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IntroductionEarly evidence confirms lower COVID-19 vaccine uptake in established ethnic minority populations, yet there has been little focus on understanding vaccine hesitancy and barriers to vaccination in migrants. Growing populations of precarious migrants (including undocumented migrants, asylum seekers and refugees) in the UK and Europe are considered to be under-immunised groups and may be excluded from health systems, yet little is known about their views on COVID-19 vaccines specifically, which are essential to identify key solutions and action points to strengthen vaccine roll-out.MethodsWe did an in-depth semi-structured qualitative interview study of recently arrived migrants (foreign-born, >18 years old; ResultsWe approached 20 migrant support groups nationwide, recruiting 32 migrants (mean age 37.1 years; 21 [66%] female; mean time in the UK 5.6 years [SD 3.7 years]), including refugees (n = 3), asylum seekers (n = 19), undocumented migrants (n = 8) and migrants with limited leave to remain (n = 2) from 15 different countries (5 WHO regions). 23 (72%) of 32 migrants reported being hesitant about accepting a COVID-19 vaccine and communicated concerns over vaccine content, side-effects, lack of accessible information in an appropriate language, lack of trust in the health system and low perceived need. Participants reported a range of barriers to accessing the COVID-19 vaccine and expressed concerns that their communities would be excluded from or de-prioritised in the roll-out. Undocumented migrants described fears over being charged and facing immigration checks if they present for a vaccine. All participants (n = 10) interviewed after recent government announcements that COVID-19 vaccines can be accessed without facing immigration checks remained unaware of this. Participants stated that convenience of access would be a key factor in their decision around whether to accept a vaccine and proposed alternative access points to primary care services (for example, walk-in centres in trusted places such as foodbanks, community centres and charities), alongside promoting registration with primary care for all, and working closely with communities to produce accessible information on COVID-19 vaccination.ConclusionsPrecarious migrants may be hesitant about accepting a COVID-19 vaccine and face multiple and unique barriers to access, requiring simple but innovative solutions to ensure equitable access and uptake. Vaccine hesitancy and low awareness around entitlement and relevant access points could be easily addressed with clear, accessible, and tailored information campaigns, co-produced and delivered by trusted sources within marginalised migrant communities. These findings have immediate relevance to the COVID-19 vaccination initiatives in the UK and in other European and high-income countries with diverse migrant populations.FundingNIHR

BACKGROUND: US immigration policy changes may affect health care use among Latinx children. We hypothesized that January 2017 restrictive immigration executive actions would lead to decreased health care use among Latinx children. METHODS: We used controlled interrupted time series to estimate the effect of executive actions on outpatient cancellation or no-show rates from October 2016 to March 2017 (“immigration action period”) among Latinx children in 4 health care systems in North Carolina. We included control groups of (1) non-Latinx children and (2) Latinx children from the same period in the previous year (“control period”) to account for natural trends such as seasonality. RESULTS: In the immigration action period, 114 627 children contributed 314 092 appointments. In the control period, 107 657 children contributed 295 993 appointments. Relative to the control period, there was an immediate 5.7% (95% confidence interval [CI]: 0.40%–10.9%) decrease in cancellation rates among all Latinx children, but no sustained change in trend of cancellations and no change in no-show rates after executive immigration actions. Among uninsured Latinx children, there was an immediate 12.7% (95% CI: 2.3%–23.1%) decrease in cancellations; however, cancellations then increased by 2.4% (95% CI: 0.89%–3.9%) per week after immigration actions, an absolute increase of 15.5 cancellations per 100 appointments made. CONCLUSIONS: There was a sustained increase in cancellations among uninsured Latinx children after immigration actions, suggesting decreased health care use among uninsured Latinx children. Continued monitoring of effects of immigration policy on child health is needed, along with measures to ensure that all children receive necessary health care.

This cohort study evaluates the first 22 months of implementation of the Cherokee Nation Heath Services community-based program designed to eliminate hepatitis C virus (HCV) infection., Key Points Question Can a community-based tribal hepatitis C virus (HCV) elimination program be implemented successfully in a rural setting? Findings In this cohort study, first-time HCV screening coverage increased from 20.9% to 38.2% from 3 years before to 22 months into implementation of the Cherokee Nation Health Services HCV elimination program. Identification, treatment, and cure of newly identified current HCV infections increased. Meaning In this study, implementation of a community-based HCV elimination program was associated with an improved cascade of care; this information may serve other organizations planning to implement similar programs in large rural areas., Importance In 2019, hepatitis C virus (HCV) infection contributed to more deaths in the US than 60 other notifiable infectious diseases combined. The incidence of and mortality associated with HCV infection are highest among American Indian and Alaska Native individuals. Objective To evaluate the association of the Cherokee Nation (CN) HCV elimination program with each element of the cascade of care: HCV screening, linkage to care, treatment, and cure. Design, Setting, and Participants This cohort study used data from the CN Health Services (CNHS), which serves approximately 132 000 American Indian and Alaska Native individuals residing in the 14-county CN reservation in rural northeastern Oklahoma. Data from the first 22 months of implementation (November 1, 2015, to August 31, 2017) of an HCV elimination program were compared with those from the pre–elimination program period (October 1, 2012, to October 31, 2015). The analysis included American Indian and Alaska Native individuals aged 20 to 69 years who accessed care through the CNHS between October 1, 2012, and August 31, 2017. Cure data were recorded through April 15, 2018. Exposure The CN HCV elimination program. Main Outcomes and Measures The main outcomes were the proportions of the population screened for HCV, diagnosed with current HCV infection, linked to care, treated, and cured during the initial 22 months of the elimination program period and the pre–elimination program period. Data from electronic health records and an HCV treatment database were analyzed. The cumulative incidence of HCV infection in this population was estimated using bayesian analyses. Results Among the 74 039 eligible individuals accessing care during the elimination program period, the mean (SD) age was 36.0 (13.5) years and 55.9% were women. From the pre–elimination program period to the elimination program period, first-time HCV screening coverage increased from 20.9% to 38.2%, and identification of current HCV infection and treatment in newly screened individuals increased from a mean (SD) of 170 (40) per year to 244 (4) per year and a mean of 95 (133) per year to 215 (9) per year, respectively. During the implementation period, of the 793 individuals with current HCV infection accessing the CNHS, 664 were evaluated (83.7%), 394 (59.3%) initiated treatment, and 335 (85.0%) had documented cure. In less than 2 years, the 85% 3-year goal was reached for cure (85.0%), and the goal for linkage to care was nearly reached (83.7%), whereas screening (44.1%) and treatment initiation (59.3%) required more time and resources. Conclusions and Relevance This cohort study found that after 22 months of implementation, the CNHS community-based HCV elimination program was associated with an improved cascade of care. The facilitators and lessons learned in this program may be useful to other organizations planning similar programs.

