ALF). The present paper analyzes the pathogenesis, clinical features, prognostic indicators, and therapeutic strategies of ALF secondary to ingestion of Amanita phalloides, which represents the most common and deadly cause of mushroom poisoning. Liver damage from Amanita phalloides is related to the amanitins, powerful toxins that inhibit RNA polymerase II resulting in a deficient protein synthesis and cell necrosis. After an asymptomatic lag phase, the clinical picture is characterized by gastrointestinal symptoms, followed by the liver and kidney involvement. Amatoxin poisoning may progress into ALF and eventually death if liver transplantation is not performed. The mortality rate after Amanita phalloides poisoning ranges from 10 to 20%. The management of amatoxin poisoning consists of preliminary medical care, supportive measures, detoxification therapies, and orthotopic liver transplantation. The clinical efficacy of any modality of treatment is difficult to demonstrate since randomized, controlled clinical trials have not been reported. The use of extracorporeal liver assist devices as well as auxiliary liver transplantation may represent additional therapeutic options.

Azithromycin, a semisynthetic macrolides, is frequently prescribed for the treatment of middle ear and upper respiratory tract infections, bronchitis, and community-acquired pneumonia. This antibiotic is usually well tolerated, and a rapid resolving cholestatic hepatitis has been described up to now only in six patients all, except one, over 65 years of age. We here report the case of a prolonged cholestatic hepatitis after administration of azithromycin in a young woman with no history of liver disease.

Anthropogenic disturbance elicits adaptive responses in wildlife, generally aimed at risk-avoidance, ultimately imposing constraints on their spatial and temporal niches. Previous studies have largely focused on long-term adaptive responses to stable human pressure, but rapid adjustments in wildlife’s diel and habitat use patterns in response to fine-scale variations in human presence have so far been overlooked. In this study we estimate short-term spatio-temporal deviations in local habitat use and diel activity of medium and large mammal species in response to rapid variations in human disturbance. We employed a year-long camera-trapping within a small private reserve, and recorded spatio-temporal information on all sources of anthropogenic disturbance in the area. By controlling for the average habitat use and diel activity, we explored fine-scale spatiotemporal adjustments in seven mammal species. We found evidence of spatial and/or temporal avoidance across all species, except wild boar, with variations in magnitude and direction coherent with species traits and expected levels of human-tolerance. Most species exhibited temporal avoidance of human activities, with porcupine and roe deer eliciting particularly strong responses. Notably, foxes concurrently displayed temporal avoidance and spatial attraction, likely driven by the presence of anthropogenic trophic resources. Our study underscores the role of behavioral plasticity in enabling wildlife to adjust daily habitat use and activity patterns to varying levels of human pressure across space and time. Understanding these nuanced behavioral strategies can help to promote wildlife-human coexistence and mitigating the adverse impacts of human presence on wildlife fitness.

Acoustic indices are cost-efficient tools for monitoring acoustically active taxa. Despite their increasing popularity, their suitability as biodiversity proxies remains debated due to theoretical and practical issues. Existing research has predominantly focused on assessing their capacity to capture species richness and abundance of sounds, with limited attention given to other biodiversity facets like phylogenetic and functional diversity. Yet, phylogenetic distance and trait diversity may influence acoustic communication, so acoustic indices may be better suited to capture their changes than changes in the mere number of species. Here, we investigated the ability of acoustic indices to represent the species, phylogenetic, and functional diversity of acoustically active avian species across three habitat types in Italy: urban, riparian forest and deciduous woodland.Recordings were collected at dawn by a trained ornithologist, who also identified acoustically active species captured, first in the field and secondarily from recordings. We then applied eleven widely used acoustic indices for each recording and tested their ability to capture differences in species, functional and phylogenetic diversity across sites (i.e., listening points) within each habitat type using a linear mixed effect model. We then reduced the acoustic indices dimensionality to a few axes and repeated the analysis to test if compound indices delivered comparable information.Species richness and phylogenetic diversity correlated with at least one acoustic index across the three habitat types, while functional diversity correlated with an index only in the urban habitat. However, the nature of the relationships identified was often opposite to what expected by the indices’ formulation. Furthermore, across the three habitat types the interrelations among indices varied, as well as the observed relationships with diversity indices. Compound indices also exhibited inconsistent relationships across sites and contrary to what expected based on their correlation with acoustic indices.Our results cast doubts on the suitability of acoustic indices as proxies for biodiversity for biodiversity monitoring. Additionally, the inconsistent relationship among indices across the three areas suggests they are unsuitable for geographic comparisons. Temporal comparisons are possible but require local validation and may need adjustments over time of the community composition changes. Despite the attractiveness of acoustic indices as easy and cheap tools for biodiversity monitoring, we urge caution on their application.

