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Due to an increased policy focus on informal care in many Western countries, professionals and informal caregivers increasingly grow more interdependent. Increased involvement of informal caregivers in professional care has consequences for the work of professionals, the care that is received by care recipients, and the role of informal caregivers. Care needs to be negotiated between them within the dynamic networks of care recipients and caregivers (i.e., "care convoys"). Scant attention has been given to objects as part of these convoys and negotiations. Therefore, in this paper, we answer the question: How do objects become part of and what is their role in the negotiations between healthcare professionals and informal caregivers? We use interview data from 48 participants (care recipients, professionals, informal caregivers, and persons in managerial positions). In the results, we discuss how objects, in terms of their affordances and the values they embody, become important in the relationship between professionals and informal caregivers and how they become part of negotiations on quality of care. We find that seemingly mundane objects become topics of conversation to address more fundamental concerns in how healthcare is organized for and provided to individual care recipients. Our study helps to open the care convoys model to objects as important actors and further understand the politics within care convoys., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

In the wealthy and orderly city of Geneva, Switzerland, accommodation centres built in haste between the 1950s and the 1980s to house seasonal guestworkers from southern Europe are still standing and still inhabited. Today's residents are precarious workers, undocumented or with temporary permits as well as asylum seekers. While the seasonal status disappeared in the early 2000s, the demand for low-skilled, flexible labour did not. Analysing the historical trajectories of specific buildings helps us to answer the question of who replaced the seasonal workers, not only in the labour and the housing markets, but also in the symbolic spectrum of legitimacy. This article introduces the notion of 'Subaltern Housing Policies' to account for the public action that leads to the production and subsequent use of forms of housing characterised by standards of comfort and security far below those of the rental and social housing stock, but considered 'good enough' for their occupants. We argue that 'subaltern' relates not only to housing conditions, but also to the policies themselves, and last but not least to the people who are subjected to them. This notion allows us to trace a link between the production of substandard forms of housing and the production of categories of people who are kept on the margins of full citizenship., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article., (© The Author(s) 2023.)

Background: The majority of experimental approaches for cancer immunotherapy are tested against relatively small tumors in tumor-bearing mice, because in most cases advanced cancers are resistant to the treatments. In this study, we asked if even late-stage mouse tumors can be eradicated by a rationally designed combined radio-immunotherapy (CRI) regimen., Methods: CRI consisted of local radiotherapy, intratumoral IL-12, slow-release systemic IL-2 and anti- CTLA-4 antibody. Therapeutic effects of CRI against several weakly immunogenic and immunogenic mouse tumors including B78 melanoma, MC38 and CT26 colon carcinomas and 9464D neuroblastoma were evaluated. Immune cell depletion and flow cytometric analysis were performed to determine the mechanisms of the antitumor effects., Results: Tumors with volumes of 2,000 mm 3 or larger were eradicated by CRI. Flow analyses of the tumors revealed reduction of T regulatory (Treg) cells and increase of CD8/Treg ratios following CRI. Rapid shrinkage of the treated tumors did not require T cells, whereas T cells were involved in the systemic effect against the distant tumors. Cured mice developed immunological memory., Conclusions: These findings underscore that rationally designed combination immunotherapy regimens can be effective even against large, late-stage tumors., Competing Interests: Author WO was formerly employed by the company Nektar Therapeutics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Rakhmilevich, Tsarovsky, Felder, Zaborek, Moram, Erbe, Pieper, Spiegelman, Cheng, Witt, Overwijk, Morris and Sondel.)

The persistence of multiple educational pathways into the nursing profession continues to occupy scholars internationally. In the Netherlands, various groups within the Dutch healthcare sector have tried to differentiate nursing practice on the basis of educational backgrounds for over 50 years. Proponents argue that such reforms are needed to retain bachelor-trained nurses, improve quality of care and strengthen nurses' position in the sector. Opponents have actively resisted reforms because they would mainly benefit bachelor-trained nurses and neglect practical experience and technical skills. This historical case study aims to provide insight in this apparent stalemate. Our analysis of this debate is informed by literature on institutional work and current debates within the historiography of nursing. This study contributes to a better understanding of this contemporary debate by examining a broader timeframe than is usually studied, and by highlighting nurses' roles in complex processes of change. We argue that, rather than being stuck in their professional development, different groups of nurses have forged their own path forward in their professional development, albeit via different strategies., (© 2024 The Authors. Nursing Inquiry published by John Wiley & Sons Ltd.)

The emergence of SARS-CoV-2 variants with increased fitness has had a strong impact on the epidemiology of COVID-19, with the higher effective reproduction number of the viral variants leading to new epidemic waves. Tracking such variants and their genetic signatures, using data collected through genomic surveillance, is therefore crucial for forecasting likely surges in incidence. Current methods of estimating fitness advantages of variants rely on tracking the changing proportion of a particular lineage over time, but describing successful lineages in a rapidly evolving viral population is a difficult task. We propose a method of estimating fitness gains directly from nucleotide information generated by genomic surveillance, without a priori assigning isolates to lineages from phylogenies, based solely on the abundance of single nucleotide polymorphisms (SNPs). The method is based on mapping changes in the genetic population structure over time. Changes in the abundance of SNPs associated with periods of increasing fitness allow for the unbiased discovery of new variants, thereby obviating a deliberate lineage assignment and phylogenetic inference. We conclude that the method provides a fast and reliable way to estimate fitness advantages of variants without the need for a priori assigning isolates to lineages., Competing Interests: Competing interests statement:The authors declare no competing interest.

Due to processes of financialisation, financial parties increasingly penetrate the healthcare domain and determine under which conditions care is delivered. Their influence becomes especially visible when healthcare organisations face financial distress. By zooming-in on two of such cases, we come to know more about the considerations, motives and actions of financial parties in healthcare. In this research, we were able to examine the social dynamics between healthcare executives, banks and health insurers involved in a Dutch hospital and mental healthcare organisation on the verge of bankruptcy. Informed by interviews, document analysis and translation theory, we reconstructed the motives and strategies of executives, banks and health insurers and show how they play a crucial role in decision-making processes surrounding the survival or downfall of healthcare organisations. While parties are bound by legislation and company procedures, the outcome of financial distress can still be influenced. Much depends on how executives are perceived by financial stakeholders and how they deal with threats of destabilisation of the network. We further draw attention to the consequences of financialisation processes on the practices of healthcare organisations in financial distress., (© 2023 The Authors. Sociology of Health & Illness published by John Wiley & Sons Ltd on behalf of Foundation for the Sociology of Health & Illness.)