Investigation of the metabolome of the ascomycete Annulohypoxylon truncatum led to the identification of novel oxygenated brasilane glycosides and the revision of the stereochemistry of the brasilane A octahydro-1H-indene core scaffold to trans. The bra biosynthetic gene cluster containing five genes (braA–braE) was identified and verified by heterologous expression experiments in Aspergillus oryzae demonstrating that BraC is a multifunctional P450 monooxygenase. In vitro studies of BraB revealed it to be a very rare fungal UDP-GlcNAc dependent N-acetylglucosamine transferase. UDP-glucose is also accepted as a donor, and a broad acceptor substrate tolerance for various primary and secondary alcohols was observed.

Background: Stroma plays a crucial role in shaping tumor growth dynamics, invasion, and metastasis. High stroma to tumor ratio in the clinic is associated with poor outcomes and shorter remission periods for lung cancer patients. Recent studies suggest that stroma shelters tumor cells during drug administration, but the precise mechanisms to confer this protection remain unclear. We hypothesize that stroma secretes paracrine factors that enhance tumor cells' proliferation rate in proximity, hence outcompeting the death rate due to therapies. In this context, the residual disease is an inherent stage in tumors' eco-evolutionary dynamics under treatment. Therefore, understanding the nature of stroma-tumor cell interactions is crucial for designing effective therapies. Methods: The spatial relationship between the stroma and proliferating tumor cells was interrogated via spatial analysis of 2D samples from mouse xenograft models and subsequent spatial agent-based modeling (ABM). Results: First, we built a pipeline to quantify the spatial extent and amplitude of stroma shielding the presence or absence of treatment. The spatial distributions of tumor cells, their proliferating rates, and the spatial extent of stroma protective effects are used to parametrize the ABM and simulate the spatio-temporal dynamics of tumor growth with and without treatment. Our preliminary results show moderately higher clustering of proliferating and stroma cells than stroma and non-proliferating cells or random distribution in the absence of treatment. In contrast, during therapy, stroma-proliferating tumor cell clustering is considerably higher than stroma-non proliferating tumor cells and stroma-random distribution. Moreover, stroma's protective effect during treatment seems limited to cells either in direct contact with stromal cells or in their immediate proximity. Conclusions: We expect our results to lead to novel therapeutic interventions that aim to shift eco-evolutionary dynamics rather than maximize short-term tumor cell killing efficiency. Citation Format: Tatiana Miti, Anna Miller, Daria Myroshnychenko, Bina Desai, Andriy Marusyk, David Basanta. Integrating spatial analysis and agent-based modeling for studies of stroma sheltering effects in NSCLC [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr A032.

The bone is the organ of origin of several types of cancer including multiple myeloma, as well as a host to many metastatic lesions such as those characterizing prostate and breast cancer. The evolutionary dynamics that drive primary and metastatic progression in the bone, as well as those that explain the emergence of resistance to treatments such as proteosome inhibitors and hormonal deprivation therapies, result from the interactions between the tumor and the bone ecosystem. Models that can capture the complex ecological interactions in the bone are key to define the selective pressures underpinning somatic evolution in the bone. Our approach combines computational agent-based models with both in vitro and pre-clinical models in order to shed lights on some open questions in regard to tumor-stromal interactions. As well as the integration of biological and computational models, our approach is hypotheses-driven and captures the homeostasis of the bone that emerges from the interactions of key cellular species such as osteoblasts and osteoclasts. We have explored our models to investigate explore how prostate cancer cells can successfully initiate metastases in the bone, novel therapeutic approaches to treat bone metastatic prostate cancer, explore the emergence of treatment resistance in multiple myeloma and tease apart the contribution of environmentally-mediated drug resistance from cell-intrinsic resistance to proteosome inhibitors. Citation Format: David Basanta, Conor Lynch, Anna Miller, Ryan Bishop. Selective pressures on bone cancer evolution and treatment resistance emerging from the interactions with the bone ecosystem [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr A028.

Stakeholder engagement, specifically integration of patient and family perspectives about what matters, is increasingly recognized as a critical component of patient-centered healthcare delivery. This study describes a structured approach to and evaluation of stakeholder engagement in the development of novel sexual and reproductive health (SRH) educational resources for adolescent and young adult (AYA) women with cystic fibrosis (CF). Key stakeholders participated in a systematic series of steps to iteratively develop and adapt patient educational resources. Process measures (stakeholder recruitment, composition, co-learning, and transparency) and proximal outcomes of stakeholder involvement (impact on the development process and satisfaction) were measured via recorded stakeholder recommendations and a stakeholder survey. Seventeen stakeholders participated in seven group and two patient-only conference calls. The majority of stakeholders understood their roles, had their expectations met or exceeded, and were satisfied with the frequency and quality of engagement in the project. All stakeholders in attendance provided multiple concrete recommen-dations during the development process. Stakeholders explored the motivations of AYA women with CF related to SRH and agreed that the ideal resource should be online. After reviewing the design of existing resources, stakeholders decided by consensus to partner with a pre-existing young women’s health website and created 11 CF-specific SRH guides. This study illuminates a path for a formal process of stakeholder engagement and evaluation in educational resource development centered on the SRH care needs of AYA women with CF. Similar systematic, planned processes could be extended to other populations and aspects of healthcare.

