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Abstract Objective This study identified biomarkers of neurological outcome in Sturge‐Weber syndrome (SWS) via urine angiogenic factors and captured longitudinally derived natural history data within an SWS cohort. Methods This longitudinal, prospective, multicentered study of 61 people with SWS aged 0.4–55 years reports port‐wine birthmark score, Neuroscore, Neuro‐Quality of Life, and urine angiogenic factors over a two‐year period. Results Cognitive Neuroscore worsened over time for children aged 0–2 years. Male sex was associated with worsening Cognitive Function Neuroscore during the study. Age of seizure onset before 2 years was strongly associated with worse Neuroscore. Children with SWS had low Neuro‐Quality of Life related to cognitive function. Seizure severity, male sex, and earlier age of seizure onset were associated with worse Neuro‐Quality of Life in school‐aged children. Children with SWS have elevated basic fibroblast growth factor in their urine compared with controls, whereas higher vascular endothelial growth factor was associated with better Neuroscore. Interpretation This study is the first multicenter, prospective, and longitudinal study of people with SWS. It identifies significant clinical prognostic factors such as age of seizure onset and male sex, informs symptom progression over time by age group, and suggests that further study of angiogenic mechanisms and potential biomarkers are needed.

Climate change has emerged across many regions. Some observed regional climate changes, such as amplified Arctic warming and land-sea warming contrasts have been predicted by climate models. However, many other observed regional changes, such as changes in tropical sea surface temperature and monsoon rainfall are not well simulated by climate model ensembles even when taking into account natural internal variability and structural uncertainties in the response of models to anthropogenic radiative forcing. This suggests climate model predictions may not fully reflect what our future will look like. The discrepancies between models and observations are not well understood due to several real and apparent puzzles and limitations such as the “signal-to-noise paradox” and real-world record-shattering extremes falling outside of the possible range predicted by models. Addressing these discrepancies, puzzles and limitations is essential, because understanding and reliably predicting regional climate change is necessary in order to communicate effectively about the underlying drivers of change, provide reliable information to stakeholders, enable societies to adapt, and increase resilience and reduce vulnerability. The challenges of achieving this are greater in the Global South, especially because of the lack of observational data over long time periods and a lack of scientific focus on Global South climate change. To address discrepancies between observations and models, it is important to prioritize resources for understanding regional climate predictions and analyzing where and why models and observations disagree via testing hypotheses of drivers of biases using observations and models. Gaps in understanding can be discovered and filled by exploiting new tools, such as artificial intelligence/machine learning, high-resolution models, new modeling experiments in the model hierarchy, better quantification of forcing, and new observations. Conscious efforts are needed toward creating opportunities that allow regional experts, particularly those from the Global South, to take the lead in regional climate research. This includes co-learning in technical aspects of analyzing simulations and in the physics and dynamics of regional climate change. Finally, improved methods of regional climate communication are needed, which account for the underlying uncertainties, in order to provide reliable and actionable information to stakeholders and the media.

Abstract Real‐world data derived from electronic health records often exhibit high levels of missingness in variables, such as laboratory results, presenting a challenge for statistical analyses. We developed a systematic workflow for gathering evidence of different missingness mechanisms and performing subsequent statistical analyses. We quantify evidence for missing completely at random (MCAR) or missing at random (MAR), mechanisms using Hotelling's multivariate t‐test, and random forest classifiers, respectively. We further illustrate how to apply sensitivity analyses using the not at random fully conditional specification procedure to examine changes in parameter estimates under missing not at random (MNAR) mechanisms. In simulation studies, we validated these diagnostics and compared analytic bias under different mechanisms. To demonstrate the application of this workflow, we applied it to two exemplary case studies with an advanced non‐small cell lung cancer and a multiple myeloma cohort derived from a real‐world oncology database. Here, we found strong evidence against MCAR, and some evidence of MAR, implying that imputation approaches that attempt to predict missing values by fitting a model to observed data may be suitable for use. Sensitivity analyses did not suggest meaningful departures of our analytic results under potential MNAR mechanisms; these results were also in line with results reported in clinical trials.

Paroxysmal sympathetic hyperactivity (PSH) syndrome is a potentially life-threatening complication after traumatic brain injuries that results from a massive release of catecholamines in the brain. Fat embolism syndrome (FES) is a complication of long bone fractures that results in cerebral or pulmonary fat emboli. We describe PSH in the setting of cerebral FES in an adolescent female following polytrauma secondary to a motor vehicle collision to highlight the importance of rapid diagnosis and treatment of this rare complication.

Background: Traumatic rib fractures are associated with increased morbidity and mortality, with complications including pneumothorax, difficult to control pain, and pneumonia. Use of a bundled, multi-disciplinary approach to the care of patients with multiple rib fractures has been shown to reduce morbidity and mortality. In this study, we investigate the implementation of a checklist for the multidisciplinary management of patients with multiple rib fractures who present to an urban, level 1 trauma center and safety-net hospital. Study design: This was a single-institution, retrospective cohort study to assess changes in treatment characteristics and patient outcomes before and after implementation of a comprehensive checklist for the management of high-risk patients with three or more traumatic rib fractures at a level-one trauma center. The primary outcome was pneumonia rates with secondary outcomes of mechanical ventilation rates and mechanical ventilation days, ICU length of stay, mortality, and non-opioid and opioid consumption (morphine milligram equivalents). Results: A total of 104 patients met study eligibility, including 51 patients who presented during the pre-protocol period and 53 patients who received care after implementation. We observed that the checklist was utilized and reviewed in 83% of patients during the post-protocol period. Pneumonia rates were significantly lower in the post-protocol group (35.3% vs 15.1%, p = 0.017). There was no difference in the number of patients who required mechanical ventilation or the duration of mechanical ventilation. On unadjusted analysis, median overall length of stay (11.5 days vs 13 days, p = 0.71), median ICU stay (4 days vs 5 days, p = 0.18), and rate of in-hospital mortality (11.8% vs 7.6%, p = 0.47) was not different between the two time periods. Conclusion: In patients with chest wall trauma and associated rib fractures, implementation of a standardized, multidisciplinary checklist to ensure utilization of multimodal analgesia and non-pharmacological interventions was associated with decreased pneumonia rates at our institution.

