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A common concern among pathologists scoring PD-L1 immunohistochemical staining is interobserver and intraobserver variability. We assessed the interobserver and intraobserver reproducibility of PD-L1 scoring among trained pathologists using a combined positive score (CPS; tumour cell and tumour-associated immune cell staining).Data were collected for 2 years (2017-2019) from 456 pathologists worldwide. Digital training encompassed unique, tumour-specific training, and test sets. Samples were stained using PD-L1 IHC 22C3 pharmDx and evaluated at specific CPS cutoffs for gastric cancer (GC), cervical cancer (CC), urothelial cancer (UC), oesophageal cancer (OC), and head and neck squamous cell carcinoma (HNSCC). Pathologists underwent expert-to-peer training and scored 20 blinded samples on day 1 and 25 blinded samples on day 2 (including 15 of the day 1 samples). Interobserver and intraobserver reproducibility were assessed. For GC (120 observers) and CC (32 observers) samples assessed at CPS ≥1, average interobserver agreement was 91.5% and 91.0%, respectively, and average intraobserver agreement was 90.2% and 96.6%, respectively. For UC (139 observers) and OC (52 observers) samples measured at CPS ≥10, average interobserver agreement was 93.4% and 93.7%, respectively, and average intraobserver agreement was 92.0% and 92.5%, respectively. For HNSCC samples (113 observers), average interobserver agreement was 94.1% at CPS ≥1 and 86.5% at CPS ≥20; intraobserver agreement was 94.7% at CPS ≥1 and 90.5% at CPS ≥20.The consistently high interobserver and intraobserver concordance rates support the effectiveness of face-to-face training of many global pathologists for scoring PD-L1 CPS across multiple indications at several specific cutoffs.

This study presents the results of a refined numerical investigation meant at understanding the time-dependent cyclic behavior of reinforced concrete (RC) bridge columns under chlorides-induced corrosion. The chloride ingress in the cross-section of the bridge column is simulated, taking into account the effects of temperature, humidity, aging, and corrosion-induced cover cracking. Once the partial differential equations governing such multiphysics problem are solved through the finite-element method, the loss of reinforcement steel bars cross-section is calculated based on the estimated corrosion current density. The nonlinear cyclic response of the RC bridge column under corrosion is, thus, determined by discretizing its cross-sections into several unidirectional fibers. In particular, the nonlinear modeling of the corroded longitudinal rebars exploits a novel proposal for the estimation of the ultimate strain in tension and also accounts for buckling under compression. A parametric numerical study is finally conducted for a real case study to unfold the role of corrosion pattern and buckling mode of the longitudinal rebars on the time variation of capacity and ductility of RC bridge columns.

A generalized cyclic steel model characterized by isotropic and kinematic hardening, inelastic buckling in compression and corrosion of rebars in reinforced concrete (RC) structures is presented. This model has been implemented in in-house fiber code CYRUS-M developed in MATLAB, to perform seismic analysis of RC sections. The model is particularly accurate with respect to experimental cyclic behavior of rebars with buckling in compression when the strain does not exceed 1.5 %. 12 configurations of RC cross-sections were selected as case studies for 3 geometries and different steel configurations, assumed representative of RC columns or bridge piers (in a suitable scale). Each section was subjected to two groups of cyclic curvature histories representative of severe seismic loads, not far from collapse. Different axial loads and corrosion percentages (no corrosion, moderate or high) have been selected to perform cyclic parametric analyses. The results of the comparison among RC sections with uncorroded and corroded rebars have been discussed. Numerical results show that the maximum compressive strain is always smaller than 1.5 %, therefore the proposed steel model is a valid tool for structural assessment. Corrosion reduces the section capacity in terms of strength and energy dissipation and hysteretic damping.

OBJECTIVES To describe the X/Y shaped periorbital reconstruction technique following enucleation or exenteration in dogs and cats and to evaluate its cosmetic and functional results. MATERIALS AND METHODS Medical records of dogs and cats from two different institutions that required enucleation or exenteration, followed by an additional X or Y plasty using fibrous periorbital tissue for cosmetic reasons, were retrospectively reviewed. All patients were evaluated clinically at 1-2 weeks, 2 months and 6 months. The eyelid sinking was scored as absent or present. RESULTS Nineteen dogs and five cats were included in the study. Twelve dogs and three cats had an enucleation, while the remaining seven dogs and two cats underwent exenteration. In the short-term follow up, three patients had periorbital oedema. Sixty days and 6 months post-surgery, two cats and two dogs showed eyelid depression. These two dogs were both dolichocephalic breeds. The rest of the patients showed no eyelid sinking, while the periorbital oedema observed in the short-term follow up in the two dogs and one cat had completely resolved. The four patients with ocular neoplasia did not have the 6 months follow up, because of fatal metastatic disease or euthanasia. CLINICAL SIGNIFICANCE The X/Y periorbital reconstructive procedure is quick, easy to perform and it provided satisfying long-term cosmetic results, except for four cases that developed eyelid depression.