Background COPD patients have increased risk of pneumonia when treated with fluticasone propionate (FP), whereas this is generally not the case with budesonide (BUD) treatment. We hypothesized that BUD and FP differentially affect the expression of immune defense genes. Methods Human bronchial epithelial 16HBE cells and air-liquid interface (ALI)-cultured primary bronchial epithelial cells (PBECs) were pre-treated with clinically equipotent concentrations of BUD or FP (0.16–16 nM BUD and 0.1–10 nM FP), and the expression of immune defense genes was studied at baseline and after exposure to rhinovirus (RV16). Results Using microfluidic cards, we observed that both BUD and FP significantly suppressed CXCL8, IFNB1 and S100A8 mRNA expression in unstimulated 16HBE cells. Interestingly, BUD, but not FP, significantly increased lactotransferrin (LTF) expression. The difference between the effect of BUD and FP on LTF expression was statistically significant and confirmed by qPCR and at the protein level by western blotting. RV16 infection of ALI-cultured PBECs significantly increased the expression of CCL20, IFNB1 and S100A8, but not of LTF or CAMP/LL-37. In these RV16-exposed cells, LTF expression was again significantly higher upon pre-treatment with BUD than with FP. The same was observed for S100A8, but not for CCL20, IFNB1 or CAMP/LL-37 expression. Conclusions Treatment of human bronchial epithelial cells with BUD results in significantly higher expression of specific immune defense genes than treatment with FP. The differential regulation of these immune defense genes may help to explain the clinical observation that BUD and FP treatment differ with respect to the risk of developing pneumonia in COPD.

The paper concentrates on two feature films based upon Henryk Sienkiewicz’s novel about ancient Rome – Quo Vadis? (dir. Enrico Guazzoni [1913]) and Quo Vadis? (dir. Gabriellino D’Annunzio, Georg Jacoby [1925]). Both films belong to the peplum genre, popular during the era of silent cinema. The paper reconstructs production circumstances of both films as well as their historical reception. It is argued that both films can be seen through the prism of socio-political contexts, including the colonial ambitions of the Italian state.

The field of media and health is continually evolving, requiring ongoing evaluation and interpretation of the research examining this burgeoning environmental health issue. Creating educational materials for specialized topics, such as how media and technology affect children’s health and development, is a complex process best accomplished with the support of an embedded librarian. Embedded librarianship, in which a librarian is a core member of a research team, allows for the development of specific subject knowledge. Subsequently, having an embedded health sciences librarian as a collaborator in the creation of specialized resources ensures that these materials are grounded in the latest science and tailored to fit their intended audiences’ interests and needs.

Inhaled corticosteroids (ICSs) treatment combined with long-acting β2-adrenoceptor agonists (LABAs) reduces the risk of exacerbations in COPD, but the use of ICSs is associated with increased incidence of pneumonia. There are indications that this association is stronger for fluticasone propionate than for budesonide. We have examined systematic reviews assessing the risk of pneumonia associated with fluticasone propionate and budesonide COPD therapy. Compared with placebo or LABAs, we found that fluticasone propionate was associated with 43%–78% increased risk of pneumonia, while only slightly increased risk or no risk was found for budesonide. We have evaluated conceivable mechanisms which may explain this difference and suggest that the higher pneumonia risk with fluticasone propionate treatment is caused by greater and more protracted immunosuppressive effects locally in the airways/lungs. These effects are due to the much slower dissolution of fluticasone propionate particles in airway luminal fluid, resulting in a slower uptake into the airway tissue and a much longer presence of fluticasone propionate in airway epithelial lining fluid.

The current paper describes an urban university-anchored but community-based consortium of early childhood centers and community partners in a large Midwestern US city. The goal of the Consortium i...

A wide range of concentrations are frequently observed when measuring drugs of abuse in urine toxicology samples; this is especially true for amphetamine and methamphetamine. Routine liquid chromatography-tandem mass spectrometry confirmatory methods commonly anchored at a 50 ng/mL lower limit of quantitation can span approximately a 100-fold concentration range before regions of non-linearity are reached deteriorating accurate quantitation and qualitative assessments. In our experience, approximately a quarter of amphetamine and methamphetamine positive samples are above a 5,000 ng/mL upper limit of quantitation and thus require reanalysis with dilution for accurate quantitative and acceptable qualitative results. We present here the development of an analytical method capable of accurately quantifying samples with concentrations spanning several orders of magnitude without the need for sample dilution and reanalysis. For each analyte the major isotopes were monitored for analysis through the lower concentration ranges (50-5,000 ng/mL), and the naturally occurring, low probability 13C2 isotopes were monitored for the analysis of the high concentration samples (5,000-100,000 ng/mL amphetamine and 5,000-200,000 ng/mL methamphetamine). The method simultaneously monitors transitions for the molecules containing only 12C and 13C2 isotopologues eliminating the need for re-extraction and reanalysis of high concentration samples.