Abstract Cardiovascular magnetic resonance (CMR) has been utilized in the management and care of pediatric patients for nearly 40 years. It has evolved to become an invaluable tool in the assessment of the littlest of hearts for diagnosis, pre-interventional management and follow-up care. Although mentioned in a number of consensus and guidelines documents, an up-to-date, large, stand-alone guidance work for the use of CMR in pediatric congenital 36 and acquired 35 heart disease endorsed by numerous Societies involved in the care of these children is lacking. This guidelines document outlines the use of CMR in this patient population for a significant number of heart lesions in this age group and although admittedly, is not an exhaustive treatment, it does deal with an expansive list of many common clinical issues encountered in daily practice.

New Zealand is a remote country in the South Pacific Ocean. The isolation and relatively late arrival of humans into New Zealand has meant there is a recorded history of the introduction of domestic species. Honey bees (Apis mellifera) were introduced to New Zealand in 1839, and the disease American foulbrood was subsequently found in the 1870s. Paenibacillus larvae, the causative agent of American foulbrood, has been genome sequenced in other countries. We sequenced the genomes of P. larvae obtained from 164 New Zealand apiaries where American foulbrood was identified in symptomatic hives during visual inspection. Multi-locus sequencing typing (MLST) revealed the dominant sequence type to be ST18, with this clonal cluster accounting for 90.2% of isolates. Only two other sequence types (with variants) were identified, ST5 and ST23. ST23 was only observed in the Otago area, whereas ST5 was limited to two geographically non-contiguous areas. The sequence types are all from the enterobacterial repetitive intergenic consensus I (ERIC I) genogroup. The ST18 and ST5 from New Zealand and international P. larvae all clustered by sequence type. Based on core genome MLST and SNP analysis, localized regional clusters were observed within New Zealand, but some closely related genomes were also geographically dispersed, presumably due to hive movements by beekeepers.

Abstract Cholera toxin (CT) and Escherichia coli heat-labile enterotoxin (LT) are structurally similar AB5-type protein toxins. They move from the cell surface to the endoplasmic reticulum where the A1 catalytic subunit is separated from its holotoxin by protein disulfide isomerase (PDI), thus allowing the dissociated A1 subunit to enter the cytosol for a toxic effect. Despite similar mechanisms of toxicity, CT is more potent than LT. The difference has been attributed to a more stable domain assembly for CT as compared to LT, but this explanation has not been directly tested and is arguable as toxin disassembly is an indispensable step in the cellular action of these toxins. We show here that PDI disassembles CT more efficiently than LT, which provides a possible explanation for the greater potency of the former toxin. Furthermore, direct examination of CT and LT domain assemblies found no difference in toxin stability. Using novel analytic geometry approaches, we provide a detailed characterization of the positioning of the A subunit with respect to the B pentamer and demonstrate significant differences in the interdomain architecture of CT and LT. Protein docking analysis further suggests that these global structural differences result in distinct modes of PDI-toxin interactions. Our results highlight previously overlooked structural differences between CT and LT that provide a new model for the PDI-assisted disassembly and differential potency of these toxins.

Abstract Background Higher education is responsible for providing education that meets international benchmarks relevant to the needs of the international community. Due to the increase of digital tools in higher education, the possibility of sharing learning resources across nations has expanded. In the current project, a Norwegian university invited universities in Spain and the United Kingdom to adapt and translate e-learning resources originally developed for Norwegian nursing students for use within their respective Bachelor in Nursing programmes. Aim The aim of the current study was to gain insights into the usability and value for learning of e-compendiums shared and implemented across three European universities. Methods The study adopted a descriptive cross-sectional design and included nursing students from the University of Nottingham, Valencia Catholic University, and the University of Stavanger. Data were collected in Autumn 2017 through a questionnaire adapted from the validated “Centre for Excellence in Teaching and Learning Reusable Learning Object evaluation questionnaire” The questionnaire consisted of 19 items that included two aspects: e-compendiums’ value for learning and e-compendiums’ usability. The different study sites were compared using a binary logistic regression analysis. Subgroups of students were compared based on their gender and age. Results A total of 480 nursing students participated in the study. The e -compendiums were overall positively rated, especially for reinforcing and retaining knowledge. Compared to the students from the University of Stavanger, students from Valencia Catholic University rated the e-compendiums more positively in most aspects of learning. Students from University of Nottingham found the e-compendiums to be more important for learning engagement compared to students at the Norwegian study site, and no differences were found in any other aspects of learning. Younger students rated the interactivity and visual components as more important compared to older students. Conclusions Students from the University of Nottingham and Valencia Catholic University seem to accept the e-compendiums despite the fact that they were originally developed for use in another country. We argue that, when sharing e-learning resources across countries, an adaptation and translation process that includes a multicultural and multidisciplinary perspective should be carried out.

Regional patterns of fish diversity, abundance, distribution, and assemblage composition are driven by a combination of biotic and abiotic conditions in the marine environment, but these conditions can be altered through anthropogenic activities, such as those associated with oil and gas extraction. The present study utilises data on fish relative abundance and diversity obtained from 1546 baited remote underwater video deployments conducted between 2004 – 2019 in depths of 9 – 170 m across 2000 km of coastline in north-west Australia on natural habitats and subsea pipelines to understand the influence of oil and gas infrastructure on fish assemblages. A total of 450 fish taxa from 56 families was observed, with populations dominated by generalist and invertebrate carnivore taxa. At the regional scale, subsea pipelines had lower diversity (lower taxonomic richness) than natural environments, but possessed a higher abundance of piscivorous and herbivorous fish taxa. Clear patterns in fish assemblage composition were observed in multivariate analyses, reflecting the proximity of oceanic shoals and banks, depth, and to a lesser extent, oil and gas infrastructure. Shallow-water and close to shoals assemblages were characterised by a diversity of site-attached (e.g., wrasses, tuskfish), reef-associated taxa (e.g., emperors). Mesophotic fish assemblages were characterised by commercially important (e.g., goldband snapper), wide-ranging (e.g., sharks) and sand-affiliated (e.g., toadfish, threadfin bream) taxa. Proximity to pipelines and platforms ranked low as predictors in the multivariate analyses suggesting a negligible regional influence of these structures on fish communities in comparison to depth and shoal habitats. Local-scale influences of subsea infrastructure, however, may be important for some fish species (infrastructure vs. immediate surrounds). Our study highlights the influence of abiotic factors on regional-scale patterns in fish assemblage structure across north-west Australia.

