Role of STIL overexpression in supernumerary centriole formation, chromosomal instability and cancer development in mice

Centrosome is the major microtubule-organizing center in mammalian cell and consists of a pair of centrioles embedded in pericentriolar material. Centrosomes are important for bipolar spindle formation and correct chromosome segregation during mitosis. Disruption of normal centrosome function leads to aneuploidy and chromosome missegregation. Many cancer cells harbor supernumerary centrosomes, which were shown to correlate to chromosomal instability, clinical aggressiveness, and poor prognosis. Nevertheless, the question, whether amplified centrosomes can drive tumorigenesis in vivo remains unresolved. The process of centrosome duplication is tightly controlled by a small set of proteins including the kinase protein PLK4 and the structural centriole proteins as STIL and SAS6. Depletion of any one of these proteins’ blocks centrosome duplication and, conversely, overexpression causes centrosome amplification. In different PLK4 overexpression in vivo models, it remains arguable, whether extra centrosomes could derive tumorigenesis and whether the generated tumors might be induced by the additional serine/threonine kinase functions of PLK4 besides its role in regulating centriole duplication. On the other hand, the structural centrosome protein STIL is involved only in centriole replication without any other known functions up to now and its overexpression leads to the formation of supernumerary centrioles in tissue culture. Therefore, investigating the role of centrosome aberrations in chromosomal instability and tumor formation in vivo using STIL overexpression (STILOE) mouse model will add important information to the conflicting data generated by PLK4 overexpressing mice. Accordingly, we generated a new transgenic Cre-LoxP mouse model, B6-STIL, that overexpresses STIL when bred with a Cre-deleter line leading to STOP cassette excision. These mice were used for (i) generation and characterization of mice with ubiquitous STIL overexpression (STILOE) for the assessment of spontaneous centrosome amplification-driven tumor development; (ii) generation and characterization of mouse embryonic fibroblasts (MEFs) derived from these STILOE mice to determine STIL overexpression levels and the development of centrosome amplification, mitotic aberrations; (iii) generation and characterization of mice with tamoxifen-inducible epithelium-specific STIL overexpression (K14(CreERT2);STILOE) with and without active TP53, which were used in skin carcinogenesis assays, to determine the relative contribution of supernumerary centrosomes and chromosomal instability to chemical tumor induction and progression. Our results showed a graded overexpression of STIL mRNA and protein in early MEFs passages and tissues from heterozygous STILOE and homozygous STILOE mice, leading to significant centrosome amplification and chromosomal aberrations via aberrant mitoses. Importantly, MEFs with high levels of STIL-induced centrosome amplification showed a proliferative disadvantage with a strong selective pressure to eliminate cells overexpressing STIL by apoptosis and senescence. In line, rates of both, spontaneous tumor formation in STILOE mice and chemically induced skin tumors in K14(CreERT2);STILOE animals are largely reduced as compared to controls. Thus, centrosome amplification induced by STIL overexpression seems to inhibit tumor formation rather than enhancing it in vivo in mammals

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

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

Twelve-month observational study of children with cancer in 41 countries during the COVID-19 pandemic

Introduction Childhood cancer is a leading cause of death. It is unclear whether the COVID-19 pandemic has impacted childhood cancer mortality. In this study, we aimed to establish all-cause mortality rates for childhood cancers during the COVID-19 pandemic and determine the factors associated with mortality. Methods Prospective cohort study in 109 institutions in 41 countries. Inclusion criteria: children &lt;18 years who were newly diagnosed with or undergoing active treatment for acute lymphoblastic leukaemia, non-Hodgkin's lymphoma, Hodgkin lymphoma, retinoblastoma, Wilms tumour, glioma, osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, medulloblastoma and neuroblastoma. Of 2327 cases, 2118 patients were included in the study. The primary outcome measure was all-cause mortality at 30 days, 90 days and 12 months. Results All-cause mortality was 3.4% (n=71/2084) at 30-day follow-up, 5.7% (n=113/1969) at 90-day follow-up and 13.0% (n=206/1581) at 12-month follow-up. The median time from diagnosis to multidisciplinary team (MDT) plan was longest in low-income countries (7 days, IQR 3-11). Multivariable analysis revealed several factors associated with 12-month mortality, including low-income (OR 6.99 (95% CI 2.49 to 19.68); p&lt;0.001), lower middle income (OR 3.32 (95% CI 1.96 to 5.61); p&lt;0.001) and upper middle income (OR 3.49 (95% CI 2.02 to 6.03); p&lt;0.001) country status and chemotherapy (OR 0.55 (95% CI 0.36 to 0.86); p=0.008) and immunotherapy (OR 0.27 (95% CI 0.08 to 0.91); p=0.035) within 30 days from MDT plan. Multivariable analysis revealed laboratory-confirmed SARS-CoV-2 infection (OR 5.33 (95% CI 1.19 to 23.84); p=0.029) was associated with 30-day mortality. Conclusions Children with cancer are more likely to die within 30 days if infected with SARS-CoV-2. However, timely treatment reduced odds of death. This report provides crucial information to balance the benefits of providing anticancer therapy against the risks of SARS-CoV-2 infection in children with cancer

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Pharmaceutical Applications of Molecular Tweezers, Clefts and Clips