Abstract Conservation funding is currently limited; cost‐effective conservation solutions are essential. We suggest that the thousands of field stations worldwide can play key roles at the frontline of biodiversity conservation and have high intrinsic value. We assessed field stations’ conservation return on investment and explored the impact of COVID‐19. We surveyed leaders of field stations across tropical regions that host primate research; 157 field stations in 56 countries responded. Respondents reported improved habitat quality and reduced hunting rates at over 80% of field stations and lower operational costs per km2 than protected areas, yet half of those surveyed have less funding now than in 2019. Spatial analyses support field station presence as reducing deforestation. These “earth observatories” provide a high return on investment; we advocate for increased support of field station programs and for governments to support their vital conservation efforts by investing accordingly.

Abstract Aims The HeartLogic algorithm combines multiple implantable defibrillator (ICD) sensor data and has proved to be a sensitive and timely predictor of impending heart failure (HF) decompensation in cardiac resynchronization therapy (CRT‐D) patients. We evaluated the performance of this algorithm in non‐CRT ICD patients and in the presence of co‐morbidities. Methods and results The HeartLogic feature was activated in 568 ICD patients (410 with CRT‐D) from 26 centres. The median follow‐up was 26 months [25th–75th percentile: 16–37]. During follow‐up, 97 hospitalizations were reported (53 cardiovascular) and 55 patients died. We recorded 1200 HeartLogic alerts in 370 patients. Overall, the time IN the alert state was 13% of the total observation period. The rate of cardiovascular hospitalizations or death was 0.48/patient‐year (95% CI: 0.37–0.60) with the HeartLogic IN the alert state and 0.04/patient‐year (95% CI: 0.03–0.05) OUT of the alert state, with an incidence rate ratio of 13.35 (95% CI: 8.83–20.51, P

Abstract Knowledge of species’ functional traits is essential for understanding biodiversity patterns, predicting the impacts of global environmental changes, and assessing the efficiency of conservation measures. Bats are major components of mammalian diversity and occupy a variety of ecological niches and geographic distributions. However, an extensive compilation of their functional traits and ecological attributes is still missing. Here we present EuroBaTrait 1.0, the most comprehensive and up-to-date trait dataset covering 47 European bat species. The dataset includes data on 118 traits including genetic composition, physiology, morphology, acoustic signature, climatic associations, foraging habitat, roost type, diet, spatial behaviour, life history, pathogens, phenology, and distribution. We compiled the bat trait data obtained from three main sources: (i) a systematic literature and dataset search, (ii) unpublished data from European bat experts, and (iii) observations from large-scale monitoring programs. EuroBaTrait is designed to provide an important data source for comparative and trait-based analyses at the species or community level. The dataset also exposes knowledge gaps in species, geographic and trait coverage, highlighting priorities for future data collection.

Knowledge of biodiversity is unevenly distributed across the Tree of Life. In the long run, such disparity in awareness unbalances our understanding of life on Earth, influencing policy decisions and the allocation of research and conservation funding. We investigated how humans accumulate knowledge of biodiversity by searching for consistent relationships between scientific (number of publications) and societal (number of views in Wikipedia) interest, and species-level morphological, ecological, and sociocultural factors. Across a random selection of 3019 species spanning 29 Phyla/Divisions, we show that sociocultural factors are the most important correlates of scientific and societal interest in biodiversity, including the fact that a species is useful or harmful to humans, has a common name, and is listed in the International Union for Conservation of Nature Red List. Furthermore, large-bodied, broadly distributed, and taxonomically unique species receive more scientific and societal attention, whereas colorfulness and phylogenetic proximity to humans correlate exclusively with societal attention. These results highlight a favoritism toward limited branches of the Tree of Life, and that scientific and societal priorities in biodiversity research broadly align. This suggests that we may be missing out on key species in our research and conservation agenda simply because they are not on our cultural radar.

We call for journals to commit to requiring open data be archived in a format that will be simple and clear for readers to understand and use. If applied consistently, these requirements will allow contributors to be acknowledged for their work through citation of open data, and facilitate scientific progress.

