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ABSTRACTIntroduction Diabetic patients are at a higher risk of getting pneumococcal disease and are therefore recommended to get vaccinated. The aim of our systematic review is the retrieval and analysis of all available evidence on the effect of pneumococcal vaccination on the risk of hospitalization and death in adult patients with diabetes.Research design and methods MEDLINEand EMBASE were searched from inception until January 2023. We included all studies investigating whether pneumococcal vaccination reduces the risk of dying or being hospitalized in diabetic patients. The Newcastle-Ottawa scale was used to assess risk of bias. Results Only two studies, encompassing a total of 68,246 subjects, were considered eligible for inclusion and of high quality. In both studies polysaccharide pneumococcal vaccination was associated with a reduction of the risk of hospitalization or death in adult diabetic patients (aHR: 0.76 in one study, aOR: 0.97 in the other one). However, in neither of the two included studies the lower risk was statistically significant.Conclusions Further research is needed due to the potentially major clinical implications for diabetic patients. The results of this systematic review can serve as a foundation for future studies, indicating the importance of continuing research in this area to improve patient outcomes.

Abstract Testing density-dependence and path-dependence in long-term population dynamics under differentiated local contexts contributes to delineate the changing role of socioeconomic forces at the base of regional disparities. Despite a millenary settlement history, such issue has been rarely investigated in Europe, and especially in highly divided countries such as those in the Mediterranean region. Using econometric modeling to manage spatial heterogeneity, our study verifies the role of selected drivers of population growth at ten times between 1921 and 2021 in more than 8000 Italian municipalities verifying density-dependent and path-dependent dynamics. Results of global and quantile (spatial) regressions highlight a differential impact of density and (lagged) population growth on demographic dynamics along the urban cycle in Italy. Being weakly significant in the inter-war period (1921–1951), econometric models totalized a high goodness-of-fit in correspondence with compact urbanization (1951–1981). Model’s fit declined in the following decades (1981–2021) reflecting suburbanization and counter-urbanization. Density-dependence and path-dependence were found significant and, respectively, positive or negative, with compact urbanization, and much less intense with suburbanization and counter-urbanization. A spatial econometric investigation of density-dependent and path-dependent mechanisms of population dynamics provided an original explanation of metropolitan cycles, delineating the evolution of socioeconomic (local) systems along the urban-rural gradient.

Abstract Background Lynch syndrome (LS) is the most common cause of inherited colorectal cancer (CRC). Universal tumor screening (UTS) of newly diagnosed CRC cases is recommended to aid in diagnosis of LS and reduce cancer-related morbidity and mortality. However, not all health systems have adopted UTS processes and implementation may be inconsistent due to system and patient-level complexities. Methods To identify barriers, facilitators, and suggestions for improvements of the UTS process from the patient perspective, we conducted in-depth, semi-structured interviews with patients recently diagnosed with CRC, but not screened for or aware of LS. Patients were recruited from eight regionally diverse US health systems. Interviews were conducted by telephone, 60-minutes, audio-recorded, and transcribed. An inductive, constant comparative analysis approach was employed. Results We completed 75 interviews across the eight systems. Most participants were white (79%), about half (52%) were men, and the mean age was 60 years. Most self-reported either no (60%) or minimal (40%) prior awareness of LS. Overall, 96% of patients stated UTS should be a routine standard of care for CRC tumors, consistently citing four primary motivations for wanting to know their LS status and engage in the process for LS identification: “knowledge is power”; “family knowledge”; “prevention and detection”; and “treatment and surveillance.” Common concerns pertaining to the process of screening for and identifying LS included: creating anticipatory worry for patients, the potential cost and the accuracy of the genetic test, and possibly having one’s health insurance coverage impacted by the LS diagnosis. Patients suggested health systems communicate LS results in-person or by phone from a trained expert in LS; offer proactive verbal and written education about LS, the screening steps, and any follow-up surveillance recommendations; and support patients in communicating their LS screening to any of their blood relatives. Conclusion Our qualitative findings demonstrate patients with CRC have a strong desire for healthcare systems to regularly implement and offer UTS. Patients offer key insights for health systems to guide future implementation and optimization of UTS and other LS screening programs and maximize diagnosis of individuals with LS and improve cancer-related surveillance and outcomes. Trial registration Not available: not a clinical trial.