Aerosol-cloud interactions are a source of high uncertainties in predicting future climate. One important aerosol-cloud interaction is ice nucleation of supercooled liquid water droplets caused by ice nucleating particles (INPs). Predicting the distribution and concentration of INPs is a challenge because of their spatial and temporal heterogeneity in source, number, and composition. Organic aerosols are particularly diverse and complex in chemical and physical composition and can be highly ice active to varying degrees. Here we present the development of our drop Freezing Ice Nucleation Chamber (FINC) for the quantification of INP concentration of aerosol in the immersion freezing mode. As part of the development and validation of FINC, we show results from an intercomparison using lignin as a comparison standard with three other drop-freezing instruments (ETH’s Drop Freezing Ice Nucleation counter Zurich (DRINCZ), University of Basel’s LED-based Ice Nucleation Detection Apparatus (LINDA), and Weizmann Institute’s Supercooled Droplet Observation of Microarray (WISDOM)). In addition, we present here preliminary findings of FINC’s application for determining predictors of the ice nucleating ability of organic matter, using several standards and field-collected samples of dissolved organic matter as a proxy for organic aerosol emitted from natural waters. These methods and results can aid in the community’s search for predictors and parameterizations of organic aerosol induced ice nucleation.

Cloud glaciation is an atmospheric process with important implications for climate and weather. Indeed, clouds made of liquid water and of ice crystals impact the global radiative balance of the atmosphere by reflecting incoming solar radiation and by absorbing outgoing terrestrial radiation. The relevance of ice nucleating particles (INPs) to the atmosphere depends on three main factors, namely on (1) their atmospheric concentration, (2) their freezing temperature and relative humidity, and (3) their freezing mechanism (Cziczo et al., 2013). Research on characterizing ice nucleating organic matter often takes a “top-down” approach where a whole sample of a complex mixture of organic, often biological, macromolecules is subjected to separation techniques and heat treatments to identify IN active sub-components. Studies have used this approach for characterizing bulk soil organic matter, volcanic ash and biological macromolecules from pollen, fungi, and bacteria. We and others have recently found that dissolved organic matter collected from rivers and swamps surprisingly contain active INP (Borduas-Dedekind et al., 2019; Knackstedt et al., 2018; Moffett et al., 2018). Yet, all three studies state that it is unclear which sub-component of the dissolved organic matter is responsible for the ice nucleating ability. There are clear challenges in attributing the ice nucleating ability when starting with a complex mixture of organic and/or biological material, including matrix effects, impurities accumulated through the separation and/or heating process and lack of molecule identity. We present here a “bottom-up” approach to compliment the top-down approach for atmospheric ice nucleation research of macromolecules. Using our home-built drop Freezing Ice Nuclei Counter (FINC) with automated imaging, a range of macromolecules were investigated. Indeed, we have analysed a wide range of dissolved organic matter subcomponents including proteins and fulvic acids. We find a range of ice nucleating ability. We find that lignin, the second most abundant biopolymer in plants, is ice active with 50% frozen fraction temperatures (T50) at –18 °C at a concentration of 100 mg C/L. Furthermore, we have investigated the ice nucleation ability of common diatom exudates and found that at atmospherically relevant concentration they are likely not ice active in immersion freezing within the detection of our FINC instrument. We are currently investigating the effect of atmospheric processing on these macromolecules with the goal of understanding how macromolecules’ ice activity evolves over their one-week lifetime in the atmosphere.

The study goal was to evaluate the transplacental transfer of two corticosteroids, budesonide (BUD) and fluticasone propionate (FP), in pregnant mice and investigate whether P-glycoprotein (P-gp) might be involved in reducing BUD transplacental transfer. Pregnant mice (N = 18) received intravenously either low (104.9 μg/kg) or high (1049 μg/kg) dose of [3H]-BUD or a high dose of [3H]-FP (1590 μg/kg). In a separate experiment, pregnant mice (N = 12) received subcutaneously either the P-gp inhibitor zosuquidar (20 mg/kg) or vehicle, followed by an intravenous infusion of [3H]-BUD (104.9 μg/kg). Total and free (protein unbound) corticosteroid concentrations were determined in plasma, brain, fetus, placenta, kidney, and liver. The ratios of free BUD concentrations in fetus versus plasma K(fetus, plasma, u, u) 0.42 ± 0.17 (mean ± SD) for low-dose and 0.38 ± 0.18 for high-dose BUD were significantly different from K = 1 (P

The potential for enhancing the effect of drugs, radiation or other modalities is one of the potential benefits of ketogenic diets for cancer therapy. Cancer cells grown in culture provide a model ...

Objectives This rapid health needs assessment was undertaken to urgently identify the needs of socially vulnerable groups arising during the first wave of cases of the COVID-19 pandemic in England. The objective was to develop recommendations for policy makers and stakeholders to mitigate adverse impacts on socially vulnerable groups throughout the COVID-19 response and recovery period. Study design Rapid health needs assessment. Methods The needs assessment employed qualitative methods to systematically collect data about the knowledge and views of key informants through semi-structured interviews and focus groups. Participants were either topic experts providing services to socially vulnerable groups who routinely face barriers to healthcare access or experts by experience. Participants included people experiencing homelessness, sex workers, people from Gypsy, Roma and Traveller communities and people facing challenges due to their immigration status. Data was collected over a week period in April/May 2020 and followed by thematic analysis to examine interview transcripts. Results Forty-two participants were included in the study, half of whom were experts by experience. Challenges with accessing and following COVID-19 information and government guidance were described as affecting all groups, due to exclusion from digital technology, translated resources, tailored support and adequate housing. Altered delivery of healthcare services, such as the closure of outreach and drop-in services, remote consultations, and online patient registration, were noted by interviewees as worsening existing barriers to accessing healthcare. Being charged for NHS care remained a key fear for migrants. All groups’ access to income, education and social support were reported as being impacted by service closures and job losses, putting them at higher risk of destitution. Isolation, loneliness and deteriorating mental health were frequently reported. Conclusions This assessment has highlighted the disproportionate impact of the COVID-19 pandemic on socially vulnerable groups and demonstrated a plethora of unmet needs. As the effects of COVID-19 continue, it is imperative that the needs of these groups are urgently and explicitly addressed and prioritised. This is essential to promote engagement with test and trace services, enable isolation adherence, and achieve high vaccine uptake in socially vulnerable populations.

