Parallel Manipulators with Lower Mobility

A review of the criteria to be used for designing parallel manipulators with lower mobility (LM-PMs) is presented. This chapter attempts to provide a unified frame for the study of this type of machines together with a critical analysis of the vast literature about them. The chapter starts with the classification of the LM-PMs, and, then, analyzes the specific subjects involved in the functional design of these machines. Special attention is paid to the definition of the limb topology, the singularity analysis and the discussion of the characteristics of some machines

Performance-Based Design of the CRS-RRC Schoenflies-Motion Generator

Rigid-body displacements obtained by combining spatial translations and rotations around axes whose direction is fixed in the space are named Shoenflies' motions. They constitute a 4-dimensional (4-D) subgroup, named Shoenflies' subgroup, of the 6-D displacement group. Since the set of rotation-axis' directions is a bi-dimensional space, the set of Shoenflies' subgroups is a bi-dimensional space, too. Many industrial manipulations (e.g., pick-and-place on a conveyor belt) require displacements that belong to only one Schoenflies' subgroup and can be accomplished by particular 4-degrees-of-freedom (4-DOF) manipulators (Shoenflies-motion generators (SMGs)). The first author has recently proposed a novel parallel SMG of type CRS-RRC (1). Such SMG features a single-loop architecture with actuators on the base and a simple decoupled kinematics. Here, firstly, an organic review of the previous results on this SMG is presented; then, its design is addressed by considering its kinetostatic performances. The adopted design procedure optimizes two objective functions, one (global conditioning index (GCI)) that measures the global performance and the other (CImin) that evaluates the worst local performance in the useful workspace. The results of this optimization procedure are the geometric parameters' values that make the studied SMG have performances comparable with those of commercial SMGs. In addition, a realistic 3D model that solves all the manufacturing doubts with simple and cheap solutions is presented

Contact-dependent growth inhibition systems in Acinetobacter

In bacterial contact-dependent growth inhibition (CDI) systems, CdiA proteins are exported to the outer membrane by cognate CdiB proteins. CdiA binds to receptors on susceptible bacteria and subsequently delivers its C-terminal toxin domain (CdiA-CT) into neighbouring target cells. Whereas self bacteria produce CdiI antitoxins, non-self bacteria lack antitoxins and are therefore inhibited in their growth by CdiA. In silico surveys of pathogenic Acinetobacter genomes have enabled us to identify >40 different CDI systems, which we sorted into two distinct groups. Type-II CdiAs are giant proteins (3711 to 5733 residues) with long arrays of 20-mer repeats. Type-I CdiAs are smaller (1900-2400 residues), lack repeats and feature central heterogeneity (HET) regions, that vary in size and sequence and can be exchanged between CdiA proteins. HET regions in most type-I proteins confer the ability to adopt a coiled-coil conformation. CdiA-CT and pretoxin modules differ significantly between type-I and type-II CdiAs. Moreover, type-II genes only have remnants of genes in their 3' end regions that have been displaced by the insertion of novel cdi sequences. Type-I and type-II CDI systems are equally abundant in A. baumannii, whereas A. pittii and A. nosocomialis predominantly feature type-I and type-II systems, respectively

Contact-Dependent Growth Inhibition Proteins in Acinetobacter baylyi ADP1

Bacterial contact-dependent growth inhibition (CDI) systems are two-partner secretion systems in which toxic CdiA proteins are exported on the outer membrane by cognate transporter CdiB proteins. Upon binding to specific receptors, the C-terminal toxic (CT) domain, detached from CdiA, is delivered to neighbouring cells. Contacts inhibit the growth of not-self-bacteria, lacking immunity proteins co-expressed with CdiA, but promote cooperative behaviours in “self” bacteria, favouring the formation of biofilm structures. The Acinetobacter baylyi ADP1 strain features two CdiA, which differ significantly in size and have different CT domains. Homologous proteins sharing the same CT domains have been identified in A. baumannii. The growth inhibition property of the two A. baylyi CdiA proteins was supported by competition assays between wild-type cells and mutants lacking immunity genes. However, neither protein plays a role in biofilm formation or adherence to epithelial cells, as proved by assays carried out with knockout mutants. Inhibitory and stimulatory properties may be similarly uncoupled in A. baumannii proteins

Performance of Ground Anchors Built in a Flysch Deposit

AbstractThe ultimate pull-out tensile load of ground anchors is strongly dependent onsoil nature,grout injection and effective stress state around the bulb. In this paper, the comparison between the results of conventional pull-out testson instrumented anchors built in a flysch formation and those of small scale pull-out tests performed in the laboratory,on undisturbed soil samples recovered at the depth of the anchor bulb,allowed to closely examine the skin friction that can be mobilizedin undrained conditionsat the soil-structure interface. The experiments highlight a strong scale effect, probably depending on the real size androughness ofthe lateral surface of the bulb. In fact, theirregular bulb profiledue to flysch features strongly contributes to the pull-outstrength