Nursing shortages in the global north are soaring. Of particular concern is the high turnover among bachelor-trained nurses. Nurses tend to leave the profession shortly after graduating, often citing a lack of appreciation and voice in clinical and organisational decision-making. Healthcare organisations seek to increase the sustainability of the nursing workforce by enhancing nursing roles and nurses' organisational positions. In the Netherlands, hospitals have introduced pilots in which nurses craft new roles. We followed two pilots ethnographically and examined how nurses and managers shaped new nursing roles and made sense of their (expected) impact on workforce resilience. Informed by the literature on professional ecologies and job crafting, we show how managers and nurses defined new roles by differentiating between training levels and the uptake of care-related organisational responsibilities beyond the traditional nursing role. We also show how, when embedding such new roles, nurses needed to negotiate specific challenges associated with everyday nursing practice, manifested in distinct modes of organising, work rhythms, embodied expertise, socio-material arrangements, interprofessional relationships, and conventions about what is considered important in nursing. We argue that our in-depth case study provides a relational and socio-material understanding of the organisational politics implicated in organising care work in the face of workforce shortages., (© 2024 The Authors. The International Journal of Health Planning and Management published by John Wiley & Sons Ltd.)

This article draws on ethnographic research investigating experimental reform projects in local nursing practices. These are aimed at strengthening nursing work and fostering nurses' position within healthcare through bottom-up nurse-driven innovations. Based on literature on epistemic politics and critical nursing studies, the study examines and conceptualizes how these nurses promote professional and organizational change. The research draws on data from two pilot projects to show how epistemic politics frame the production and use of knowledge within reform efforts. The study finds that knowledge produced through such experimenting is often not considered valid within the contexts of broader organizational transitions. The nurse-driven innovations fail to meet established legitimate criteria for informing change, both among stakeholders in the nurses' socio-political environment, as well as within the nursing community. The research reveals that the processes inadvertently reinforce normative knowledge hierarchies, perpetuating forms of epistemic injustice, limiting both nurses' ability to function as change agents and healthcare organizations' capacity to learn., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Comparative phylogenetic analyses are of potential value to establish the essential components of genetic networks underlying physiological traits. For species that naturally lack particular lymphocyte lineages, we show here that this strategy readily distinguishes trait-specific actors from pleiotropic components of the genetic network governing lymphocyte differentiation. Previously, three of the four members of the DNA polymerase X family have been implicated in the junctional diversification process during the somatic assembly of antigen receptors. Our phylogenetic analysis indicates that the presence of terminal deoxynucleotidyl transferase is strictly associated with the facility of V(D)J recombination, whereas PolL and PolM genes are retained even in species lacking Rag-mediated somatic diversification of antigen receptor genes., (© 2023 The Authors. European Journal of Immunology published by Wiley-VCH GmbH.)

Health care systems are facing soaring workforce shortages, challenging their ability to secure timely access to good-quality care. In this context, nurses make difficult decisions about which patients to deliver care to, transfer to other providers, or strategically ignore. Yet, we still know little about how nurses engage in situated practices of bedside rationing. Building on the work of Giorgio Agamben and Judith Butler, we have developed a research agenda that homes in on a politics of bedside rationing. We argue that this agenda is essential to better understand the implications of scarcity for nursing and to explore new ways to cope with challenges faced., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc.)

The creation and maintenance of a dialysis access is vital for the reduction of morbidity, mortality, and cost of treatment for end stage renal disease patients. One's longevity on dialysis is directly dependent upon the quality of dialysis. This quality hinges on the integrity and reliability of the access to the patient's vascular system. All methods of dialysis access will eventually result in dialysis dysfunction and failure. Arteriovenous access dysfunction includes 3 distinct classes of events, namely thrombotic flow-related complications or dysfunction, nonthrombotic flow-related complications or dysfunction, and infectious complications. The restoration of any form of arteriovenous access dysfunction may be supported by diagnostic imaging, clinical consultation, percutaneous interventional procedures, surgical management, or a combination of these methods. This document provides a rigorous evaluation of how variants of each form of dysfunction may be appraised and approached systematically. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation., (Copyright © 2023 American College of Radiology. Published by Elsevier Inc. All rights reserved.)

Objective: The present research sought to examine whether cohabitation with a smoker undermines smoking cessation among people engaged in a cessation programme and whether the components of the Theory of Planned Behaviour (TPB) act as mediating mechanisms., Design: A prospective longitudinal study with online questionnaires was conducted among smokers living in Switzerland who enrolled in a 6-months smoking cessation programme., Main Outcome Measures: Cohabitation with a smoker and the TPB constructs were assessed 10 days after the start of the programme (T1; N  = 820). Smoking abstinence was measured at T1, and at 3-months (T2; N  = 624) and 6-months follow-ups (T3; N  = 354)., Results: Results showed that living with a smoker decreased the odds that smokers remained abstinent throughout the cessation programme. Furthermore, we found that cohabitation was negatively associated with subjective norm. Afterwards, subjective norm predicted intention to maintain smoking cessation, which, in turn, predicted smoking abstinence. Such mediation effects persisted at each time point., Conclusion: The present research provided evidence that living with other smokers at home can lead to greater risks of relapsing among people engaged in a cessation programme. We discussed the role of smoking-related norms in the efficacy of cessation interventions., Supplemental data for this article is available online at https://doi.org/10.1080/08870446.2022.2041638 .

Introduction: We have previously shown that an intratumoral (IT) injection of the hu14.18-IL2 immunocytokine (IC), an anti-GD2 antibody linked to interleukin 2, can serve as an in situ vaccine and synergize with local radiotherapy (RT) to induce T cell-mediated antitumor effects. We hypothesized that cyclophosphamide (CY), a chemotherapeutic agent capable of depleting T regulatory cells (Tregs), would augment in situ vaccination. GD2 + B78 mouse melanoma cells were injected intradermally in syngeneic C57BL/6 mice., Methods: Treatments with RT (12Gy) and/or CY (100 mg/kg i.p.) started when tumors reached 100-300 mm 3 (day 0 of treatment), followed by five daily injections of IT-IC (25 mcg) on days 5-9. Tumor growth and survival were followed. In addition, tumors were analyzed by flow cytometry., Results: Similar to RT, CY enhanced the antitumor effect of IC. The strongest antitumor effect was achieved when CY, RT and IC were combined, as compared to combinations of IC+RT or IC+CY. Flow cytometric analyses showed that the combined treatment with CY, RT and IC decreased Tregs and increased the ratio of CD8+ cells/Tregs within the tumors. Moreover, in mice bearing two separate tumors, the combination of RT and IT-IC delivered to one tumor, together with systemic CY, led to a systemic antitumor effect detected as shrinkage of the tumor not treated directly with RT and IT-IC. Cured mice developed immunological memory as they were able to reject B78 tumor rechallenge., Conclusion: Taken together, these preclinical results show that CY can augment the antitumor efficacy of IT- IC, given alone or in combination with local RT, suggesting potential benefit in clinical testing of these combinations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Tsarovsky, Felder, Heck, Slowinski, Rasmussen, VandenHeuvel, Zaborek, Morris, Erbe, Sondel and Rakhmilevich.)

