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Therapies that modulate and appropriately direct the immune response are promising candidates for the treatment of infectious diseases. One such candidate therapeutic is DZ13, a short, synthetic, single-stranded DNA molecule. This molecule has enzymatic activity and can modulate the immune response by binding to and degrading the mRNA encoding a key immuno-regulatory molecule. Originally developed and entering clinical trials as an anti-cancer agent, DZ13 has also been evaluated as a treatment for viral infections, and has been shown to provide protection against infection with influenza virus in a mouse model of infection. In this work, we evaluated whether the immuno-modulatory properties of DZ13 could provide protection against the potential biothreat pathogen Burkholderia pseudomallei which causes the neglected tropical disease melioidosis. Treatment of mice infected with B. pseudomallei demonstrated that DZ13 did indeed provide excellent protection after only two post-exposure treatments. However, our data indicated that the enzymatic activity contained in DZ13 was not required for protection, with control oligonucleotide treatments lacking activity against the target mRNA equally as protective against B. pseudomallei. We have designed new sequences to study the mechanism of protection further. These novel sequences offer enhanced protection against infection, but are not directly anti-microbial and do not appear to be stimulating the immune system via TLR9 or other key innate immune sensors, despite containing CpG motifs. The molecular mechanism of these novel sequences remains to be elucidated, but the data highlights that these oligonucleotide-sensing pathways are attractive and relevant targets to modulate during bacterial and viral infections.

In 2021, a ‘call to action’ was published to highlight the need for professional regulation of clinical exercise physiologists to be established within UK healthcare systems to ensure patient safety and align training and regulation with other health professions. This manuscript provides a progress report on the actions that Clinical Exercise Physiology UK (CEP-UK) has undertaken over the past 4 years, during which time clinical exercise physiologists have implemented regulation and gained formal recognition as healthcare professionals in the UK. An overview of the consultation process involved in creating a regulated health profession, notably the development of policies and procedures for both individual registration and institutional master’s degree (MSc) accreditation is outlined. Additionally, the process for developing an industry-recognised scope of practice, a university MSc-level curriculum framework, the Academy for Healthcare Science Practitioner standards of proficiency and Continuing Professional Development opportunities is included. We outline the significant activities and milestones undertaken by CEP-UK and provide insight and clarity for other health professionals to understand the training and registration process for a clinical exercise physiologist in the UK. Finally, we include short, medium and long-term objectives for the future advocacy development of this workforce in the UK.

A satellite-based vegetation index model that tracks daily crop growth and evapotranspiration (ETc) is developed, tested, and validated over irrigated farms in Yuma irrigation districts of Arizona and California. Model inputs are remotely sensed normalized difference vegetation index (NDVI) images, crop type maps, and local weather. The utility and novelty of the model is a more accurate assessment of ETc than currently provided by the US Bureau of Reclamation’s evapotranspiration modeling system. The model analyzes NDVI time series data from the European Space Agency’s Sentinel-2 satellites using the Google Earth Engine, constructs FAO-56 style crop growth stages from NDVI, and then estimates daily ETc using pre-defined crop coefficients (Kc) and grass reference evapotranspiration (ETos). Four crops were selected to test and evaluate model performance: short-season broccoli, mid-season cotton and wheat, and perennial alfalfa. Comparison of model results showed that Reclamation reports overestimate alfalfa and wheat ETc by 21–25%, cotton ETc by 6%, and underestimate broccoli ETc by 21%. Variability resolved by the model ranged 6–18% of median total ETc. Comparison of model results with those obtained from 13 eddy covariance sites showed validation discrepancies ranging 1–14%: average total actual ETc differences were 12, − 14, 78, and 87 mm/season, respectively, for alfalfa, broccoli, cotton, and wheat. The wide availability of Sentinel-2 data, collected every 5 days or less, and the rapid processing via Google Earth Engine make the vegetation index model implementation fast and practical. Its accuracy and ability to resolve ETc for every field would benefit the Reclamation water accounting system and provide valuable consumptive water use data for any Colorado River stakeholder.

Introduction: Chlorpromazine is a first-generation antipsychotic used for behavioral problems in pediatric patients. However, other therapies may demonstrate both improved outcomes and fewer side effects. Within our institution, chlorpromazine has been the standard medication used for treatment of pediatric agitation. The study objective was to evaluate the appropriateness of chlorpromazine use (including efficacy, appropriate dosing, drug interactions, and tolerability) to optimize the treatment of pediatric agitation. Methods: Data regarding drug interactions, patient behavior, dosing, and side effects was collected for each patient administered chlorpromazine from January 2019 through June 2019. Data were analyzed using descriptive statistics assessing the incidence of drug-drug interactions (DDIs), incidences of inefficacy, inappropriate dosing, and side effects. Results: A total of 70 patients and 130 administrations of oral or intramuscular chlorpromazine were evaluated. Of these administrations, 49 (38%) resulted in a DDI. Eighteen (14%) administrations were ineffective for managing symptoms of agitation. Eleven (8%) administrations were dosed inappropriately, and 46 (35%) administrations resulted in side effects possibly caused by chlorpromazine. Discussion: Results from this study demonstrate opportunities for improvement in patient care due to instances of drug interactions, inefficacy, inappropriate dosing, and side effects with the use of chlorpromazine.