Abstract Background Colorectal cancer (CRC) is the third most deadly and fourth most diagnosed cancer worldwide. Despite the progress in early diagnosis and advanced therapeutic options, CRC shows a poor prognosis with a 5 year survival rate of ~ 45%. PRDM2/RIZ, a member of PR/SET domain family (PRDM), expresses two main molecular variants, the PR-plus isoform (RIZ1) and the PR-minus (RIZ2). The imbalance in their expression levels in favor of RIZ2 is observed in many cancer types. The full length RIZ1 has been extensively investigated in several cancers where it acts as a tumor suppressor, whereas few studies have explored the RIZ2 oncogenic properties. PRDM2 is often target of frameshift mutations and aberrant DNA methylation in CRC. However, little is known about its role in CRC. Methods We combined in-silico investigation of The Cancer Genome Atlas (TCGA) CRC datasets, cellular and molecular assays, transcriptome sequencing and functional annotation analysis to assess the role of RIZ2 in human CRC. Results Our in-silico analysis on TCGA datasets confirmed that PRDM2 gene is frequently mutated and transcriptionally deregulated in CRC and revealed that a RIZ2 increase is highly correlated with a significant RIZ1 downregulation. Then, we assayed several CRC cell lines by qRT-PCR analysis for the main PRDM2 transcripts and selected DLD1 cell line, which showed the lowest RIZ2 levels. Therefore, we overexpressed RIZ2 in these cells to mimic TCGA datasets analysis results and consequently to assess the PRDM2/RIZ2 role in CRC. Data from RNA-seq disclosed that RIZ2 overexpression induced profound changes in CRC cell transcriptome via EGF pathway deregulation, suggesting that RIZ2 is involved in the EGF autocrine regulation of DLD1 cell behavior. Noteworthy, the forced RIZ2 expression increased cell viability, growth, colony formation, migration and organoid formation. These effects could be mediated by the release of high EGF levels by RIZ2 overexpressing DLD1 cells. Conclusions Our findings add novel insights on the putative RIZ2 tumor-promoting functions in CRC, although additional efforts are warranted to define the underlying molecular mechanism.

Ixodes ricinus ticks are ubiquitous in Europe, including in North-East Italy. These ticks are important vectors of several zoonotic pathogens of public health relevance. In this study, the habitat suitability range of I. ricinus ticks infected with zoonotic pathogens was predicted in North-East Italy, and relevant spatial predictors were identified. In 2015–2021, ticks were collected at 26 sampling sites in the study area. The collected ticks were screened for the presence of pathogens using PCR assays. For Borrelia, Rickettsia and Anaplasma/Ehrlichia species, data allowed for ecological niche modelling using Maxent. Environmental determinants potentially related to tick habitat suitability were used as model inputs. Predicted suitable habitat distributions revealed hotspots of the probability of pathogen presence in I. ricinus ticks mainly in the central and upper parts of the study area. Key environmental predictors were temperature, rainfall and altitude, and vegetation index for specific pathogens (Rickettsia and Anaplasma/Ehrlichia species). Increased risk of exposure to tick-borne pathogens upon tick bites in the predicted hotspot areas can, therefore, be expected. This provides useful information for public health risk managers in this and other similar regions.

Biological drugs, including monoclonal antibodies, represent a revolutionary strategy in all fields of medicine, offering promising results even in the treatment of osteoarthritis (OA). However, their safety and efficacy have not been fully validated, highlighting the need for in-depth studies. Therefore, we provided a comprehensive systematic review of the intra-articular use of monoclonal antibodies for the treatment of OA in animal models, reflecting ongoing efforts to advance therapeutic strategies and improve patient outcomes. A systematic literature search was conducted in December 2023 following the PRISMA guidelines, using the Web of Science, Google Scholar, and PUBMED databases. Out of a total of 456, 10 articles were included in the study analyzing intra-articular antibodies and focusing on various targets, including vascular endothelial growth factor (VEGF), nerve growth factor (NGF), interleukin 4-10 (IL4-10), tumor necrosis factor α (TNF-α), a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5), and matrix metalloproteinase 13 (MMP-13). Most studies administered the antibodies weekly, ranging from 1 to 10 injections. Animal models varied, with mean follow-up periods of 8.9 ± 4.1 weeks. The methods of assessing outcomes, including pain and morpho-functional changes, varied. Some studies reported only morphological and immunohistochemical data, while others included a quantitative analysis of protein expression. In conclusion, monoclonal antibodies represent a promising avenue in the treatment of OA, offering targeted approaches to modulate disease pathways. Further research and clinical trials are needed to validate their safety and efficacy, with the potential to revolutionize the management of OA and reduce reliance on prosthetic interventions.