Abstract There is the urgent need to study the effects of immunomodulating agents as therapy for Covid-19. An observational, cohort, prospective study with 30 days of observation was carried out to assess clinical outcomes in 88 patients hospitalized for Covid-19 pneumonia and treated with canakinumab (300 mg sc). Median time from diagnosis of Covid-19 by viral swab to administration of canakinumab was 7.5 days (range 0–30, IQR 4–11). Median PaO2/FiO2 increased from 160 (range 53–409, IQR 122–210) at baseline to 237 (range 72–533, IQR 158–331) at day 7 after treatment with canakinumab (p

Background. Cardiac resynchronization therapy (CRT) is a treatment for heart failure (HF) patients with prolonged QRS and impaired left ventricular (LV) systolic function. We aim to evaluate how the baseline PR interval is associated with outcomes (all-cause death or HF hospitalizations) and LV reverse remodeling (>15% relative reduction in LV end-systolic volume). Methods. Among 2224 patients with CRT defibrillators, 1718 (77.2%) had a device programmed at out-of-the-box settings (sensed AV delay: 100 ms and paced AV delay: 130 ms). Results. In this cohort of 1718 patients (78.7% men, mean age 66 years, 71.6% in NYHA class III/IV, LVEF = 27 ± 6%), echocardiographic assessment at 6-month follow-up showed that LV reverse remodeling was not constant as a function of the PR interval; in detail, it occurred in 56.4% of all patients but was more frequent (76.6%) in patients with a PR interval of 160 ms. In a median follow-up of 20 months, the endpoint of death or HF hospitalizations occurred in 304/1718 (17.7%) patients; in the multivariable regression analysis it was significantly less frequent when the PR interval was between 150 and 170 ms (hazard ratio = 0.79, 95% confidence interval (CI): 0.63–0.99, p = 0.046). The same PR range was associated with higher probability of CRT response (odds ratio = 2.51, 95% CI: 1.41–4.47, p = 0.002). Conclusions. In a large population of CRT patients, with fixed AV pacing delays, specific PR intervals are associated with significant benefits in terms of LV reverse remodeling and lower morbidity. These observational data suggest the importance of optimizing pacing programming as a function of the PR interval to maximize CRT response and patient outcome.

Aims: The utilization of remote monitoring platforms was recommended amidst the COVID-19 pandemic. The HeartLogic index combines multiple implantable cardioverter defibrillator (ICD) sensors and has proved to be a predictor of impending heart failure (HF) decompensation. We examined how multiple ICD sensors behave in the periods of anticipated restrictions pertaining to physical activity. Methods: The HeartLogic feature was active in 349 ICD and cardiac resynchronization therapy ICD patients at 20 Italian centers. The period from 1 January to 19 July 2020, was divided into three phases: pre-lockdown (weeks 1–11), lockdown (weeks 12–20), post-lockdown (weeks 21–29). Results: Immediately after the implementation of stay-at-home orders (week 12), we observed a significant drop in median activity level whereas there was no difference in the other contributing parameters. The median composite HeartLogic index increased at the end of the Lockdown. The weekly rate of alerts was significantly higher during the lockdown (1.56 alerts/week/100 pts, 95%CI: 1.15–2.06; IRR = 1.71, p = 0.014) and post-lockdown (1.37 alerts/week/100 pts, 95%CI: 0.99–1.84; IRR = 1.50, p = 0.072) than that reported in pre-lockdown (0.91 alerts/week/100 pts, 95%CI: 0.64–1.27). However, the median duration of alert state and the maximum index value did not change among phases, as well as the proportion of alerts followed by clinical actions at the centers and the proportion of alerts fully managed remotely. Conclusions: During the lockdown, the system detected a significant drop in the median activity level and generated a higher rate of alerts suggestive of worsening of the HF status.

Background: The incidence of infections associated with cardiac implantable electronic devices (CIEDs) and patient outcomes are not fully known. Aim: To provide a contemporary assessment of the risk of CIEDs infection and associated clinical outcomes. Methods: In Italy, 18 centres enrolled all consecutive patients undergoing a CIED procedure and entered a 12-months follow-up. CIED infections, as well as a composite clinical event of infection or all-cause death were recorded. Results: A total of 2675 patients (64.3% male, age 78 (70–84)) were enrolled. During follow up 28 (1.1%) CIED infections and 132 (5%) deaths, with 152 (5.7%) composite clinical events were observed. At a multivariate analysis, the type of procedure (revision/upgrading/reimplantation) (OR: 4.08, 95% CI: 1.38–12.08) and diabetes (OR: 2.22, 95% CI: 1.02–4.84) were found as main clinical factors associated to CIED infection. Both the PADIT score and the RI-AIAC Infection score were significantly associated with CIED infections, with the RI-AIAC infection score showing the strongest association (OR: 2.38, 95% CI: 1.60–3.55 for each point), with a c-index = 0.64 (0.52–0.75), p = 0.015. Regarding the occurrence of composite clinical events, the Kolek score, the Shariff score and the RI-AIAC Event score all predicted the outcome, with an AUC for the RI-AIAC Event score equal to 0.67 (0.63−0.71) p < 0.001. Conclusions: In this Italian nationwide cohort of patients, while the incidence of CIED infections was substantially low, the rate of the composite clinical outcome of infection or all-cause death was quite high and associated with several clinical factors depicting a more impaired clinical status.