Knowledge of forces and yaw moments which exist between a pair of vessels moving parallel to each other is crucial to the design of their automatic motion control system. Studies involving measurements of forces and moments occurring between a pair of ships were undertaken. The research was carried out on the basis of two real floating training ship models made at 1:24 scale in real conditions on the Silm Lake in Ilawa Kamionka. As a result, suction forces and yaw moments occurring between the pair of vessels calculated according to semi-empirical formula were verified. It was found that the process of overtaking and parallel motion (which is a quasi-stationary motion) could not be modelled in the same way. Nevertheless, the results confirmed the presence of forces and moments with values similar to those in the catch-up and parallel motion phases during the ships’ overtaking manoeuvre. Thanks to this confirmation, it was possible to use the results of the analytical calculation for the catch-up phase during design of the ships' parallel motion automatic control system.

Fix two points $p$ and $q$ in the plane and a positive number $k \neq 1$. A result credited to Apollonius of Perga states that the set of points $x$ that satisfy $d(x, p)/d(x, q) = k$ forms a circle. In this paper we study the analogous set in taxicab geometry. We find that while Apollonian sets are not taxicab circles, more complicated Apollonian sets can be characterized in terms of simpler ones., 16 pages, 8 figures

Background: Glucocorticoids act on the glucocorticoid receptor (GR; NR3C1) to resolve inflammation and, as inhaled corticosteroids (ICS), are the cornerstone of treatment for asthma. However, reduced efficacy in severe disease or exacerbations indicates a need to improve ICS actions. Methods: Glucocorticoid-driven transcriptomes were compared using PrimeView microarrays between primary human bronchial epithelial (HBE) cells and the model cell lines, pulmonary type II A549 and bronchial epithelial BEAS-2B cells. Results: In BEAS-2B cells, budesonide induced (≥2-fold, P ≤ 0.05) or, in a more delayed fashion, repressed (≤0.5-fold, P ≤ 0.05) the expression of 63, 133, 240, and 257 or 15, 56, 236, and 344 mRNAs at 1, 2, 6, and 18 h, respectively. Within the early-induced mRNAs were multiple transcriptional activators and repressors, thereby providing mechanisms for the subsequent modulation of gene expression. Using the above criteria, 17 (BCL6, BIRC3, CEBPD, ERRFI1, FBXL16, FKBP5, GADD45B, IRS2, KLF9, PDK4, PER1, RGCC, RGS2, SEC14L2, SLC16A12, TFCP2L1, TSC22D3) induced and 8 (ARL4C, FLRT2, IER3, IL11, PLAUR, SEMA3A, SLC4A7, SOX9) repressed mRNAs were common between A549, BEAS-2B and HBE cells at 6 h. As absolute gene expression change showed greater commonality, lowering the cut-off (≥1.25 or ≤ 0.8-fold) within these groups produced 93 induced and 82 repressed genes in common. Since large changes in few mRNAs and/or small changes in many mRNAs may drive function, gene ontology (GO)/pathway analyses were performed using both stringency criteria. Budesonide-induced genes showed GO term enrichment for positive and negative regulation of transcription, signaling, proliferation, apoptosis, and movement, as well as FOXO and PI3K-Akt signaling pathways. Repressed genes were enriched for inflammatory signaling pathways (TNF, NF-κB) and GO terms for cytokine activity, chemotaxis and cell signaling. Reduced growth factor expression and effects on proliferation and apoptosis were highlighted. Conclusions: While glucocorticoids repress mRNAs associated with inflammation, prior induction of transcriptional activators and repressors may explain longer-term responses to these agents. Furthermore, positive and negative effects on signaling, proliferation, migration and apoptosis were revealed. Since many such gene expression changes occurred in human airways post-ICS inhalation, the effects observed in cell lines and primary HBE cells in vitro may be relevant to ICS in vivo.

Background Surviving Sepsis Campaign guidelines recommend antibiotics be administered within 1 hour of severe sepsis (SS) onset, but do not suggest which agents to give. Vancomycin (VAN) is often chosen as empiric therapy for severe sepsis (SS) in children without evidence of the prevalence or risk factors for infections requiring VAN. As VAN is associated with significant nephrotoxicity, this study was performed to measure the risk-benefit ratio of empiric VAN use in pediatric sepsis. Methods This was a retrospective study of children with SS between 1/1/2015 to 6/30/2018 at the Women and Children’s Hospital of Buffalo, as captured by billing data and sent to state Department of Health for mandated reporting. SS cases were assessed for risk factors for Gram-positive infections, including presence of a central venous line (CVL) or other invasive device; history of MRSA infection or nasal colonization within the last 2 years; skilled nursing facility (SNF) residence; and prolonged hospitalization of >1 month. Invasive infections for which vancomycin is an optimal agent, specifically culture-proven methicillin-resistant Staphylococcus aureus (MRSA), coagulase-negative Staphylococcus (CoNS), and ampicillin-resistant Enterococcus infections, were defined as vancomycin requiring (VAN-req). Acute kidney injury (AKI) was defined as having a serum Creatinine of twice normal per age-related reference values. Results Of 304 identified SS cases, 8.9% had VAN-req infections. VAN was empirically given to 58.2% of cases (177); 86.4% ultimately did not have VAN-req infections. 9.2% of all SS cases had AKI at SS onset; this included 15.8% of patients (28) receiving VAN, of which only 1 (3.6%) had a VAN-req infection. History of a past MRSA infection, prolonged hospitalization, SNF residence, and CVL presence were found to be independent risk factors for a VAN-req infection (Table 1). VAN-req infections in patients lacking these four risk factors was 3.1% (4/130). Conclusion VAN was given empirically in the majority of pediatric SS cases, but culture-proven infections requiring the drug were infrequent, especially in patients without specific risk factors. The use of empiric VAN for SS should be guided by well-defined criteria, as the drug’s potential risks are likely to outweigh any benefit in most patients. Disclosures All authors: No reported disclosures.