Over the past decade, many health care systems across the Global North have implemented elements of market mechanisms while also dealing with the consequences of the financial crisis. Although effects of these two developments have been researched separately, their combined impact on the governance of health care organizations has received less attention. The aim of this study is to understand how health care reforms and the financial crisis together shaped new roles and interactions within health care. The Netherlands - where dynamics between health care organizations and their financial stakeholders (i.e., banks and health insurers) were particularly impacted - provides an illustrative case. Through semi-structured interviews, additional document analysis and insights from institutional change theory, we show how banks intensified relationship management, increased demands on loan applications and shifted financial risks onto health care organizations, while health insurers tightened up their monitoring and accountability practices towards health care organizations. In return, health care organizations were urged to rearrange their operations and become more risk-minded. They became increasingly dependent on banks and health insurers for their existence. Moreover, with this study, we show how institutional arenas come about through both the long-term efforts of institutional agents and unpredictable implications of economic and societal crises.

In Brief: Developing novel therapies to cure and manage endometriosis is a major unmet need that will benefit over 180 million women worldwide. Results from the current study suggest that inhibitors of oxidative phosphorylation may serve as novel agents for the treatment of endometriosis., Abstract: Current therapeutic strategies for endometriosis focus on symptom management and are not curative. Here, we provide evidence supporting the inhibition of oxidative phosphorylation (OXPHOS) as a novel treatment strategy for endometriosis. Additionally, we report an organotypic organ-on-a-chip luminal model for endometriosis. The OXPHOS inhibitors, curcumin, plumbagin, and the FDA-approved anti-malarial agent, atovaquone, were tested against the endometriosis cell line, 12Z, in conventional as well as the new organotypic model. The results suggest that all three compounds inhibit proliferation and cause cell death of the endometriotic cells by inhibiting OXPHOS and causing an increase in intracellular oxygen radicals. The oxidative stress mediated by curcumin, plumbagin, and atovaquone causes DNA double-strand breaks as indicated by the elevation of phospho-γH2Ax. Mitochondrial energetics shows a significant decrease in oxygen consumption in 12Z cells. These experiments also highlight differences in the mechanism of action as curcumin and plumbagin inhibit complex I whereas atovaquone blocks complexes I, II, and III. Real-time assessment of cells in the lumen model showed inhibition of migration in response to the test compounds. Additionally, using two-photon lifetime imaging, we demonstrate that the 12Z cells in the lumen show decreased redox ratio (NAD(P)H/FAD) and lower fluorescence lifetime of NAD(P)H in the treated cells confirming major metabolic changes in response to inhibition of mitochondrial electron transport. The robust chemotoxic responses observed with atovaquone suggest that this anti-malarial agent may be repurposed for the effective treatment of endometriosis.

This study describes a novel, neutralizing monoclonal antibody (mAb), 11D7, discovered by mouse immunization and hybridoma generation, against the parental Wuhan-Hu-1 RBD of SARS-CoV-2. We further developed this mAb into a chimeric human IgG and recombinantly expressed it in plants to produce a mAb with human-like, highly homogenous N-linked glycans that has potential to impart greater potency and safety as a therapeutic. The epitope of 11D7 was mapped by competitive binding with well-characterized mAbs, suggesting that it is a Class 4 RBD-binding mAb that binds to the RBD outside the ACE2 binding site. Of note, 11D7 maintains recognition against the B.1.1.529 (Omicron) RBD, as well neutralizing activity. We also provide evidence that this novel mAb may be useful in providing additional synergy to established antibody cocktails, such as Evusheld™ containing the antibodies tixagevimab and cilgavimab, against the Omicron variant. Taken together, 11D7 is a unique mAb that neutralizes SARS-CoV-2 through a mechanism that is not typical among developed therapeutic mAbs and by being produced in ΔXFT Nicotiana benthamiana plants, highlights the potential of plants to be an economic and safety-friendly alternative platform for generating mAbs to address the evolving SARS-CoV-2 crisis., (© 2022 The Authors. Plant Biotechnology Journal published by Society for Experimental Biology and The Association of Applied Biologists and John Wiley & Sons Ltd.)

Background Programmes for collective smoking cessation, based on the British model Stoptober, are proposed by public health units in many countries. There is a need for data estimating the rate at which participants in these programmes are successful in quitting smoking. We report a prospective study carried out as part of a large-scale collective cessation programme conducted in Switzerland in 2017. Methods 1112 participants among the 7008 smokers enrolled in the collective cessation programme were recruited before the start of the attempt. Continuous abstinence was measured 10 days, 3 months and 6 months after the start of the attempt. Participants who dropped out at follow-up were considered to have failed the attempt (worst-case scenario). Results The continuous abstinence rate was at least 37.9% at 10-day follow-up, 18.8% at 3-month follow-up and 13.1% at 6-month follow-up. Similar levels of continuous abstinence as the worst-case scenario were found in sensitivity analyses including those whose quit attempt started before the beginning of the programme and where multiple imputation was used to replace dropouts. Sensitivity analyses using complete cases or an indicator of abstinence which allows occasional lapses found around double the abstinence rates. Conclusions Our results support the potential usefulness of large-scale collective cessation campaigns and suggest that such programmes based on social networks are promising areas for future smoking cessation programme activity., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

This article draws on ethnographic research to conceptualise how nurses mobilise assemblages of caring to organise and deliver COVID care; particularly so by reorganising organisational infrastructures and practices of safe and good care. Based on participatory observations, interviews and nurse diaries, all collected during the early phase of the pandemic, the research shows how the organising work of nurses unfolds at different health-care layers: in the daily care for patients and their families, in the coordination of care in and between hospitals, and at the level of the health-care system. These findings contrast with the dominant pandemic-image of nurses as 'heroes at the bedside', which fosters the classic and microlevel view of nursing and leaves the broader contribution of nurses to the pandemic unaddressed. Theoretically, the study adds to the literature on translational mobilisation and assemblage theory by focussing on the layered and often invisible organising work of nurses in health care., (© 2022 The Authors. Sociology of Health & Illness published by John Wiley & Sons Ltd on behalf of Foundation for the Sociology of Health & Illness.)

Oxidative phosphorylation is an active metabolic pathway in cancer. Atovaquone is an oral medication that inhibits oxidative phosphorylation and is FDA-approved for the treatment of malaria. We investigated its potential anti-cancer properties by measuring cell proliferation in 2D culture. The clinical formulation of atovaquone, Mepron, was given to mice with ovarian cancers to monitor its effects on tumor and ascites. Patient-derived cancer stem-like cells and spheroids implanted in NSG mice were treated with atovaquone. Atovaquone inhibited the proliferation of cancer cells and ovarian cancer growth in vitro and in vivo. The effect of atovaquone on oxygen radicals was determined using flow and imaging cytometry. The oxygen consumption rate (OCR) in adherent cells was measured using a Seahorse XFe96 Extracellular Flux Analyzer. Oxygen consumption and ATP production were inhibited by atovaquone. Imaging cytometry indicated that the majority of the oxygen radical flux triggered by atovaquone occurred in the mitochondria. Atovaquone decreased the viability of patient-derived cancer stem-like cells and spheroids implanted in NSG mice. NMR metabolomics showed shifts in glycolysis, citric acid cycle, electron transport chain, phosphotransfer, and metabolism following atovaquone treatment. Our studies provide the mechanistic understanding and preclinical data to support the further investigation of atovaquone's potential as a gynecologic cancer therapeutic.