Abstract During a conflict, having a greater number of allies than the opposition can improve one’s success in a conflict. However, allies must be aware that has a conflict has occurred, and this is often influenced by what they are able to see. Here, we explored whether infants’ assessment of social dominance is influenced by whether or not social allies have visual access to an episode of intergroup conflict. In Experiment 1, 9–12-month-olds only expected an agent to be socially dominant if their allies were able to witness the conflict. Experiment 2 provided further support for this finding, as infants did not expect an agent from a numerically larger group to be socially dominant when allies were unable to witness the conflict. Together, these results suggest that infants do not simply use a heuristic in which “numerically larger groups are always more dominant”. Importantly, infants are able to incorporate social allies’ ability to witness a conflict when predicting social dominance between groups.

Introduction:In vitro approaches are an essential tool in screening for toxicity of new chemicals, products and therapeutics. To increase the reproducibility and human relevance of these in vitro assessments, it is advocated to remove animal-derived products such as foetal bovine serum (FBS) from the cell culture system. Currently, FBS is routinely used as a supplement in cell culture medium, but batch-to-batch variability may introduce inconsistency in inter- and intra-lab assessments. Several chemically defined serum replacements (CDSR) have been developed to provide an alternative to FBS, but not every cell line adapts easily and successfully to CDSR-supplemented medium, and the long-term effect on cell characteristics remains uncertain.Aim: The aim of this study was to adapt the TK6 cell line to animal-product free CDSR-supplemented medium and evaluate the long-term effects on cell health, growth, morphology, phenotype, and function. This included a provisional assessment to determine the suitability of the transitioned cell line for standardised genotoxicity testing using the “in vitro mammalian cell micronucleus test” (OECD TG 487).Materials and methods: Gradual adaptation and direct adaptation methodologies were compared by assessing the cell proliferation, size and viability every passage until the cells were fully adapted to animal-free CDSR. The metabolic activity and membrane integrity was assessed every 4-8 passages by PrestoBlue and CytoTox-ONE™ Homogeneous Membrane Integrity Assay respectively. A detailed morphology study by high content imaging was performed and the expression of cell surface markers (CD19 and CD20) was conducted via flow cytometry to assess the potential for phenotypic drift during longer term culture of TK6 in animal-free conditions. Finally, functionality of cells in the OECD TG 487 assay was evaluated.Results: The baseline characteristics of TK6 cells cultured in FBS-supplemented medium were established and variability among passages was used to set up acceptance criteria for CDSR adapted cells. TK6 were adapted to CDSR supplemented medium either via direct or gradual transition reducing from 10% v/v FBS to 0% v/v FBS. The cell growth rate was compromised in the direct adaptation and therefore the gradual adaptation was preferred to investigate the long-term effects of animal-free CDSR on TK6 cells. The new animal cells showed comparable (p > 0.05) viability and cell size as the parent FBS-supplemented cells, with the exception of growth rate. The new animal free cells showed a lag phase double the length of the original cells. Cell morphology (cellular and nuclear area, sphericity) and phenotype (CD19 and CD20 surface markers) were in line (p > 0.05) with the original cells. The new cells cultured in CDSR-supplemented medium performed satisfactory in a pilot OECD TG 487 assay with compounds not requiring metabolic activation.Conclusion: TK6 cells were successfully transitioned to FBS- and animal product-free medium. The new cell cultures were viable and mimicked the characteristics of FBS-cultured cells. The gradual transition methodology utilised in this study can also be applied to other cell lines of interest. Maintaining cells in CDSR-supplemented medium eliminates variability from FBS, which in turn is likely to increase the reproducibility of in vitro experiments. Furthermore, removal of animal derived products from cell culture techniques is likely to increase the human relevance of in vitro methodologies.

The uncertainty behind a warming climate produces significant risk for communities that rely on tourism, but vulnerability assessment can help inform planning for adaptation and mitigation efforts. Since coastal regions have significant tourism economies, and rely on the tourism sector for socio-economic stability, we seek to understand how assessments of vulnerability have been applied in coastal communities by systemically assessing literature that describes the concepts of adaptation, resilience, and vulnerability. We conducted a systematic search across three peer-reviewed journal databases (Web of Science, Scopus, and PubMed) to compare the types of methods and models used to determine coastal adaptation and vulnerability in various geographical and demographic settings. The systematic process found 205 unique articles; 143 were deemed relevant as they focused on adaptation, resilience, or vulnerability assessment. A qualitative analysis of the key themes of relevant studies, identified using thematic coding, found that vulnerability and adaptation research in tourism-based coastal communities is predominantly done through qualitative methods, researched more frequently in higher-populated areas of Europe and North America, have a focus on water as a driver of vulnerability, focus on socio-economic impacts of vulnerability, and emphasize locally-based knowledge in understanding adaptive capacity. Bibliometric analysis of citations and mentions in social-media reveal a larger number of papers with a higher citation rate focused on coastal-based systems (salt-water) with an emphasis on regional studies rather than those with a specific urban or rural focus. We found few studies aimed at coastal communities using tourism operators as informants, but rural coastal communities had higher social-media metrics indicating their comparative public importance. Thus, we highlight the need for locally-informed case studies in vulnerability and adaptation assessment for small coastal communities.