The present study investigates territorial disparities in selected socioeconomic forces and environmental factors underlying soil degradation that may lead to early desertification processes in a dry Mediterranean region exposed to increasing human pressure. To verify if spatial disparities in land resources have increased over time, a standard approach based on the Environmentally Sensitive Area Index (ESAI) was adopted to evaluate sixty years of territorial transformations in Latium, Central Italy, a region prone to intense processes of land resource depletion. The ESAI provides a standard, holistic assessment of soil degradation based on the estimation of four different ‘resource qualities’ (climate, soil, vegetation, and land use) and their change over sufficiently long time windows; in this study, the procedure was run at three reference years (1960, 1990, and 2020). The observed divergence in soil degradation levels between coastal and inland districts arose during the study period, with a consequent reduction in the local-scale variability of the ESAI. Such differential processes observed along the elevation gradient in Central Italy are likely due to anthropogenic factors affecting land use and leveraging crop intensification in flat districts and farmland abandonment in steep areas. New findings to be achieved in the context of human impacts on land resource depletion are regarded as an original contribution to the study of early desertification processes in advanced economies.

Background: Varicella infections follow a benign course in around 90% of cases, with more severe forms occurring in adults. To identify potential pockets of susceptibility and to improve targeted immunization strategies, this study aims to critically assess immunological status by evaluating varicella seroprevalence among adults (18–99 years) in the province of Florence (Italy), nearly a decade after Tuscany introduced the vaccination program. Methods: A convenience sample of 430 subjects aged 18 to 94 years (mean age 51.8 ± 18.8 years), stratified by age and sex (53.7% of subjects were female; N = 231), was collected between 2018 and 2019. Sero-analytical analyses were conducted utilizing EUROIMMUN Anti-VZV ELISA (IgG) kits. Results: Most of them were of Italian nationality (87.4%; N = 376). Among the 430 tested samples, 385 (89.5%) were positive and 39 (9.1%) were negative. The remaining six sera (1.4%), confirmed as equivocal, were excluded from further analysis. No significant differences were found based on sex (p-value = 0.706) or nationality (p-value = 0.112). The application of trend tests (Mantel–Haenszel; Kendall Tau-b) showed a significant trend (p < 0.024 and p < 0.032, respectively), with an increasing probability of finding a positive anti-varicella serological status passing from a lower age group (84.2%) to a higher one (93.0%). By considering the female population aged 18–49 years, the seroprevalence of anti-varicella antibodies was found to be 88.4%, with a susceptibility of 11.6%, highlighting the risk of acquiring infection during pregnancy. Conclusions: The introduction of varicella vaccination has had a significant impact on public health in Tuscany and in Italy more generally. However, further efforts should be made to reduce the number of individuals still susceptible in adulthood, with particular attention given to women of childbearing age and the promotion of vaccination through mass and social media and institutional websites.

Being intertwined with economic development, urbanization determines the present and future development path of regions and countries. The intimate relationship between urban expansion and economic development is of particular interest in the case of large regions with complex (and mostly non-linear) socio-demographic dynamics and a relevant primacy in the metropolitan system of a given country. Typical examples of advanced economies with settlement systems characterized by a high degree of city primacy are peripheral and disadvantaged European countries such as Portugal and Greece. For instance, the administrative region of Attica—centered on Athens, the Greek capital city—represents the largest metropolitan area of the country, hosting almost 3.8 million inhabitants in 2021 (36.2% of the Greek population). In this context, this study investigates the internal redistribution of the resident population in metropolitan Athens and the progressive development of satellite cities over a relatively longtime interval, testing the assumptions of the Spatial Cycle Theory (SCT) between 1951 and 2021 and predicting future development paths up to 2051. To investigate past, present, and future intra-regional population trends, we used data released from decadal (1951–2021) censuses and demographic forecasts for the years 2031, 2041, and 2051. Being in line with the SCT, the empirical results of our study document how demographic dynamics of individual centers influence largely—and independently—the long-term development of metropolitan regions, both with policy/planning regulation and in conditions of non-intervention (spontaneous urban growth).