Helicobacter pylori (HP) infection is a common and persistent disorder acting as a major cofactor for the development of upper gastrointestinal diseases and several extraintestinal disorders including osteoporosis. However, no prospective study assessed the effects of HP on bone health and fracture risk. We performed a HP screening in a population-based cohort of 1149 adults followed prospectively for up to 11 years. The presence of HP infection was assessed by serologic testing for serum antibodies to HP and the cytotoxin associated gene-A (CagA). The prevalence of HP infection did not differ among individuals with normal bone mineral density (BMD), osteoporosis, and osteopenia. However, HP infection by CagA-positive strains was significantly increased in osteoporotic (30%) and osteopenic (26%) patients respect to subjects with normal BMD (21%). Moreover, anti-CagA antibody levels were significantly and negatively associated with lumbar and femoral BMD. Consistent with these associations, patients affected by CagA-positive strains had a more than fivefold increased risk to sustain a clinical vertebral fracture (HR 5.27; 95% CI, 2.23-12.63; p < .0001) and a double risk to sustain a nonvertebral incident fracture (HR 2.09; 95% CI, 1.27-2.46; p < .005). Reduced estrogen and ghrelin levels, together with an impaired bone turnover balance after the meal were also observed in carriers of CagA-positive HP infection. HP infection by strains expressing CagA may be considered a risk factor for osteoporosis and fractures. Further studies are required to clarify in more detail the underlying pathogenetic mechanisms of this association. © 2020 American Society for Bone and Mineral Research (ASBMR).

Mutations in SQSTM1 are strongly associated with Paget's disease of bone (PDB), but little is known about the clinical characteristics of those with early disease. Radionuclide bone scans, biochemical markers of bone turnover, and clinical characteristics were analyzed in SQSTM1 mutation carriers who took part in the Zoledronic acid in the Prevention of Paget's disease (ZiPP) study. We studied 222 individuals, of whom 54.9% were female, with mean ± SE age of 50.1 ± 0.6 years. Twelve SQSTM1 mutations were observed, including p.Pro392Leu, which was present in 141 of 222 (63.5%) subjects. Bone scan examination revealed evidence of PDB in 20 subjects (9.0%), ten of whom (50%) had a single affected site. Participants with lesions were older than those without lesions but the difference was not significant (53.6 ± 9.1 versus 49.8 ± 8.9; p = .07). The mean age of participants with lesions was not significantly different from the age at which their parents were diagnosed with PDB (55 years versus 59 years, p = .17). All individuals with lesions were asymptomatic. Serum concentrations of total alkaline phosphatase (ALP) normalized to the upper limit of normal in each center were higher in those with lesions (0.75 ± 0.69 versus 0.42 ± 0.29 arbitary units; p

The global surge in bacterial resistance against traditional antibiotics triggered intensive research for novel compounds, with antimicrobial peptides (AMPs) identified as a promising candidate. Automated methods to systematically generate and screen AMPs according to their membrane preference, however, are still lacking. We introduce a novel microfluidic system for the simultaneous cellfree production and screening of AMPs for their membrane specificity. On our device, AMPs are cell-free produced within water-in-oil-inwater double emulsion droplets, generated at high frequency. Within each droplet, the peptides can interact with different classes of coencapsulated liposomes, generating a membrane-specific fluorescent signal. The double emulsions can be incubated and observed in a hydrodynamic trapping array or analyzed via flow cytometry. Our approach provides a valuable tool for the discovery and development of membrane-active antimicrobials., Angewandte Chemie. International Edition, 61 (13), ISSN:1433-7851, ISSN:1521-3773, ISSN:0570-0833

In recent years there has been renewed interest on integral abutment bridges (IABs), mainly due to their low construction and maintenance cost. Owing to the monolithic connection between deck and abutments, there is strong soil structure interaction between the bridge and the backfill under both thermal action and earthquake shaking. Although some of the regions where IABs are adopted qualify as highly seismic, there is limited knowledge as to their dynamic behaviour and vulnerability under strong ground shaking. To develop a better understanding on the seismic behaviour of IABs, an extensive experimental campaign involving over 75 shaking table tests and 4800 time histories of recorded data, was carried out at EQUALS Laboratory, University of Bristol, under the auspices of EU sponsored SERA project (Seismology and Earthquake Engineering Research Infrastructure Alliance for Europe). The tests were conducted on a 5 m long shear stack mounted on a 3 m 3 m 6 DOF earthquake simulator, focusing on interaction effects between a scaled bridge model, abutments, foundation piles and backfill soil. The study aims at (a) developing new scaling procedures for physical modelling of IABs, (b) investigating experimentally the potential benefits of adding compressible inclusions (CIs) between the abutment and the backfill and (c) exploring the influence of different types of connection between the abutment and the pile foundation. Results indicate that the CI reduces the accelerations on the bridge deck and the settlements in the backfill, while disconnecting piles from the cap decreases bending near the pile head.

