Cancer metastases are the most common causes of cancer-related deaths. The formation of secondary tumors at different sites in the human body can impair multiple organ function and dramatically decrease the survival of the patients. In this stage, it is difficulty to treat tumor growth and spreading due to arising therapy resistances. Therefore, it is important to prevent cancer metastases and to increase subsequent cancer therapy success. Cancer metastases are conventionally treated with radiation or chemotherapy. However, these treatments elicit lots of side effects, wherefore novel local treatment approaches are currently discussed. Recent studies already showed anticancer activity of specially designed degradable magnesium (Mg) alloys by reducing the cancer cell proliferation. In this work, we investigated the impact of these Mg-based materials on different steps of the metastatic cascade including cancer cell migration, invasion, and cancer-induced angiogenesis. Both, Mg and Mg–6Ag reduced cell migration and invasion of osteosarcoma cells in coculture with fibroblasts. Furthermore, the Mg-based materials used in this study diminished the cancer-induced angiogenesis. Endothelial cells incubated with conditioned media obtained from these Mg and Mg–6Ag showed a reduced cell layer permeability, a reduced proliferation and inhibited cell migration. The tube formation as a last step of angiogenesis was stimulated with the presence of Mg under normoxia and diminished under hypoxia.
Background Congenital anomalies are the leading cause of perinatal, neonatal and infant mortality in developed countries. Large long-term follow-up studies investigating survival beyond the first year of life in children with rare congenital anomalies are costly and sufficiently large standardized cohorts are difficult to obtain due to the rarity of some anomalies. This study aimed to investigate the survival up to 10 years of age of children born with a rare structural congenital anomaly in the period 1995–2014 in Western Europe. Methods Live births from thirteen EUROCAT (European network for the epidemiological surveillance of congenital anomalies) population-based registries were linked to mortality records. Survival for 12,685 live births with one of the 31 investigated rare structural congenital anomalies (CAs) was estimated at 1 week, 4 weeks and 1, 5 and 10 years of age within each registry and combined across Europe using random effects meta-analyses. Differences between registries were evaluated for the eight rare CAs with at least 500 live births. Results Amongst the investigated CAs, arhinencephaly/holoprosencephaly had the lowest survival at all ages (58.1%, 95% Confidence Interval (CI): 44.3–76.2% at 1 week; 47.4%, CI: 36.4–61.6% at 1 year; 35.6%, CI: 22.2–56.9% at 10 years). Overall, children with rare CAs of the digestive system had the highest survival (> 95% at 1 week, > 84% at 10 years). Most deaths occurred within the first four weeks of life, resulting in a 10-year survival conditional on surviving 4 weeks of over 95% for 17 out of 31 rare CAs. A moderate variability in survival between participating registries was observed for the eight selected rare CAs. Conclusions Pooling standardised data across 13 European CA registries and the linkage to mortality data enabled reliable survival estimates to be obtained at five ages up to ten years. Such estimates are useful for clinical practice and parental counselling.
Abstract Background The use of palatal miniscrew offers the possibility to improve the effectiveness of orthodontic expansion devices. Palatal expanders supported by miniscrew can be applied with different clinical protocols. Some authors proposed the use of four palatal miniscrews during miniscrew-supported palatal expansion to maximize skeletal effects in young adults’ treatment. However, bone availability decreases in the posterior paramedian palatal regions, making the positioning of the two-posterior paramedian palatal miniscrews challenging, when it is performed avoiding nasal cavities invasion. Some authors proposed miniscrews insertion in a specific region located laterally to the palatal process of the maxillary bone, and apically relatively to the dento-alveolar process. The aim of this study was to evaluate the bone thickness, cortical bone thickness, and mucosae depth of this anatomical site that, in this study, was defined as palatal posterior supra-alveolar insertion site. Results The evaluation of bone availability of palatal posterior supra-alveolar insertion site at different antero-posterior levels showed that the maximum amount of total bone thickness was found between the second premolar and the first molar. At this level total bone, thickness is significantly (p
