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In today’s environment, organizations need new corporate strategies and models to protect profitability and competitiveness, as well as the heritage of natural resources. A circular economy is a model of production and consumption in which all resources and products are reused in the economic cycle, which can significantly reduce waste generation and create additional economic benefits for business. This is especially important in the context of the recovery from the economic crisis caused by the COVID-19 pandemic. Implemented quarantine restrictions have revealed how sensitive to global risks and inflexible the linear economic system is. The purpose of this study is to identify and analyze ways to implement circular economy models in the corporate strategy of the organization. The objectives of the article are to study the latest publications on the definition of circular economy, corporate strategy and their relationship, description of the strategic planning process taking into account the models of circular economy, identification of basic business models of circular economy, analysis of examples of implementation of circular models conclusions. To achieve the goal of the study, the authors’ different approaches to the interpretation of the concept of “corporate strategy” and its formation within the circular economy were analyzed, the process of strategic planning was highlighted and the main types of values created by the circular economy were identified. The key circular business models and their relationship with the corporate strategy of the organization are highlighted. The main part of the article analyzes examples of implementation of the concept of circular economy in the corporate strategies of four selected Italian companies in various industries. A comparative description of the roles of the circular economy in the corporate strategy of each company and the benefits gained in the process of its implementation was carried out. Conclusions were drawn on the importance of implementing the ideas of the circular economy at the stage of forming the strategy of the enterprise to achieve economic, environmental and social benefits.

INTRODUCTION Rib fracture fixation is becoming more popular and widely accepted among trauma surgeons worldwide as the recommended treatment method for flail chest injury. Recent data demonstrate improved results when compared with non-operative treatment. Improved outcomes were reported regarding ICU stay, need for tracheostomy, length of hospital stay, ventilator-associated pneumonia (VAP), and even death. The objective of this study was to ascertain whether clinical respiratory para-meters are improved after rib fracture fixation procedure. MATERIAL AND METHODS This is a prospective study using a retrospective cohort for control, which took place at the Soroka University Medical Centre, Israel. Inclusion criteria included all patients over 18 years of age with flail chest injury or multiple ribs fractures, who were admitted to the General Intensive Care Unit (GICU). Between October 2015 and December 2018, we identified 24 patients who had their rib fractures operatively fixed and compared them to 61 patients with flail chest and multiple rib fractures, who were admitted to our GICU between the years 2010 and 2015 and were treated non-opera-tively. In all the surgical cases operations were performed within 72 hours of arrival in accordance with our treatment algorithm. All fractures were fixed using specialised anatomic locking plates/nails. Demographic data were collected, and respiratory parameters before and after the surgery were recorded and analysed. RESULTS We compared patients who had had their rib fractures fixed with a cohort group of patients who had been treated non-operatively in the past. No demographic differences were found between the 2 groups, nor were there any differences in their clinical trauma scoring, mechanical ventilation days, length of ICU stay, VAP, and death rates. The respiratory parameters (paO2/FiO2 ratio and chest wall compliance) were significantly higher during the 3 ensuing days after surgery and continued to improve in Group 1 (rib fixation group), in comparison to group 2 (non-operative) patients (P = 0.007 and P < 0.0001, respectively). The peak inspiratory pressure and PEEP para-meters were significantly lower in group 1 in comparison to group 2 during the 3 days, in favour of the operated group, with significant improvement noted over the 3 days post-surgery (P = 0.007 and P = 0.02, respectively). CONCLUSIONS We suggest that surgical treatment of flail chest and multiple rib fractures has clinical benefit and improves respiratory parameters even in the presence of multiple trauma injuries.

For over three decades federal child welfare policy has promoted three goals to achieve permanent outcomes for children: 1) making reasonable efforts to prevent out of home placement; 2) reunifying...

The article is devoted to the description of interlingual interference in Spanish-speaking countries on the example of the phenomenon of “Spanglish”. The article outlines the content of language interference and bilingualism. The definition of the term “language interference” is given. The concept of Spanglish is specified and the main characteristics of the studied phenomenon are presented. The causes, content, and consequences of the formation of the “Spanglish” phenomenon are singled out. The main models of functioning of the phenomenon on the material of dialogic speech of Spanish and English-speaking students, Internet resources, literary and film works are revealed. The geographical areas most prone to the formation, spread and popularization of the phenomenon of “Spanglish” are outlined. In the end of the research we came to the conclusion that because translation is an integral part of intercultural communication, interference in this case is the result of bilingualism (or multilingualism) of the translator with a subsequent impact on the translation process – often negative. The problem of interference is considered in the framework of language contacts, when a person who speaks two languages violates the rules of correlation of these languages. Languages interact with each other, resulting not only in the borrowing of language units, but also the convergence of languages as a whole. We figured out that the main reason and condition for the manifestation of interference is bilingualism/multilingualism and linguistic contact. The place of manifestation of interference is the bilingual himself or the person who performs the translation, when he tries to compensate some linguistic units with units from another language, which can involuntarily lead to literalism, accent and distortion of the meaning of the original text. We found out what are the methods of overcoming unwanted interference, as well as what a teacher can do at school or university to prevent the introduction of signs of speech interference in students’ speech.

Gender incongruence is defined as disharmony between assigned gender and gender identity. Several interventions are liable in this case including genital affirming surgery among other surgical interventions such as harmonization, and also the use of gonadotropin-releasing hormone agonists (GnRHa) for gonadal shielding. This aids in preventing the development of secondary sexual characteristics related to the genetic sex. Systematically review the treatment of gender incongruity with GnRHa analogues. The data source of this research is from Pubmed-Medline and Embase. Articles published between 2009 and 2019 which studied transgender adolescents treated with GnRHa were carefully selected. Were extracted: design, sample size, study context, targeted subjects of intervention, outcome measures, and results. Eleven studies were included. The use of GnRHa seems to be well tolerated by the studied population. When started in pubertal transition, it was associated with a more distinct resemblance to body shape than to the affirmed sex. In addition to preventing the irreversible phenotypic changes that occur in cross-hormonal therapy, the use of GnRHa can equally contribute to the mental health of these adolescents. There are few consistent studies on the use of GnRHa for gender incongruence. As the population of transgender children and adolescents grows, they acquire knowledge and greater access to the various forms and stages of treatment for sex reassignment. The medical community needs to be adequately prepared to better serve this population and offer the safest resources available.

