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Abstract Background The International Classification of Headache Disorders (ICHD-3) uses moderate or severe pain intensity in the diagnostic criterion for migraine. However, few studies have analyzed pain rating on a visual analog scale to identify the numerical intensity that correlates with migraine. Objective To evaluate the impact of daily self-rated headache pain among patients with either episodic or chronic migraine. This study specifically aims to evaluate the probability of patients labeling their head pain as a headache vs. migraine based on the pain level reported. Methods A retrospective chart review was conducted on patients with a clinical diagnosis of migraine from July 1, 2014, to July 1, 2019. Results Data of 114 subjects (57 episodic migraine and 57 chronic migraine) were used for analysis. Patients with episodic migraine on average rated a migraine more severe than a headache (4.1 vs. 6.4; p

Background Treatment burden is the workload of healthcare for people with long-term conditions and the impact on wellbeing. A validated measure of treatment burden after stroke is needed. We aim to adapt a patient-reported measure (PRM) of treatment burden in multimorbidity, PETS (Patient Experience with Treatment and Self-Management version 2.0), to create a stroke-specific measure, PETS-stroke. We aim to examine content validity, construct validity, reliability and feasibility in a stroke survivor population. Methods 1) Adaptation of 60-item PETS to PETS-stroke using a taxonomy of treatment burden. 2) Content validity testing through cognitive interviews that will explore the importance, relevance and clarity of each item. 3) Evaluation of scale psychometric properties through analysis of data from stroke survivors recruited via postal survey (n=340). Factor structure will be tested with confirmatory factor analysis and Cronbach’s alpha will be used to index internal consistency. Construct validity will be tested against: The Stroke Southampton Self-Management Questionnaire; The Satisfaction with Stroke Care Measure; and The Shortened Stroke Impact Scale. We will explore known-groups validity by exploring the association between treatment burden, socioeconomic deprivation and multimorbidity. Test-retest reliability will be examined via re-administration after 2 weeks. Acceptability and feasibility of use will be explored via missing data rates and telephone interviews with 30 participants. Conclusions We aim to create a validated PRM of treatment burden after stroke. PETS-stroke is designed for use as an outcome measure in clinical trials of stroke treatments and complex interventions to ascertain if treatments are workable for patients in the context of their everyday lives.

Background Treatment burden is the workload of healthcare for people with long-term conditions and the impact on wellbeing. A validated measure of treatment burden after stroke is needed. We aim to adapt a patient-reported measure (PRM) of treatment burden in multimorbidity, PETS (Patient Experience with Treatment and Self-Management version 2.0), to create a stroke-specific measure, PETS-stroke. We aim to examine content validity, construct validity, reliability and feasibility in a stroke survivor population. Methods 1) Adaptation of 60-item PETS to PETS-stroke using a taxonomy of treatment burden. 2) Content validity testing through cognitive interviews that will explore the importance, relevance and clarity of each item. 3) Evaluation of scale psychometric properties through analysis of data from stroke survivors recruited via postal survey (n=340). Factor structure will be tested with confirmatory factor analysis and Cronbach’s alpha will be used to index internal consistency. Construct validity will be tested against: The Stroke Southampton Self-Management Questionnaire; The Satisfaction with Stroke Care Measure; and The Shortened Stroke Impact Scale. We will explore known-groups validity by exploring the association between treatment burden, socioeconomic deprivation and multimorbidity. Test-retest reliability will be examined via re-administration after 2 weeks. Acceptability and feasibility of use will be explored via missing data rates and telephone interviews with 30 participants. Conclusions We aim to create a validated PRM of treatment burden after stroke. PETS-stroke is designed for use as an outcome measure in clinical trials of stroke treatments and complex interventions to ascertain if treatments are workable for patients in the context of their everyday lives.

Abstract Domestication leads to changes in traits that are under directional selection in breeding programmes, though unintentional changes in nonproduction traits can also arise. In offspring of escaping fish and any hybrid progeny, such unintentionally altered traits may reduce fitness in the wild. Atlantic salmon breeding programmes were established in the early 1970s, resulting in genetic changes in multiple traits. However, the impact of domestication on eye size has not been studied. We measured body size corrected eye size in 4000 salmon from six common garden experiments conducted under artificial and natural conditions, in freshwater and saltwater environments, in two countries. Within these common gardens, offspring of domesticated and wild parents were crossed to produce 11 strains, with varying genetic backgrounds (wild, domesticated, F1 hybrids, F2 hybrids and backcrosses). Size‐adjusted eye size was influenced by both genetic and environmental factors. Domesticated fish reared under artificial conditions had smaller adjusted eye size when compared to wild fish reared under identical conditions, in both the freshwater and marine environments, and in both Irish and Norwegian experiments. However, in parr that had been introduced into a river environment shortly after hatching and sampled at the end of their first summer, differences in adjusted eye size observed among genetic groups were of a reduced magnitude and were nonsignificant in 2‐year‐old sea migrating smolts sampled in the river immediately prior to sea entry. Collectively, our findings could suggest that where natural selection is present, individuals with reduced eye size are maladapted and consequently have reduced fitness, building on our understanding of the mechanisms that underlie a well‐documented reduction in the fitness of the progeny of domesticated salmon, including hybrid progeny, in the wild.