Underway Replenishment is a procedure whose importance is rising in shipping. It is applied both to the naval and civil vessels. That is the reason why research in this area was undertaken. In this paper idea of the ship motion control system for replenishment operations was presented. The outline of the system is described in a detail way. This system incorporates Model Predictive Controller as a main part of the proposed algorithm. The other important part of the control system is a reference trajectory for the approaching ship generation. Conducted computer simulations prove that there is a possibility to synthesize MPC controller to maintain the pair of ships parallel motion during the UNREP operation.

In asthma, the clinical efficacy of inhaled corticosteroids (ICSs) is enhanced by long-acting β(2)-adrenoceptor agonists (LABAs). ICSs, or more accurately, glucocorticoids, promote therapeutically relevant changes in gene expression, and, in primary human bronchial epithelial cells (pHBECs) and airway smooth muscle cells, this genomic effect can be enhanced by a LABA. Modeling this interaction in human bronchial airway epithelial BEAS-2B cells transfected with a 2× glucocorticoid response element (2×GRE)–driven luciferase reporter showed glucocorticoid-induced transcription to be enhanced 2- to 3-fold by LABA. This glucocorticoid receptor (GR; NR3C1)–dependent effect occurred rapidly, was insensitive to protein synthesis inhibition, and was maximal when glucocorticoid and LABA were added concurrently. The ability of LABA to enhance GR-mediated transcription was not associated with changes in GR expression, serine (Ser(203), Ser(211), Ser(226)) phosphorylation, ligand affinity, or nuclear translocation. Chromatin immunoprecipitation demonstrated that glucocorticoid-induced recruitment of GR to the integrated 2×GRE reporter and multiple gene loci, whose mRNAs were unaffected or enhanced by LABA, was also unchanged by LABA. Transcriptomic analysis revealed glucocorticoid-induced mRNAs were variably enhanced, unaffected, or repressed by LABA. Thus, events leading to GR binding at target genes are not the primary explanation for how LABAs modulate GR-mediated transcription. As many glucocorticoid-induced genes are independently induced by LABA, gene-specific control by GR- and LABA-activated transcription factors may explain these observations. Because LABAs promote similar effects in pHBECs, therapeutic relevance is likely. These data illustrate the need to understand gene function(s), and the mechanisms leading to gene-specific induction, if existing ICS/LABA combination therapies are to be improved.

Promoting understanding of quality in the context of good governance can be a challenging classroom exercise not only because of the potential for hijacking politicization of the discussion, but also because of the variety of ways in which public sector goals can be defined, even in the context of a single policy. Standards of quality in the present in the contemporary practice of public administration include many words beginning with “E” in the English language. Employing the “E’s are Good” taxonomy helps communicate different aspects of good governance to students in public administration and policy courses. In this article, literature surrounding the public sector standards of quality is reviewed using this framework. Examples of discussion of the E concepts drawn from legislative discourse surrounding Canadian health and social policy designed are then considered as an empirical case study.

The recent increase in illicit opioids sold on the black market, cut into heroin and masqueraded as prescription pills prompts a significant public health concern. Most designer opioids possess unknown potencies and unknown pharmacokinetics and their unregulated, variable dosages lead to rashes of overdoses. Additionally, many of the designer opioids, especially the fentanyl analogs are significantly more potent than heroin. High-profile cases involving overdoses of U-47700 and carfentanil have been reported in the media; however, the true prevalence of these and other designer opioids is unknown. Independent LC-MS-MS screen and confirmation methods have been developed and validated to identify and quantify fentanyl, and 18 designer opioids and their metabolites; methods were then exercised on urine specimens from contract pain management clients. Assuming patients in a pain management program may have a higher probability to seek out self-medication, samples from pain management patients were investigated for designer opioids. Similarly, pain management patients identified as using heroin may be more likely to experiment with or be accidentally exposed to designer opioids, specimens screening positive for the heroin metabolite 6-acetylmorphine were specifically chosen for designer opioid screening. Within this small group of pain management and heroin-positive samples, nine designer opioids were detected at a total prevalence of 25%. When screening random pain management samples not positive for heroin, a considerably lower percentage of samples (

Students entering North Carolina public schools must have documentation of a health assessment and immunizations by the 30th day of class, or they are excluded from attending school until they submit documentation. A community collaborative was essential in decreasing the number of students excluded from school for noncompliant documentation in the Winston-Salem Forsyth County school district.

NK cells are innate immune lymphocytes that express a vast repertoire of germ-line encoded receptors for target recognition. These receptors include inhibitory and activating proteins, among the latter of which is CD16, a low affinity binding Fc receptor. Here, we show that human NK cells expand in response to stimulation with various tumor cell lines. We further demonstrate that the tumor-derived expansion of NK cells is accompanied by rapid, cell-dependent, changes in CD16 expression levels. We show that in NK cells expanded in response to the EBV-transformed cell line 721.221, CD16 is shed and therefore approximately half of the expanded 721.221-derived NK-cell population does not express CD16. We also show, in contrast, that in response to 1106mel cells, CD16 expression is maintained on the cell surface of the expanded NK cells due to an antibody-dependent mechanism. Our results may provide a basis for the selective expansion of NK cells that may be used for tumor immunotherapy.