Flecainide is an IC antiarrhythmic drug (AAD) that received in 1984 Food and Drug Administration approval for the treatment of sustained ventricular tachycardia (VT) and subsequently for rhythm control of atrial fibrillation (AF). Currently, flecainide is mainly employed for sinus rhythm maintenance in AF and the treatment of idiopathic ventricular arrhythmias (IVA) in absence of ischaemic and structural heart disease on the basis of CAST data. Recent studies enrolling patients with different structural heart diseases demonstrated good effectiveness and safety profile of flecainide. The purpose of this review is to assess current evidence for appropriate and safe use of flecainide, 30 years after CAST data, in the light of new diagnostic and therapeutic tools in the field of ischaemic and non-ischaemic heart disease.

This paper presents the statistical power estimation of goodness-of-fit tests for Extreme Value Theory (EVT) distributions. The presented dataset provides quantitative information on the statistical power, in order to enable the sample size selection in external validation scenario. In particular, high precision estimations of the statistical power of KS, AD, and MAD goodness-of-fit tests have been computed using a Monte Carlo approach. The full raw dataset resulting from this analysis has been published as reference for future studies: https://doi.org/10.17632/hh2byrbbmf.1.

Tropical forests are increasingly degraded by industrial logging, urbanization, agriculture, and infrastructure, with only 20% of the remaining area considered intact. However, this figure does not include other, more cryptic but pervasive forms of degradation, such as overhunting. Here, we quantified and mapped the spatial patterns of mammal defaunation in the tropics using a database of 3,281 mammal abundance declines from local hunting studies. We simultaneously accounted for population abundance declines and the probability of local extirpation of a population as a function of several predictors related to human accessibility to remote areas and species' vulnerability to hunting. We estimated an average abundance decline of 13% across all tropical mammal species, with medium-sized species being reduced by >27% and large mammals by >40%. Mammal populations are predicted to be partially defaunated (i.e., declines of 10%-100%) in ca. 50% of the pantropical forest area (14 million km2), with large declines (>70%) in West Africa. According to our projections, 52% of the intact forests (IFs) and 62% of the wilderness areas (WAs) are partially devoid of large mammals, and hunting may affect mammal populations in 20% of protected areas (PAs) in the tropics, particularly in West and Central Africa and Southeast Asia. The pervasive effects of overhunting on tropical mammal populations may have profound ramifications for ecosystem functioning and the livelihoods of wild-meat-dependent communities, and underscore that forest coverage alone is not necessarily indicative of ecosystem intactness. We call for a systematic consideration of hunting effects in (large-scale) biodiversity assessments for more representative estimates of human-induced biodiversity loss.

Transcatheter ablation was increasingly and successfully used to treat symptomatic drug refractory patients affected by supraventricular arrhythmias. Antiarrhythmic drug treatment still plays a major role in patient management, alone or combined with non-pharmacological therapies. Flecainide is an IC antiarrhythmic drug approved in 1984 from the Food and Drug Administration for the suppression of sustained ventricular tachycardia and later for acute cardioversion of atrial fibrillation and for sinus rhythm maintenance. Currently, flecainide is mostly used for sinus rhythm maintenance in atrial fibrillation (AF) patients without structural cardiomyopathy although recent studies enrolling different patient populations have demonstrated a good effectiveness and safety profile. How should we interpret the results of the CAST after the latest evidence? Is it possible to expand the indications of flecainide, and therefore, its use? This review aims to highlight the main characteristics of flecainide, as well as its optimal clinical use, delineating drug indications and contraindications and appropriate monitoring, based on the most recent evidence.

A feeling of uncertainty about the future as well as the perception that the past classical securities are gone are widely spread among people. Criticism or disaffection affects the majority of the traditional political forces of the European continent. It is not possible to talk about the European crisis without referring to the crisis of the wage-based society. All political options of the past century have de facto put labour at the centre of society. The post-classical era got its start in the ’80s when, for the first time since World War II, the phenomenon of mass unemployment affected Europe. The crisis of wage labour cannot be regarded as a temporary economic conjuncture of an otherwise unlimited growth, all consequences of the phase must be contemplated in order to design at once a society based on new principles. For years, after the end of the Fordist system, nothing has been done to cope with the conditions of precarious workers. The issue of a guaranteed income is, therefore, crucial and inescapable in order to exit this long-term European crisis. The European Union should take a stand on the protection of human dignity and on the “right to exist”. Could basic income at the continental level be the basis for a social Europe? We are looking forward to it.