Since 1998, over 120 upper extremity transplants have been successfully performed around the world; however, the field of vascularized composite allotransplantation (VCA) continues to face various medical challenges and ethical controversies. This article summarizes the worldwide experience with transplantation of vascularized composite upper extremities in children and discusses the unique considerations facing potential pediatric VCA recipients. Three children have successfully received composite upper or lower extremity transplants, of which two involved isografts and one involved allografts. Numerous research and clinical advances relevant to VCA have been made, including patient screening, perioperative rehabilitation, allograft preservation and transportation, enhancement of nerve regeneration, understanding of cortical plasticity, and immunomodulatory strategies. Ethical and psychosocial issues remain at the forefront when evaluating potential pediatric VCA recipients. For ethically and rigorously screened pediatric patients with debilitating upper extremity absence, VCA is a compelling option to restore form and function and has a promising future.

Accumulating evidence demonstrates the impact of bias that reflects social inequality on the performance of machine learning (ML) models in health care. Given their intended placement within healthcare decision making more broadly, ML tools require attention to adequately quantify the impact of bias and reduce its potential to exacerbate inequalities. We suggest that taking a patient safety and quality improvement approach to bias can support the quantification of bias-related effects on ML. Drawing from the ethical principles underpinning these approaches, we argue that patient safety and quality improvement lenses support the quantification of relevant performance metrics, in order to minimize harm while promoting accountability, justice, and transparency. We identify specific methods for operationalizing these principles with the goal of attending to bias to support better decision making in light of controllable and uncontrollable factors.

The recent success of checkpoint blockade therapies has established immunotherapy as one of the most promising treatments for melanoma. Nonetheless, a complete curative response following immunotherapy is observed only in a fraction of patients. To identify what factors limit the efficacy of immunotherapies, we established mouse models that cease to respond to immunotherapies once their tumors exceed a certain stage. Analysis of the immune systems of the organisms revealed that the numbers of tumor-infiltrating dendritic cells (TIDC) drastically decreased with time. Further, in contrast to the current paradigm, once melanoma was established, TIDC did not migrate into sentinel lymph nodes. Instead, they underwent local cell death due to excessive phagocytosis of lysosomes. Importantly, TIDC were required to license the cytotoxic activity of tumor CD8+ T cells, and in their absence, T cells did not lyse melanoma cells. Our results offer a paradigm shift regarding the role of TIDC and a framework to increase the efficacy of immunotherapies. Significance: This work redefines the role of monocyte-derived dendritic cells in melanoma and provides a novel strategy to increase the efficacy of T-cell–based immunotherapies in nonresponding individuals.

The scientific approaches of Ukrainian and foreign scientists to the interpretation of the concept of strategic enterprise management and compares their characteristics are systematized in this article; different stages of evolution of strategic management systems in the context of functioning of scientific schools are analyzed, their basic principles are presented and their key representatives are singled out; the comparative analysis of approaches of different scientific schools is carried out, advantages and disadvantages of their views on strategic management and strategy formation are determined. For further structuring of knowledge in the field of strategic management, the essence of the concept of strategy was determined according to the interpretation of different scientists and the organization strategies were classified by key characteristics and levels of implementation; their key characteristics have been identified. Particular attention is paid to basic models of strategic enterprise management, taking into account their features, advantages and disadvantages; the structure and algorithms of strategic management based on the analyzed models are graphically demonstrated. According to the results of the research, conclusions were drawn regarding the theoretical bases of understanding the essence of strategic management of enterprises and differences in their interpretation in the works of different authors, characteristics of basic models of strategic management are generalized, the importance of strategic management to ensure the effective operation of the organization is emphasized; the features of strategic management in the conditions of the modern changing environment are characterized and the expediency of basic models of strategic management for modern enterprises is determined, the proposals for the further development and deepening of the investigated topic are developed.

Coxiella burnetii is an obligate intracellular bacterium and the causative agent of Q fever. C. burnetii is considered a potential bioterrorism agent because of its low infectious dose; resistance to heat, drying, and common disinfectants; and lack of prophylactic therapies. Q-Vax, a formalin-inactivated whole-bacteria vaccine, is currently the only prophylactic measure that is protective against C. burnetii infections but is not U.S. Food and Drug Administration approved. To overcome the safety concerns associated with the whole-bacteria vaccine, we sought to generate and evaluate recombinant protein subunit vaccines against C. burnetii. To accomplish this, we formulated C. burnetii Ags with a novel TLR triagonist adjuvant platform, which used combinatorial chemistry to link three different TLR agonists together to form one adjuvanting complex. We evaluated the immunomodulatory activity of a panel of TLR triagonist adjuvants and found that they elicited unique Ag-specific immune responses both in vitro and in vivo. We evaluated our top candidates in a live C. burnetii aerosol challenge model in C56BL/6 mice and found that several of our novel vaccine formulations conferred varying levels of protection to the challenged animals compared with sham immunized mice, although none of our candidates were as protective as the commercial vaccine across all protection criteria that were analyzed. Our findings characterize a novel adjuvant platform and offer an alternative approach to generating protective and effective vaccines against C. burnetii.

The accumulation of circulating low-density neutrophils (LDN) has been described in cancer patients and associated with tumor-supportive properties, as opposed to the high-density neutrophils (HDN). Here we aimed to evaluate the clinical significance of circulating LDN in lung cancer patients, and further assessed its diagnostic vs prognostic value. Using mass cytometry (CyTOF), we identified major subpopulations within the circulating LDN/HDN subsets and determined phenotypic modulations of these subsets along tumor progression. LDN were highly enriched in the low-density (LD) fraction of advanced lung cancer patients (median 7.0%; range 0.2%-80%, n = 64), but not in early stage patients (0.7%; 0.05%-6%; n = 35), healthy individuals (0.8%; 0%-3.5%; n = 15), or stable chronic obstructive pulmonary disease (COPD) patients (1.2%; 0.3%-7.4%, n = 13). Elevated LDN (>10%) remarkably related with poorer prognosis in late stage patients. We identified three main neutrophil subsets which proportions are markedly modified in cancer patients, with CD66b+ /CD10low /CXCR4+ /PDL1inter subset almost exclusively found in advanced lung cancer patients. We found substantial variability in subsets between patients, and demonstrated that HDN and LDN retain a degree of inherent spontaneous plasticity. Deep phenotypic characterization of cancer-related circulating neutrophils and their modulation along tumor progression is an important advancement in understanding the role of myeloid cells in lung cancer.