Summary: The outcome for children with high-risk neuroblastoma is poor despite intensive multi-modal treatment protocols. Toxicity from current treatments is significant, and novel approaches are needed to improve outcome. Cyclophosphamide (CPM) is a key component of current chemotherapy regimens and is known to have immunomodulatory effects. However, this has not been investigated in the context of tumor infiltrating lymphocytes in neuroblastoma. Using murine models of neuroblastoma, the immunomodulatory effects of low-dose CPM were investigated using detailed immunophenotyping. We demonstrated that CPM resulted in a specific depletion of intratumoral T regulatory cells by apoptosis, and when combined with anti-PD-1 antibody therapy, this resulted in improved therapeutic efficacy. CPM combined with anti-PD-1 therapy was demonstrated to be an effective combinational therapy, with metronomic CPM found to be more effective than single dosing in more resistant tumor models. Overall, this pre-clinical data strongly support clinical evaluation of such combination strategies in neuroblastoma.

Abstract Background Following the initial identification of the 2019 coronavirus disease (covid-19), the subsequent months saw substantial increases in published biomedical research. Concerns have been raised in both scientific and lay press around the quality of some of this research. We assessed clinical research from major clinical journals, comparing methodological and reporting quality of covid-19 papers published in the first wave (here defined as December 2019 to May 2020 inclusive) of the viral pandemic with non-covid papers published at the same time. Methods We reviewed research publications (print and online) from The BMJ, Journal of the American Medical Association (JAMA), The Lancet, and New England Journal of Medicine, from first publication of a covid-19 research paper (February 2020) to May 2020 inclusive. Paired reviewers were randomly allocated to extract data on methodological quality (risk of bias) and reporting quality (adherence to reporting guidance) from each paper using validated assessment tools. A random 10% of papers were assessed by a third, independent rater. Overall methodological quality for each paper was rated high, low or unclear. Reporting quality was described as percentage of total items reported. Results From 168 research papers, 165 were eligible, including 54 (33%) papers with a covid-19 focus. For methodological quality, 18 (33%) covid-19 papers and 83 (73%) non-covid papers were rated as low risk of bias, OR 6.32 (95%CI 2.85 to 14.00). The difference in quality was maintained after adjusting for publication date, results, funding, study design, journal and raters (OR 6.09 (95%CI 2.09 to 17.72)). For reporting quality, adherence to reporting guidelines was poorer for covid-19 papers, mean percentage of total items reported 72% (95%CI:66 to 77) for covid-19 papers and 84% (95%CI:81 to 87) for non-covid. Conclusions Across various measures, we have demonstrated that covid-19 research from the first wave of the pandemic was potentially of lower quality than contemporaneous non-covid research. While some differences may be an inevitable consequence of conducting research during a viral pandemic, poor reporting should not be accepted.

Abstract Understanding trade‐offs in wild populations is difficult, but important if we are to understand the evolution of life histories and the impact of ecological variables upon them. Markers that reflect physiological state and predict future survival would be of considerable benefit to unraveling such trade‐offs and could provide insight into individual variation in senescence. However, currently used markers often yield inconsistent results. One underutilized measure is hematocrit, the proportion of blood comprising erythrocytes, which relates to the blood's oxygen‐carrying capacity and viscosity, and to individual endurance. Hematocrit has been shown to decline with age in cross‐sectional studies (which may be confounded by selective appearance/disappearance). However, few studies have tested whether hematocrit declines within individuals or whether low hematocrit impacts survival in wild taxa. Using longitudinal data from the Seychelles warbler (Acrocephalus sechellensis), we demonstrated that hematocrit increases with age in young individuals (