Abstract In the last few years we are witnessing a dramatic increase in the number of CIEDs implanted. At the same time new emitters are constantly entering the marketplace and more and more medical procedures are based on electromagnetic fields as well. Therefore, the topic of the interaction of CIEDs with the EMI is a real, actual and challenging one. In the non‐medical environment several types of devices may be intentional or non‐intentional sources of EMI. Most of the studies reported in literature focused on mobile phones, metal detectors, as well as on headphones or digital players, but many other instruments and tools may generate electromagnetic fields. In the medical environment most of the attention is paid to MRI and recently new PM and MRI conditional ICDs have been developed and launched in the market, but the risk of interaction is present also with ionizing radiation, electrical nerve stimulation and electrosurgery. Pacemaker/ICD manufacturers are incorporating state of the art technology to make implantable devices less susceptible to EMI. However, patients and emitter manufacturers should be aware that limitations exist and that there is not complete immunity to EMI.

Generation length (GL) is defined as the average age of parents of the current cohort, reflecting the turnover rate of breeding individuals in a population. GL is a fundamental piece of information for population ecology as well as for measuring species threat status (e.g. in the IUCN Red List). Here we present a dataset including GL records for all extant mammal species (n=5427). We first reviewed all data on GL published in the IUCN Red List database. We then calculated a value for species with available reproductive parameters (reproductive life span and age at first reproduction). We assigned to missing-data species a mean GL value from congeneric or confamilial species (depending on data availability). Finally, for a few remaining species, we assigned mean GL values from species with similar body mass and belonging to the same order. Our work provides the first attempt to complete a database of GL for mammals; it will be an essential reference point for all conservation-related studies that need pragmatic information on species GL, such as population dynamics and applications of the IUCN Red List assessment.

One of the biggest challenges in large-scale conservation is quantifying connectivity at broad geographic scales and for a large set of species. Because connectivity analyses can be computationally intensive, and the planning process quite complex when multiple taxa are involved, assessing connectivity at large spatial extents for many species turns to be often intractable. Such limitation results in that conducted assessments are often partial by focusing on a few key species only, or are generic by considering a range of dispersal distances and a fixed set of areas to connect that are not directly linked to the actual spatial distribution or mobility of particular species. By using a graph theory framework, here we propose an approach to reduce computational effort and effectively consider large assemblages of species in obtaining multi-species connectivity priorities. We demonstrate the potential of the approach by identifying defragmentation priorities in the Italian road network focusing on medium and large terrestrial mammals. We show that by combining probabilistic species graphs prior to conducting the network analysis (i) it is possible to analyse connectivity once for all species simultaneously, obtaining conservation or restoration priorities that apply for the entire species assemblage; and that (ii) those priorities are well aligned with the ones that would be obtained by aggregating the results of separate connectivity analysis for each of the individual species. This approach offers great opportunities to extend connectivity assessments to large assemblages of species and broad geographic scales.

No previous reports are available about the potential dramatic effects resulting from the combination of acquired long QT interval not associated to bradycardia and myocardial ischemia. We report the case of a man that during acute necrotic pancreatitis presented QT interval prolongation without bradycardia, TdP, and two episodes of cardiac arrest. A coronary angiogram revealed a subocclusive stenosis of left anterior descending coronary artery, treated with a percutaneous coronary intervention. After myocardial revascularization, even in presence of long QT interval, no arrhythmic events occurred suggesting the key role of myocardial ischemia in triggering TdP in acquired long QT even without bradycardia. ECG performed six months later, after complete recovery from pancreatitis, showed a normal QT interval.

Atrial fibrillation is a common clinical disease especially in the elderly and in patients with organic heart disease. Electrical cardioversion is the first choice therapeutic approach for patients in which sinus rhythm could improve the quality of life and where the maintenance of sinus rhythm is considered likely. There are different techniques to perform an electrical cardioversion, each with specific indications, advantages, and limitations. The method most frequently used to restore sinus rhythm is external direct current cardioversion; however, this technique has some disadvantages, since it requires a high energy and usually general anesthesia. Esophageal cardioversion is an alternative method to obtain restoration of sinus rhythm, warranting acute and long-term results absolutely comparable with those obtained by the conventional transthoracic technique, especially in obese and COPD patients with high thoracic impedance for whom the standard technique may be less effective.