Background: Statins are commonly prescribed for primary and secondary prevention of atherosclerotic disease. They reduce cholesterol biosynthesis by inhibiting hydroxymethylglutaryl-coenzyme A-reductase (HMG-CoA-reductase) and therefore mevalonate synthesis. Several studies reported a small, but significant increase in the diagnosis of diabetes mellitus with statin treatment. The molecular mechanisms behind this adverse effect are not yet fully understood. Brown adipose tissue (BAT), which plays a role in thermogenesis, has been associated with a reduced risk of insulin resistance. Statins inhibit adipose tissue browning and have been negatively linked to the presence of BAT in humans. We therefore speculated that inhibition of BAT by statins contributes to increased insulin resistance in humans., Methods: A prospective study was conducted in 17 young, healthy men. After screening whether significant cold-induced thermogenesis (CIT) was present, participants underwent glucose tolerance testing (oGTT) and assessment of BAT activity by FDG-PET/MRI after cold-exposure and treatment with a β3-agonist. Fluvastatin 2x40mg per day was then administered for two weeks and oGTT and FDG-PET/MRI were repeated., Results: Two weeks of fluvastatin treatment led to a significant increase in glucose area under the curve (AUC) during oGTT (p=0.02), reduction in total cholesterol and LDL cholesterol (both p<0.0001). Insulin AUC (p=0.26), resting energy expenditure (REE) (p=0.44) and diet induced thermogenesis (DIT) (p=0.27) did not change significantly. The Matsuda index, as an indicator of insulin sensitivity, was lower after fluvastatin intake, but the difference was not statistically significant (p=0.09). As parameters of BAT activity, mean standard uptake value (SUV mean ) (p=0.12), volume (p=0.49) and total glycolysis (p=0.74) did not change significantly during the intervention. Matsuda index, was inversely related to SUV mean and the respiratory exchange ratio (RER) (both R 2 = 0.44, p=0.005) at baseline, but not after administration of fluvastatin (R 2 = 0.08, p=0.29, and R 2 = 0.14, p=0.16, respectively)., Conclusions: Treatment with fluvastatin for two weeks reduced serum lipid levels but increased glucose AUC in young, healthy men, indicating reduced glucose tolerance. This was not associated with changes in cold-induced BAT activity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Felder, Maushart, Gashi, Senn, Becker, Müller, Balaz, Wolfrum, Burger and Betz.)

Objective: Treatment of high-grade serous ovarian cancer (HGSOC) will benefit from early detection of cancer. Here, we provide proof-of-concept data supporting the hypothesis that circulating immune cells, because of their early recognition of tumors and the tumor microenvironment, can be considered for biomarker discovery., Methods: Longitudinal blood samples from C57BL/6 mice bearing syngeneic ovarian tumors and peripheral blood mononuclear cells (PBMC) from healthy postmenopausal women and newly diagnosed for HGSOC patients were subjected to RNASeq. The results from human immune cells were validated using Affymetrix microarrays. Differentially expressed transcripts in immune cells from tumor-bearing mice and HGSOC patients were compared to matching controls., Results: A total of 1282 transcripts (798 and 484, up- and downregulated, respectively) were differentially expressed in the tumor-bearing mice as compared with controls. Top 100 genes showing longitudinal changes in gene expression 2, 4, 7, and 18 days after tumor implantation were identified. Analysis of the PBMC from healthy post-menopausal women and HGSOC patients identified 4382 differentially expressed genes and 519 of these were validated through Affymetrix microarray analysis. A total of 384 genes, including IL-1R2, CH3L1, Infitm1, FP42, CXC42, Hdc, Spib, and Sema6b, were differentially expressed in the human and mouse datasets., Conclusion: The PBMC transcriptome shows longitudinal changes in response to the progressing tumor. Several potential biomarker transcripts were identified in HGSOC patients and mouse models. Monitoring their expression in individual PBMC subsets can serve as additional discriminator for the diagnosis of HGSOC., (© 2021 John Wiley & Sons A/S . Published by John Wiley & Sons Ltd.)

In this commentary, we reflect on Rinaldi and Bekker's scoping review of the literature on populist radical right (PRR) parties and welfare policies. We argue that their review provides political scientists and healthcare scholars with a firm basis to further explore the relationships between populism and welfare policies in different political systems. In line with the authors, we furthermore (re)emphasize the need for additional empirical inquiries into the relationship between populism and healthcare. But instead of expanding the research agenda suggested - for instance by adding categories or niches in which this relationship can be observed - we would like to challenge some of the premises of the studies conducted and reviewed thus far. We do so by identifying two concerns and by illustrating these concerns with two examples from the Netherlands., (© 2021 The Author(s); Published by Kerman University of Medical Sciences. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.)

Objective: To determine the Weibull modulus m, the characteristic strength σ 0 ,the subcritical crack growth (SCG) parameters (n &A * ) as well as the lifetime durability of three dental ceramic materials in water: a polycrystalline yttria-stabilized zirconia (Zenostar MT O, YSZ, Ivoclar Vivadent/Wieland, Germany), a lithium disilicate glass ceramic (IPS e.max CAD, LD, Ivoclar Vivadent, Liechtenstein), and a zirconia-containing lithium silicate glass ceramic (Celtra Duo, ZLS, Dentsply Sirona Inc, USA)., Methods: 30 specimens (Ø12 mm × 0.9 mm thickness) of each material were fabricated. The biaxial ring-on-ring bending tests at four stress rates σ˙ (100, 10, 1, 0.1 MPa/s) were performed in water for all three ceramics. The results were used to determine the Weibull and SCG parameters, and to plot the Strength-Probability-Time (SPT) diagram., Results: YSZ showed the highest m (12.5) and highest σ 0 (542 MPa), while the values for the glass ceramic materials were lower: for LD m = 4.7, σ 0 = 407 MPa, and for ZLS m = 2.7, σ 0 = 279 MPa. The n for YSZ, LD and ZLS in water were 31.1, 13.7 and 16.6, respectively. The strength of YSZ decreased by 50% within a simulated period of 10 years, and for the glass ceramic materials the decrease was up to 80%., Significance: Determining the Weibull and SCG parameters from the constant stress rate testing is an efficient methodology for ranking materials in terms of durability and longevity., (Copyright © 2020 The Academy of Dental Materials. Published by Elsevier Inc. All rights reserved.)