Gastrointestinal (GI) cancers, including esophageal, gastroesophageal junction, gastric, duodenal and distal small bowel, biliary tract, pancreatic, colon, rectal, and anal cancer, comprise a heterogeneous group of malignancies that impose a significant global burden. Immunotherapy has transformed the treatment landscape for several GI cancers, offering some patients durable responses and prolonged survival. Specifically, immune checkpoint inhibitors (ICIs) directed against programmed cell death protein 1 (PD-1), either as monotherapies or in combination regimens, have gained tissue site-specific regulatory approvals for the treatment of metastatic disease and in the resectable setting. Indications for ICIs in GI cancer, however, have differing biomarker and histology requirements depending on the anatomic site of origin. Furthermore, ICIs are associated with unique toxicity profiles compared with other systemic treatments that have long been the mainstay for GI cancer, such as chemotherapy. With the goal of improving patient care by providing guidance to the oncology community, the Society for Immunotherapy of Cancer (SITC) convened a panel of experts to develop this clinical practice guideline on immunotherapy for the treatment of GI cancer. Drawing from published data and clinical experience, the expert panel developed evidence- and consensus-based recommendations for healthcare professionals using ICIs to treat GI cancers, with topics including biomarker testing, therapy selection, and patient education and quality of life considerations, among others.

Summary: Background: Anti-programmed cell death protein 1 antibodies plus multikinase inhibitors have shown encouraging activity in several tumour types, including colorectal cancer. This study assessed regorafenib plus nivolumab in patients with microsatellite stable/mismatch repair-proficient metastatic colorectal cancer. Methods: This single-arm, open-label, multicentre phase 2 study enrolled adults from 13 sites in the USA with previously treated advanced microsatellite stable/mismatch repair-proficient metastatic colorectal cancer. Eligible patients had known extended RAS and BRAF status, progression or intolerance to no more than two (for extended RAS mutant) or three (for extended RAS wild type) lines of systemic chemotherapy and an Eastern Cooperative Oncology Group performance status of 0 or 1. Regorafenib 80 mg/day was administered orally for 3 weeks on/1 week off (increased to 120 mg/day if 80 mg/day was well tolerated) with intravenous nivolumab 480 mg every 4 weeks. Primary endpoint was objective response rate. Secondary endpoints included safety, overall survival, and progression-free survival. Exploratory endpoints included biomarkers associated with antitumour activity. Patients who received at least one dose of study intervention were included in the efficacy and safety analyses. Tumour assessments were carried out every 8 weeks for the first year, and every 12 weeks thereafter until progressive disease/end of the study, and objective response rate was analysed after all patients had met the criteria for primary completion of five post-baseline scans and either 10-months’ follow-up or drop out. This trial is registered with ClinicalTrials.gov, number NCT04126733. Findings: Between 14 October 2019 and 14 January 2020, 94 patients were enrolled, 70 received treatment. Five patients had a partial response, yielding an objective response rate of 7% (95% CI 2.4–15.9; p = 0.27). All responders had no liver metastases at baseline. Median overall survival (data immature) and progression-free survival were 11.9 months (95% CI 7.0–not evaluable) and 1.8 months (95% CI 1.8–2.4), respectively. Most patients (97%, 68/70) experienced a treatment-related adverse event; 51% were grade 1 or 2, 40% were grade 3, 3% were grade 4, and 3% were grade 5. The most common (≥20%) events were fatigue (26/70), palmar-plantar erythrodysesthesia syndrome (19/70), maculopapular rash (17/70), increased blood bilirubin (14/70), and decreased appetite (14/70). Higher baseline expression of tumour biomarkers of immune sensitivity correlated with antitumour activity. Interpretation: Further studies are warranted to identify subgroups of patients with clinical characteristics or biomarkers that would benefit most from treatment with regorafenib plus nivolumab. Funding: Bayer/Bristol Myers Squibb.

Abstract Smart Grids are electrical grids that require a decentralised way of controlling electric power conditioning and thereby control the production and distribution of energy. Yet, the integration of Distributed Renewable Energy Sources (DRESs) in the Smart Grid introduces new challenges with regards to electrical grid balancing and storing of electrical energy, as well as additional monetary costs. Furthermore, the future smart grid also has to take over the provision of Ancillary Services (ASs). In this paper, a distributed ICT infrastructure to solve such challenges, specifically related to ASs in future Smart Grids, is described. The proposed infrastructure is developed on the basis of the Smart Grid Architecture Model (SGAM) framework, which is defined by the European Commission in Smart Grid Mandate M/490. A testbed that provides a flexible, secure, and low-cost version of this architecture, illustrating the separation of systems and responsibilities, and supporting both emulated DRESs and real hardware has been developed. The resulting system supports the integration of a variety of DRESs with a secure two-way communication channel between the monitoring and controlling components. It assists in the analysis of various inter-operabilities and in the verification of eventual system designs. To validate the system design, the mapping of the proposed architecture to the testbed is presented. Further work will help improve the architecture in two directions; first, by investigating specific-purpose use cases, instantiated using this more generic framework; and second, by investigating the effects a realistic number and variety of connected devices within different grid configurations has on the testbed infrastructure.