The global effects of climate change will increase the frequency and intensity of extreme events such as heatwaves and power outages, which have consequences for buildings and their cooling systems. Buildings and their cooling systems should be designed and operated to be resilient under such events to protect occupants from potentially dangerous indoor thermal conditions. This study performed a critical review on the state-of-the-art of cooling strategies, with special attention to their performance under heatwaves and power outages. We proposed a definition of resilient cooling and described four criteria for resilience—absorptive capacity, adaptive capacity, restorative capacity, and recovery speed —and used them to qualitatively evaluate the resilience of each strategy. The literature review and qualitative analyses show that to attain resilient cooling, the four resilience criteria should be considered in the design phase of a building or during the planning of retrofits. The building and relevant cooling system characteristics should be considered simultaneously to withstand extreme events. A combination of strategies with different resilience capacities, such as a passive envelope strategy coupled with a low-energy space-cooling solution, may be needed to obtain resilient cooling. Finally, a further direction for a quantitative assessment approach has been pointed out.

Impaired synaptic neurotransmission may underly circuit alterations contributing to behavioral autism spectrum disorder (ASD) phenotypes. A critical component of impairments reported in somatosensory and prefrontal cortex of ASD mouse models are parvalbumin (PV)-expressing fast-spiking interneurons. However, it remains unknown whether PV interneurons mediating hippocampal networks crucial to navigation and memory processing are similarly impaired. Using PV-labeled transgenic mice, a battery of behavioral assays, in vitro patch-clamp electrophysiology, and in vivo 32-channel silicon probe local field potential recordings, we address this question in a Cntnap2-null mutant mouse model representing a human ASD risk factor gene. Cntnap2-/- mice show a reduction in hippocampal PV interneuron density, reduced inhibitory input to CA1 pyramidal cells, deficits in spatial discrimination ability, and frequency-dependent circuit changes within the hippocampus, including alterations in gamma oscillations, sharp-wave ripples, and theta-gamma modulation. Our findings highlight hippocampal involvement in ASD and implicate interneurons as a potential therapeutical target.

We conducted a preregistered multilaboratory project (k = 36; N = 3,531) to assess the size and robustness of ego-depletion effects using a novel replication method, termed the paradigmatic replication approach. Each laboratory implemented one of two procedures that was intended to manipulate self-control and tested performance on a subsequent measure of self-control. Confirmatory tests found a nonsignificant result (d = 0.06). Confirmatory Bayesian meta-analyses using an informed-prior hypothesis (δ = 0.30, SD = 0.15) found that the data were 4 times more likely under the null than the alternative hypothesis. Hence, preregistered analyses did not find evidence for a depletion effect. Exploratory analyses on the full sample (i.e., ignoring exclusion criteria) found a statistically significant effect (d = 0.08); Bayesian analyses showed that the data were about equally likely under the null and informed-prior hypotheses. Exploratory moderator tests suggested that the depletion effect was larger for participants who reported more fatigue but was not moderated by trait self-control, willpower beliefs, or action orientation.

Abstract In the current accelerated process of global warming, forest conservation is becoming more difficult to address in developing countries, where woodlands are often fueling the illegal economy. In Colombia, the issue of narcodeforestation is of great concern, because of the ramification of narcoactivities that are affecting forests, such as agribusinesses and cattle ranching for money laundering. In this study, we use spatially explicit regressions incorporating a factor decomposition of predictors through principal component analysis to understand the impact of coca plantations on global and local-scale deforestation in Colombia. At national level we find a positive and statistically significant relationship between coca crops and deforestation. At the regional level, in two out of four regions, it appears that coca is causing deforestation, especially in the Department of Northern Santander and on the Pacific coast. The spatial models used reveal not only a direct effect but also positive and significant spillover effects, in line with the conjecture that narcodeforestation is not only due to the quest for new areas to expand coca-cultivation, which would determine a loss of forest only in the municipality where coca cultivation increases, but also to the need to launder illegal profits, or create clandestine routes and airplane strips, which can affect forests also in nearby municipalities.

