The shielding effect of phospholipidic bilayers on zinc oxide nanocrystals for biomedical applications

Zinc oxide nanocrystals (ZnO NCs), thanks to their unique properties, are receiving much attention for their use in nanomedicine, in particular for therapy against cancer [1]. To be efficiently employed as diagnostic and therapeutic (yet theranostic) tools [2], highly dispersed, stable and non-toxic nanoparticles are required. In the case of ZnO NCs, there is still a lack of knowledge about cytotoxicity mechanisms and stability in the biological context, as well as immunological response and haemocompatible features. Most of these above-mentioned behaviours strongly depends on physico-chemical and surface properties of the nanoparticles. We thus propose a novel approach to stabilize the ZnO NCs in various biological media, focusing on NC aggregation and biodegradation as a function of the surface functionalization. We synthesized bare ZnO NCs, amino-propyl functionalized ones, and lipid bilayer-shielded NCs, and we characterized their morphological, chemical and physical properties. The stability behavior of the three different samples was evaluated, comparing their biodegradation profiles in different media, i.e. organic solvents, water, and different simulated and biological fluids. The studies aim to investigate how the particle surface functionalizations, and thus chemistry and charge, could influence their hydrodynamic size, zeta potential and consequent aggregation and degradation in the different solvents. We demonstrated that bare and amino-functionalized ZnO NCs strongly and rapidly aggregate when suspended in both simulated and biological media. Long-term biodegradation analysis showed small dissolution into potentially cytotoxic Zn-cations, also slightly affecting their crystalline structure. In contrast, high colloidal stability and integrity was retained for lipid-shielded ZnO NCs in all media, rendering them the ideal candidates for further theranostic applications [3]. [1] P. Zhu, Z. Weng, X. Li, X. Liu, S. Wu Adv. Mater. Interfaces 3 (2016) 1500494. [2] E. Lim, T. Kim, S. Paik, S. Haam, Y. Huh, and K. Lee, Chem. Rev. 115 (2015) 327−394. [3] B. Dumontel, M. Canta, H. Engelke, A. Chiodoni, L. Racca, A. Ancona, T. Limongi, G. Canavese and V. Cauda, J. Mater. Chem. B, under review The support from ERC Starting Grant – Project N. 678151 “Trojananohorse” and Compagnia di Sanpaolo are gratefully acknowledged

Biomimetic Non-Immunogenic Nanoassembly for the Antitumor Therapy

Nanoassembly (1) for inducing apoptosis in cancer cells comprising: a core (2) comprising at least a nanoparticle of a nano structured and semiconductor metal oxide, said nanoparticle being monocrystalline or polycrystalline; a shell (3) formed by a double phospholipid layer and proteins derived from an extracellular biovesicole chosen between an exosome, an ectosome, a connectosome, an oncosome and an apoptotic body, and an oncosome, said core (2) being enclosed inside said shell (3); and a plurality of targeting molecules (4, 4', 4") of said cancer cells, preferably monoclonal antibodies (4, 4', 4"), said molecules (4, 4', 4") being anchored to the external surface of said biovesicole

Enhanced Biostability and Cellular Uptake of Zinc Oxide Nanocrystals Shielded with Phospholipid Bilayer

The widespread use of ZnO nanomaterials for biomedical applications, including therapeutic drug delivery or stimuli-responsive activation, as well as imaging, imposes a careful control over the colloidal stability and long-term behaviour of ZnO in biological media. Moreover, the effect of ZnO nanostructures on living cells, in particular cancer cells, is still under debate. This paper discusses the role of surface chemistry and charge of zinc oxide nanocrystals, of around 15 nm in size, which influence their behaviour in biological fluids and effect on cancer cells. In particular, we address this problem by modifying the surface of pristine ZnO nanocrystals (NCs), rich of hydroxyl groups, with positively charged amino-propyl chains or, more innovatively, by self-assembling a double-lipidic membrane, shielding the ZnO NCs. Our findings show that the prolonged immersion in simulated human plasma and in the cell culture medium leads to highly colloidally dispersed ZnO NCs only when coated by the lipidic bilayer. In contrast, the pristine and amine-functionalized NCs form huge aggregates after already one hour of immersion. Partial dissolution of these two samples into potentially cytotoxic Zn2+ cations takes place, together with the precipitation of phosphate and carbonate salts on the NCs’ surface. When exposed to living HeLa cancer cells, higher amounts of lipid-shielded ZnO NCs are internalized with respect to the other samples, thus showing a reduced cytotoxicity, based on the same amount of internalized NCs. These results pave the way for the development of novel theranostic platforms based on ZnO NCs. The new formulation of ZnO shielded with a lipid-bilayer will prevent strong aggregation and premature degradation into toxic by-products, and promote a highly efficient cell uptake for further therapeutic or diagnostic functions

Systematic review of machine-learning models in orthopaedic trauma an overview and quality assessment of 45 studies