Objective(s): 18F-FDG PET/CT is increasingly performed in patients with differen-tiated thyroid cancer. The aim of this study was to assess the clinical impact of 18F-FDG PET/CT on the management of patients with differentiated thyroid carcinoma who had elevated serum thyroglobulin (Tg) and negative 131I whole body scan (WBS). Methods: 67 patients with differentiated thyroid carcinoma were included in this study. The findings of 18F-FDG PET/CT imaging were compared with histo-pathology, follow up imaging, or clinical follow-up results. The diagnostic accuracy of 18F-FDG PET/CT was evaluated for the entire patient group and for those patients with stimulated serum thyroglobulin levels of less than 5, 5–10, and more than 10 pmol/L as well as for local recurrences and metastases sites. The impact of 18F-FDG PET/CT on therapeutic management was also evaluated. Results: 30/67 patients had positive findings on 18F-FDG PET/CT; 28 were true-positive and 2 were false-positive. 18F-FDG PET/CT results were true-negative in 36 patients and false-negative in 1 patient. The overall sensitivity, specificity, accuracy, PPV and NPV of 18F-FDG PET/CT were, 96.5%, 94.5%, 95.5%, 93.3%, and 97.2% respectively. Positive 18F-FDG PET/CT findings were directly correlated with stimulated serum thyroglobulin levels, 7.1% had Tg between 5–10, and 92.9% had Tg greater than 10 pmol/L. 18F-FDG PET/CT had a high or moderate impact on treatment management in 28 (41.8%) of patients. Conclusion: 18F-FDG PET/CT is able to improve diagnostic accuracy and have management impact in a therapeutically relevant way in patients with differentiated thyroid carcinoma who present with rising thyroglobulin level, negative 131I WBS, and clinical suspicion of recurrent disease.

Programmable soft materials have shown applications in artificial muscles, soft robotics, flexible electronics, and biomedicines due to their adaptive structural transformations. As an ordered soft material, directional shape changes of liquid crystal elastomer (LCE) can be easily achieved via external stimuli thanks to its anisotropic elasticity. However, harnessing the interplay between molecular ordering, geometry, and shape morphing in this anisotropic material to create programmable and complex shape changes remains a challenge. Here, by integrating the concepts of kirigami or Chinese paper cutting “JianZhi” in the light‐actuated LCE encoded with controlled molecular orientations, various complex 3D shape morphing behaviors are demonstrated. Versatile combinations of fundamental shape changes such as bending, folding, twisting, and rolling are enabled by fine‐tuning the molecular orientations and geometries in the monolithic LCE kirigami. Furthermore, various functions such as fluttering of the Chinese crane bird “QianZhiHe,” arbitrary directional locomotion in the annulus and linear locomotion in the complex Chinese character are also realized. These complex, fast‐response, untethered, remote, reversible, and programmable shape morphologies actuated in a monolith of LCE kirigami will open opportunities in soft robotics and smart materials.

Loss-of-function mutations in the human potassium chloride cotransporter-3 (KCC3) cause a hereditary motor sensory neuropathy associated with agenesis of the corpus callosum. While recapitulating the neuropathy, KCC3-knockout mice also exhibit high blood pressure. This phenotype is believed to have neurogenic and/or vascular origins. The role of KCC3 in the kidney is poorly understood. KCC3 is encoded by two major isoforms originating from alternative promoters: KCC3a and KCC3b, with KCC3b being the predominant transcript in the kidney. Although the transporter has previously been localized to the proximal tubule, we show here the unique expression of the KCC3a isoform in the connecting tubule. Using a KCC3a-specific polyclonal antibody validated for both immunofluorescence and immunoblotting, we showed an intense KCC3a signal restricted to cortical intercalated cells. No overlap is detected between KCC3a and sodium chloride cotransporter (NCC), a distal convoluted tubule (DCT) marker; or between KCC3a and ENaC or calbindin, which are both principal cell markers. KCC3a signal was observed in cells expressing the apical V-ATPase and pendrin, establishing a unique expression pattern characteristic of intercalated cells of type-B or type-nonA/nonB. We further show that treatment of wild-type mice with hydrochlorothiazide, amiloride, or fed a K+-deficient diet up-regulates KCC3a level, suggesting that volume depletion increases KCC3a abundance. This hypothesis was confirmed by showing a higher abundance of KCC3a protein after 23-h water restriction or after placing the mice on a low-salt diet. More importantly, abundance of the Cl−/HCO3− exchanger, pendrin, which is known to secrete bicarbonate in alkalotic conditions, was significantly diminished in KCC3-knockout mice. In addition, KCC3a abundance increased significantly alongside pendrin abundance in bicarbonate-treated alkalotic mice, providing a credible mechanism for K+ loss in metabolic alkalosis.

Vulnerability can measure an ecosystem’s susceptibility to change as a result of pressure or disturbance, but can be difficult to quantify. Reconstructions of past climate using paleolimnological methods can create a baseline to calibrate future projections of vulnerability, which can improve ecosystem management and conservation plans. Here, we conduct a systematic map to analyze the range and extent that paleolimnological published studies incorporated the concept of vulnerability. Additional themes of monitoring, management, conservation, restoration, or ecological integrity were also included. A total of 52 relevant unique articles were found, a majority of which were conducted in Europe or North America since 2011. Common themes identified included management and adaptation, with the latter heavily focussed on climate change or disturbance. From this, we can infer that the use of paleolimnology to discuss the concept of vulnerability is an emerging field. We argue that paleolimnology plays a valid role in the reconstruction of ecosystem vulnerability due to its capacity to broaden the scope of long-term monitoring, as well as its potential to help establish management and restoration plans. The use of paleolimnology in vulnerability analysis will provide a clearer lens of changes over time; therefore, it should be frequently implemented as a tool for vulnerability assessment.