Abstract Background Tracheal compression (TC) due to vascular anomalies is an uncommon, but potentially serious cause of chronic respiratory disease in childhood. Vascular slings are congenital malformations resulting from abnormal development of the great vessels; in this group of disorders the most prevalent entity is the aberrant innominate artery (AIA). Here we provide a report on diagnosis and treatment of AIA in nine children with unexplained chronic respiratory symptoms. We describe the cases, perform a literature review, and provide a discussion on the diagnostic workup and treatment that can help manage AIA. Methods Clinical history, diagnostic procedures and treatment before and after the AIA diagnosis were retrospectively reviewed in nine children (5 boys and 4 girls), who were referred for recurrent-to-chronic respiratory manifestations over 10 years (2012–2022). We performed a comprehensive report on the ongoing clinical course and treatment as well as an electronic literature search on the topic. Results Diagnoses at referral, before AIA was identified, were chronic dry barking cough associated with recurrent pneumonia (n = 8, 89%), lobar/segmental atelectasis (n = 3, 33%), atopic/non atopic asthma (n = 3, 33%); pneumomediastinum with subcutaneous emphysema complicated the clinical course in one case. When referred to our Unit, all patients had been previously treated with repeated antibiotic courses (n = 9, 100%), alone (n = 6, 67%) or combined with prolonged antiasthma medications (n = 3, 33%) and/or daily chest physiotherapy (n = 2, 22%), but reported only partial clinical benefit. Median ages at symptom onset and at AIA diagnosis were 1.5 [0.08–13] and 6 [4–14] years, respectively, with a relevant delay in the definitive diagnosis (4.5 years). Tracheal stenosis at computed tomography (CT) was ≥ 51% in 4/9 cases and ≤ 50% in the remaining 5 subjects. Airway endoscopy was performed in 4 cases with CT evidence of tracheal stenosis ≥ 51% and confirmed CT findings. In these 4 cases, the decision of surgery was made based on endoscopy and CT findings combined with persistence of clinical symptoms despite medical treatment. The remaining 5 children were managed conservatively. Conclusions TC caused by AIA may be responsible for unexplained chronic respiratory disease in childhood. Early diagnosis of AIA can decrease the use of expensive investigations or unsuccessful treatments, reduce disease morbidity, and accelerate the path toward a proper treatment.

Abstract Systematic and timely documentation of triggered (i.e. event) landslides is fundamental to build extensive datasets worldwide that may help define and/or validate trends in response to climate change. More in general, preparation of landslide inventories is a crucial activity since it provides the basic data for any subsequent analysis. In this work we present an event landslide inventory map (E-LIM) that was prepared through a systematic reconnaissance field survey in about 1 month after an extreme rainfall event hit an area of about 5000 km2 in the Marche-Umbria regions (central Italy). The inventory reports evidence of 1687 triggered landslides in an area of ~550 km2. All slope failures were classified according to type of movement and involved material, and documented with field pictures, wherever possible. The database of the inventory described in this paper as well as the collection of selected field pictures associated with each feature is publicly available at figshare.

Abstract In terms of lipid nanoparticle (LNP) engineering, the relationship between particle composition, delivery efficacy, and the composition of the biocoronas that form around LNPs, is poorly understood. To explore this we analyze naturally efficacious biocorona compositions using an unbiased screening workflow. First, LNPs are complexed with plasma samples, from individual lean or obese male rats, and then functionally evaluated in vitro. Then, a fast, automated, and miniaturized method retrieves the LNPs with intact biocoronas, and multiomics analysis of the LNP-corona complexes reveals the particle corona content arising from each individual plasma sample. We find that the most efficacious LNP-corona complexes were enriched with high-density lipoprotein (HDL) and, compared to the commonly used corona-biomarker Apolipoprotein E, corona HDL content was a superior predictor of in-vivo activity. Using technically challenging and clinically relevant lipid nanoparticles, these methods reveal a previously unreported role for HDL as a source of ApoE and, form a framework for improving LNP therapeutic efficacy by controlling corona composition.