Many investigators of human-monkey competition (HMC) in Sri Lanka have revealed some common threads. Except at temple and protected sites, all monkeys were considered as household or agricultural pests wherever they shared space with humans. This included the widely distributed toque macaque (Macaca sinica), the grey langur (Semnopithecus priam thersites) of the Dry Zone, and the purple-faced langur (S. vetulus) of the southwestern and central rain forests where human densities and habitat fragmentation were greatest. People sharing space with monkeys resorted to various non-lethal methods to chase monkeys away from their properties and most preferred to have monkeys removed to protected areas; such translocations have been politically popular, though contrary to ecological principles. The main cause of HMC near primate habitats has been environmental conversion to agriculture, whereas in many towns the refuse generated in the wake of widespread growing tourism lured omnivorous macaques towards human habitation and stimulated macaque population growth. While most Sri Lankans share space with monkeys reluctantly, only a minority, flouting cultural restraints, want monkeys destroyed. Nonetheless, a major threat to primate conservation has been habitat loss and the killing of monkeys, especially in the densely populated southwestern area of the island where recent surveys showed that most macaques have been wiped out. Two subspecies, S. v. nestor of the rain forest lowlands and M. s. opisthomelas of the montane forests, are Critically Endangered. Sharing space with monkeys rests on public tolerance, understanding, and empathy with monkeys. Religious concepts venerating monkeys provide fertile ground for this. Our science-based educational documentaries (n > 35), among other efforts, also have contributed to these human sentiments in Sri Lanka and globally. The trends in HMC suggest that protected nature reserves for all wildlife are more secure for primate survival than ethnoprimatology by itself would be. Rudran [Folia Primatologica 2021, DOI: 10.1159/000517176] criticized our recent publication on HMC in Sri Lanka [Dittus et al., Folia Primatologica 2019, 90: 89-108]. We consider his comments as misconstruing efforts in primate conservation through denying the importance of traditional protected areas, overlooking our achievements in educating the public and reducing HMC, as well as misunderstanding the limits of marketing monkeys to tourists as a source of income to support conservation., (© 2022 S. Karger AG, Basel.)

Human brown adipose tissue (BAT) is a thermogenic tissue activated by the sympathetic nervous system in response to cold exposure. It contributes to energy expenditure (EE) and takes up glucose and lipids from the circulation. Studies in rodents suggest that BAT contributes to the transient rise in EE after food intake, so-called diet-induced thermogenesis (DIT). We investigated the relationship between human BAT activity and DIT in response to glucose intake in 17 healthy volunteers. We assessed DIT, cold-induced thermogenesis (CIT), and maximum BAT activity at three separate study visits within 2 wk. DIT was measured by indirect calorimetry during an oral glucose tolerance test. CIT was assessed as the difference in EE after cold exposure of 2-h duration as compared with warm conditions. Maximal activity of BAT was assessed by 18-F-fluoro-deoxyglucose ( 18 F-FDG) 18 F-FDG-PET/MRI after cold exposure and concomitant pharmacological stimulation with mirabegron. Seventeen healthy men (mean age = 23.4 yr, mean body mass index = 23.2 kg/m 2 ) participated in the study. EE increased from 1,908 (±181) kcal/24 h to 2,128 (±277) kcal/24 h ( P < 0.0001, +11.5%) after mild cold exposure. An oral glucose load increased EE from 1,911 (±165) kcal/24 h to 2,096 (±167) kcal/24 h at 60 min ( P < 0.0001, +9.7%). The increase in EE in response to cold was significantly associated with BAT activity ( R 2  = 0.43, P = 0.004). However, DIT was not associated with BAT activity ( R 2  = 0.015, P = 0.64). DIT after an oral glucose load was not associated with stimulated 18 F-FDG uptake into BAT, suggesting that DIT is independent from BAT activity in humans (Clinicaltrials.gov Registration No. NCT03189511). NEW & NOTEWORTHY Cold-induced thermogenesis (CIT) was related to BAT activity as determined by FDG-PET/MRI after stimulation of BAT. Diet-induced thermogenesis (DIT) was not related to stimulated BAT activity. Supraclavicular skin temperature was related to CIT but not to DIT. DIT in humans is probably not a function of BAT.

We critically examine the discussion on the role of evidence-based medicine (EBM) in healthcare governance. We take the institutionally layered Dutch healthcare system as our case study. Here, different actors are involved in the regulation, provision and financing of healthcare services. Over the last decades, these actors have related to EBM to inform their actor specific roles. At the same time, EBM has increasingly been problematised. To better understand this problematisation, we organised focus groups and interviews. We noticed that particularly EBM's reductionist epistemology and its uncritical use by 'professional others' are considered problematic. However, our analysis also reveals that something else seems to be at stake. In fact, all the actors involved underwrite EBM's reductionist epistemology and emphasise that evidence should be contextualised. They however do so in different ways and with different contexts in mind. Moreover, the ways in which some actors contextualise evidence has consequences for the ways in which others can do the same. We therefore emphasise that behind EBM's scientific problematisation lurks a political issue. A dispute over who should contextualise evidence how, in a layered healthcare system with interdependent actors that cater to both individual patients and the public. We urge public administration scholars and policymakers to open-up the political confrontation between healthcare actors and their sometimes irreconcilable, yet evidence-informed perspectives., Competing Interests: Declaration of Competing Interest This work was financially supported by the ‘Vereniging van Artsen Automobilisten’ (VvAA), a member organisation and insurer for healthcare professionals in the Netherlands. The data used in this paper has been gathered during the development of a policy advice by the ‘Raad voor de Volksgezondheid en Samenleving (RVenS). See further, materials and methods section., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Importance: Sleep-related impairment in physicians is an occupational hazard associated with long and sometimes unpredictable work hours and may contribute to burnout and self-reported clinically significant medical error., Objective: To assess the associations between sleep-related impairment and occupational wellness indicators in physicians practicing at academic-affiliated medical centers and the association of sleep-related impairment with self-reported clinically significant medical errors, before and after adjusting for burnout., Design, Setting, and Participants: This cross-sectional study used physician wellness survey data collected from 11 academic-affiliated medical centers between November 2016 and October 2018. Analysis was completed in January 2020. A total of 19 384 attending physicians and 7257 house staff physicians at participating institutions were invited to complete a wellness survey. The sample of responders was used for this study., Exposures: Sleep-related impairment., Main Outcomes and Measures: Association between sleep-related impairment and occupational wellness indicators (ie, work exhaustion, interpersonal disengagement, overall burnout, and professional fulfillment) was hypothesized before data collection. Assessment of the associations of sleep-related impairment and burnout with self-reported clinically significant medical errors (ie, error within the last year resulting in patient harm) was planned after data collection., Results: Of all physicians invited to participate in the survey, 7700 of 19 384 attending physicians (40%) and 3695 of 7257 house staff physicians (51%) completed sleep-related impairment items, including 5279 women (46%), 5187 men (46%), and 929 (8%) who self-identified as other gender or elected not to answer. Because of institutional variation in survey domain inclusion, self-reported medical error responses from 7538 physicians were available for analyses. Spearman correlations of sleep-related impairment with interpersonal disengagement (r = 0.51; P < .001), work exhaustion (r = 0.58; P < .001), and overall burnout (r = 0.59; P < .001) were large. Sleep-related impairment correlation with professional fulfillment (r = -0.40; P < .001) was moderate. In a multivariate model adjusted for gender, training status, medical specialty, and burnout level, compared with low sleep-related impairment levels, moderate, high, and very high levels were associated with increased odds of self-reported clinically significant medical error, by 53% (odds ratio, 1.53; 95% CI, 1.12-2.09), 96% (odds ratio, 1.96; 95% CI, 1.46-2.63), and 97% (odds ratio, 1.97; 95% CI, 1.45-2.69), respectively., Conclusions and Relevance: In this study, sleep-related impairment was associated with increased burnout, decreased professional fulfillment, and increased self-reported clinically significant medical error. Interventions to mitigate sleep-related impairment in physicians are warranted.