Purpose – The purpose of this paper is to provide an experiential learning exercise that develops student understanding of social networks within organizations. Understanding these networks can foster complete access to information and inclusive decision-making that translates into career success. Design/methodology/approach – This experiential learning classroom exercise supports all student learning styles using a puzzle to teach students to apply social network theory toward real-world decision-making. This exercise is best used in small and medium-sized classrooms with ideally 15–40 students. This simulation could be used during 50 up through 120-min class sessions. Findings – The game-like environment created by this exercise helps extend real-world understanding that may traditionally be lost with a lecture. Components within this simulation provide balanced consideration for many different learning styles. This exercise has been used successfully within a graduate-level leadership and decision-making course in at least ten sessions over 5 years. Practical implications – This is a real-time theory to practice application exercise where an experiential activity is deployed for students to understand the practical implications and application of a theoretical concept. Social implications – Organizations have internal social networks connecting employees. These connections are how information is dispersed and knowledge is shared. When these networks are understood and effectively used, it can result in more comprehensive problem-solving, valuable collaboration and the maximization of subject matter expertise within the organization. Originality/value – This is a “how-to” teaching and pedagogical exercise. It is original with the benefit of its flexibility and adaptability in the classroom.

Objective: Endovascular chemical angioplasty has been in practice in patients with symptomatic cerebral vasospasm secondary to aneurysmal subarachnoid haemorrhage in many neurosurgical centres. However, the evidence base is derived from clinical case series and expert consensus. The aim of this retrospective cohort study is to evaluate the immediate and functional outcomes of endovascular intervention in aneurysmal subarachnoid haemorrhage cerebral vasospasm treated with a combination of vasodilators. Methods: A cohort of 25 patients was identified. Each patient underwent surgical clipping, and endovascular treatment for vasospasm. A combination of Verapamil and Nimodipine was intra-arterially administered. Statistical analysis was performed to determine the rate of response. The angiographic response and functional outcome on discharge (modified Rankin score - MRS) were used as markers of outcome. Results: The study cohort consisted of 25 patients with a mean age of 50.3 (SD 11.2). A total of 135 therapeutic DSA’s were performed. There was an associated between MRS outcomes and number of vasodilation’s each patient received. For each additional vasodilation episode, the odds of a poor outcome increased by 1.190. An angiographic response was demonstrated in 88% of patients, a clinical response in 27%. A good functional outcome was achieved in 17/25, 71% at discharge. Conclusion: The combination therapy of Intra-arterial nimodipine and verapamil in patients with aneurysmal subarachnoid haemorrhage vasospasm appears to have a synergistic, if not comparable, outcome to from solitary vasodilatory treatment results and potentially promote future studies with prospective designs to measure the outcomes.

Abstract Purpose The European Society for Sports Traumatology, Knee Surgery and Arthroscopy (ESSKA) identified the need to develop a competency-based core curriculum for ESSKA specialists, against which all their educational activities, resources and priorities for development could be mapped. The aim of this study was to take a research-based approach to developing a competency-based core curriculum for ESSKA specialists. Methods A Core Curriculum Working Group, with experts representing the ESSKA Board, Sections and Committees, reviewed existing curricula and literature in their own specialist areas and developed a draft list of 285 core competencies for ESSKA specialists. All ESSKA members were asked to comment and rate the importance of these competencies, and the Working Group used these results to refine the curriculum. Results Four hundred-forty responses to the online survey contained meaningful data. Almost all were ESSKA members, with broad representation of the countries, ages and backgrounds of the membership. All 285 core competencies were considered at least ‘Important’ for ESSKA specialists so are retained in the final curriculum, and no new competencies were added. 82 (29%) were considered ‘Essential’, constituting between 19% and 37% of the competencies within each specialist area. 96 (33.5%) were considered ‘Very Important’, and 107 (37.5%) ‘Important’. Conclusions A competency-based core curriculum for ESSKA specialists was achieved through a systematic and scholarly approach, involving both expert opinion and engagement of the wider ESSKA membership. The core curriculum addresses the identified need in terms of educational development for ESSKA and should also be of interest to the wider orthopaedic and sports medicine communities.

Previous reports of paraneoplastic encephalitis occurring in primary fallopian tube carcinoma have been exclusively classified as paraneoplastic cerebellar degeneration, with MR imaging either unremarkable or demonstrating cerebellar atrophy. We report a case of paraneoplastic encephalitis in a 64-year-old female with primary fallopian tube carcinoma, reminiscent of N-methyl d-aspartate receptor encephalitis, with MR imaging demonstrating bilateral subcortical and deep white matter T2-FLAIR hyperintensities sparing cerebellar and brainstem structures. To our knowledge, this represents the first reported case of noncerebellar paraneoplastic encephalitis related to primary fallopian tube carcinoma.

From its earliest inception, FOLIO was conceived not as an ILS (Integrated Library System), but as a true Services Platform, composed of many independent but interdependent modules, and forming a foundation on which an ILS or other library software could be built out of relevant modules. This vision of modularity is crucial to FOLIO’s appeal to the library community, because it lowers the bar to participation: individual libraries may create modules that meet their needs, or hire developers to do so, or contribute to funding modules that will be of use to a broader community — all without needing “permission” from a central authority. The technical design of FOLIO is deeply influenced by the requirements of modularity, with the establishment of standard specifications and an emphasis on machine-readable API descriptions. While FOLIO’s modular design has proved advantageous, it also introduces difficulties, including cross-module searching and data consistency. Some conventions have been established to address these difficulties, and others are in the process of crystallizing. As the ILS built on FOLIO’s platform grows and matures, and as other application suites are built on it, it remains crucial to resist the shortcuts that monolithic systems can benefit from, and retain the vision of modularity that has so successfully brought FOLIO this far.