Zebrafish Patient-Derived Xenograft Model to Predict Treatment Outcomes of Colorectal Cancer Patients

The use of zebrafish embryos for personalized medicine has become increasingly popular. We present a co-clinical trial aiming to evaluate the use of zPDX (zebrafish Patient-Derived Xenografts) in predicting the response to chemotherapy regimens used for colorectal cancer patients. zPDXs are generated by xenografting tumor tissues in two days post-fertilization zebrafish embryos. zPDXs were exposed to chemotherapy regimens (5-FU, FOLFIRI, FOLFOX, FOLFOXIRI) for 48 h. We used a linear mixed effect model to evaluate the zPDX-specific response to treatments showing for 4/36 zPDXs (11%), a statistically significant reduction of tumor size compared to controls. We used the RECIST criteria to compare the outcome of each patient after chemotherapy with the objective response of its own zPDX model. Of the 36 patients enrolled, 8 metastatic colorectal cancer (mCRC), response rate after first-line therapy, and the zPDX chemosensitivity profile were available. Of eight mCRC patients, five achieved a partial response and three had a stable disease. In 6/8 (75%) we registered a concordance between the response of the patient and the outcomes reported in the corresponding zPDX. Our results provide evidence that the zPDX model can reflect the outcome in mCRC patients, opening a new frontier to personalized medicine

Elotuzumab plus pomalidomide and dexamethasone in relapsed/refractory multiple myeloma: a multicenter, retrospective real-world experience with 200 cases outside of controlled clinical trials

In the ELOQUENT-3 trial, the combination of elotuzumab, pomalidomide and dexamethasone (EloPd) proved a superior clinical benefit over Pd with a manageable toxicity profile, leading to its approval in relapsed/refractory multiple myeloma (RRMM), who had received at least two prior therapies, including lenalidomide and a proteasome inhibitor (PI). We report here a real-world experience of 200 RRMMs treated with EloPd in 35 Italian centers outside of clinical trials. In our dataset, the median number of prior lines of therapy was 2, with 51% of cases undergoing autologous stem cell transplant (ASCT) and 73% exposed to daratumumab. After a median follow-up of 9 months, 126 patients stopped EloPd, most of them (88.9%) because of disease progression. The overall response rate (ORR) was 55.4%, in line with the pivotal trial results. Regarding adverse events, our cohort experienced a toxicity profile similar to the ELOQUENT-3 trial, with no significant differences between younger (<70 years) and older patients. The median progression-free survival (PFS) was 7 months, shorter than that observed in the ELOQUENT-3, probably due to the different clinical characteristics of the two cohorts. Interestingly, the ISS stage III (HR:2.55) was associated with worse PFS. Finally, our series's median overall survival (OS) was shorter than that observed in the ELOQUENT-3 trial (17.5 versus 29.8 months). In conclusion, our real-world study confirms EloPd as a safe and possible therapeutic choice for RRMM who received at least two prior therapies, including lenalidomide and a PI

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

Off–label long acting injectable antipsychotics in real–world clinical practice: a cross-sectional analysis of prescriptive patterns from the STAR Network DEPOT study

Introduction: Information on the off–label use of Long–Acting Injectable (LAI) antipsychotics in the real world is lacking. In this study, we aimed to identify the sociodemographic and clinical features of patients treated with on– vs off–label LAIs and predictors of off–label First– or Second–Generation Antipsychotic (FGA vs. SGA) LAI choice in everyday clinical practice. Method: In a naturalistic national cohort of 449 patients who initiated LAI treatment in the STAR Network Depot Study, two groups were identified based on off– or on–label prescriptions. A multivariate logistic regression analysis was used to test several clinically relevant variables and identify those associated with the choice of FGA vs SGA prescription in the off–label group. Results: SGA LAIs were more commonly prescribed in everyday practice, without significant differences in their on– and off–label use. Approximately 1 in 4 patients received an off–label prescription. In the off–label group, the most frequent diagnoses were bipolar disorder (67.5%) or any personality disorder (23.7%). FGA vs SGA LAI choice was significantly associated with BPRS thought disorder (OR = 1.22, CI95% 1.04 to 1.43, p = 0.015) and hostility/suspiciousness (OR = 0.83, CI95% 0.71 to 0.97, p = 0.017) dimensions. The likelihood of receiving an SGA LAI grew steadily with the increase of the BPRS thought disturbance score. Conversely, a preference towards prescribing an FGA was observed with higher scores at the BPRS hostility/suspiciousness subscale. Conclusion: Our study is the first to identify predictors of FGA vs SGA choice in patients treated with off–label LAI antipsychotics. Demographic characteristics, i.e. age, sex, and substance/alcohol use co–morbidities did not appear to influence the choice towards FGAs or SGAs. Despite a lack of evidence, clinicians tend to favour FGA over SGA LAIs in bipolar or personality disorder patients with relevant hostility. Further research is needed to evaluate treatment adherence and clinical effectiveness of these prescriptive patterns