Oxidative stress inhibits Na + /K + -ATPase (NKA), the ion channel that maintains membrane potential. Here, we investigate the role of oxidative stress-mediated by plumbagin and atovaquone in the inhibition of NKA activity. We confirm that plumbagin and atovaquone inhibit the proliferation of three human (OVCAR-3, SKOV-3, and TYKNu) and one mouse (ID8) ovarian cancer cell lines. The oxygen radical scavenger, N-acetylcysteine (NAC), attenuates the chemotoxicity of plumbagin and atovaquone. Whole-cell patch clamping demonstrates that plumbagin and atovaquone inhibit outward and the inward current flowing through NKA in SKOV-3 and OVCAR-3. Although both drugs decrease cellular ATP; providing exogenous ATP (5 mM) in the pipet solution used during patch clamping did not recover NKA activity in the plumbagin or atovaquone treated SKOV-3 and OVCAR-3 cells. However, pretreatment of the cells with NAC completely abrogated the NKA inhibitory activity of plumbagin and atovaquone. Exposure of the SKOV-3 cells to either drug significantly decreases the expression of NKA. We conclude that oxidative stress caused by plumbagin and atovaquone degrades NKA, resulting in the inability to maintain ion transport. Therefore, when evaluating compounds that induce oxidative stress, it is important to consider the contribution of NKA inhibition to their cytotoxic effects on tumor cells.

Purpose: The combination of irinotecan, temozolomide, dintuximab, and granulocyte-macrophage colony-stimulating factor (I/T/DIN/GM-CSF) demonstrated activity in patients with relapsed/refractory neuroblastoma in the randomized Children's Oncology Group ANBL1221 trial. To more accurately assess response rate and toxicity, an expanded cohort was nonrandomly assigned to I/T/DIN/GM-CSF., Patients and Methods: Patients were eligible at first relapse or first designation of refractory disease. Oral T and intravenous (IV) irinotecan were administered on days 1 to 5 of 21-day cycles. DIN was administered IV (days 2-5), and GM-CSF was administered subcutaneously (days 6-12). The primary end point was objective response, analyzed on an intent-to-treat basis per the International Neuroblastoma Response Criteria., Results: Seventeen eligible patients were randomly assigned to I/T/DIN/GM-CSF (February 2013 to March 2015); 36 additional patients were nonrandomly assigned to I/T/DIN/GM-CSF (August 2016 to May 2017). Objective (complete or partial) responses were observed in nine (52.9%) of 17 randomly assigned patients (95% CI, 29.2% to 76.7%) and 13 (36.1%) of 36 expansion patients (95% CI, 20.4% to 51.8%). Objective responses were seen in 22 (41.5%) of 53 patients overall (95% CI, 28.2% to 54.8%); stable disease was also observed in 22 of 53. One-year progression-free and overall survival for all patients receiving I/T/DIN/GM-CSF were 67.9% ± 6.4% (95% CI, 55.4% to 80.5%) and 84.9% ± 4.9% (95% CI, 75.3% to 94.6%), respectively. Two patients did not receive protocol therapy and were evaluable for response but not toxicity. Common grade ≥ 3 toxicities were fever/infection (18 [35.3%] of 51), neutropenia (17 [33.3%] of 51), pain (15 [29.4%] of 51), and diarrhea (10 [19.6%] of 51). One patient met protocol-defined criteria for unacceptable toxicity (grade 4 hypoxia). Higher DIN trough levels were associated with response., Conclusion: I/T/DIN/GM-CSF has significant antitumor activity in patients with relapsed/refractory neuroblastoma. Study of chemoimmunotherapy in the frontline setting is indicated, as is further evaluation of predictive biomarkers.

Importance: Inflammation is a key driver of malnutrition during illness and is often accompanied by metabolic effects, including insulin resistance and reduction of appetite. However, it still remains unclear if inflammation influences the response to nutritional support among patients with disease-related malnutrition., Objective: To examine whether patients' baseline inflammatory status is associated with the effect of nutritional support on 30-day mortality., Design, Setting, and Participants: This is a secondary analysis of the Effect of Early Nutritional Support on Frailty, Functional Outcomes, and Recovery of Malnourished Medical Inpatients Trial (EFFORT), a randomized clinical trial conducted in 8 Swiss hospitals from April 2014 to February 2018. A total of 1950 participants who had C-reactive protein measurements at the time of admission were included in this secondary analysis. Data analysis was conducted between June and July 2019., Interventions: Hospitalized patients at risk for malnutrition were randomly assigned to receive protocol-guided individualized nutritional support to reach protein and energy goals (intervention group) or standard hospital food (control group)., Main Outcomes and Measures: The primary end point was 30-day mortality. Based on C-reactive protein levels at admission, patients were stratified into groups with low, moderate, or high inflammation (<10 mg/L, 10-100 mg/L, and >100 mg/L, respectively)., Results: A total of 1950 patients (median [interquartile range] age, 75 [65-83] years; 1025 [52.6%] men) were included; 533 (27.3%) had low levels of inflammation, 894 (45.9%) had moderate levels of inflammation, and 523 (26.8%) had high levels of inflammation. Compared with the control group, patients receiving nutritional support showed a significant reduction in 30-day mortality, regardless of C-reactive protein level (adjusted odds ratio, 0.61; 95% CI, 0.43-0.86; P = .005). In the subgroup of patients with high inflammation, there was no beneficial effect of nutritional support (adjusted odds ratio, 1.32; 95% CI, 0.70-2.50; P = .39), providing evidence that inflammation has a significant modifying association (P for interaction = .005)., Conclusions and Relevance: Based on this secondary analysis of a multicenter randomized trial, a patient's admission inflammatory status was associated with their response to nutritional support. If validated in future clinical trials, nutritional support may need to be individualized based on a patient's initial presentation and markers of inflammation. These results may also help to explain some of the heterogeneity in treatment effects of nutrition seen in previous critical care trials., Trial Registration: ClinicalTrials.gov Identifier: NCT02517476.