The hydraulic fracturing is a nonlinear, fluid-solid coupling and transient problem, in most cases it is always time-consuming to simulate this process numerically. In recent years, although many numerical methods were proposed to settle this problem, most of them still require a large amount of computer resources. Thus it is a high demand to develop more effificient numerical approaches to achieve the real-time monitoring of the fracture geometry during the hydraulic fracturing treatment. In this study, a reduced order modeling technique namely Proper Generalized Decomposition (PGD), is applied to accelerate the simulations of the transient, non-linear coupled system of hydraulic fracturing problem, to match this extremely tight response time constraint. The separability of the solution in space and time dimensions is studied for a simplifified model problem. The solid and flfluid equations are coupled explicitly by inverting the solid discrete problem, and a simple iterative procedure to handle the non-linear characteristic of the hydraulic fracturing problem is proposed in this work. Numeral validation illustrates that the results of PGD match well with these of standard fifinite element method in terms of fracture opening and fluid pressure in the hydro-fracture. Moreover, after the off-line calculations, the numerical results can be obtained in real time. This work is financially supported by the National Science Foundation of China (Grant Nos. 51804033 and 51936001), China Postdoctoral Science and Foundation (Grant No. 2018M641254), Beijing Postdoctoral Research Foundation (2018- ZZ-045), the Project of Construction of Innovative Teams and Teacher Career Development for Universities and Colleges Under Beijing Municipality (Grant No. IDHT20170507) and Program of Great Wall Scholar (Grant No. CIT&TCD20180313) and Jointly Projects of Beijing Natural Science Foundation and Beijing Municipal Education Commission (Grant No. KZ201810017023).

Importance: Tracheal intubation is one of the most commonly performed and high-risk interventions in critically ill patients. Limited information is available on adverse peri-intubation events. Objective: To evaluate the incidence and nature of adverse peri-intubation events and to assess current practice of intubation in critically ill patients. Design, Setting, and Participants: The International Observational Study to Understand the Impact and Best Practices of Airway Management in Critically Ill Patients (INTUBE) study was an international, multicenter, prospective cohort study involving consecutive critically ill patients undergoing tracheal intubation in the intensive care units (ICUs), emergency departments, and wards, from October 1, 2018, to July 31, 2019 (August 28, 2019, was the final follow-up) in a convenience sample of 197 sites from 29 countries across 5 continents. Exposures: Tracheal intubation. Main Outcomes and Measures: The primary outcome was the incidence of major adverse peri-intubation events defined as at least 1 of the following events occurring within 30 minutes from the start of the intubation procedure: cardiovascular instability (either: systolic pressure 30 minutes, new or increase need of vasopressors or fluid bolus >15 mL/kg), severe hypoxemia (peripheral oxygen saturation

Post-stroke depression (PSD) is a common and serious complication following stroke. Both stroke and depression have independently been associated with pathologically elevated glutamate levels in the brain's extra-cerebral fluid (ECF). Here we evaluate an alternative therapeutic approach to PSD with pyruvate. Rats were randomly assigned into one of 3 groups: Middle Cerebral Artery Occlusion (MCAO) plus pyruvate treatment, MCAO plus placebo treatment, and sham operated rats. Post-MCAO depressive and anxiety-like behavior was assessed, along with neurological status, brain infarct zone, brain edema, blood brain barrier (BBB) breakdown, cerebrospinal fluid and blood glutamate levels. Anxiety-like behavior and levels of blood alanine and α-ketoglutarate were measured in naive rats treated with pyruvate, as a control. Post-stroke neurological deficit with concurrent elevation in glutamate levels were demonstrated, with peak glutamate levels 24 h after MCAO. Treatment with pyruvate led to reduced glutamate levels 24 h after MCAO and improved neurologic recovery. Pyruvate treatment reduced lesion volume, brain edema and the extent of BBB permeability 24 h post-MCAO. Naive rats treated with pyruvate showed increased levels of α-ketoglutarate. Rats demonstrated post-stroke depressive behavior that was improved by the administration of pyruvate. There was less anxiety-like behavior in post-stroke rats treated with placebo in comparison to the post-stroke rats treated with pyruvate or sham operated rats. Glutamate scavenging with pyruvate appears to be an effective as a method in providing neuroprotection following stroke and as a therapeutic option for the treatment of PSD by reducing the consequent elevations in CNS glutamate levels.

Here we evaluate an alternative protocol to histologically examine blood-brain barrier (BBB) breakdown, brain edema, and lesion volume following traumatic brain injury (TBI) in the same set of rodent brain samples. We further compare this novel histological technique to measurements determined by magnetic resonance imaging (MRI) and a neurological severity score (NSS). Sixty-six rats were randomly assigned to a sham-operated, mild TBI, moderate TBI, or severe TBI group. 48 h after TBI, NSS, MRI and histological techniques were performed to measure TBI severity outcome. Both the histological and MRI techniques were able to detect measurements of severity outcome, but histologically determined outcomes were more sensitive. The two most sensitive techniques for determining the degree of injury following TBI were NSS and histologically determined BBB breakdown. Our results demonstrate that BBB breakdown, brain edema, and lesion volume following TBI can be accurately measured by histological evaluation of the same set of brain samples.