Abstract With the increased penetration of distributed renewable energy sources (DRES) in the grid, new pathways are required to keep the electricity distribution system stable. The provision of ancillary services (AS) by the DRES can contribute in this regard. However, it is necessary to communicate the need for AS from the third party providers such as distribution system operator (DSO) to the DRES in an efficient and scalable manner. To this end, a flexible information and communication technology (ICT) architecture is presented in this paper, and the requirements for the architecture are elaborated. We argue that this architecture is capable of supporting the present and future needs of electricity distribution networks. To illustrate its utility and effectiveness, an accounting use case for DSOs has been presented; it describes a remuneration scheme for the AS provision. A dashboard has been developed to enable communication via this architecture and to allow control of the grid. In addition, a distributed ledger technology for the realization of accounting has been analysed with respect to its scalability and performance capabilities.

Severe Acute Malnutrition (SAM) is a leading cause of childhood disease and death. Existing SAM data are sparse and depend on point prevalence measures that underestimate its true burden. Given the significance of SAM as an indicator of humanitarian progress and a driver of human development, a forecast of its long-term burden is needed. We use UNICEF prevalence data of severe wasting for 150 countries to measure SAM prevalence and build a model that we embed in International Futures. We estimate that, in 2014, there were 28.8 million SAM cases globally among children under age five and that this will decline to 21.7 million cases by 2030, with India accounting for 52% of this reduction, and growth (from 8.1 to 9.0 million cases) in Sub-Saharan Africa. Forecasts are sensitive to uncertainty around the drivers of SAM, particularly conflict. A 0.5 s d. variation in conflict relative to the Base Case forecast yields a range of 19.5–29.3 million cases globally in 2030. We also find that the drivers of SAM are forecast to decline more slowly than traditional drivers of undernutrition. SAM will therefore account for a growing share of children under five who are undernourished in the future. This growing share of SAM cases will be heavily concentrated in societies burdened by poor governance and conflict. The future of SAM is most sensitive to uncertainty associated with the future of internal conflict.

Implicit math = male stereotypes have been found in early childhood and are linked to girls’ disproportionate disengagement from math-related activities and later careers. Yet, little is known about how malleable children’s automatic stereotypes are, especially in response to brief interventions. In a sample of 336 six- to eleven-year-olds, we experimentally tested whether exposure to a brief story vignette intervention with either stereotypical, neutral, or counter-stereotypical content (three conditions: math = boy vs. neutral vs. math = girl) could change implicit math-gender stereotypes. Results suggested that children’s implicit math = male stereotypes were indeed responsive to brief stories that either reinforced or countered the widespread math = male stereotype. Children exposed to the counter-stereotypical stories showed significantly lower (and non-significant) stereotypes compared to children exposed to the stereotypical stories. Critically, exposure to stories that perpetuated math = male stereotypes significantly increased math-gender stereotypes over and above baseline, underscoring that implicit gender biases that are readily formed during this period in childhood and even brief exposure to stereotypical content can strengthen them. As a secondary question, we also examined whether changes in stereotypes might also lead to changes in implicit math self-concept. Evidence for effects on implicit self-concept were not statistically significant.

Enterococci are Gram-positive bacteria that can be isolated from a variety of environments including soil, water, plants, and the intestinal tract of humans and animals. Although they are considered commensals in humans, Enterococcus spp. are important opportunistic pathogens. Due to their presence and persistence in diverse environments, Enterococcus spp. are ideal for studying antimicrobial resistance (AMR) from the One Health perspective. We undertook a comparative genomic analysis of the virulome, resistome, mobilome, and the association between the resistome and mobilome of 246 E. faecium and 376 E. faecalis recovered from livestock (swine, beef cattle, poultry, dairy cattle), human clinical samples, municipal wastewater, and environmental sources. Comparative genomics of E. faecium and E. faecalis identified 31 and 34 different antimicrobial resistance genes (ARGs), with 62% and 68% of the isolates having plasmid-associated ARGs, respectively. Across the One Health continuum, tetracycline (tetL and tetM) and macrolide resistance (ermB) were commonly identified in E. faecium and E. faecalis. These ARGs were frequently associated with mobile genetic elements along with other ARGs conferring resistance against aminoglycosides [ant(6)-la, aph(3′)-IIIa], lincosamides [lnuG, lsaE], and streptogramins (sat4). Study of the core E. faecium genome identified two main clades, clade ‘A’ and ‘B’, with clade A isolates primarily originating from humans and municipal wastewater and carrying more virulence genes and ARGs related to category I antimicrobials. Overall, despite differences in antimicrobial usage across the continuum, tetracycline and macrolide resistance genes persisted in all sectors.

Introduction The impact of the COVID-19 pandemic (caused by the SARS-CoV-2 virus) on individuals with cancer has been profound. It has led to increased anxiety, distress and deconditioning due to reduced physical activity. We aim to investigate whether SafeFit, a multimodal intervention of physical activity, nutrition and psychological support delivered virtually by cancer exercise specialists (CES), can improve physical and emotional functionings during the COVID-19 pandemic.Methods and analysis A phase III non-randomised intervention trial, target recruitment of 1050 adults with suspected or confirmed diagnosis of cancer. All recruited participants will receive the multimodal intervention delivered by CES for 6 months. Sessions will be delivered 1-to-1 using telephone/video conferencing consultations. CES will work with each participant to devise a personalised programme of (1) physical activity, (2) basic dietary advice and (3) psychological support, all underpinned by behaviour change support.Primary outcome Physical and emotional functioning as measured by the European Organisation for Research and Treatment of Cancer-Quality of Life Questionnaire (EORTC-QLQ-C30). Secondary outcomes: overall quality of life measured by EORTC-QLQ-C30 and EQ-5D-5L, health economics, patient activation, self-efficacy to self-manage chronic disease, distress, impact of COVID-19 on emotional functioning, self-reported physical activity, functional capacity and nutrition. Adherence to the intervention will also be measured and a process evaluation conducted.Ethics and dissemination Ethical approval was obtained from the Health Research Authority (reference number 20/NW/0254). Results of this trial will be disseminated through publication of peer-reviewed articles, presentations at scientific conferences, and to the public and people with cancer in collaboration with our patient and public involvement representatives and partners.Trial registration number NCT04425616.