Tobacco dependence is a complex phenomenon in which physical and psychological components go hand in hand, and it is often considered as one of the major barriers to quit smoking. However, we still need to increase our understanding of the processes through which tobacco dependence relates to smoking cessation. This research aimed to investigating whether changes in smoker versus ex-smoker (abstainer) self-concept account for the association between tobacco dependence and successful smoking cessation. We used longitudinal data drawn from the evaluation of a smoking cessation intervention. A sample of smokers enrolled in the program filled in a questionnaire at the beginning of the intervention (baseline: N = 779), 6 months later (i.e., at the end of the intervention: T1, N = 532), and 9 months later (T2; N = 387). We assessed tobacco dependence (baseline), smoker versus ex-smoker self-concept (baseline, T1, and T2) and smoking status (baseline, T1 and T2). Tobacco dependence was negatively associated with smoking cessation maintenance, and this effect was mediated by changes in self-concept: The greater tobacco dependence, the lower the likelihood that former smokers develop an ex-smoker self-concept during the program, which results in relapse at T1 or T2. Successful smoking cessation interventions should provide strategies preventing the negative effects of tobacco dependence on identity transition., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Rhodococcus qingshengii RL1 was isolated from surface-sterilized leaves of Eruca sativa Mill. and shows plant growth-promoting (PGP) properties. The de novo genome assembly consists of one chromosome with 6,253,838 bp and two plasmids with 144,038 bp and 448,745 bp. Many genes could be identified reflecting its PGP potential., (Copyright © 2019 Kuhl et al.)

The Na + /K + -ATPase (NKA) complex is the master regulator of membrane potential and a target for anti-cancer therapies. Here, we investigate the effect of drug-induced oxidative stress on NKA activity. The natural product, plumbagin increases oxygen radicals through inhibition of oxidative phosphorylation. As a result, plumbagin treatment results in decreased production of ATP and a rapid increase in intracellular oxygen radicals. We show that plumbagin induces apoptosis in canine cancer cells via oxidative stress. We use this model to test the effect of oxidative stress on NKA activity. Using whole-cell patch-clamp electrophysiology we demonstrate that short-term exposure (4 min) to plumbagin results in 48% decrease in outward current at +50 mV. Even when exogenous ATP was supplied to the cells, plumbagin treatment resulted in 46% inhibition of outward current through NKA at +50 mV. In contrast, when the canine cancer cells were pre-treated with the oxygen radical scavenger, N-acetylcysteine, the NKA inhibitory activity of plumbagin was abrogated. These experiments demonstrate that the oxidative stress-causing agents such as plumbagin and its analogues, are a novel avenue to regulate NKA activity in tumors.

Background: The Italian Liver Cancer (ITA.LI.CA) prognostic system for patients with hepatocellular carcinoma (HCC) has recently been proposed and validated. We sought to explore the relationship among the ITA.LI.CA prognostic variables (ie tumour stage, functional score based on performance status and Child-Pugh score, and alpha-fetoprotein), treatment selection and survival outcome in HCC patients., Patients and Methods: We analysed 4,867 consecutive HCC patients undergoing six main treatment strategies (liver transplantation, LT; liver resection, LR; ablation, ABL; intra-arterial therapy, IAT; Sorafenib, SOR; and best supportive care, BSC) and enrolled during 2002-2015 in a multicenter Italian database. In order to control pretreatment imbalances in observed variables, a machine learning methodology was used and inverse probability of treatment weights (IPTW) was calculated. An IPTW-adjusted multivariate survival model that included ITA.LI.CA prognostic variables, treatment period and treatment strategy was then developed. The survival benefit of HCC treatments was described as a hazard ratio (95% confidence interval), using BSC as a reference value and as predicted median survival., Results: After the IPTW, the six treatment groups became well balanced for most baseline characteristics. In the IPTW-adjusted multivariate survival model, treatment strategy was found to be the strongest survival predictor, irrespective of ITA.LI.CA prognostic variables and treatment period. The survival benefit of different therapies over BSC was: LT = 0.19 (0.18-0.20); RES = 0.40 (0.37-0.42); ABL 0.42 (0.40-0.44); IAT = 0.58 (0.55-0.61); SOR = 0.92 (0.87-0.97). This multivariate model was then used to predict median survival for each therapy within each ITA.LI.CA stage., Conclusion: The concept of therapeutic hierarchy was established within each ITA.LI.CA stage., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Dinoflagellates are microbial eukaryotes that have exceptionally large nuclear genomes; however, their organelle genomes are small and fragmented and contain fewer genes than those of other eukaryotes. The genus Amoebophrya (Syndiniales) comprises endoparasites with high genetic diversity that can infect other dinoflagellates, such as those forming harmful algal blooms (e.g., Alexandrium ). We sequenced the genome (~100 Mb) of Amoebophrya ceratii to investigate the early evolution of genomic characters in dinoflagellates. The A. ceratii genome encodes almost all essential biosynthetic pathways for self-sustaining cellular metabolism, suggesting a limited dependency on its host. Although dinoflagellates are thought to have descended from a photosynthetic ancestor, A. ceratii appears to have completely lost its plastid and nearly all genes of plastid origin. Functional mitochondria persist in all life stages of A. ceratii , but we found no evidence for the presence of a mitochondrial genome. Instead, all mitochondrial proteins appear to be lost or encoded in the A. ceratii nucleus.

Objective: MUC16, the mucin that contains the CA125 epitopes, suppresses the cytolytic responses of human NK cells and inhibits the efficacy of therapeutic antibodies. Here, we provide further evidence of the regulatory role of MUC16 on human and murine NK cells and macrophages., Methods: Target cell cytolysis and doublet formation assays were performed to assess effects of MUC16 on human NK cells. The effect of MUC16 on ovarian tumor growth was determined in a mouse model by monitoring survival and ascites formation. Innate immune cells from spleens and peritoneal cavities of mice were isolated and stimulated in vitro with anti-CD40 antibody, lipopolysaccharide and IFN-γ and their ability to cytolyse MUC16 expressing and non-expressing cells was determined., Results: We confirm that MUC16 inhibits cytolysis by human NK cells as well as the formation of NK-tumor conjugates. Mice implanted with MUC16-knockdown OVCAR-3 show >2-fold increase in survival compared to controls. Murine NK cells and macrophages are more efficient at lysing MUC16-knockdown cells. In vitro cytotoxicity assays with NK cells and macrophages isolated from mice stimulated with anti-CD40 antibody showed 2-3-fold increased activity against the MUC16-knockdown cells as compared to matching target cells expressing this mucin. Finally, knockdown of MUC16 increased the susceptibility of cancer cells to ADCC by murine splenocytes., Conclusions: For the first time, we demonstrate the immunoregulatory effects of MUC16 on murine NK cells and macrophages. Our study implies that the immunoregulatory role of MUC16 on murine NK cells and macrophages should be considered when examining the biology of MUC16 in mouse models., (Copyright © 2019 Elsevier Inc. All rights reserved.)