Introduction: A pressure gradient of over 8 mm Hg across the stenosis (usually located in the transverse-sigmoid junction) is one of the criteria for cerebral venous stenting in idiopathic intracranial hypertension (IIH) patients. The possible inaccuracy of the traditional microcatheter-based pressure measurements has been discussed in previous studies. In the cardiology field, a dual-sensor pressure wire is routinely used for the evaluation of stenotic lesions. Using a pressure wire for cerebral vasculature was previously discussed in a small case series and case reports. In this study, we compared venous pressure measurements obtained using both a microcatheter and a pressure wire in patients who were candidates for stenting.Methods: A retrospective study was conducted, comparing the two methods of pressure measurements in 26 patients with venous stenosis. Altogether, 120 measurements were performed using both methods. Demographic characteristics, medical history, procedural details, medications, indications for the procedure, and complications were collected from the patient charts.Results: Based on an 8-mm Hg pressure gradient cutoff indication, 19 patients were found eligible to go through unilateral venous stenting based on catheter measurements alone. The wire results corroborated the catheter results in detecting all cases indicated for a stent. This finding implies a sensitivity equal to 100% for the wire measurements. There were no wire-related complications, demonstrating its safety.Conclusions: We conclude that the pressure wire is as safe as the microcatheter and can identify cases requiring intervention. A larger-scale study is needed to assess the measurement accuracy of the pressure wire in brain vasculature.

BACKGROUND: There is little information regarding diaphragmatic dysfunction (DD) following thoracic surgery. Ultrasound allows for non-invasive repeated assessments of diaphragmatic excursion (DE) and thickening fraction (DTF) at the bedside, reflecting DD. We aimed at determining the prevalence of DD and the time-course of DE and DTF following elective thoracic surgery. Secondary endpoints included the association between DD and postoperative complications. METHODS: We led a prospective, single center, observational study in consecutive patients undergoing thoracic surgery. DE and DTF were measured by two observers blinded to each other at 3 different time-points: prior to surgery (D-1), immediately after extubation (D0) and on postoperative day 3 (D3). The changes in excursion and thickening fraction of both hemi-diaphragms over time were compared according to the side (operated or non-operated) using a two-way ANOVA. The association with postoperative complications was assessed using logistic regression.RESULTS: Fifty patients, 60% males, aged 60±15 years were included. Surgical procedures included lobectomy (n=30), wedge-resection (n=17) or pneumonectomy (n=3). DD was highly prevalent after thoracic surgery and was observed on the operated side (or both sides) in, at least, 68% of patients immediately after surgery (D0). Among those patients, 46% still had this DD on the operated side on D3. On the operated side, we observed a decrease in DE and DTF at D0 (-0.71±0.12mm, PPPPP=0.001), ICU-admission (P=0.04) according to univariate analysis and a prolonged length in hospital (OR:1.3, 95% CI [1.1-1.7], P=0.016) according to multivariate analysis.CONCLUSIONS: Diaphragmatic Dysfunction (DD) was very common after thoracic surgery, mainly concerned the operated side and was associated with an increase in the diaphragmatic excursion on the non-operated side. When this dysfunction failed to regress within 72 hours, it was associated with a significant increase in the length of hospital stay.

Retroperitoneal sarcoma is a rare malignancy arising from mesenchymal cells.[1][1] Surgical resection with wide negative margins remains the cornerstone of treatment as it decreases the risk of recurrence.[2][2] The proximity to critical abdominal structures makes a total resection with nerve and

Achievement of initial remission remains the most important clinical factor predicting long term survival in acute myeloid leukemia (AML) patients treated with intensive chemotherapy. Yet, whether the patient subset in need of a second cycle of intensive induction chemotherapy to reach remission experiences inferior outcomes compared to patients reaching remission after a single cycle of therapy, remains uncertain.Retrospective analysis of 302 consecutive AML patients treated with intensive induction chemotherapy in our institution in 2007-2020.Median patient age was 55 years with a median follow-up duration of 23 months. In terms of European LeukemiaNet (ELN) 2017 classification, 122 patients (40%) were designated as favorable risk disease, 108 patients (36%) were intermediate risk, and 71 patients (24%) were adverse risk. A hundred and seventy-seven patients (60%) attained remission following initial chemotherapy while 58 patients (20%) required an additional cycle of intensive chemotherapy for remission. Patients requiring 2 cycles to reach remission were less likely to be NPM1 mutated (33% versus 51%; P=.025) or be in the ELN 2017 favorable risk category (25% versus 57%; P.001). In multivariate analysis achievement of remission following 2 cycles of intensive compared with a single cycle resulted in significantly inferior survival [hazard ratio (HR)=1.67, 95% CI, 1.07-2.59; P=.025] whereas leukemia-free survival was not significantly impacted (HR=1.26, 95% CI, 0.85-1.85) (P=.23). Relapse rates also did not differ to a significant degree between groups (45% versus 47%, P=.8).Attainment of an early remission significantly impacts long term survival in AML patients.

Critically ill patients with severe hypoxemia are often treated in the intensive care unit (ICU) with inhaled nitric oxide (iNO). These patients are at higher risk when they require intrahospital transportation. In this study, we collected clinical and laboratory data from 221 patients who were hospitalized in the general ICU and treated with iNO at Soroka Medical Center, Israel, between January 2010 and December 2019. We retrospectively compared the 65 patients who received iNO during intrahospital transportation to the 156 patients who received iNO without transportation. Among critically ill patients who were transported while being administered iNO, only one patient had an adverse event (atrial fibrillation) on transport. We found that maximal iNO dosage during ICU stay, duration of mechanical ventilation, and percent of vasopressor support were the only independent risk factors for ICU mortality in both study groups. No difference in primary outcome of ICU mortality rate was found between the critically ill patients treated with iNO during intrahospital transportation and those who were treated with iNO but not transported during the ICU stay. We anticipate that this study will advise clinical decision-making in the ICU, especially when treating patients who are administered iNO.

Char and colleagues provide a useful conceptual framework for the proactive identification of ethical issues arising throughout the lifecycle of machine learning (ML) applications in healthcare. Th...

Children and adolescents with complex medical conditions are often uprooted from their environments and isolated in hospital while undergoing treatment. Little is known about how they perceive this isolation and its subsequent impact on their relationships with peers, both during and after isolation for treatment. This study describes the experience of hospital isolation from the perspectives of children and adolescents with a malignant brain tumor. The use and impact of information and communication technologies (ICT) as a possible bridge for contact is also explored. Following a qualitative approach utilizing interpretive phenomenological analysis, in-depth interviews were conducted with eight youth participants who had undergone treatment for medulloblastoma. Data analysis generated three main themes: (1) transforming children and relationships, (2) hospitalization in a digital world, and (3) ICTs as a promising bridge back to school. Study findings provide insight into the experience of hospital isolation for children and adolescents, while highlighting the positive social as well as academic outcomes of frequent, open ended ICT use throughout hospital isolation. This is timely, given the context of the COVID-19 pandemic and its resulting isolation. Considerations for hospital social workers to promote relationships and connection, while facilitating a smooth transition as these children return to school are included.