Despite the global importance of science, engineering, and math-related fields, women are consistently underrepresented in these areas. One source of this disparity is likely the prevalence of gender stereotypes that constrain girls’ and women’s math performance and interest. The current research explores the developmental roots of these effects by examining the impact of stereotypes on young girls’ intuitive number sense, a universal skill that predicts later math ability. Across four studies, 762 children ages 3–6 were presented with a task measuring their Approximate Number System accuracy. Instructions given before the task varied by condition. In the two control conditions, the task was described to children either as a game or a test of eyesight ability. In the experimental condition, the task was described as a test of math ability and that researchers were interested in whether boys or girls were better at math and counting. Separately, we measured children’s explicit beliefs about math and gender. Results conducted on the combined dataset indicated that while only a small number of girls in the sample had stereotypes associating math with boys, these girls performed significantly worse on a test of Approximate Number System accuracy when it was framed as a math test rather than a game or an eyesight test. These results provide novel evidence that for young girls who do endorse stereotypes about math and gender, contextual activation of these stereotypes may impair their intuitive number sense, potentially affecting their acquisition of formal mathematics concepts and developing interest in math-related fields.

Recent studies indicate that a preference for people from one's own race emerges early in development. Arguably, one potential process contributing to such a bias has to do with the increased discriminability of own- vs. other-race faces-a process commonly attributed to perceptual narrowing of unfamiliar groups' faces, and analogous to the conceptual homogenization of out-groups. The present studies addressed two implications of perceptual narrowing of other-race faces for infants' social categorization capacity. In Experiment 1, White 11-month-olds' (N = 81) looking time at a Black vs. White face was measured under three between-subjects conditions: a baseline "preference" (i.e., without familiarization), after familiarization to Black faces, or after familiarization to White faces. Compared to infants' a priori looking preferences as revealed in the baseline condition, only when familiarized to Black faces did infants look longer at the "not-familiarized-category" face at test. According to the standard categorization paradigm used, such longer looking time at the novel (i.e., "not-familiarized-category") exemplar at test, indicated that categorization of the familiarized faces had ensued. This is consistent with the idea that prior to their first birthday, infants already tend to represent own-race faces as individuals and other-race faces as a category. If this is the case, then infants might also be less likely to form subordinate categories within other-race than own-race categories. In Experiment 2, infants (N = 34) distinguished between an arbitrary (shirt-color) based sub-categories only when shirt-wearers were White, but not when they were Black. These findings confirm that perceptual narrowing of other-race faces blurs distinctions among members of unfamiliar categories. Consequently, infants: a) readily categorize other-race faces as being of the same kind, and b) find it hard to distinguish between their sub-categories.

The World Health Organization Global Action Plan recommends integrated surveillance programs as crucial strategies for monitoring antibiotic resistance. Although several national surveillance programs are in place for clinical and veterinary settings, no such schemes exist for monitoring antibiotic-resistant bacteria in the environment. In this transnational study, we developed, validated, and tested a low-cost surveillance and easy to implement approach to evaluate antibiotic resistance in wastewater treatment plants (WWTPs) by targeting cefotaxime-resistant (CTX-R) coliforms as indicators. The rationale for this approach was: i) coliform quantification methods are internationally accepted as indicators of fecal contamination in recreational waters and are therefore routinely applied in analytical labs; ii) CTX-R coliforms are clinically relevant, associated with extended-spectrum β-lactamases (ESBLs), and are rare in pristine environments. We analyzed 57 WWTPs in 22 countries across Europe, Asia, Africa, Australia, and North America. CTX-R coliforms were ubiquitous in raw sewage and their relative abundance varied significantly (

Human small intestinal crypts are the source of intestinal stem cells (ISCs) that are capable of undergoing self-renewal and differentiation to an epithelial layer. The development of methods to expand the ISCs has provided opportunities to model human intestinal epithelial disorders. Human crypt samples are usually obtained from either endoscopic or discarded surgical samples, and are thereby exposed to warm ischemia, which may impair their in vitro growth as three-dimensional culture as spheroids or enteroids. In this study we compared duodenal samples obtained from discarded surgical samples to those isolated from whole-body preserved cadaveric donors to generate in vitro cultures. We also examined the effect of storage solution (phosphate-buffered saline or University of Wisconsin [UW] solution) as well as multiple storage times on crypt isolation and growth in culture. We found that intestinal crypts were successfully isolated from cadaveric tissue stored for up to 144 h post-procurement and also were able to generate enteroids and spheroids in certain media conditions. Surgical samples stored in UW after procurement were sufficiently viable up to 24 h and also allowed the generation of enteroids and spheroids. We conclude that surgical samples stored for up to 24 h post-procurement in UW solution allowed for delayed crypt isolation and viable in vitro cultures. Furthermore, in situ, hypothermic preservation in cadaveric duodenal samples permitted crypt/ISC isolation, and successful culture of spheroids and enteroids from tissues held for up to 6 days post-procurement.