We reported the efficacy and safety data for daclatasvir (DCV)-based all-oral antiviral therapy in patients treated in the Italian compassionate-use program. 275 patients were included (202 male-73.5%, mean age: 57.4 years, 62 HIV-coinfected, 94 with recurrence of hepatitis C post-OLT). Forty-nine patients (17.8%) had Child-Pugh B, Genotype(G) distribution was: G1a:72 patients (26.2%), G1b:137 (49.8%); G3:40 (14.5%) and G4:26 (9.5%). Patients received DCV with sofosbuvir(SOF) (n = 221, 129 with ribavirin(RBV) or with simeprevir (SMV) or asunaprevir (ASU) (n = 54, 19 with RBV) for up to 24 weeks. Logistic regression was used to identify baseline characteristics associated with sustained virological response at week 12 post-treatment (SVR12). Liver function changes between baseline and follow up were assessed in 228 patients. 240 patients achieved SVR12 (87.3%), post transplant and HIV co-infected patients were equally distributed among SVR and no SVR (35% vs 34.3%; p = 0.56 and 24.2% vs 11.4%, p = 0.13, respectively). SVR rate was significantly higher with the combination DCV + SOF compared with DCV + SIM or ASU (93.2% vs 63.0%, p < 0.0001). Bilirubin value (OR: 0.69, CI95%: 0.54-0.87, p = 0.002) and regimen containing SOF (OR: 9.99, CI95%: 4.09-24.40; p < 0.001) were independently related with SVR. Mean albumin and bilirubin values significantly improved between baseline and follow-up week 12. DCV-based antiviral therapy was well tolerated and resulted in a high SVR when combined with SOF either in pre-transplant and in OLT patients and in "difficult to treat" HCV genotypes. Regimens containing DCV in combination with NS3 protease inhibitors obtained suboptimal results.

The lung alveolar region experiences remodeling during several acute and chronic lung diseases, as for instance idiopathic pulmonary fibrosis (IPF), a fatal disease, whose onset is correlated with repetitive microinjuries to the lung alveolar epithelium and abnormal alveolar wound repair. Although a high degree of mechanical stress (>20% linear strain) is thought to potentially induce IPF, the effect of lower, physiological levels of strain (5-12% linear strain) on IPF pathophysiology remains unknown. In this study, we examined the influence of mechanical strain on alveolar epithelial wound healing. For this purpose, we adopted the "organ-on-a-chip" approach, which provides the possibility of reproducing unique aspects of the in vivo cellular microenvironment, in particular its dynamic nature. Our results provide the first demonstration that a wound healing assay can be performed on a breathing lung-on-a-chip equipped with an ultra-thin elastic membrane. We cultured lung alveolar epithelial cells to confluence, the cells were starved for 24 h, and then wounded by scratching with a standard micropipette tip. Wound healing was assessed after 24 h under different concentrations of recombinant human hepatic growth factor (rhHGF) and the application of cyclic mechanical stretch. Physiological cyclic mechanical stretch (10% linear strain, 0.2 Hz) significantly impaired the alveolar epithelial wound healing process relative to culture in static conditions. This impairment could be partially ameliorated by administration of rhHGF. This proof-of-concept study provides a way to study of more complex interactions, such as a co-culture with fibroblasts, endothelial cells, or immune cells, as well as the study of wound healing at an air-liquid interface.

Sri Lanka is a biodiversity hotspot with high human density that contributes to increasing human-monkey conflict (HMC). In 50 years of primate studies there, the development of HMC has been documented, and many workshops and interventions organized to ameliorate HMC. These activities prompted the present survey. In the extensive lowland dry zone of Sri Lanka, the affected nonhuman primates are the toque macaque, gray and purple-faced langurs and slender loris. We surveyed and evaluated the attitudes of rural residents towards these four species in an effort to contribute to an ethnoprimatological approach to conservation, i.e., promote a coexistence and sharing of habitat between humans and monkeys. We selected 13 villages near Polonnaruwa, located centrally in the dry zone. The four nonhuman primate species differ in their behavioral ecologies, and this influenced how frequently they were thought of as pests. Most HMC was with the macaque and gray langur, less with the purple-faced langur and least with the loris. The underlying sentiment among stakeholders towards monkeys was generally either neutral or positive. Nonetheless, the majority (80%) of people desired a translocation of the troublesome monkeys from their properties to protected areas, which is impractical. Few (< 1%) openly wanted monkeys destroyed. While a traditional reverence for monkeys provides a solid basis for science and media-based education, it also contributes to the feeding of monkeys and consequent unnatural population growth, and enhanced HMC. Public understanding of the underlying causes of HMC was poor, hindering effective solutions. A combination of a feeding ban, possibly contraceptive intervention at localized HMC trouble spots, and extensive education may be the only benign alternatives to the destruction of wild primates by a powerful minority. Coexistence through strengthening and expansion of exclusive suitable protected habitats for all wildlife is a priority., (© 2019 S. Karger AG, Basel.)

Immunotherapies against solid tumors face additional challenges compared with hematological cancers. In solid tumors, immune cells and antibodies need to extravasate from vasculature, find the tumor, and migrate through a dense mass of cells. These multiple steps pose significant obstacles for solid tumor immunotherapy and their study has remained difficult using classic in vitro models based on Petri dishes. In this work, a microfluidic model has been developed to study natural killer cell response. The model includes a 3D breast cancer spheroid in a 3D extracellular matrix, and two flanking lumens lined with endothelial cells, replicating key structures and components during the immune response. Natural Killer cells and antibodies targeting the tumor cells were either embedded in the matrix or perfused through the lateral blood vessels. Antibodies that were perfused through the lateral lumens extravasated out of the blood vessels and rapidly diffused through the matrix. However, tumor cell-cell junctions hindered antibody penetration within the spheroid. On the other hand, natural killer cells were able to detect the presence of the tumor spheroid several hundreds of microns away and penetrate the spheroid faster than the antibodies. Once inside the spheroid, natural killer cells were able to destroy tumor cells at the spheroid periphery and, importantly, also at the innermost layers. Finally, the combination of antibody-cytokine conjugates and natural killer cells led to an enhanced cytotoxicity located mostly at the spheroid periphery. Overall, these results demonstrate the utility of the model for informing immunotherapy of solid tumors.