BACKGROUND Esophageal cancer represents a global challenge. Despite significant evolution of treatment protocols in the past decade, recurrence rates are still high and survival rates are poor. Current treatment paradigm for localized gastroesophageal junction (GEJ) carcinoma remains to be further elucidated as for the role of neoadjuvant chemoradiation versus perioperative chemotherapy. AIM To identify biomarkers for response to chemoradiation in esophageal and gastroesophageal cancer, we performed an in-depth proteomic analysis of esophageal and gastroesophageal tumors, to describe differences in pathway activation between patients with favorable and poor prognosis following neoadjuvant chemoradiation. METHODS Patients with locally advanced esophageal and gastroesophageal cancer following neoadjuvant chemoradiation were included in the cohort. The study cohort was dichotomized into two groups of patients, named "favorable prognosis" and "poor prognosis" according to the postoperative disease-free interval. We performed a mass spectrometry analysis of proteins extracted from the malignant regions of surgical specimens and analyzed data from electronic medical records. Clinical data was correlated with differences in protein expression between patient with a favorable and poor prognosis using validated gene expression pathways. RESULTS The study included 35 patients with adenocarcinoma. All patients in this cohort had esophageal adenocarcinoma. Patients median age was 62 years. Twenty-five (71.3%) patients underwent neoadjuvant chemoradiation, and 28.7% underwent neoadjuvant chemotherapy only. A proteomic analysis of our cohort identified 2885 proteins. Enrichment levels of 98 of these proteins differed significantly between favorable and poor prognosis cohorts in patients who underwent neoadjuvant chemoradiation (p

[This corrects the article DOI: 10.3389/fimmu.2021.633297.].

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), is a global health threat with the potential to cause severe disease manifestations in the lungs. Although COVID-19 has been extensively characterized clinically, the factors distinguishing SARS-CoV-2 from other respiratory viruses are unknown. Here, we compared the clinical, histopathological, and immunological characteristics of patients with COVID-19 and pandemic influenza A(H1N1). We observed a higher frequency of respiratory symptoms, increased tissue injury markers, and a histological pattern of alveolar pneumonia in pandemic influenza A(H1N1) patients. Conversely, dry cough, gastrointestinal symptoms and interstitial lung pathology were observed in COVID-19 cases. Pandemic influenza A(H1N1) was characterized by higher levels of IL-1RA, TNF-α, CCL3, G-CSF, APRIL, sTNF-R1, sTNF-R2, sCD30, and sCD163. Meanwhile, COVID-19 displayed an immune profile distinguished by increased Th1 (IL-12, IFN-γ) and Th2 (IL-4, IL-5, IL-10, IL-13) cytokine levels, along with IL-1β, IL-6, CCL11, VEGF, TWEAK, TSLP, MMP-1, and MMP-3. Our data suggest that SARS-CoV-2 induces a dysbalanced polyfunctional inflammatory response that is different from the immune response against pandemic influenza A(H1N1). Furthermore, we demonstrated the diagnostic potential of some clinical and immune factors to differentiate both diseases. These findings might be relevant for the ongoing and future influenza seasons in the Northern Hemisphere, which are historically unique due to their convergence with the COVID-19 pandemic.

Background Patients with GBS may develop hypoalbuminemia following treatment with Intravenous Immunoglobulin (IVIG), which is related to a poorer outcome. This report presents a patient with GBS and his clinical response to two courses of IVIG treatments in association with his albumin level. Case report: A previously healthy 21-year-old male was admitted to the GICU due to GBS with severity grade 5 (required assisted ventilation). IVIG treatment was initiated. Over the next two weeks there was no clinical improvement and Albumin level dropped from 4.5 gr/dL to a nadir of 2.3 gr/dL. A second course of IVIG was initiated. After initiation of the second course the patient’s albumin began rising to 3.0 gr/dL and a clinical improvement followed this rise. Subsequently, he was weaned from mechanical ventilation within a few days. Conclusions When considering a second course of IVIG treatment, serum albumin levels may be considered a biomarker as part of the decision algorithm.

Increasing use of natural gas for electricity production places added strains on pipeline systems that are used for transporting fuel. Pipeline constraints require power system operators to account for natural gas-supply restrictions in their operational processes. This paper proposes separate optimization models for clearing day-ahead wholesale markets for scheduling power and natural gas systems. We then develop a market-based mechanism that allows for efficient co-ordination of the two systems. Importantly, the co-ordination mechanism only requires the exchange of fuel-price, -supply, and -demand information between the two markets. This can be contrasted with other co-ordination mechanisms that require operations of the two systems by a single entity. Thus, we provide a computationally tractable co-ordination mechanism that does not require the exchange of proprietary information between natural gas and electricity system operators. We demonstrate the effectiveness and scalability of the technique using a numerical example.

Background Patients who undergo surgical procedures that impair the integrity of the chest wall frequently experience extremely severe postoperative pain. Opiates and weaker analgesics, such as nonsteroidal anti-inflammatory drugs (NSAIDs), are not sufficiently effective in achieving control of severe pain and might cause respiratory and gastrointestinal complications. In the past decade, there has been an increased interest in the use of regional nerve blocks for post-thoracoscopy and post-thoracotomy analgesia. Methods This is a prospective, randomized, double-blind and single-center study. We recruited 104 patients who underwent elective thoracoscopy. Prior to surgery, the participating patients were randomized into one of two study groups: Group 1- the "standard control group" that received standard postoperative pain control with intravenous opioids, NSAIDs and acetaminophen (paracetamol) and Group 2- the "block group" that was treated by ultrasound-guided serratus anterior plane (SAP) block (a single injection of 0.25% bupivacaine hydrochloride 2 mg/kg plus dexamethasone 8 mg) with standard postoperative pain control regimen. We compared the clinical, laboratory, and postoperative pain assessment data of both groups. Results Patients in the SAP block Group 2 reported significantly lower levels of pain after thoracic surgery as assessed by their visual analog scale scores, as compared to the patients in the standard pain control Group 1 (P