Background Findings from the T.O.S.CA. Registry recently reported that patients with concomitant chronic heart failure (CHF) and impairment of insulin axis (either insulin resistance—IR or diabetes mellitus—T2D) display increased morbidity and mortality. However, little information is available on the relative impact of IR and T2D on cardiac structure and function, cardiopulmonary performance, and their longitudinal changes in CHF. Methods Patients enrolled in the T.O.S.CA. Registry performed echocardiography and cardiopulmonary exercise test at baseline and at a patient-average follow-up of 36 months. Patients were divided into three groups based on the degree of insulin impairment: euglycemic without IR (EU), euglycemic with IR (IR), and T2D. Results Compared with EU and IR, T2D was associated with increased filling pressures (E/e′ratio: 15.9 ± 8.9, 12.0 ± 6.5, and 14.5 ± 8.1 respectively, p < 0.01) and worse right ventricular(RV)-arterial uncoupling (RVAUC) (TAPSE/PASP ratio 0.52 ± 0.2, 0.6 ± 0.3, and 0.6 ± 0.3 in T2D, EU and IR, respectively, p < 0.05). Likewise, impairment in peak oxygen consumption (peak VO 2 ) in TD2 vs EU and IR patients was recorded (respectively, 15.8 ± 3.8 ml/Kg/min, 18.4 ± 4.3 ml/Kg/min and 16.5 ± 4.3 ml/Kg/min, p < 0.003). Longitudinal data demonstrated higher deterioration of RVAUC, RV dimension, and peak VO 2 in the T2D group (+ 13% increase in RV dimension, − 21% decline in TAPSE/PAPS ratio and − 20% decrease in peak VO 2 ). Conclusion The higher risk of death and CV hospitalizations exhibited by HF-T2D patients in the T.O.S.CA. Registry is associated with progressive RV ventricular dysfunction and exercise impairment when compared to euglycemic CHF patients, supporting the pivotal importance of hyperglycaemia and right chambers in HF prognosis. Trial registration ClinicalTrials.gov identifier: NCT023358017
Background Transthyretin amyloidosis (ATTR amyloidosis) is a rare, life-threatening disease caused by the accumulation of variant or wild-type (ATTRwt amyloidosis) transthyretin amyloid fibrils in the heart, peripheral nerves, and other tissues and organs. Methods Established in 2007, the Transthyretin Amyloidosis Outcomes Survey (THAOS) is the largest ongoing, global, longitudinal observational study of patients with ATTR amyloidosis, including both inherited and wild-type disease, and asymptomatic carriers of pathogenic TTR mutations. This descriptive analysis examines baseline characteristics of symptomatic patients and asymptomatic gene carriers enrolled in THAOS since its inception in 2007 (data cutoff: August 1, 2021). Results This analysis included 3779 symptomatic patients and 1830 asymptomatic gene carriers. Symptomatic patients were predominantly male (71.4%) and had a mean (standard deviation [SD]) age of symptom onset of 56.3 (17.8) years. Val30Met was the most common genotype in symptomatic patients in South America (80.9%), Europe (55.4%), and Asia (50.5%), and more patients had early- versus late-onset disease in these regions. The majority of symptomatic patients in North America (58.8%) had ATTRwt amyloidosis. The overall distribution of phenotypes in symptomatic patients was predominantly cardiac (40.7%), predominantly neurologic (40.1%), mixed (16.6%), and no phenotype (2.5%). In asymptomatic gene carriers, mean (SD) age at enrollment was 42.4 (15.7) years, 42.4% were male, and 73.2% carried the Val30Met mutation. Conclusions This 14-year global overview of THAOS in over 5000 patients represents the largest analysis of ATTR amyloidosis to date and highlights the genotypic and phenotypic heterogeneity of the disease. ClinicalTrials.gov Identifier : NCT00628745.
We consider a reaction–diffusion equation with a convection term in one space variable, where the diffusion changes sign from the positive to the negative and the reaction term is bistable. We study the existence of wavefront solutions, their uniqueness and regularity. The presence of convection reveals several new features of wavefronts: according to the mutual positions of the diffusivity and reaction, profiles can occur either for a single value of the speed or for a bounded interval of such values; uniqueness (up to shifts) is lost; moreover, plateaus of arbitrary length can appear; profiles can be singular where the diffusion vanishes.