Exacerbations of asthma, a chronic inflammatory respiratory disease, are associated with viral upper respiratory tract infections involving human rhinovirus. Although glucocorticoids (corticosteroids) effectively control airways inflammation in many asthmatics, human rhinovirus-associated exacerbations show reduced glucocorticoid responsiveness. Using human bronchial epithelial BEAS-2B cells, we show that human rhinovirus reduced glucocorticoid-inducible activation of glucocorticoid response element (GRE) reporter systems in a time- and concentration-dependent manner. The synthetic double-stranded viral RNA mimetic, polyinosinic:polycytidylic acid (poly(I:C)), also reduced activation of GRE reporter systems in BEAS-2B and pulmonary A549 cells. In addition, poly(I:C) decreased transcription from cAMP response element (CRE)-, TATA-, simian virus 40- and nuclear factor-kappa B (NF-κB)-dependent reporter systems. The effects of poly(I:C) on GRE-reporter activation were countered by the long-acting β2-adrenoceptor agonists, formoterol and salmeterol. Likewise, increased expression of the gene cyclin-dependent kinase inhibitor 1C (CDKN1C; p57(KIP2)) by dexamethasone was reduced by poly(I:C), but was substantially enhanced by the addition of formoterol. Poly(I:C) induced the expression of interleukin-8 (IL8; CXCL8) and this was significantly decreased by dexamethasone, formoterol or their combination. This confirms that not all transcriptional responses were attenuated by poly(I:C) and that decreased glucocorticoid-dependent transcription can be counteracted by the addition of long-acting β2-adrenoceptor agonists. These data show how human rhinovirus may attenuate glucocorticoid-induced transcription to reduce anti-inflammatory activity. However, addition of long-acting β2-adrenoceptor agonist to the glucocorticoid functionally restored this response and shows how glucocorticoid plus long-acting β2-adrenoceptor agonist combinations may prove beneficial during virus-induced exacerbations of asthma.

Rationale: COPD patients have a high risk of community-acquired pneumonia (CAP). We studied Streptococcus pneumoniae (SP) and non-typeable Haemophilus influenzae (NTHI) effects on COPD macrophage responses and how budesonide (BUD) and fluticasone propionate (FP) alter host-pathogen interactions. Methods: Blood monocytes from 10 controls, 20 healthy smokers and moderate-severe COPD [19 current smokers (CS), 21 ex-smokers (ES)] were cultured with GM-CSF to generate monocyte-derived macrophages (MDM). MDM were pre-treated with 10nM BUD, FP or vehicle for 24h and exposed to live SP or NTHI. After 24h cell surface bacterial recognition receptor expression was analyzed by flow cytometry and supernatant cytokines by bead array. Data at p≤0.05 (2-sided paired t-test) are shown. Results: SP and NTHI reduced receptor expression on MDM from COPD (mainly in ES) and healthy smokers but not controls. SP and NTHI reduced SRA-1 in CS & ES and MARCO in ES. SP also reduced CD1d, TLR2 and TLR4 in CS & ES and CD93 in ES. NTHI also reduced CD11b in CS & ES and CD35 and CD206 in ES. BUD prevented reductions by SP on SRA-1 and by NTHI on CD206, both in ES. FP prevented SP reductions of TLR2 in CS & ES and TLR4 in ES but had no effect on reductions by NTHI. BUD and FP inhibited NTHI- and SP-induced cytokines. Conclusions: Reduction of bacterial recognition receptors on macrophages may be part of the enhanced risk of CAP in COPD. BUD prevented receptor reductions induced in ex-smokers by both SP and NTHI while FP affected only SP-induced reductions. These differential effects may contribute to the difference in pneumonia risk between inhaled BUD and FP treatments in COPD. Support: AstraZeneca.

Urine drug testing is common for workplace drug testing, prescription management, emergency medicine and the criminal justice system. Unsurprisingly, with the significant consequences based upon the results of urine drug testing, a donor in need of concealing the contents of their sample is highly motivated to cheat the process. Procedures and safeguards ensuring sample validity are well known, and include measuring sample temperature at the time of collection, and laboratory measurements of creatinine, specific gravity and pH. Synthetic urine samples are available and are designed to deceive all aspects of urine drug testing, including validity testing. These samples are sophisticated enough to contain biological levels of creatinine, and are at a physiological pH and specific gravity. The goal of our research was to develop new procedures designed to distinguish authentic samples from masquerading synthetic samples. We aimed to identify substances in commercial synthetic urines not expected to be present in a biological sample distinguishing fake specimens. Additionally, we aimed to identify and employ endogenous compounds in addition to creatinine for identifying biological samples. We successfully identified two compounds present in synthetic urines that are not present in biological samples and use them as markers of invalidity. Four new endogenous markers for validity were successfully evaluated. Validity assessment was further aided by monitoring metabolites of nicotine and caffeine. When the method was applied to patient samples, 2% of samples were identified as inconsistent with natural urine samples, even though they met the current acceptance criteria for creatinine, pH and specific gravity.

Although inhaled glucocorticoids, or corticosteroids (ICS), are generally effective in asthma, understanding their anti‐inflammatory actions in vivo remains incomplete. To characterize glucocorticoid‐induced modulation of gene expression in the human airways, we performed a randomized placebo‐controlled crossover study in healthy male volunteers. Six hours after placebo or budesonide inhalation, whole blood, bronchial brushings, and endobronchial biopsies were collected. Microarray analysis of biopsy RNA, using stringent (≥2‐fold, 5% false discovery rate) or less stringent (≥1.25‐fold, P ≤ 0.05) criteria, identified 46 and 588 budesonide‐induced genes, respectively. Approximately two third of these genes are transcriptional regulators (KLF9, PER1, TSC22D3, ZBTB16), receptors (CD163, CNR1, CXCR4, LIFR, TLR2), or signaling genes (DUSP1, NFKBIA, RGS1, RGS2, ZFP36). Listed genes were qPCR verified. Expression of anti‐inflammatory and other potentially beneficial genes is therefore confirmed and consistent with gene ontology (GO) terms for negative regulation of transcription and gene expression. However, GO terms for transcription, signaling, metabolism, proliferation, inflammatory responses, and cell movement were also associated with the budesonide‐induced genes. The most enriched functional cluster indicates positive regulation of proliferation, locomotion, movement, and migration. Moreover, comparison with the budesonide‐induced expression profile in primary human airway epithelial cells shows considerable cell type specificity. In conclusion, increased expression of multiple genes, including the transcriptional repressor, ZBTB16, that reduce inflammatory signaling and gene expression, occurs in the airways and blood and may contribute to the therapeutic efficacy of ICS. This provides a previously lacking insight into the in vivo effects of ICS and should promote strategies to improve glucocorticoid efficacy in inflammatory diseases.