Nuclear power plants collect and store large volumes of heterogeneous data from various components and systems. With recent advances in machine learning (ML) techniques, these data can be leveraged to develop diagnostic and short-term forecasting models to better predict future equipment condition. Maintenance operations can then be planned in advance whenever degraded performance is predicted, thus resulting in fewer unplanned outages and the optimization of maintenance activities. This enables lower maintenance costs and improves the overall economics of nuclear power. This paper focuses on developing a short-term forecasting process that leverages a feature selection process to distill large volumes of heterogeneous data and predict specific equipment parameters. A variety of feature selection methods, including Shapley Additive Explanations (SHAP) and variance inflation factor (VIF), were used to select the optimal features as inputs for three ML methods: long short-term memory (LSTM) networks, support vector regression (SVR), and random forest (RF). Each combination of model and input features was used to predict a pump bearing temperature both 1 and 24 hours in advance, based on actual plant system data. The optimal inputs for the LSTM and SVR were selected using the SHAP values, while the optimal input for the RF consisted solely of the response variable itself. Each model produced similar 1-hour-ahead predictions, with root mean square errors (RMSEs) of roughly 0.006. For the 24-hour-ahead predictions, differences could be seen between LSTM, SVR, and RF, as reflected by model performances of 0.036 +- 0.014, 0.0026 +- 0, and 0.063 +- 0.004 RMSE, respectively. As big data and continuous online monitoring become more widely available, the proposed feature selection process can be used for many applications beyond the prediction of process parameters within nuclear infrastructure.

BackgroundEffective knowledge transfer of eLearning objects can hasten the adoption and dissemination of technology in teaching and learning. However, challenges exist which hinder inter-organisational knowledge transfer, particularly across continents. The ACoRD project aimed to transfer knowledge on digital learning development from UK/EU (provider) to Malaysian (receiver) higher education institutions (HEIs). This study explores the challenges encountered during the knowledge transfer process and lessons learned.MethodsThis is a qualitative study involving both the knowledge providers and receivers in focus group discussions (n = 25). Four focus group discussions were conducted in the early (n = 2) and mid-phase (n = 2) of the project by trained qualitative researchers using a topic guide designed to explore experiences and activities representing knowledge transfer in multi-institutional and multi-cultural settings. The interviews were audio-recorded, transcribed verbatim, and checked. The transcripts were analysed using thematic analysis.ResultsFive main themes emerged from this qualitative study: mismatched expectations between providers and receivers; acquiring new knowledge beyond the professional "comfort zone"; challenges in cascading newly acquired knowledge to colleagues and management; individual and organisational cultural differences; and disruption of knowledge transfer during the COVID-19 pandemic.ConclusionThis study highlights the need to create a conducive platform to facilitate continuous, timely and bi-directional needs assessment and feedback; this should be done in the early phase of the knowledge transfer process. The challenges and strategies identified in this study could guide more effective knowledge transfer between organisations and countries.

BackgroundEngaging students in the e-learning development process enhances the effective implementation of e-learning, however, students' priority on the topics for e-learning may differ from that of the educators. This study aims to compare the differences between the students and their educators in prioritising the topics in three healthcare curricula for reusable e-learning object (RLO) development.MethodA modified Delphi study was conducted among students and educators from University Malaya (UM), Universiti Putra Malaysia (UPM) and Taylor's University (TU) on three undergraduate programmes. In Round 1, participants were asked to select the topics from the respective syllabi to be developed into RLOs. Priority ranking was determined by using frequencies and proportions. The first quartile of the prioritised topics was included in Round 2 survey, which the participants were asked to rate the level of priority of each topic using a 5-point Likert scale. The mean score of the topics was compared between students and educators.ResultA total of 43 educators and 377 students participated in this study. For UM and TU Pharmacy, there was a mismatch in the prioritised topics between the students and educators. For UPM, both the educators and students have prioritised the same topics in both rounds. To harmonise the prioritisation of topics between students and educators for UM and TU Pharmacy, the topics with a higher mean score by both the students and educators were prioritised.ConclusionThe mismatch in prioritised topics between students and educators uncovered factors that might influence the prioritisation process. This study highlighted the importance of conducting needs assessment at the beginning of eLearning resources development.

Background and purpose: Accurate quantification of the relatively small radiation doses delivered to untargeted regions during breast irradiation in patients with breast cancer is of increasing clinical interest for the purpose of estimating long-term radiation-related risks. Out-of-field dose calculations from commercial planning systems however may be inaccurate which can impact estimates for long-term risks associated with treatment. This work compares calculated and measured dose out-of-field and explores the application of a correction for leakage radiation. Materials and methods: Dose calculations of a Boltzmann transport equation solver, pencil beam-type, and superposition-type algorithms from a commercial treatment planning system (TPS) were compared with in vivo thermoluminescent dosimetry (TLD) measurements conducted out-of-field on the contralateral chest at points corresponding to the thyroid, axilla and contralateral breast of eleven patients undergoing tangential beam radiotherapy for breast cancer. Results: Overall, the TPS was found to under-estimate doses at points distal to the radiation field edge with a modern linear Boltzmann transport equation solver providing the best estimates. Application of an additive correction for leakage (0.04% of central axis dose) improved correlation between the measured and calculated doses at points greater than 15 cm from the field edge. Conclusions: Application of a correction for leakage doses within peripheral regions is feasible and could improve accuracy of TPS in estimating out-of-field doses in breast radiotherapy. Keywords: Breast radiotherapy, TLD, Leakage dose, Dose calculation algorithm

Stem cells exert their beneficial effects through secretion of regenerative factors. Here, the authors take the membranes and secreted factors from cardiac stem cells and generate a synthetic cell-mimicking microparticle, which, on injection in a mouse model of myocardial infarction, improves cardiac function.