Congenital myopathies (CM) are a group of early-onset, genetically diverse muscle disorders of variable severity with characteristic muscle biopsy findings. Mutations in RYR1, the gene encoding the RYR1, are the most common genetic cause, responsible for ∼30% of all human CM. They are linked to the pharmacogenetic disorder malignant hyperthermia susceptibility and to various disease phenotypes, including central core disease (which is primarily dominantly inherited), multiminicore disease (which is predominantly recessively inherited), some forms of centronuclear myopathy and congenital fiber-type disproportion (which can be either dominantly or recessively inherited), and King–Denborough syndrome (a CM characterized by skeletal abnormalities, dysmorphic features, and malignant hyperthermia susceptibility). The recessive forms of RYR1-linked CM are more severe, affecting children at birth and, in addition to profound muscle weakness, may also affect facial and extraocular muscles and cause skeletal deformities and feeding difficulties. To study the mechanism leading to the profound muscle weakness characterized by recessive RYR1-CM, we created transgenic mice knocked in for the compound heterozygous RYR1 p.Q1970fsX16+p.A4329D mutations (double knock-in mouse, or DKI) identified in a severely affected child. The in vivo and ex vivo physiological functions of fast twitch, slow twitch, and extraocular muscles were severely impaired in DKI mice; in addition, the mutations were accompanied by a >50% decrease in RYR1 protein in all muscles examined, as well as changes in the expression of many proteins important for muscle function and chromatin structure. Muscle ultrastructure was disorganized, with fewer CRU and mitochondria and presence of cores. MyHC-EO, the superfast and ocular-muscle−specific myosin heavy isoform, was almost undetectable in EOMs from DKI mutant mice. Thus, the DKI mouse model faithfully recapitulates the human disease and could be exploited for preclinical studies aimed at developing therapeutic strategies to treat neuromuscular disorders linked to recessive RYR1 mutations.
Industrial hemp (Cannabis sativa L.) female inflorescences have long been considered as waste material in the hemp production chain. However, past studies focused on the valorization of female inflorescences as high-quality byproducts with promising health-promoting applications. In line with this evidence, the present research investigated the phytochemical and pharmacological properties with a comparative approach on two essential oils (EOs) obtained from the inflorescences of the industrial hemp varieties Kompolti and Tisza. The EOs composition in terpenes and terpenophenols was determined. The effects of the EOs in modulating the viability of different cancer cell lines was investigated. Whereas, in hypothalamic HypoE22 cells, the release of dopamine, norepinephrine, and serotonin was measured, as an index of neuromodulatory activity. Moreover, the EO mycostatic properties were explored towards different dermatophyte species. The prominent terpenes were iso-caryophyllene, α-humulene, and β-caryophyllene oxide in both Kompolti and Tisza EOs, whereas cannabidiol and cannabigerolic acid were the main terpenophenols, respectively. Both essential oils inhibited the viability of different cancer cells; particularly, the essential oil of Tisza variety displayed a marked cytotoxicity in chol-angiocarcinoma cells. A possible role of both terpenophenols and caryophyllane sesquiterpenes as bioactive anticancer compounds has been hypothesized. While cannabidiol could contribute to the stimulation of hypo-thalamic serotonin release by Kompolti EO. The essential oils also produced antimycotic effects, for which β-caryophyllene oxide could be partly responsible. Overall, the present findings highlight pharmacological properties of Kompolti and Tisza EOs, which deserve further investigations and strengthen the interest in industrial hemp inflorescences as valuable source of bioactive extracts and compounds.
The adoption of new technologies by smallholder farmers to support economic and human development has received increased attention from scholars and development policymakers. This is particularly true for Africa, given the importance of the agricultural sector for economic growth and poverty reduction. Nevertheless, profitable innovations, such as improved seeds, fertilizers, and crop-protection chemicals, are not sufficiently adopted by farmers. This paper aims to contribute to a better understanding of this limited adoption by examining the drivers and obstacles to innovation by smallholder farmers in Sub-Saharan Africa, with a special focus on cultural and behavioural aspects. The concepts of social norms and peer approval are considered in the farmers’ decisions on innovation adoption. The focus is mainly on the social norm of being a ‘good farmer’, a distinction made amongst farming peers, based on the characteristics that are socially approved in the rural community. Adherence to the social norm of being a good farmer is considered one of the main drivers of farmers’ decisions, including innovation adoption. The study is based on a survey of 300 smallholder farmers in Mozambique. The results of our study show that the social norm of being a good farmer differs from that mostly shared in developed countries mainly connected to maximizing farming production. What emerges from our investigation is a socially accepted idea of a good farmer being one who is extremely concerned about others in her or his community. The results of various quantitative analyses on the intensity and adoption of innovations show that this prosocial idea of the good farmer does not prevent farmers from adopting innovations and has a significant impact on the adoption of the most radical innovations. The present study reveals the need to contextualize the analysis of farmers’ decisions in the cultural and social context in which they operate.