Background: Combination of inhaled corticosteroids (ICS) and long-acting β2-adrenergic agonists (LABA) offer clinical benefits in COPD compared with ICS alone or LABA alone, especially in reduction of exacerbations. In asthma, LABA enhance glucocorticoid receptor (GR) nuclear translocation in airway macrophages in the presence of corticosteroid, which may explain why low-dose ICS combined with LABA is as effective as high-dose ICS. Whether this mechanism occurs in COPD is not fully studied. Method: In a cross-over study, 35 mild-to-moderate COPD patients inhaled a single dose of budesonide (BUD) 400µg and formoterol (FM) 12µg combination (Symbicort 400/12µg), or BUD/FM 800/24µg (Symbicort 800/24µg), or budesonide (Pulmicort) 800µg, or FM (Oxis) 24µg. Induced sputum was collected after 2h. GR activity and level of inflammatory marker, CXCL8, were analysed in sputum. GR activity was assessed as binding of GR to glucocorticoid response elements (GRE) in sputum macrophages. Data were analysed by non-parametric tests. Results: A single BUD/FM 400/12µg dose enhanced GR-GRE binding to similar extent as BUD 800µg dose and high-dose BUD/FM 800/24µg; 60-90% increase vs basal levels (p 1 (p Conclusions: A single, low inhaled dose of BUD/FM 400/12µg triggers anti-inflammatory effects in the airways and improves lung function in COPD patients as effective as double dose of BUD/FM or BUD alone. Support: AstraZeneca.

An estimated 3.5 million persons in the United States are living with hepatitis C virus (HCV) infection, resulting in approximately 20,000 deaths each year, primarily from cirrhosis or hepatocellular carcinoma (1,2). American Indian/Alaska Native (AI/AN) populations have the highest incidence of acute HCV infection among all U.S. racial/ethnic groups and are at greater risk for HCV-related mortality compared with the general population (3). In 2013, new antiviral drugs became available that make possible 8-12 week treatment regimens with fewer adverse events and are able to achieve sustained virologic response (SVR) in >90% of treated patients (4), equivalent to a cure of HCV infection. Also of note, HCV testing recommendations were expanded in 2012 by CDC and in 2013 by the U.S. Preventive Services Task Force to include one-time testing of persons born during 1945-1965 (the "baby boomer" cohort) in addition to anyone at increased risk for HCV infection (5,6). Given the availability of new HCV drugs, expanded testing recommendations, and high incidence of HCV infection in AI/AN populations, in October 2012, Cherokee Nation Health Services (CNHS) implemented a tribal HCV testing policy.* As part of the policy, CNHS added a reminder in the electronic health record (EHR) for clinical decision support and provided HCV education to primary care clinicians. From October 2012 to July 2015, among 92,012 persons with at least one CNHS clinic encounter, the cumulative number who received HCV screening for the first time increased from 3,337 (3.6%) to 16,772 (18.2%). The largest percentage of HCV screening was among persons born during 1945-1965. Of 715 persons who tested positive for HCV antibodies, 488 (68.3%) were tested for HCV RNA; among those 488 persons, 388 (79.5%) were RNA positive and were thus confirmed to have chronic HCV infection. Treatment was initiated for 223 (57.5%) of the 388 with chronic infection; 201 (90.1%) completed treatment, of whom 180 (89.6%) achieved SVR. CNHS has successfully increased HCV testing and treatment and is now collaborating with CDC and other external partners to develop an HCV elimination program for the Cherokee Nation that might serve as a model for similar settings.

The inflammatory processes associated with pulmonary disorders remains incompletely understood. CCAAT/enhancer-binding protein (C/EBP)β is implicated in inflammatory lung disorders as well as in β(2)-adrenoceptor signaling. We hypothesized that C/EBPβ in the lung epithelium contributes to lipopolysaccharide (LPS)-induced airway neutrophilia and expression of neutrophil chemoattractant chemokine (C-X-C) motif ligand (CXCL)1, as well as the suppressive effects of long-acting β(2)-agonists (LABAs) and glucocorticoids (GCs). To investigate this, mice with a lung epithelial-specific deletion of C/EBPβ (Cebpb(ΔLE)) and control littermates (Cebpb(fl/fl)) were pre-treated with a LABA, formoterol and/or a GC, budesonide, and challenged with LPS. Inflammatory cell recruitment in bronchoalveolar lavage (BAL) fluid and pulmonary expression of inflammatory mediators were investigated. In addition, the ability of formoterol to increase C/EBP transactivation was assessed in vitro. LPS-challenged Cebpb(ΔLE) mice exhibited fewer BAL neutrophils and lower pulmonary expression of CXCL1 versus Cebpb(fl/fl) mice. Suppression of LPS-induced neutrophilia by formoterol was impaired in Cebpb(ΔLE) mice and Cxcl1 expression was increased. However, suppression of the neutrophilia by budesonide with/without formoterol was preserved. Further studies indicated that C/EBP transactivation was increased by the cAMP elevating agent forskolin and formoterol in a β(2)-adrenoceptor dependent manner. Thus, C/EBPβ in the lung epithelium contributes to LPS-induced CXCL1 expression and airway neutrophilia as well as to the suppressive effects of formoterol. Reduced C/EBPβ activity, observed in smokers with chronic obstructive pulmonary disease, may impair the responsiveness to LABAs when used without GCs.