Ingestion of food- or waterborne antibiotic-resistant bacteria may lead to the dissemination of antibiotic-resistance genes in the gut microbiota and the development of antibiotic-resistant bacterial infection, a significant threat to animal and public health. Food or water may be contaminated with multiple resistant bacteria, but animal models on gene transfer were mainly based on single-strain infections. In this study, we investigated the mobility of β-lactam resistance following infection with single- versus multi-strain of resistant bacteria under ampicillin treatment. We characterized three bacterial strains isolated from food-animal production systems, Escherichia coli O80:H26 and Salmonella enterica serovars Bredeney and Heidelberg. Each strain carries at least one conjugative plasmid that encodes a β-lactamase. We orally infected mice with each or all three bacterial strain(s) in the presence or absence of ampicillin treatment. We assessed plasmid transfer from the three donor bacteria to an introduced E. coli CV601gfp recipient in the mouse gut, and evaluated the impacts of the bacterial infection on gut microbiota and gut health. In the absence of ampicillin treatment, none of the donor or recipient bacteria established in the normal gut microbiota and plasmid transfer was not detected. In contrast, the ampicillin treatment disrupted the gut microbiota and enabled S. Bredeney and Heidelberg to colonize and transfer their plasmids to the E. coli CV601gfp recipient. E. coli O80:H26 on its own failed to colonize the mouse gut. However, during co-infection with the two Salmonella strains, E. coli O80:H26 colonized and transferred its plasmid to the E. coli CV601gfp recipient and a residential E. coli O2:H6 strain. The co-infection significantly increased plasmid transfer frequency, enhanced Proteobacteria expansion and resulted in inflammation in the mouse gut. Our findings suggest that single-strain infection models for evaluating in vivo gene transfer may underrepresent the consequences of multi-strain infections following the consumption of heavily contaminated food or water.

As traditional education transitioned from face-to-face interactions to virtual learning during the COVID-19 pandemic, faculty and staff in dental hygiene, nursing, and exercise science programs placed students at the center of every educational decision and promoted stability in learning with their commitments to excellence in teaching and the delivery of content using educational and communication technology. This experiential narrative review explains how faculty members and administrators addressed online education with technology specific to health professions and how universities managed to assist students with innovative services for mental health. It also provides an insight into how degree-specific academic personnel embraced technology-based hands-on activities in community health clinics and clinical laboratories, with sustainable and impactful lessons in equity, affordability, and transformative education. Finally, health administrators gather their top-10 leadership recommendations to continue moving forward during the pandemic and present a unique self-reflection on the process of caring considerations required for a successful experience for faculty members, staff, and students.

We report on a 59-year-old female patient with an infected vascular graft investigated with 18F FDG-PET/CT. The first of two studies showed FDG activity in the left deltoid and ipsilateral axillary lymph nodes explained by influenza vaccination the day prior. The second 18F FDG-PET/CT showed multiple FDG-avid lymph nodes on both sides of the diaphragm without tracer accumulation at the vaccination site. Three months later the CT was negative for lymphadenopathy within the chest or abdominal region. Although influenza vaccination is a potential source of false positive results in FDG PET studies, generalised lymph node activation post vaccination is a rare finding with only one prior published report in individuals infected with HIV-1. This case emphasizes the necessity of taking a history of vaccination prior to a FDG PET study, and consideration of a vaccine-related immune response even without evidence of tracer activity at the vaccination site when generalised FDG-avid lymphadenopathy is encountered.

Enterohemorrhagic Escherichia coli (EHEC) has consistently been one of the foremost foodborne pathogen threats worldwide based on the past 30 years of surveillance. EHEC primarily colonizes the bovine gastrointestinal (GI) tract from which it can be transmitted to nearby farm environments and remain viable for months. There is an urgent need for effective and easily implemented pre-harvest interventions to curtail EHEC contamination of the food and water supply. In an effort to address this problem, we isolated single-domain antibodies (VHHs) specific for intimin, an EHEC adhesin required for colonization, and designed chimeric VHH fusions with secretory IgA functionality intended for passive immunotherapy at the mucosal GI surface. The antibodies were produced in leaves of Nicotiana benthamiana with production levels ranging between 1 and 3% of total soluble protein. in vivo assembly of all subunits into a hetero-multimeric complex was verified by co-immunoprecipitation. Analysis of multivalent protection across the most prevalent EHEC strains identified one candidate antibody, VHH10-IgA, that binds O145:Hnm, O111:Hnm, O26:H11, and O157:H7. Fluorometric and microscopic analysis also indicated that VHH10-IgA completely neutralizes the capacity of the latter three strains to adhere to epithelial cells in vitro. This study provides proof of concept that a plant-produced chimeric secretory IgA can confer cross-serotype inhibition of bacterial adhesion to epithelial cells.

Adult intestinal epithelial stem cells are a promising resource for treatment of intestinal epithelial disorders that cause intestinal failure and for intestinal tissue engineering. We developed two different animal models to study the implantation of cultured murine and human intestinal epithelial cells in the less differentiated "spheroid" state and the more differentiated "enteroid" state into the denuded small intestine of mice. Engraftment of donor cells could not be achieved while the recipient intestine remained in continuity. However, we were able to demonstrate successful implantation of murine and human epithelial cells when the graft segment was in a bypassed loop of jejunum. Implantation of donor cells occurred in a random fashion in villus and crypt areas. Engraftment was observed in 75% of recipients for murine and 36% of recipients for human cells. Engrafted spheroid cells differentiated into the full complement of intestinal epithelial cells. These findings demonstrate for the first time successful engraftment into the small bowel which is optimized in a bypassed loop surgical model.