Aims Machine-learning (ML) prediction models in orthopaedic trauma hold great promise in assisting clinicians in various tasks, such as personalized risk stratification. However, an overview of current applications and critical appraisal to peer-reviewed guidelines is lacking. The objectives of this study are to 1) provide an overview of current ML prediction models in orthopaedic trauma; 2) evaluate the completeness of reporting following the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) statement; and 3) assess the risk of bias following the Prediction model Risk Of Bias Assessment Tool (PROBAST) tool. Methods A systematic search screening 3,252 studies identified 45 ML-based prediction models in orthopaedic trauma up to January 2023. The TRIPOD statement assessed transparent reporting and the PROBAST tool the risk of bias. Results A total of 40 studies reported on training and internal validation; four studies performed both development and external validation, and one study performed only external validation. The most commonly reported outcomes were mortality (33%, 15/45) and length of hospital stay (9%, 4/45), and the majority of prediction models were developed in the hip fracture population (60%, 27/45). The overall median completeness for the TRIPOD statement was 62% (interquartile range 30 to 81%). The overall risk of bias in the PROBAST tool was low in 24% (11/45), high in 69% (31/45), and unclear in 7% (3/45) of the studies. High risk of bias was mainly due to analysis domain concerns including small datasets with low number of outcomes, complete-case analysis in case of missing data, and no reporting of performance measures. Conclusion The results of this study showed that despite a myriad of potential clinically useful applications, a substantial part of ML studies in orthopaedic trauma lack transparent reporting, and are at high risk of bias. These problems must be resolved by following established guidelines to instil confidence in ML models among patients and clinicians. Otherwise, there will remain a sizeable gap between the development of ML prediction models and their clinical application in our day-to-day orthopaedic trauma practice

Multi-Target Drugs: The Trend of Drug Research and Development

Summarizing the status of drugs in the market and examining the trend of drug research and development is important in drug discovery. In this study, we compared the drug targets and the market sales of the new molecular entities approved by the U.S. Food and Drug Administration from January 2000 to December 2009. Two networks, namely, the target–target and drug–drug networks, have been set up using the network analysis tools. The multi-target drugs have much more potential, as shown by the network visualization and the market trends. We discussed the possible reasons and proposed the rational strategies for drug research and development in the future

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Larger is Better: The Scale Effects of the Italian Local Healthcare Authorities Amalgamation Program

Consolidation is often considered as a means to lower service delivery costs and enhance accountability. This paper uses a prospective evaluation design to derive estimates of the potential cost savings that may arise from Local Healthcare Authorities (LHAs) amalgamation process, which is concerning the Itali an National Health System. We focus specifically on cost savings due to scale economies with reference to a particular subset of the production costs of the LHAs, i.e. the administrative costs together with the purchasing costs of both goods as well as non-healthcare related services. Our results demonstrate the existence of economies of scale linked to the size of the LHA population. Hence, the decision to reduce the number of LHAs may result in larger local health authorities that are more cost efficient, especially when the consolidation process concerns merging a large number of LHA

Clinical autonomic nervous system laboratories in Europe. A joint survey of the European Academy of Neurology and the European Federation of Autonomic Societies

Background and purpose: Disorders of the autonomic nervous system (ANS) are common conditions, but it is unclear whether access to ANS healthcare provision is homogeneous across European countries. The aim of this study was to identify neurology-driven or interdisciplinary clinical ANS laboratories in Europe, describe their characteristics and explore regional differences. Methods: We contacted the European national ANS and neurological societies, as well as members of our professional network, to identify clinical ANS laboratories in each country and invite them to answer a web-based survey. Results: We identified 84 laboratories in 22 countries and 46 (55%) answered the survey. All laboratories perform cardiovascular autonomic function tests, and 83% also perform sweat tests. Testing for catecholamines and autoantibodies are performed in 63% and 56% of laboratories, and epidermal nerve fiber density analysis in 63%. Each laboratory is staffed by a median of two consultants, one resident, one technician and one nurse. The median (interquartile range [IQR]) number of head-up tilt tests/laboratory/year is 105 (49–251). Reflex syncope and neurogenic orthostatic hypotension are the most frequently diagnosed cardiovascular ANS disorders. Thirty-five centers (76%) have an ANS outpatient clinic, with a median (IQR) of 200 (100–360) outpatient visits/year; 42 centers (91%) also offer inpatient care (median 20 [IQR 4–110] inpatient stays/year). Forty-one laboratories (89%) are involved in research activities. We observed a significant difference in the geographical distribution of ANS services among European regions: 11 out of 12 countries from North/West Europe have at least one ANS laboratory versus 11 out of 21 from South/East/Greater Europe (p = 0.021). Conclusions: This survey highlights disparities in the availability of healthcare services for people with ANS disorders across European countries, stressing the need for improved access to specialized care in South, East and Greater Europe