Aims Although loop diuretics are the most commonly used drugs in acute heart failure (AHF) treatment, their short-term and long-term effects are relatively unknown. The significance of worsening renal function occurrence during intravenous treatment is not clear enough. This trial aims to clarify all these features and contemplate whether continuous infusion is better than an intermittent strategy in terms of decongestion efficacy, diuretic efficiency, renal function, and long-term prognosis. Methods and results This is a prospective, multicentre, randomized study that compares continuous infusion to intermittent infusion and a low vs. high diuretic dose of furosemide in patients with a diagnosis of acute heart failure, BNP ≥ 100 pg/mL, and specific chest X-ray signs. Randomization criteria have been established at a 1:1 ratio using a computer-generated scheme of either twice-daily bolus injection or continuous infusion for a time period ranging from 72 to 120 h. The initial dose will be 80 mg/day of intravenous furosemide and, in the case of poor response, will be doubled using an escalation algorithm. A high diuretic dose is defined as a furosemide daily amount >120 mg/day respectively. Conclusions Continuous and high dose groups could reveal a more intensive diuresis and a greater decongestion with respect to intermittent and low dose groups; high dose and poor loop diuretic efficiency should be related to increased diuretic resistance, renal dysfunction occurrence, and greater congestion status. Poor diuretic response will be associated with less decongestion and an adverse prognosis.

Summary eHealth is expected to contribute in tackling challenges for health care systems. However, it also imposes challenges. Financing strategies adopted at national as well regional levels widely affect eHealth long‐term sustainability. In a public health care system, the public actor is among the main “buyers” eHealth. However, public interventions have been increasingly focused on cost containment. How to match these 2 aspects? This article explores some central issues, mainly related to financial aspects, in the development of effective and valuable eHealth strategies in a public health care system: How can the public health care system (as a “buyer”) improve long‐term success and sustainability of eHealth solutions? What levers are available to match in the long period different interests of different stakeholders in the eHealth field? A case study was performed in the Region of Tuscany, Italy. According to our results, win‐win strategies should be followed. Investments should take into account the need to long‐term finance solutions, for sustaining changes in health care organizations for obtaining benefits. To solve the interoperability issues, the concept of the “platform approach” emerged, based on collaboration within and between organizations. Private sector as well as beneficiaries and final users of the eHealth solutions should participate in their design, provision, and monitoring. For creating value for all, the evidence gap and the financial needs could be addressed with a pull mechanism of funding, aimed at paying according to the outcomes produced by the eHealth solution, on the base of an ongoing monitoring, measurement, and evaluation of the outcomes.

In patients with age-related macular degeneration (AMD), choroidal neovascularization is the major cause of severe visual loss. In these patients, the persistence of neovascular growth despite vascular endothelial growth factor-A blockage needs the discovery of new endothelial cell targets. The glycoprotein CD93, highly expressed in activated endothelial cells, has been recently involved in the regulation of the angiogenic process both as transmembrane and soluble protein. Choroidal neovascular membranes from patients affected by AMD were examined by immunofluorescence using anti-CD93 and anti-von Willebrand factor antibodies. Blood vessels within intraocular and extraocular neoplasias were used as controls for CD93 expression. All choroidal neovascular membranes displayed strong CD93 staining in the von Willebrand factor-positive endothelial cells, consistently with the analyses showing a high colocalization coefficient in the blood vessels. Intraocular and extraocular tumor vessels showed similar results, whereas the normal choroid displayed blood vessels with only faint CD93 staining. Additionally, the concentration of soluble CD93 was determined in the aqueous humor of patients affected by naive neovascular AMD by enzyme-linked immunosorbent assays. Age-matched cataract patients served as controls. Soluble CD93 was significantly increased in the aqueous humor of naive neovascular AMD patients and tended to decrease after treatment with an antiangiogenic drug. In conclusion, both transmembrane and soluble CD93 are overexpressed in patients with neovascular AMD, indicating that CD93 may represent a potential new antiangiogenic target in the treatment of choroidal neovascularization. J. Cell. Physiol. 232: 1767-1773, 2017. © 2016 Wiley Periodicals, Inc.