The exceptional physical and chemical properties of nickel nanomaterials have been exploited in a range of applications such as electrical conductors, batteries, and biomaterials. However, it has been suggested that these unique properties may allow for increased bioavailability, bio-reactivity, and potential adverse health effects. Thus, the purpose of this review was to critically evaluate data regarding the toxicity of oxidic nickel nanoparticles (nickel oxide (NiO) and nickel hydroxide (Ni(OH)2) nanoparticles) with respect to: (1) physico-chemistry properties; (2) nanomaterial characterization in the defined delivery media; (3) appropriateness of model system and translation to potential human effects; (4) biodistribution, retention, and clearance; (5) routes and relevance of exposure; and (6) current research data gaps and likely directions of future research. Inhalation studies were prioritized for review as this represents a potential exposure route in humans. Oxidic nickel particle size ranged from 5 to 100 nm in the 60 studies that were identified. Inflammatory responses induced by exposure of oxidic nickel nanoparticles via inhalation in rodent studies was characterized as acute in nature and only displayed chronic effects after relatively large (high concentration and long duration) exposures. Furthermore, there is no evidence, thus far, to suggest that the effects induced by oxidic nickel nanoparticles are related to preneoplastic events. There are some data to suggest that nano- and micron-sized NiO particles follow a similar dose response when normalized to surface area. However, future experiments need to be conducted to better characterize the exposure–dose–response relationship according to specific surface area and reactivity as a dose metric, which drives particle dissolution and potential biological responses.

Stem cells and biomaterials have been studied for therapeutic cardiac repair. Previous studies have shown the beneficial effects of platelet fibrin gel and cardiac stem cells when cotransplanted into rodent hearts with myocardial infarction (MI). We hypothesized that matrix metalloproteinases (MMPs) play an important role in such protection. Thus, the present study is designed to elucidate the effects of MMP inhibition on the therapeutic benefits of intramyocardial injection of platelet fibrin gel spiked with cardiac stem cells (cell‐gel) in a rat model of acute MI. In vitro, broad‐spectrum MMP inhibitor GM6001 undermines cell spreading and cardiomyocyte contraction. In a syngeneic rat model of myocardial infarction, MMP inhibition blunted the recruitment of endogenous cardiovascular cells into the injected biomaterials, therefore hindering de novo angiogenesis and cardiomyogenesis. Echocardiography and histology 3 weeks after treatment revealed that metalloproteinase inhibition diminished the functional and structural benefits of cell‐gel in treating MI. Reduction of host angiogenesis, cardiomyocyte cycling, and MMP‐2 activities was evident in animals treated with GM6001. Our findings suggest that MMPs play a critical role in the therapeutic benefits of platelet fibrin gel spiked with cardiac stem cells for treating MI. Significance In this study, the effects of matrix metalloproteinase inhibition on the performance of platelet gel spiked with cardiac stem cells (cell‐gel) for heart regeneration are explored. The results demonstrate that matrix metalloproteinases are required for cell‐gel to exert its benefits in cardiac repair. Inhibition of matrix metalloproteinases reduces cell engraftment, host angiogenesis, and recruitment of endogenous cardiovascular cells in rats with heart attack.

Saipan is a United States (US) territory Western Pacific island where little recent data exists regarding epidemiology, clinical presentation, and standard of care for pediatric seizures. This paper characterizes these features in Saipan’s pediatric population with comparisons to mainland US. This is a retrospective chart review of all pediatric patients with a history of seizures at the island’s only hospital and major private neurology clinic over a 10-year period. Variables regarding demographics, presentation, diagnosis, and treatment were collected. A total of 144 patients were included, with 101 patients diagnosed with febrile seizures and 31 patients diagnosed with non-febrile seizures. Age at first presentation peaked at 1 year old overall. The most common identified etiology of epilepsy was found to be hypoxic injury (39%), hemorrhagic injury (10%), cerebral malformation (6%), and brain mass (6%). Simple versus complex classification of febrile seizures, etiologies, and first-line treatment for non-febrile seizures were comparable to the mainland US. Electroencephalogram (EEG) was not used consistently in diagnosis. The findings from this study demonstrate that clinical presentations of pediatric seizures in Saipan are comparable to those in the mainland US.

Cholera toxin (CT) consists of a catalytic A1 subunit, an A2 linker, and a homopentameric cell-binding B subunit. The intact holotoxin moves by vesicle carriers from the cell surface to the endoplasmic reticulum (ER) where CTA1 is released from the rest of the toxin. The dissociated CTA1 subunit then shifts to an unfolded conformation, which triggers its export to the cytosol by a process involving the quality control system of ER-associated degradation (ERAD). We hypothesized that the unfolding of dissociated CTA1 would prevent its non-productive reassociation with CTA2/CTB5. To test this prediction, we monitored the real-time reassociation of CTA1 with CTA2/CTB5 by surface plasmon resonance. Folded but not disordered CTA1 could interact with CTA2/CTB5 to form a stable, functional holotoxin. Our data, thus, identified another role for the intrinsic instability of the isolated CTA1 polypeptide in host-toxin interactions: in addition to activating the ERAD translocation mechanism, the spontaneous unfolding of free CTA1 at 37 °C prevents the non-productive reassembly of a CT holotoxin in the ER.

Protein disulfide isomerase (PDI) is mainly located in the endoplasmic reticulum (ER) but is also secreted into the bloodstream where its oxidoreductase activity is involved with thrombus formation. Quercetin-3-rutinoside (Q3R) blocks this activity, but its inhibitory mechanism against PDI is not fully understood. Here, we examined the potential inhibitory effect of Q3R on another process that requires PDI: disassembly of the multimeric cholera toxin (CT). In the ER, PDI physically displaces the reduced CTA1 subunit from its non-covalent assembly in the CT holotoxin. This is followed by CTA1 dislocation from the ER to the cytosol where the toxin interacts with its G protein target for a cytopathic effect. Q3R blocked the conformational change in PDI that accompanies its binding to CTA1, which, in turn, prevented PDI from displacing CTA1 from its holotoxin and generated a toxin-resistant phenotype. Other steps of the CT intoxication process were not affected by Q3R, including PDI binding to CTA1 and CT reduction by PDI. Additional experiments with the B chain of ricin toxin found that Q3R could also disrupt PDI function through the loss of substrate binding. Q3R can thus inhibit PDI function through distinct mechanisms in a substrate-dependent manner.