Synthetic acyclic receptors, composed of two arms connected with a spacer enabling molecular recognition, have been intensively explored in host-guest chemistry in the past decades. They fall into the categories of molecular tweezers, clefts and clips, depending on the geometry allowing the recognition of various guests. The advances in synthesis and mechanistic studies have pushed them forward to pharmaceutical applications, such as neurodegenerative disorders, infectious diseases, cancer, cardiovascular disease, diabetes, etc. In this review, we provide a summary of the synthetic molecular tweezers, clefts and clips that have been reported for pharmaceutical applications. Their structures, mechanism of action as well as in vitro and in vivo results are described. Such receptors were found to selectively bind biological guests, namely, nucleic acids, sugars, amino acids and proteins enabling their use as biosensors or therapeutics. Particularly interesting are dynamic molecular tweezers which are capable of controlled motion in response to an external stimulus. They proved their utility as imaging agents or in the design of controlled release systems. Despite some issues, such as stability, cytotoxicity or biocompatibility that still need to be addressed, it is obvious that molecular tweezers, clefts and clips are promising candidates for several incurable diseases as therapeutic agents, diagnostic or delivery tools

First record of Olive Pyralid Moth, Euzophera pinguis (Haworth, 1811) on olive trees in Lebanon (Lepidoptera, Pyralidae)

Olive tree, Olea europaea L., is one of the oldest and the most important cultivated tree in Lebanon. However, olive production is affected by several pests and diseases, mainly the olive fruit fly Bactrocera oleae (Gmelin) and the peacock spot caused by the ascomycetous fungus Spilocaea oleagina (Castagne) S. Hughes. In September 2015, swelling and cracking of olive tree barks were observed in the region of Hasbaya and West Bekaa. Examination of infected trees showed larvae of Olive Pyralid Moth Euzophera pinguis (Haworth) burrowing into bark and branches. The survey conducted in these two regions shows that this pest is well established in Hasbaya, while no other infection is reported in West Bekaa. E. pinguis is a new invasive pest on olive trees in Lebanon and the potential risk to disseminate to other areas of olive production is very high.Premier signalement de la Pyrale des troncs de l’olivier, Euzophera pinguis (Haworth, 1811) au Liban (Lepidoptera, Pyralidae). L’oléiculture est l’une des cultures les plus anciennes et la plus importante au Liban. Cependant, la production des olives est menacée par plusieurs ravageurs et maladies, principalement la Mouche de l’olive Bactrocera oleae (Gmelin) et l’ OEil de paon, maladie provoquée par le champignon Ascomycète Spilocaea oleagina (Castagne) S. Hughes, causant des pertes économiques très importantes. En septembre 2015, un nouveau ravageur, Euzophera pinguis (Haworth), la Pyrale des troncs de l’olivier, a été détecté pour la première fois dans les régions de Hasbaya et de Bekaa-Ouest. Les chenilles de ce ravageur invasif ont creusé des galeries dans l’écorce des troncs et des branches entraînant le dépérissement des arbres infectés. La surveillance effectuée dans ces deux régions a montré que l’insecte est bien installé à Hasbaya alors qu’aucune nouvelle infestation est signalée à Bekaa-Ouest. E. pinguis est un nouveau ravageur pour les oliveraies libanaises et le risque potentiel d’extension à d’autres régions est très élevé.Moussa Zinette, Choueiri Elia, Youssef Amira, El Riachy Milad. First record of Olive Pyralid Moth, Euzophera pinguis (Haworth, 1811) on olive trees in Lebanon (Lepidoptera, Pyralidae). In: Bulletin de la Société entomologique de France, volume 122 (1),2017. pp. 57-60

Advanced Robotic IV Pole Flyer

Project Flye

Advanced Prototype for an Automated Version of the Robotic IV Pole

International audienc

BMIVPOT, a Fully Automated Version of the Intravenous Pole: Simulation, Design, and Evaluation

Robotic intravenous poles are automated supportive instrument that needs to be triggered by patients to hold medications and needed supplies. Healthcare engineering of robotic intravenous poles is advancing in order to improve the quality of health services to patients worldwide. Existing intravenous poles in the market were supportive to patients, yet they constrained their movement, consumed the time of both the patient and the nurse, and they were expensive in regard to what they offer. Although robotic poles overcame some of the movement limitations of the commercial/market poles, they were partially automated and did not offer additional technological features. The aim of our work was to develop a fully automated Biomedical Intravenous Pole Robot (BMIVPOT) to resolve the aforementioned limitations and to offer new technological features to intravenous poles, thereby promoting the health services. Several sensors and build-up materials were empirically chosen to be cost-effective and fulfill our needs. The new prototype was divided into three steps: simulated prototype, real implementation of the prototype, and testing and evaluation. Simulation results showed the best qualitative way to fit all the specifications in the robotic system, such as the shape, sensors, and connections in order to provide the proper functionality of the system. Experimental and real results provided the manufactured parts, implemented sensors, and the final robot. Testing the tracking and the flow sensor performances were provided. Evaluation of our Biomedical Intravenous Pole Robot with alternatives showed that our robot outperforms the other poles in many aspects including the features it offers, the percentage of interventions it comprised, the reliability, and cost-effectiveness. The overall percentage of features offered by our Biomedical Intravenous Pole Robot was 60% higher than that offered by peer research poles and 80% higher than that of the market poles. In addition, the average percentage of integration of interventions (architecture, sensor, wireless, tracking, and mechanical) in the Biomedical Intravenous Pole Robot was at least 56% higher than that of the alternative poles. According to the results, Biomedical Intravenous Pole Robot offers a cost-effective price as compared to the others. As a future prospect, we intend to add more features to this prototype in order to enhance it, such as vital signs detection, and improve the tracking system