Background Sentinel lymph node biopsy (SLNB) is routinely performed during surgery for malignant melanoma, using double mapping. Still, in some cases, a sentinel lymph node identified pre-operatively by lymphoscintigraphy is not identified during surgery. We hypothesized that disease specific survival would not be significantly impacted by intra-operative lymph node mapping (IOLM) failure. Methods The patient population study included 1300 malignant melanomas operated on by a single surgical oncologist (H.G.) after sentinel lymph node scintigraphy. Patients were included in the analysis if intra-operative lymph node (IOLM) mapping failed. Results Among 1300 patients who underwent surgery for malignant melanoma during the study period and after median follow up of >10 years, 33/36 lymphatic drainage basins with failed sentinel node identification were free of disease. Disease specific survival for the entire group of 33 patients with IOLM failure was 91.0%, which is comparable to previously published disease specific survival for all melanoma patients. Conclusion We conclude that failure to identify a pre-operatively marked sentinel lymph node by an experienced melanoma surgeon has, generally, no impact on disease specific survival, as demonstrated in this review of a series of surgical melanoma patients.

The growing dependence of electric power systems on gas-fired generators to balance fluctuating and intermittent production by renewable energy sources has increased the variation and volume of flows withdrawn from natural gas transmission pipelines. Adapting pipeline operations to maintain efficiency and security under these dynamic conditions requires optimization methods that account for substantial intraday transients and can rapidly compute solutions in reaction to generator re-dispatch. Here, we present a computationally efficient method for minimizing gas compression costs under dynamic conditions where deliveries to customers are described by time-dependent mass flows. The optimization method uses a simplified representation of gas flow physics, provides a choice of discretization schemes in time and space, and exploits a two-stage approach to minimize energy costs and ensure smooth and physically meaningful solutions. The resulting large-scale NLPs are solved using an interior point method. The optimization scheme is validated by comparing the solutions with an integration of the dynamic equations using an adaptive timestepping differential equation solver, as well as a different, recently proposed optimal control scheme. The comparison shows that solutions to the discretized problem are feasible for the continuous problem and also practical from an operational standpoint. The results also indicate that our scheme produces at least an order of magnitude reduction in computation time relative to the state of the art and scales to large gas transmission networks with more than 6,000 kilometers of total pipeline. The online supplement is available at https://doi.org/10.1287/ijoc.2018.0821 .

Spinal muscular atrophy (SMA) is the most common genetic cause of infant mortality. SMA is a spectral disorder and is categorised based on symptom onset and severity. The median life expectancy for infants with SMA presenting before 6 months of age is less than 2 years without respiratory support. To date, there is no cure for SMA. In June 2017, nusinersen was approved in Canada as the first disease-modifying drug for SMA because of its demonstrated benefits on motor function and survival in clinical trials. However, with a price tag of almost 1 million dollars for the first year of therapy, careful clinical, treatment-based and ethical consideration of the principles of (i) best interests; (ii) universality; (iii) portability; (iv) public administration; (v) accessibility; and (vi) comprehensiveness are important guideposts to ensure transparent and equitable allocation of health-care resources for nusinersen and all other future orphan drugs.

This article explores the ethical challenges of providing Medical Assistance in Dying (MAID) in a paediatric setting. More specifically, we focus on the theoretical questions that came to light when we were asked to develop a policy for responding to MAID requests at our tertiary paediatric institution. We illuminate a central point of conceptual confusion about the nature of MAID that emerges at the level of practice, and explore the various entailments for clinicians and patients that would flow from different understandings. Finally, we consider the ethical challenges of building policy on what is still an extremely controversial social practice. While MAID is currently available to capable patients in Canada who are 18 years or older—a small but important subsection of the population our hospital serves—we write our policy with an eye to the near future when capable young people may gain access to MAID. We propose that an opportunity exists for MAID-providing institutions to reduce social stigma surrounding this practice, but not without potentially serious consequences for practitioners and institutions themselves. Thus, this paper is intended as a road map through the still-emerging legal and ethical landscape of paediatric MAID. We offer a view of the roads taken and considered along the way, and our justifications for travelling the paths we chose. By providing a record of our in-progress thinking, we hope to stimulate wider discussion about the issues and questions encountered in this work.

Breast cancer subtypes have not shown significant response to current immunomodulatory therapies. Although most subtypes are treatable, triple negative breast cancer (TNBC), an aggressive highly metastatic cancer, comprising 10–20% of breast cancers, remains an unmet medical need. New strategies are needed in order to overcome flaws in the responsiveness to current TNBC therapies. Our aims were: first, to determine the efficacy of a novel immunomodulatory peptide, C24D, on TNBC and second, to elucidate the molecular mechanism by which C24D induces immune-modulating tumor killing. Using mass spectrometry analysis, we identified CD45 as the C24D binding receptor. In vitro and in vivo TNBC models were used to assess the efficacy of C24D in reversing TNBC-induced immunosuppression and in triggering immune-modulated tumor cell killing. The CD45 signal transduction pathway was evaluated by western blot and FACS analyses. We revealed that addition of PBMCs from healthy female donors to TNBC cells results in a cascade of suppressive CD45 intracellular signals. On binding to CD45’s extra-cellular domain on TNBC-suppressed leukocytes, the C24D peptide re-activates the Src family of tyrosine kinases, resulting in specific tumor immune response. In vitro, immune reactivation by C24D results in an increase of CD69+ T and CD69+ NK cells, triggering specific killing of TNBC cells. In vivo, C24D induced CD8+ and activated CD56+ tumor infiltrated cells, resulting in tumor apoptosis. Our results should renew interest in molecules targeting CD45, such as the C24D peptide, as a novel strategy for TNBC immunotherapy.