Coronavirus pandemic infection is the most important health issue worldwide. Coronavirus disease 2019 is a contagious disease characterized by severe acute respiratory syndrome coronavirus 2. To date, excluding the possibility of vaccination, against SARS-CoV-2 infection it is possible to act only with supportive care and non-virus-specific treatments in order to improve the patient's symptoms. Pharmaceutical industry is investigating effects of medicinal plants, phytochemical extracts and aromatic herbs to find out natural substances which may act as antiviral drugs. Several studies have revealed how these substances may interfere with the viral life cycle, viral entry, replication, assembly or discharge, as well as virus-specific host targets or stimulating the host immune system, reducing oxidative stress and inflammatory response. A natural compound can be used as a prophylaxis by people professionally exposed to the risk of contagion and/or positive patients not in intensive care. The aim of this paper is to perform a narrative review of current literature in order to summarize the most studied natural compounds and their modes of action.
Adult atopic dermatitis (adult AD) is a systemic inflammatory disorder, whose relationship with immune-allergic and metabolic comorbidities is not well established yet. Moreover, treatment of mild-to-moderate and severe atopic dermatitis needs standardization among clinicians. The aim of this study was to evaluate the distribution of comorbidities, including metabolic abnormalities, rhinitis, conjunctivitis, asthma, alopecia and sleep disturbance, according to severity of adult AD, and describe treatments most commonly used by Italian dermatologists. Retrospective, observational, nationwide study of adult patients over a 2-year period was performed. Clinical and laboratory data were obtained through review of medical records of patients aged ≥ 18 years, followed in 23 Italian National reference centres for atopic dermatitis between September 2016 and September 2018. The main measurements evaluated were disease severity, atopic and metabolic comorbidities, treatment type and duration. Six-hundred and eighty-four adult patients with AD were included into the study. Atopic, but not metabolic conditions, except for hypertension, were significantly associated with having moderate-to-severe AD in young adult patients. Disease duration was significantly associated with disease severity. Oral corticosteroids and cyclosporine were the most widely used immunosuppressant. Our study seems confirm the close relationship between adult AD and other atopic conditions, further long-term cohort studies on patients affected by adult AD need to be performed to evaluate the complex relationship between adult AD disease severity and metabolic comorbidities.
Errors are an integral part of the learning process and an opportunity to increase skills and knowledge, but they are often discouraged, sanctioned and derided in the classroom. This study tests whether students' perceptions of being part of an error-friendly classroom context (i.e., a positive classroom error climate) is positively related to students' learning outcomes via students' adaptive reactions towards errors. A total of 563 Italian middle school students from 32 mathematics classes completed a questionnaire on their perceptions of classroom error climate and their reactions towards errors. Students' math grades were used as indicators of their level of learning outcomes. A multilevel model showed that perceived classroom error climate was positively related to math grades via increased adaptive reactions towards errors. Our findings revealed that an error-friendly classroom context is associated with students’ adaptive adjustment to errors and to better learning outcomes in mathematics.
Illegal logging is a global problem associated with deforestation, climate change, and biodiversity loss with significant negative economic, environmental, and social impacts. In response to this phenomenon, European Union has enacted the European Timber Regulation (EUTR) that imposes economic operators to exercise due diligence thanks to traceability verifications. These are mainly based on a “paper-based” approach, with implementation issues as a consequence. Italy is a interesting case study, since it is the first importer of wood-energy biomass worldwide, where tons of fuelwood without clear traceability are imported every year, and EUTR enforcement still lags behind. Here, a Living Lab involving stakeholders and key informants, carried out a participatory and open assessment of the impact of digital technologies on EUTR enforcement and traceability in the national wood-energy sector. Results reveals that, even if digitalisation is at the first stage, it is far from being only a technological phenomenon since it is already able to impact on different aspects (social, economic, territorial, institutional) related to the EUTR application. Policymakers are therefore recommended to rely on holistic evaluations and approaches that recognise such a complexity, in order to foster a creation of a viable digital ecosystem in favour of EUTR implementation and traceability in the wood-energy sector.
In this work we introduce a new class of gradient-free global optimization methods based on a binary interaction dynamics governed by a Boltzmann type equation. In each interaction the particles act taking into account both the best microscopic binary position and the best macroscopic collective position. For the resulting kinetic optimization methods, convergence to the global minimizer is guaranteed for a large class of functions under appropriate parameter constraints that do not depend on the dimension of the problem. In the mean-field limit we show that the resulting Fokker-Planck partial differential equations generalize the current class of consensus based optimization (CBO) methods. Algorithmic implementations inspired by the well-known direct simulation Monte Carlo methods in kinetic theory are derived and discussed. Several examples on prototype test functions for global optimization are reported including an application to machine learning.