Decision makers need accessible robust evidence to introduce new policies to mitigate and adapt to climate change. There is an increasing amount of environmental information available to policy makers concerning observations and trends relating to the climate. However, this data is hosted across a multitude of websites often with inconsistent metadata and sparse information relating to the quality, accuracy and validity of the data. Subsequently, the task of comparing datasets to decide which is the most appropriate for a certain purpose is very complex and often infeasible. In support of the European Union’s Copernicus Climate Change Service (C3S) mission to provide authoritative information about the past, present and future climate in Europe and the rest of the world, each dataset to be provided through this service must undergo an evaluation of its climate relevance and scientific quality to help with data comparisons. This paper presents the framework for Evaluation and Quality Control (EQC) of climate data products derived from satellite and in situ observations to be catalogued within the C3S Climate Data Store (CDS). The EQC framework will be implemented by C3S as part of their operational quality assurance programme. It builds on past and present international investment in Quality Assurance for Earth Observation initiatives, extensive user requirements gathering exercises, as well as a broad evaluation of over 250 data products and a more in-depth evaluation of a selection of 24 individual data products derived from satellite and in situ observations across the land, ocean and atmosphere Essential Climate Variable (ECV) domains. A prototype Content Management System (CMS) to facilitate the process of collating, evaluating and presenting the quality aspects and status of each data product to data users is also described. The development of the EQC framework has highlighted cross-domain as well as ECV specific science knowledge gaps in relation to addressing the quality of climate data sets derived from satellite and in situ observations. We discuss 10 common priority science knowledge gaps that will require further research investment to ensure all quality aspects of climate data sets can be ascertained and provide users with the range of information necessary to confidently select relevant products for their specific application.

We explored the potential of biomimetic thin films fabricated by means of matrix-assisted pulsed laser evaporation (MAPLE) for releasing combinations of active substances represented by flavonoids (quercetin dihydrate and resveratrol) and antifungal compounds (amphotericin B and voriconazole) embedded in a polyvinylpyrrolidone biopolymer; the antifungal activity of the film components was evaluated using in vitro microbiological assays. Thin films were deposited using a pulsed KrF* excimer laser source which were structurally characterized using atomic force microscopy (AFM) and Fourier transform infrared spectroscopy (FTIR). High-quality thin films with chemical structures similar to dropcast ones were created using an optimum laser fluence of ~80 mJ/cm2. Bioactive substances were included within the polymer thin films using the MAPLE technique. The results of the in vitro microbiology assay, which utilized a modified disk diffusion approach and were performed using two fungal strains (Candida albicans American Type Culture Collection (ATCC) 90028 and Candida parapsilosis American Type Culture Collection (ATCC) 22019), revealed that voriconazole was released in an active form from the polyvinylpyrrolidone matrix. The results of this study show that the MAPLE-deposited bioactive thin films have a promising potential for use in designing combination products and devices, such as drug delivery devices, and medical device surfaces with antifungal activity.

Pandelis Perakakis is a clinical psychophysiologist, an active advocate of green open access and a proponent of a new research evaluation model called ‘author-guided peer review’. In 2012, he and others founded Open Scholar, a not-for-profit community organization concerned with the way scientists and the rest of the world access research. Its flagship project is LIBRE (LIBerating REsearch). Michael Taylor is a mathematician working on the impact of aerosols and the use of satellites for weather forecasting.

We simulate the formation of spontaneous ruptures in supported phospholipid double bilayer membranes, using peridynamic modeling. Experiments performed on spreading double bilayers typically show two distinct kinds of ruptures, floral and fractal, which form spontaneously in the distal (upper) bilayer at late stages of double bilayer formation on high energy substrates. It is, however, currently unresolved which factors govern the occurrence of either rupture type. Variations in the distance between the two bilayers, and the occurrence of interconnections ("pinning sites") are suspected of contributing to the process. Our new simulations indicate that the pinned regions which form, presumably due to Ca2+ ions serving as bridging agent between the distal and the proximal bilayer, act as nucleation sites for the ruptures. Moreover, assuming that the pinning sites cause a non-zero shear modulus, our simulations also show that they change the rupture mode from floral to fractal. At zero shear modulus the pores appear to be circular, subsequently evolving into floral pores. With increasing shear modulus the pore edges start to branch, favoring fractal morphologies. We conclude that the pinning sites may indirectly determine the rupture morphology by contributing to shear stress in the distal membrane.

Despite long-standing threats of disruption to scholarly publishing, the community has remained remarkably unchanged over the last two decades. However, underlying this apparent inertia, there is an alternative approach that may emerge over the next few years as known problems move into the foreground, and a number of key social and technical issues are resolved. Furthermore, the industry of science and scientific communication are not isolated from the current economic epoch: collaboration and cost-effectiveness are strong drivers for change. The technological components of this new scholarly universe – natural language processing, semantic technologies such as taxonomies, ontologies and linking – will come together with collaborative innovations inspired by Web 2.0 social media. The final components in recreating a new publishing model are identity and reward, and these are being resolved by the forthcoming Open Research and Contributor ID (ORCID) project and the altmetrics movement respectively.

This study estimates the impact of dust aerosols on surface solar radiation and solar energy in Egypt based on Earth Observation (EO) related techniques. For this purpose, we exploited the synergy of monthly mean and daily post processed satellite remote sensing observations from the MODerate resolution Imaging Spectroradiometer (MODIS), radiative transfer model (RTM) simulations utilizing machine learning, in conjunction with 1-day forecasts from the Copernicus Atmosphere Monitoring Service (CAMS). As cloudy conditions in this region are rare, aerosols in particular dust, are the most common sources of solar irradiance attenuation, causing performance issues in the photovoltaic (PV) and concentrated solar power (CSP) plant installations. The proposed EO-based methodology is based on the solar energy nowcasting system (SENSE) that quantifies the impact of aerosol and dust on solar energy potential by using the aerosol optical depth (AOD) in terms of climatological values and day-to-day monitoring and forecasting variability from MODIS and CAMS, respectively. The forecast accuracy was evaluated at various locations in Egypt with substantial PV and CSP capacity installed and found to be within 5–12% of that obtained from the satellite observations, highlighting the ability to use such modelling approaches for solar energy management and planning (M&P). Particulate matter resulted in attenuation by up to 64–107 kWh/m2 for global horizontal irradiance (GHI) and 192–329 kWh/m2 for direct normal irradiance (DNI) annually. This energy reduction is climatologically distributed between 0.7% and 12.9% in GHI and 2.9% to 41% in DNI with the maximum values observed in spring following the frequent dust activity of Khamaseen. Under extreme dust conditions the AOD is able to exceed 3.5 resulting in daily energy losses of more than 4 kWh/m2 for a 10 MW system. Such reductions are able to cause financial losses that exceed the daily revenue values. This work aims to show EO capabilities and techniques to be incorporated and utilized in solar energy studies and applications in sun-privileged locations with permanent aerosol sources such as Egypt.