IntroductionAbout 50% of cutaneous melanoma (CM) patients present activating BRAF mutations that can be effectively targeted by BRAF inhibitors (BRAFi). However, 20% of CM patients exhibit intrinsic drug resistance to BRAFi, while most of the others develop adaptive resistance over time. The mechanisms involved in BRAFi resistance are disparate and globally seem to rewire the cellular signaling profile by up-regulating different receptor tyrosine kinases (RTKs), such as the epidermal growth factor receptor (EGFR). RTKs inhibitors have not clearly demonstrated anti-tumor activity in BRAFi resistant models. To overcome this issue, we wondered whether the shared up-regulated RTK phenotype associated with BRAFi resistance could be exploited by using immune weapons as the antibody-dependent cell cytotoxicity (ADCC)-mediated effect of anti-RTKs antibodies, and kill tumor cells independently from the mechanistic roots.Methods and resultsBy using an in vitro model of BRAFi resistance, we detected increased membrane expression of EGFR, both at mRNA and protein level in 4 out of 9 BRAFi-resistant (VR) CM cultures as compared to their parental sensitive cells. Increased EGFR phosphorylation and AKT activation were observed in the VR CM cultures. EGFR signaling appeared dispensable for maintaining resistance, since small molecule-, antibody- and CRISPR-targeting of EGFR did not restore sensitivity of VR cells to BRAFi. Importantly, immune-targeting of EGFR by the anti-EGFR antibody cetuximab efficiently and specifically killed EGFR-expressing VR CM cells, both in vitro and in humanized mouse models in vivo, triggering ADCC by healthy donors’ and patients’ peripheral blood cells. ConclusionOur data demonstrate the efficacy of immune targeting of RTKs expressed by CM relapsing on BRAFi, providing the proof-of-concept supporting the assessment of anti-RTK antibodies in combination therapies in this setting. This strategy might be expected to concomitantly trigger the crosstalk of adaptive immune response leading to a complementing T cell immune rejection of tumors.

We report the first case of anti-melanoma differentiation-associated gene 5 (MDA5)-positive dermatomyositis as a systemic immune-related adverse event in a 64-year-old man receiving pembrolizumab to treat advanced lung cancer. The patient experienced hypothyroidism, myalgia, skin involvement, dyspnoea and diarrhoea. Laboratory tests revealed raised inflammatory markers, hypercreatinekinasemia and anti-MDA5 autoantibodies. Electroneuromyography and pathognomonic signs on physical examination confirmed the diagnosis of pauci-myopathic dermatomyositis. Pembrolizumab was discontinued and immunosuppressive therapy led to rapid and progressive improvement, with complete remission of dermatomyositis. This case report widens the spectrum of systemic immune-related adverse events associated with pembrolizumab.

The accuracy of forest area estimates has improved over time as a result of field/cadastral surveys, enhanced remote sensing techniques, and the effectiveness of algorithms for automatical recognition of land cover types. However, forest statistics seem to be less accurate in disaggregated spatial domains such as small administrative units. To evaluate the contribution of different data sources to small-area forest cover estimation in Europe, we compared seven indicators with different spatial coverage and resolution. The analysis considered multiple information sources from innovative initiatives, such as the Copernicus Land monitoring scheme, and traditional (national) surveys. More specifically, the study examined the spatial coherence of these indicators at the municipal scale in Italy to achieve two objectives: (i) assessing the overall precision of forest cover rates and (ii) identifying spatial variations in forest cover rates associated with the technical characteristics of each data source. A spatial econometric approach was used to identify the sources of spatial divergence in forest cover rates and determine the data providers best suited to meet the information requirements of environmental reporting at the desired spatial scale. The results reveal that the selected indicators show varying degrees of internal coherence, with some indices displaying strong correlations and others delineating heterogeneous spatial patterns. Our study highlights the importance of choosing the right information source assessing forest area at the municipal level and provides a valuable approach quantifying the coherence and reliability of environmental indicators in monitoring key aspects of sustainable development.