Abstract Background Robust diagnosis of dementia requires an understanding of the accuracy of the available diagnostic tests. Informant questionnaires are frequently used to assess for dementia in clinical practice. Recent systematic reviews have sought to establish the diagnostic test accuracy of various dementia informant screening tools. However, most reviews to date have focused on a single diagnostic tool and this does not address which tool is ‘best’. A key aim of the overview of systematic reviews is to present a disparate evidence base in a single, easy to access platform. Methods We will conduct an overview of systematic reviews in which we ‘review the systematic reviews’ of diagnostic test accuracy studies evaluating informant questionnaires for dementia. As an overview of systematic reviews of test accuracy is a relatively novel approach, we will use this review to explore methods for visual representation of complex data, for highlighting evidence gaps and for indirect comparative analyses. We will create a list of informant tools by consulting with dementia experts. We will search 6 databases (EMBASE (OVID); Health and Psychosocial Instruments (OVID); Medline (OVID); CINAHL (EBSCO); PSYCHinfo (EBSCO) and the PROSPERO registry of review protocols) to identify systematic reviews that describe the diagnostic test accuracy of informant questionnaires for dementia. We will assess review quality using the AMSTAR-2 (Assessment of Multiple Systematic Reviews) and assess reporting quality using PRISMA-DTA (Preferred Reporting Items for Systematic Review and Meta-analysis of Diagnostic Test Accuracy Studies) checklists. We will collate the identified reviews to create an ‘evidence map’ that highlights where evidence does and does not exist in relation to informant questionnaires. We will pool sensitivity and specificity data via meta-analysis to generate a diagnostic test accuracy summary statistic for each informant questionnaire. If data allow, we will perform a statistical comparison of the diagnostic test accuracy of each informant questionnaire using a network approach. Discussion Our overview of systematic reviews will provide a concise summary of the diagnostic test accuracy of informant tools and highlight areas where evidence is currently lacking in this regard. It will also apply network meta-analysis techniques to a new area.

Abstract Background Cognitive impairment is an important consequence of stroke and transient ischaemic attack, but its determinants are not fully understood. Simple univariable or multivariable models have not shown clinical utility for predicting cognitive impairment. Cardiovascular risk factors may influence cognition through multiple, direct, and indirect pathways, including effects on prior cognition and stroke severity. Understanding these complex relationships may help clinical teams plan intervention and follow-up strategies. Methods We analysed clinical and demographic data from consecutive patients admitted to an acute stroke ward. Cognitive assessment comprised Abbreviated Mental Test and mini-Montreal Cognitive Assessment. We constructed bias-corrected confidence intervals to test indirect effects of cardiovascular risk factors (hypertension, vascular disease, atrial fibrillation, diabetes mellitus, previous stroke) on cognitive function, mediated through stroke severity and history of dementia, and we assessed moderation effects due to comorbidity. Results From 594 eligible patients, we included 587 in the final analysis (age range 26–100; 45% female). Our model explained R 2 = 62.10% of variance in cognitive test scores. We found evidence for an indirect effect of previous stroke that was associated with increased risk of prevalent dementia and in turn predicted poorer cognitive score (estimate = − 0.39; 95% bias-corrected CI, − 0.75 to − 0.13; p = 0.02). Atrial fibrillation was associated with greater stroke severity and in turn with a poorer cognitive score (estimate = − 0.27; 95% bias-corrected CI, − 0.49 to − 0.05; p = 0.02). Conversely, previous TIA predicted decreased stroke severity and, through that, lesser cognitive impairment (estimate = 0.38; 95% bias-corrected CI, 0.08 to 0.75; p = 0.02). Through an association with reduced stroke severity, vascular disease was associated with lesser cognitive impairment, conditional on presence of hypertension and absence of diabetes mellitus (estimate = 0.36; 95% bias-corrected CI, 0.03 to 0.68; p = 0.02), although the modelled interaction effects did not reach statistical significance. Conclusions We have shown that relationships between cardiovascular risk factors and cognition are complex and simple multivariable models may be overly reductionist. Including direct and indirect effects of risk factors, we constructed a model that explained a substantial proportion of variation in cognitive test scores. Models that include multiple paths of influence and interactions could be used to create dementia prognostic tools for use in other healthcare settings.