The coronary artery ligation model in rodents mimics human myocardial infarction (MI). Normally mechanical ventilation and prolonged anesthesia period are needed. Recently, a method has been developed to create MI by popping-out the heart (without ventilation) followed by immediate suture ligation. Mortality is high due to the time-consuming suture ligation process while the heart is exposed. We sought to improve this method and reduce mortality by rapid coronary ligation using a surgical clip instead of a suture.Mice were randomized into 3 groups: clip MI (CMI), suture MI (SMI), or sham (SHAM). In all groups, heart was manually exposed without intubation through a small incision on the chest wall. Unlike the conventional SMI method, mice in the CMI group received a metal clip on left anterior descending artery (LAD), quickly dispensed by an AutoSuture Surgiclip™. The CMI method took only 1/3 of ligation time of the standard SMI method and improved post-MI survival rate. TTC staining and Masson's trichrome staining revealed a similar degree of infarct size in the SMI and CMI groups. Echocardiograph confirmed that both SMI and CMI groups had a similar reduction of ejection fraction and fraction shortening over the time. Histological analysis showed that the numbers of CD68+ macrophages and apoptotic cells (TUNEL-positive) are indistinguishable between the two groups.This new method, taking only less than 3 minutes to complete, represents an efficient myocardial infarction model in rodents.

To generate a cytopathic effect, the catalytic A1 subunit of cholera toxin (CT) must be separated from the rest of the toxin. Protein disulfide isomerase (PDI) is thought to mediate CT disassembly by acting as a redox-driven chaperone that actively unfolds the CTA1 subunit. Here, we show that PDI itself unfolds upon contact with CTA1. The substrate-induced unfolding of PDI provides a novel molecular mechanism for holotoxin disassembly: we postulate the expanded hydrodynamic radius of unfolded PDI acts as a wedge to dislodge reduced CTA1 from its holotoxin. The oxidoreductase activity of PDI was not required for CT disassembly, but CTA1 displacement did not occur when PDI was locked in a folded conformation or when its substrate-induced unfolding was blocked due to the loss of chaperone function. Two other oxidoreductases (ERp57 and ERp72) did not unfold in the presence of CTA1 and did not displace reduced CTA1 from its holotoxin. Our data establish a new functional property of PDI that may be linked to its role as a chaperone that prevents protein aggregation.

The emergence of high-throughput, next-generation sequencing technologies has dramatically altered the way we assess genomes in population genetics and in cancer genomics. Currently, there are four commonly used whole-genome sequencing platforms on the market: Illumina's HiSeq2000, Life Technologies' SOLiD 4 and its completely redesigned 5500xl SOLiD, and Complete Genomics' technology. A number of earlier studies have compared a subset of those sequencing platforms or compared those platforms with Sanger sequencing, which is prohibitively expensive for whole genome studies. Here we present a detailed comparison of the performance of all currently available whole genome sequencing platforms, especially regarding their ability to call SNVs and to evenly cover the genome and specific genomic regions. Unlike earlier studies, we base our comparison on four different samples, allowing us to assess the between-sample variation of the platforms. We find a pronounced GC bias in GC-rich regions for Life Technologies' platforms, with Complete Genomics performing best here, while we see the least bias in GC-poor regions for HiSeq2000 and 5500xl. HiSeq2000 gives the most uniform coverage and displays the least sample-to-sample variation. In contrast, Complete Genomics exhibits by far the smallest fraction of bases not covered, while the SOLiD platforms reveal remarkable shortcomings, especially in covering CpG islands. When comparing the performance of the four platforms for calling SNPs, HiSeq2000 and Complete Genomics achieve the highest sensitivity, while the SOLiD platforms show the lowest false positive rate. Finally, we find that integrating sequencing data from different platforms offers the potential to combine the strengths of different technologies. In summary, our results detail the strengths and weaknesses of all four whole-genome sequencing platforms. It indicates application areas that call for a specific sequencing platform and disallow other platforms. This helps to identify the proper sequencing platform for whole genome studies with different application scopes.

Vibrio cholerae produces cholera toxin (CT), an AB5 protein toxin that is primarily responsible for the profuse watery diarrhea of cholera. CT is secreted into the extracellular milieu, but the toxin attacks its Gsα target within the cytosol of a host cell. Thus, CT must cross a cellular membrane barrier in order to function. This event only occurs after the toxin travels by retrograde vesicular transport from the cell surface to the endoplasmic reticulum (ER). The catalytic A1 polypeptide then dissociates from the rest of the toxin and assumes an unfolded conformation that facilitates its transfer to the cytosol by a process involving the quality control system of ER-associated degradation. Productive intoxication is blocked by alterations to the vesicular transport of CT and/or the ER-to-cytosol translocation of CTA1. Various plant compounds have been reported to inhibit the cytopathic activity of CT, so in this work we evaluated the potential anti-CT properties of grape extract. Two grape extracts currently sold as nutritional supplements inhibited CT and Escherichia coli heat-labile toxin activity against cultured cells and intestinal loops. CT intoxication was blocked even when the extracts were added an hour after the initial toxin exposure. A specific subset of host-toxin interactions involving both the catalytic CTA1 subunit and the cell-binding CTB pentamer were affected. The extracts blocked toxin binding to the cell surface, prevented unfolding of the isolated CTA1 subunit, inhibited CTA1 translocation to the cytosol, and disrupted the catalytic activity of CTA1. Grape extract could thus potentially serve as a novel therapeutic to prevent or possibly treat cholera.