The activation of the EGFR/Ras-signalling pathway in tumour cells induces a distinct chemokine repertoire, which in turn modulates the tumour microenvironment.The effects of EGFR/Ras on the expression and translation of CCL20 were analysed in a large set of epithelial cancer cell lines and tumour tissues by RT-qPCR and ELISA in vitro. CCL20 production was verified by immunohistochemistry in different tumour tissues and correlated with clinical data. The effects of CCL20 on endothelial cell migration and tumour-associated vascularisation were comprehensively analysed with chemotaxis assays in vitro and in CCR6-deficient mice in vivo.Tumours facilitate progression by the EGFR/Ras-induced production of CCL20. Expression of the chemokine CCL20 in tumours correlates with advanced tumour stage, increased lymph node metastasis and decreased survival in patients. Microvascular endothelial cells abundantly express the specific CCL20 receptor CCR6. CCR6 signalling in endothelial cells induces angiogenesis. CCR6-deficient mice show significantly decreased tumour growth and tumour-associated vascularisation. The observed phenotype is dependent on CCR6 deficiency in stromal cells but not within the immune system.We propose that the chemokine axis CCL20-CCR6 represents a novel and promising target to interfere with the tumour microenvironment, and opens an innovative multimodal strategy for cancer therapy.

The C-X-C motif chemokine ligand 17 (CXCL17) is chemotactic for myeloid cells, exhibits bactericidal activity, and exerts anti-viral functions. This chemokine is constitutively expressed in the respiratory tract, suggesting a role in lung defenses. However, little is known about the participation of CXCL17 against relevant respiratory pathogens in humans. Here, we evaluated the serum levels and lung tissue expression pattern of CXCL17 in a cohort of patients with severe pandemic influenza A(H1N1) from Mexico City. Peripheral blood samples obtained on admission and seven days after hospitalization were processed for determinations of serum CXCL17 levels by enzyme-linked immunosorbent assay (ELISA). The expression of CXCL17 was assessed by immunohistochemistry (IHQ) in lung autopsy specimens from patients that succumbed to the disease. Serum CXCL17 levels were also analyzed in two additional comparative cohorts of coronavirus disease 2019 (COVID-19) and pulmonary tuberculosis (TB) patients. Additionally, the expression of CXCL17 was tested in lung autopsy specimens from COVID-19 patients. A total of 122 patients were enrolled in the study, from which 68 had pandemic influenza A(H1N1), 24 had COVID-19, and 30 with PTB. CXCL17 was detected in post-mortem lung specimens from patients that died of pandemic influenza A(H1N1) and COVID-19. Interestingly, serum levels of CXCL17 were increased only in patients with pandemic influenza A(H1N1), but not COVID-19 and PTB. CXCL17 not only differentiated pandemic influenza A(H1N1) from other respiratory infections but showed prognostic value for influenza-associated mortality and renal failure in machine-learning algorithms and regression analyses. Using cell culture assays, we also identified that human alveolar A549 cells and peripheral blood monocyte-derived macrophages increase their CXCL17 production capacity after influenza A(H1N1) pdm09 virus infection. Our results for the first time demonstrate an induction of CXCL17 specifically during pandemic influenza A(H1N1), but not COVID-19 and PTB in humans. These findings could be of great utility to differentiate influenza and COVID-19 and to predict poor prognosis specially at settings of high incidence of pandemic A(H1N1). Future studies on the role of CXCL17 not only in severe pandemic influenza, but also in seasonal influenza, COVID-19, and PTB are required to validate our results.

The capabilities of natural neural systems have inspired new generations of machine learning algorithms as well as neuromorphic very large-scale integrated (VLSI) circuits capable of fast, low-power information processing. However, it has been argued that most modern machine learning algorithms are not neurophysiologically plausible. In particular, the workhorse of modern deep learning, the backpropagation algorithm, has proven difficult to translate to neuromorphic hardware. In this study, we present a neuromorphic, spiking backpropagation algorithm based on synfire-gated dynamical information coordination and processing, implemented on Intel's Loihi neuromorphic research processor. We demonstrate a proof-of-principle three-layer circuit that learns to classify digits from the MNIST dataset. To our knowledge, this is the first work to show a Spiking Neural Network (SNN) implementation of the backpropagation algorithm that is fully on-chip, without a computer in the loop. It is competitive in accuracy with off-chip trained SNNs and achieves an energy-delay product suitable for edge computing. This implementation shows a path for using in-memory, massively parallel neuromorphic processors for low-power, low-latency implementation of modern deep learning applications., arXiv

Methodologies for multidimensionality reduction aim at discovering low-dimensional manifolds where data ranges. Principal Component Analysis (PCA) is very effective if data have linear structure. But fails in identifying a possible dimensionality reduction if data belong to a nonlinear low-dimensional manifold. For nonlinear dimensionality reduction, kernel Principal Component Analysis (kPCA) is appreciated because of its simplicity and ease implementation. The paper provides a concise review of PCA and kPCA main ideas, trying to collect in a single document aspects that are often dispersed. Moreover, a strategy to map back the reduced dimension into the original high dimensional space is also devised, based on the minimization of a discrepancy functional.

SummaryBackgroundSepsis has no proven specific pharmacologic treatment. Reported mortality in sepsis ranges from 30%–45%. This study was designed to determine the safety preliminary efficacy of allogenic apoptotic cells administered for immunomodulation in septic patients.MethodsThe primary aim of this phase IB study was to determine the safety profile of apoptotic cell infusion in subjects presenting to the emergency room with sepsis. Sepsis was determined by clinical infections and Sequential Organ Failure Assessment (SOFA) scores >2. The secondary aims were to measure organ dysfunction, intensive care unit (ICU) and hospital stays, and mortality, that were compared to historical controls. Exploratory endpoints included measuring immune modulator agents to elucidate the mechanism of action using Luminex® analysis.FindingsTen patients were treated with apoptotic cells, administered as a single dose or two sequential doses. All 10 patients had mild-to-moderate sepsis with a SOFA score range of 2–6 upon entering the study. No serious adverse events (SAEs) and no related AEs were reported. All 10 study subjects survived while matched historical controls had a mortality rate of 27%. The study subjects exhibited rapid resolution of organ dysfunction and had significantly shorter ICU lengths of stay compared to matched historical controls (pInterpretationAdministration of apoptotic cells to patients with mild-to-moderate sepsis was safe and had a significant immuno-modulating effect, leading to early resolution of the cytokine storm.Trial registrationClinicalTrials.gov Identifier: NCT03925857FundingThe study was sponsored by Enlivex Therapeutics Ltd.