The Late Jurassic–Early Cretaceous Slottsmøya Member of the Agardhfjellet Formation in central Spitsbergen has yielded two new species of asteroids and two species of ophiuroids, one of which is described as new. Polarasterias janusensis Rousseau & Gale gen. et sp. nov. is a forcipulatid neoasteroid with elongated arms, small disc and very broad ambulacral grooves with narrow adambulacrals. Savignaster septemtrionalis Rousseau & Gale sp. nov. is a pterasterid with well-developed interradial chevrons. The Spitsbergen specimens are the first described articulated material of Savignaster and reveal the overall arrangement of the ambulacral groove ossicles. Ophiogaleus sp. is an ophiacanthid with relatively long jaws and lateral arm plates, with a coarsely reticulate outer surface. Here again, we report the first articulated skeletons of this genus, providing unprecedented insights into the disc morphology. Ophioculina hoybergia Rousseau & Thuy gen. et sp. nov. is an ophiopyrgid with a well-developed arm comb and tentacle pores reduced to within-plate perforations starting at median arm segments. These new finds are important additions to the asterozoan fossil record with regard to their good degree of articulation and the high latitudinal position of the localities. They significantly add to the set of exhaustively known fossil asterozoan taxa which play a key role in the phylogenetic analysis and reconstruction of evolutionary history.

With the literature calling for comparisons among technology-enhanced or active-learning pedagogies, a blended versus flipped instructional comparison was made for numerical methods coursework using three engineering schools with diverse student demographics. This study contributes to needed comparisons of enhanced instructional approaches in STEM and presents a rigorous and adaptable methodology for doing so. Our flipped classroom consisted mostly of in-class active learning, with micro-lectures as needed, and technology used both in and out of class, including for expected pre-class review of new content. Our blended classroom consisted mostly of lecture with some in-class active learning, and technology utilized both in and out of class. However, students were not expected to review new content before class. We compared blended vs. flipped instruction based upon multiple-choice and free-response questions on the final exam as well as the perceived classroom environment. This was done for students as a whole as well as for under-represented minorities (URMs), females, community college transfers, and Pell Grant recipients. Students provided feedback via focus groups and surveys. Upon combining data from the schools, the blended instruction was associated with slightly greater achievement on the multiple-choice questions across various demographics, but the differences were not statistically significant, and the effects were small. Our free-response final exam and classroom environment data aligned, with blended instruction showing more promise at two schools. The students identified demanding expectations with flipped instruction but pointed to benefits, such as enhanced learning or learning processes, preparation, and engagement. These results aligned with our focus group and instructor interview data. Thus, in general, it may be possible to use either instructional approach with the expectation of similar outcomes in final exam scores or the perceived classroom environment, keeping in mind the students qualitatively identified benefits with flipped instruction. Nonetheless, there were some large differences for the schools individually, suggesting further research with different demographics.

Spring-mediated distraction enterogenesis has been studied as a novel treatment for short bowel syndrome (SBS). Previous approaches are limited by multiple surgeries to restore intestinal continuity. Purely endoluminal devices require a period of intestinal attachment for enterogenesis. The purpose of this study is to modify the device to prevent premature spring migration in a porcine model. Two models were created in juvenile mini-Yucatan pigs for the placement of three-dimensionally printed springs. (1) Two Roux-en-y jejunojenostomies with two Roux limbs were made. A spring with bidirectional hooked surface features was placed in one Roux limb and a spring with smooth surface was placed in the other Roux limb. (2) The in-continuity model had both hooked and smooth surface springs placed directly in intestinal continuity. Spring location was evaluated by weekly radiographs, and the intestine was retrieved after 2 to 4 weeks. Springs with smooth surfaces migrated between 1 to 3 weeks after placement in both porcine models. Springs with bidirectional hooked surface features were anchored to the intestine for up to 4 weeks without migration. Histologically, the jejunal architecture showed significantly increased crypt depth and muscularis thickness compared to normal jejunum. Bidirectional features printed on springs prevented the premature migration of endoluminal springs. These novel spring anchors allowed for their endoluminal placement without any sutures. This approach may lead to the endoscopic placement of the device for patients with SBS.

Background and objective: The epidemiology of the forty percent of tuberculosis patients who present with disseminated and/or extrapulmonary disease is in need of further study. Further study of such dissemination using published data from international indices may provide data which assist with control of tuberculosis. Methods: For each clinical or epidemiologic factor studied, summary odds ratios and corresponding 95% confidence intervals were calculated showing associations between such factors and documented extrapulmonary dissemination of tuberculosis. Results: Eighteen studies fulfilled criteria for study of the clinical factors and nine for the cytokine studies. Significant factors associated with a greater risk of extrapulmonary dissemination were female gender (summary odds ratio, 1.92 (95% confidence intervals, 1.72–2.13), I-squared 86.9), age under 45 (1.37, 1.18–1.60, 63.7), and as well the absence of smoking, drinking and diabetes but not HIV infection (1.10, 0.91–1.32, 80.5). Among cytokines, the macrophage receptor protein P2X7 was associated most strongly associated with extrapulmonary dissemination of tuberculosis (2.28, 0.88–5.90, 92.9). Conclusion: Young age, female gender, and the macrophage purinergic receptor protein P2X7 were major factors associated with extrapulmonary dissemination of tuberculosis.