Our previous studies have shown that Dexamethasone (Dex) reduced the expression of matrix-metalloproteinases (MMPs -1,-3,-9,-13), IL-1β and IL-6, while it significantly increased MMP-8 mRNA transcripts in a concomitant dry eye and corneal alkali burn murine model (CM). To investigate if MMP-8 induction is responsible for some of the protective effects of Dex in CM, MMP-8 knock out mice (MMP-8KO) were subjected to the CM for 2 or 5 days and topically treated either with 2 μl of 0.1% Dexamethasone (Dex), or saline QID. A separate group of C57BL/6 mice were topically treated with Dex or BSS and received either 100 nM CAM12 (MMP-8 inhibitor) or vehicle IP, QD. Here we demonstrate that topical Dex treated MMP-8KO mice subjected to CM showed reduced corneal clarity, increased expression of inflammatory mediators (IL-6, CXCL1, and MMP-1 mRNA) and increased neutrophil infiltration at 2D and 5D compared to Dex treated WT mice. C57BL/6 mice topically treated with Dex and CAM12 IP recapitulated findings seen with MMP-8KO mice. These results suggest that some of the anti-inflammatory effects of Dex are mediated through increased MMP-8 expression. J. Cell. Physiol. 231: 2506-2516, 2016. © 2016 Wiley Periodicals, Inc.

Background Repetitive transcranial magnetic stimulation (rTMS) appears as a useful tool to alleviate neuropathic pain but only few data are available for the long-term benefit of this treatment. Methods Here we report the effects of rTMS sessions, considered as a possible therapy for pain relief after a failure of different medications in patients with central (neuropathic) pain. We review here the prospectively collected data of the first forty patients treated as follow: 20 Hz stimulation delivered over the contralateral primary motor cortex (M1), each 3–4 weeks. Results A total of 440 rTMS sessions was collected (mean sessions number: 11, range: 1–37, follow-up 312 days on average, maximum 2.8 years). After four sessions, nine patients (22.5%) discontinued rTMS because of a lack of efficiency (

The role of pathologic auto-antibodies against myelin oligodendrocyte glycoprotein (MOG) in multiple sclerosis is a highly controversial matter. As the use of animal models may enable to unravel the molecular mechanisms of the human disorder, numerous studies on multiple sclerosis are carried out using experimental autoimmune encephalomyelitis (EAE). In particular, the most extensively used EAE model is obtained by immunizing C57BL/6 mice with the immunodominant peptide MOG(35-55). In this scenario, we analyzed the anti-MOG antibody response in this model using the recombinant refolded extracellular domain of the protein, MOG(1-117). To assess the presence of a B-cell intramolecular epitope spreading mechanism, we tested also five synthetic peptides mapping the 1-117 sequence of MOG, including MOG(35-55). For this purpose, we cloned, expressed in Escherichia coli and on-column refolded MOG(1-117), and we applied an optimized microwave-assisted solid-phase synthetic strategy to obtain the designed peptide sequences. Subsequently, we set up a solid-phase immunoenzymatic assay testing both naive and EAE mice sera and using MOG protein and peptides as antigenic probes. The results obtained disclose an intense IgG antibody response against both the recombinant protein and the immunizing peptide, while no response was observed against the other synthetic fragments, thus excluding the presence of an intramolecular epitope spreading mechanism. Furthermore, as the properly refolded recombinant probe is able to bind antibodies with greater efficiency compared with MOG(35-55), we hypothesize the presence of both linear and conformational epitopes on MOG(35-55) sequence.

Over the past few years, right‐wing populist parties have been attracting more and more supporters across Europe and beyond. For example, in the 2014 European elections, the Front National secured a relative majority in France.1 In June 2015 the coalition including the Dansk Folkeparti won the Danish national elections; with 21.1 percent of votes, the Dansk Folkeparti became the second‐largest party in the country, doubling its support from the prior elections.2 In November 2016, Donald Trump, who conveyed right‐wing populist messages during his presidential campaign, was elected as the forty‐fifth president of the US.

Although the older adults have been studied as victims of violence, geriatric patients can display violent behavior. The purpose of the present review was to explore the phenomenon of criminal violations and violent acts in people with dementia. The authors used PubMed to search the MEDLINE database and other sources for original research and review articles on criminal and violent manifestation in demented patients combining the terms "criminal manifestation," "violence, aggressive behavior," "homicide," "suicide" and "homicide-suicide" together with "dementia". Possible biomarkers of violence are considered. The present review highlights the risk factors for violence in patients suffering from dementia, and reviews the literature about criminal violations and homicidal/suicidal behavior in this patient group. Geriatr Gerontol Int 2016; 16: 541-549.