Pipelines perform a critical function in the petroleum business by transporting hydrocarbon commodities between oil fields, refineries, and consumer markets. We formulate an optimization problem for determining the optimal pumping modes and flow configuration for liquid pipeline operations. Based on requested flow rates and commodity prices submitted by users of the pipeline system, the system manager can solve an optimization problem to determine flow rates allocated to all customers, flows on each pipeline section, and pumps station operating settings in order to maximize economic value provided by a pipeline while adhering to limitations of pump machinery and the physics of fluid flow. In particular, the optimal solution will maximize the economic benefit for the pipeline transport network users and utilization of system capacity while also minimizing the energy expended in operation. This problem is nonconvex, and solutions are only guaranteed to be locally optimal. In this study we pose a mathematical optimization formulation with minimal modeling that captures the basic phenomena involved, and an algorithm based on general-purpose interior point optimization is proposed for efficient solution. We demonstrate our approach on a realistic case study based on a pipeline system in the United States.

BackgroundCXCL17 is chemotactic for myeloid cells, exhibits broad-spectrum bactericidal activity, and is expressed in mucosal tissues. This chemokine is constitutively expressed in the respiratory tract, suggesting a role for CXCL17 in lung defenses. However, little is known about the possible participation of CXCL17 during respiratory infections in humans. Here, we evaluated the role of CXCL17 as a biomarker in patients with severe pandemic influenza A(H1N1) and coronavirus disease 2019 (COVID-19). MethodsWe conducted a prospective cohort study in hospitalized patients with severe influenza A(H1N1) and COVID-19 admitted to two national reference centers in Mexico City. Peripheral blood samples were obtained on admission for determinations of the serum levels of CXCL17 by enzyme-linked immunosorbent assay (ELISA). The expression of CXCL17 in lung autopsy specimens from patients that succumbed to both diseases was assessed by immunohistochemistry (IHQ). Serum CXCL17 levels were compared between patients grouped according to their disease and clinical outcome. The diagnostic and predictive value of serum CXCL17 levels was evaluated using machine-learning algorithms and regression analyses. ResultsA total of 92 patients were enrolled in the study, from which 68 were infected with influenza and 24 had COVID-19. Their clinical characteristics were similar, although dyspnea, rhinorrhea, and sputum production were more common during influenza, whereas dry cough and vomit were more frequent among COVID-19 patients. Both diseases induced the local expression of CXCL17 in the lung. However, serum levels of CXCL17 were increased only in patients with influenza but not COVID-19. CXCL17 not only differentiates influenza from COVID-19 but serves as a prognostic biomarker associated with mortality and renal failure in influenza patients. Using cell culture assays, we also identified that human alveolar A549 cells and peripheral blood monocyte-derived macrophages produce CXCL17 after influenza A(H1N1) pdm09 virus infection. ConclusionsOur results suggest a possible role for CXCL17 in the pathogenesis of influenza A(H1N1), supporting the use of this molecule as a prognostic biomarker. Future studies on the role of CXCL17 in COVID-19 are warranted.

Purpose According to most guidelines, medical protocol for carotid stenting includes the administration of oral Aspirin and Clopidogrel at least four days before the procedure, with intraprocedural intravenous (IV) heparin. Some publications have also reported the safety of adding glycoprotein 2b/3a inhibitors to the protocol. In this retrospective study, we evaluate the safety of a new medication protocol that includes IV aspirin and intra-arterial Eptifibatide (glycoprotein 2b/3a inhibitor) during carotid stenting. All patients who underwent carotid stenting at Soroka University Medical Center between January 2015 and May 2020 were included (emergent cases were excluded). We divided patients into two groups—patients treated under the standard protocol, and patients treated under the new protocol. In the latter, patients received both the standard protocol regimen, as well as 150 mg IV aspirin immediately before stenting, and a slow intra-arterial injection of 2–3 mg Eptifibatide (glycoprotein 2b/3a antagonist) immediately after stenting. Forty-four patients were treated according to the standard protocol (group 1), and 41 patients were treated according to the new protocol (group 2). In group 1, six patients had complications, while in group 2, no complications of any kind were noted (p = 0.027). The safety and possible efficacy of this novel protocol was preliminarily demonstrated in the present study. Future studies are needed to prove the safety and efficacy of a specific drug regimen that will further reduce the complication rates of carotid stenting.

Since 2015, endovascular thrombectomy has been established as the standard of care for re-establishing cerebral blood flow in patients with acute ischemic stroke. Several retrospective observational studies and prospective clinical trials have investigated two anesthetic techniques for endovascular stroke therapy: general anesthesia (GA) and conscious sedation (CS). The recent randomized studies suggest that GA is associated with higher rates of successful recanalization and better functional independence at 3 months compared with the CS technique. However, CS techniques are highly variable, and there is currently a lack of consensus on which anesthetic approach is best in all patients. Numerous patient and procedural factors should ultimately guide the decision of whether GA or CS should be used for a particular patient.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), is a global health threat with the potential to cause severe disease manifestations in the lungs. Although clinical descriptions of COVID-19 are currently available, the factors distinguishing SARS-CoV-2 from other respiratory viruses are unknown. Here, we compared the clinical, histopathological, and immunological characteristics of patients with COVID-19 and pandemic influenza A(H1N1). We observed a higher frequency of respiratory symptoms, increased tissue injury markers, a histological pattern of alveolar pneumonia, and higher levels of IL-1RA, TNF-α, CCL3, G-CSF, APRIL, sTNF-R1, sTNF-R2, sCD30, and sCD163 in influenza patients. Conversely, dry cough, gastrointestinal symptoms, interstitial lung pathology, increased Th1 (IL-12, IFN-γ) and Th2 (IL-4, IL-5, IL-10, IL-13) cytokine levels, along with IL-1β, IL-6, CCL11, VEGF, TWEAK, TSLP, MMP-1, and MMP-3, were observed in COVID-19 cases. We demonstrated the diagnostic potential of some clinical and immune factors to differentiate COVID-19 from pandemic influenza A(H1N1). Our data suggest that SARS-CoV-2 induces a dysbalanced polyfunctional inflammatory response that is different from the immune response against influenza. These findings might be relevant for the upcoming 2020-2021 influenza season, which is projected to be historically unique due to its convergence with COVID-19.