The use of automated methods to estimate fractional vegetation cover (FVC) from digital photographs has increased in recent years given its potential to produce accurate, fast and inexpensive FVC measurements. Wide acceptance has been delayed because of the limitations in accuracy, speed, automation and generalization of these methods. This work introduces a novel technique, the Automated Canopy Estimator (ACE) that overcomes many of these challenges to produce accurate estimates of fractional vegetation cover using an unsupervised segmentation process. ACE is shown to outperform nine other segmentation algorithms, consisting of both threshold-based and machine learning approaches, in the segmentation of photographs of four different crops (oat, corn, rapeseed and flax) with an overall accuracy of 89.6%. ACE is similarly accurate (88.7%) when applied to remotely sensed corn, producing FVC estimates that are strongly correlated with ground truth values.

Rickettsiosis is a potentially fatal tick borne disease. It is caused by the obligate intracellular bacteria Rickettsia, which is transferred to humans through salivary excretions of ticks during the biting process. Globally, the incidence of tick-borne diseases is increasing; as such, there is a need for a greater understanding of tick–host interactions to create more informed risk management strategies. Flinders Island spotted fever rickettsioses has been identified throughout Australia (Tasmania, South Australia, Queensland and Torres Strait Islands) with possible identifications in Thailand, Sri Lanka and Italy. Flinders Island spotted fever is thought to be spread through tick bites and the reptile tick Bothriocroton hydrosauri has been implicated as a vector in this transmission. This study used qPCR to assay Bothriocroton hydrosauri ticks collected from Tiliqua rugosa (sleepy lizard) hosts on mainland South Australia near where spotted fever cases have been identified. We report that, although we discovered Rickettsia in all tick samples, it was not Rickettsia honei. This study is the first to use PCR to positively identify Rickettsia from South Australian Bothriocroton hydrosauri ticks collected from Tiliqua rugosa (sleepy lizard) hosts. These findings suggest that B. hydrosauri may be a vector of multiple Rickettsia spp. Also as all 41 tested B. hydrosauri ticks were positive for Rickettsia this indicates an extremely high prevalence within the studied area in South Australia.

BACKGROUND:BAP1 has been shown to be a target of both somatic alteration in high-risk ocular melanomas (OM) and germline inactivation in a few individuals from cancer-prone families. These findings suggest that constitutional BAP1 changes may predispose individuals to metastatic OM and that familial permeation of deleterious alleles could delineate a new cancer syndrome. DESIGN:To characterize BAP1's contribution to melanoma risk, we sequenced BAP1 in a set of 100 patients with OM, including 50 metastatic OM cases and 50 matched non-metastatic OM controls, and 200 individuals with cutaneous melanoma (CM) including 7 CM patients from CM-OM families and 193 CM patients from CM-non-OM kindreds. RESULTS:Germline BAP1 mutations were detected in 4/50 patients with metastatic OM and 0/50 cases of non-metastatic OM (8% vs. 0%, p = 0.059). Since 2/4 of the BAP1 carriers reported a family history of CM, we analyzed 200 additional hereditary CM patients and found mutations in 2/7 CM probands from CM-OM families and 1/193 probands from CM-non-OM kindreds (29% vs. 0.52%, p = .003). Germline mutations co-segregated with both CM and OM phenotypes and were associated with the presence of unique nevoid melanomas and highly atypical nevoid melanoma-like melanocytic proliferations (NEMMPs). Interestingly, 7/14 germline variants identified to date reside in C-terminus suggesting that the BRCA1 binding domain is important in cancer predisposition. CONCLUSION:Germline BAP1 mutations are associated with a more aggressive OM phenotype and a recurrent phenotypic complex of cutaneous/ocular melanoma, atypical melanocytic proliferations and other internal neoplasms (ie. COMMON syndrome), which could be a useful clinical marker for constitutive BAP1 inactivation.

Cholera toxin (CT) travels as an intact AB(5) protein toxin from the cell surface to the endoplasmic reticulum (ER) of an intoxicated cell. In the ER, the catalytic A1 subunit dissociates from the rest of the toxin. Translocation of CTA1 from the ER to the cytosol is then facilitated by the quality control mechanism of ER-associated degradation (ERAD). Thermal instability in the isolated CTA1 subunit generates an unfolded toxin conformation that acts as the trigger for ERAD-mediated translocation to the cytosol. In this work, we show by circular dichroism and fluorescence spectroscopy that exposure to 4-phenylbutyric acid (PBA) inhibited the thermal unfolding of CTA1. This, in turn, blocked the ER-to-cytosol export of CTA1 and productive intoxication of either cultured cells or rat ileal loops. In cell culture studies PBA did not affect CT trafficking to the ER, CTA1 dissociation from the holotoxin, or functioning of the ERAD system. PBA is currently used as a therapeutic agent to treat urea cycle disorders. Our data suggest PBA could also be used in a new application to prevent or possibly treat cholera.

AB toxins such as ricin and cholera toxin (CT) consist of an enzymatic A domain and a receptor-binding B domain. After endocytosis of the surface-bound toxin, both ricin and CT are transported by vesicle carriers to the endoplasmic reticulum (ER). The A subunit then dissociates from its holotoxin, unfolds, and crosses the ER membrane to reach its cytosolic target. Since protein unfolding at physiological temperature and neutral pH allows the dissociated A chain to attain a translocation-competent state for export to the cytosol, the underlying regulatory mechanisms of toxin unfolding are of paramount biological interest. Here we report a biophysical analysis of the effects of anionic phospholipid membranes and two chemical chaperones, 4-phenylbutyric acid (PBA) and glycerol, on the thermal stabilities and the toxic potencies of ricin toxin A chain (RTA) and CT A1 chain (CTA1). Phospholipid vesicles that mimic the ER membrane dramatically decreased the thermal stability of RTA but not CTA1. PBA and glycerol both inhibited the thermal disordering of RTA, but only glycerol could reverse the destabilizing effect of anionic phospholipids. In contrast, PBA was able to increase the thermal stability of CTA1 in the presence of anionic phospholipids. PBA inhibits cellular intoxication by CT but not ricin, which is explained by its ability to stabilize CTA1 and its inability to reverse the destabilizing effect of membranes on RTA. Our data highlight the toxin-specific intracellular events underlying ER-to-cytosol translocation of the toxin A chain and identify a potential means to supplement the long-term stabilization of toxin vaccines.

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