District Heating Networks (DHNs) are composed of numerous pipes that can be threatened by faults that affect DHN operation and management. Thus, reliable diagnostic methodologies are essential to identify DHN health state and hinder DHN malfunctioning and performance deterioration. To this purpose, a novel diagnostic approach that couples a DHN simulation model with an optimization algorithm for detecting and identifying both thermal and hydraulic faults, i.e., water leakages, anomalous heat and pressure losses, is presented in this paper. In the current paper, the novel diagnostic approach is challenged at evaluating the health state of the DHN of the campus of the University of Parma, where different faults are artificially implanted, by using a digital twin of the DHN. The faulty datasets account for both single and multiple faults, as well as different fault types and causes. The novel diagnostic approach proves to correctly detect and identify all simulated faults, by also correctly estimating their magnitude even in the most challenging scenarios.
Nanomedicine research has advanced dramatically in recent decades. Nonetheless, traditional nanomedicine faces significant obstacles such as the low concentration of the drug at target sites and accelerated removal of the drug from blood circulation. Various techniques of nanotechnology, including cell membrane coating, have been developed to address these challenges and to improve targeted distribution and redcue cell membrane-mediated immunogenicity. Recently, stem cell (SC) membranes, owing to their immunosuppressive and regenerative properties, have grabbed attention as attractive therapeutic carriers for targeting specific tissues or organs. Bioengineering strategies that combine synthetic nanoparticles (NPs) with SC membranes, because of their homing potential and tumor tropism, have recently received a lot of publicity. Several laboratory experiments and clinical trials have indicated that the benefits of SC-based technologies are mostly related to the effects of SC-derived exosomes (SC-Exos). Exosomes are known as nano-sized extracellular vehicles (EVs) that deliver particular bioactive molecules for cell-to-cell communication. In this regard, SC-derived exosome membranes have recently been employed to improve the therapeutic capability of engineered drug delivery vehicles. Most recently, for further enhancing NPs' functionality, a new coating approach has been offered that combines membranes from two separate cells. These hybrid membrane delivery vehicles have paved the way for the development of biocompatible, high-efficiency, biomimetic NPs with varying hybrid capabilities that can overcome the drawbacks of present NP-based treatment techniques. This review explores stem cell membranes, SC-Exos, and hybrid SC-camouflaged NPs preparation methods and their importance in cancer therapy.
This paper explores electoral consensus regarding local public spending as a way for policymakers, particularly in western democracies, to secure long-term electoral support to govern the sustainability of structural change. Public spending is perceived by local electoral constituencies as immediately affecting people's lives and thus strongly influences individual voting behaviour. Focusing on the case of Italy, this paper explores the electoral consensus–public spending nexus on the municipal level. The results show that, on average, an increase in local public spending is associated with a reduction in electoral consensus towards anti-system parties, whereas an increase in local public spending does not yield a significant raise in electoral consensus for pro-system parties. We find nevertheless heterogeneous effects across different geographical areas and spending categories for both anti-system and pro-system party consensus. The results yield insights for scholarly debate and implications for policymaking to garner the electoral consensus needed for sustainable structural change.
Purpose Acute kidney injury (AKI) frequently complicates hospitalization and is associated with in-hospital mortality (IHM). It has been reported a seasonal trend in different clinical conditions. The aim of this study was to evaluate the possible relationship between seasons of the year and IHM in elderly hospitalized patients with AKI. Methods We selected all admissions complicated by AKI between 2000 and 2015 recorded in the Italian National Hospital Database. ICD-9-CM code 584.xx identified subjects with age ≥ 65 years and age, sex, comorbidity burden, need of dialysis treatment and IHM were compared in hospitalizations recorded during the four seasons. Moreover, we plotted the AKI observed/expected ratio and percentage of mortality during the study period. Results We evaluated 759,720 AKI hospitalizations (mean age 80.5 ± 7.8 years, 52.2% males). Patients hospitalized with AKI during winter months had higher age, prevalence of dialysis-dependent AKI, and number of deceased patients. In whole population IHM was higher in winter and lower in summer, while the AKI observed/expected ratio demonstrated two peaks, one in summer and one in winter. Logistic regression analysis demonstrated that parameters such as age, autumn, winter, comorbidity burden were positively associated with IHM. Conclusion We conclude that a seasonality exists in AKI, however, relationship between seasons and AKI could vary depending on the aspects considered. Both autumn and winter months are independent risk factors for IHM in patients with AKI regardless of age, sex and comorbidity burden. On the contrary, summer time reduces the risk of death during hospitalizations with AKI.
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