Background: Cognitive and mood problems have been highlighted as priorities in stroke research and guidelines recommend early screening. However, there is limited detail on the preferred approach.We aimed to (1) determine the optimal methods for evaluating psychological problems that pre-date stroke; (2) assess the test accuracy, feasibility and acceptability of brief cognitive and mood tests used at various time-points following stroke; (3) describe temporal changes in cognition and mood following stroke and explore predictors of change. Methods: We established a multi-centre, prospective, observational cohort with acute stroke as the inception point – Assessing Post-stroke Psychology Longitudinal Evaluation (APPLE). We approached patients admitted with stroke or transient ischaemic attack (TIA) from 11 different hospital sites across the United Kingdom. Baseline demographics, clinical, functional, cognitive, and mood data were collected. Consenting stroke survivors were followed up with more extensive evaluations of cognition and mood at 1, 6, 12 and 18 months. Results: Continuous recruitment was from February 2017 to February 2019. With 357 consented to full follow-up. Eighteen-month assessments were completed in September 2020 with permissions in-place for longer term in-person or electronic follow-up. A qualitative study has been completed, and a participant sample biobank and individual participant database are both available. Discussion: The APPLE study will provide guidance on optimal tool selection for cognitive and mood assessment both before and after stroke, as well as information on prognosis and natural history of neuropsychological problems in stroke. The study data, neuroimaging and tissue biobank are all available as a resource for future research.

Introduction: Several adverse outcomes have been associated with anticholinergic burden (ACB), and these risks increase with age. Several approaches to measuring this burden are available but, to date, no comparison of their prognostic abilities has been conducted. This PROSPERO-registered systematic review (CRD42019115918) compared the evidence behind ACB measures in relation to their ability to predict risk of falling in older people. Methods: Medline (OVID), EMBASE (OVID), CINAHL (EMBSCO) and PsycINFO (OVID) were searched using comprehensive search terms and a validated search filter for prognostic studies. Inclusion criteria included: participants aged 65 years and older, use of one or more ACB measure(s) as a prognostic factor, cohort or case-control in design, and reporting falls as an outcome. Risk of bias was assessed using the Quality in Prognosis Studies (QUIPS) tool. Results: Eight studies reporting temporal associations between ACB and falls were included. All studies were rated high risk of bias in ⩾1 QUIPS tool categories, with five rated high risk ⩾3 categories. All studies (274,647 participants) showed some degree of association between anticholinergic score and increased risk of falls. Findings were most significant with moderate to high levels of ACB. Most studies (6/8) utilised the anticholinergic cognitive burden scale. No studies directly compared two or more ACB measures and there was variation in how falls were measured for analysis. Conclusion: The evidence supports an association between moderate to high ACB and risk of falling in older people, but no conclusion can be made regarding which ACB scale offers best prognostic value in older people. Plain language summary A review of published studies to explore which anticholinergic burden scale is best at predicting the risk of falls in older people Introduction: One third of older people will experience a fall. Falls have many consequences including fractures, a loss of independence and being unable to enjoy life. Many things can increase the chances of having a fall. This includes some medications. One type of medication, known as anticholinergic medication, may increase the risk of falls. These medications are used to treat common health issues including depression and bladder problems. Anticholinergic burden is the term used to describe the total effects from taking these medications. Some people may use more than one of these medications. This would increase their anticholinergic burden. It is possible that reducing the use of these medications could reduce the risk of falls. We need to carry out studies to see if this is possible. To do this, we need to be able to measure anticholinergic burden. There are several scales available, but we do not know which is best. Methods: We wanted to answer: ‘Which anticholinergic scale is best at predicting the risk of falling in older people?’. We reviewed studies that could answer this. We did this in a systematic way to capture all published studies. We restricted the search in several ways. We only included studies relevant to our question. Results: We found eight studies. We learned that people who are moderate to high users of these medications (often people who will use more than one of these medications) had a higher risk of falling. It was less clear if people who have a lower burden (often people who only use one of these medications) had an increased risk of falling. The low number of studies prevented us from determining if one scale was better than another. Conclusion: These findings suggest that we should reduce use of these medications. This could reduce the number falls and improve the well-being of older people.

Livestock domestication has long been a part of agriculture, estimated to have first occurred approximately 10 000 years ago. Despite the plethora of traits studied, there is little understanding of the possible impacts domestication has had on internal organs, which are key determinants of survival. Moreover, the genetic basis of observed associated changes in artificial environments is still puzzling. Here we examine impacts of captivity on two organs in Atlantic salmon (Salar salar) that have been domesticated for approximately 50 years: heart and liver, in addition to growth. We studied multiple families of wild, domesticated, F1 and F2 hybrid, and backcrossed strains of S. salar in replicated common garden tanks during the freshwater and marine stages of development. Heart and liver weight were investigated, along with heart morphology metrics examined in just the wild, domesticated and F1 hybrid strains (heart height and width). Growth was positively linked with the proportion of the domesticated strain, and recombination in F2 hybrids (and the potential disruption of co-adapted gene complexes) did not influence growth. Despite the influence of domestication on growth, we found no evidence for domestication-driven divergence in heart or liver morphology. However, sexual dimorphism was detected in heart morphology, and after controlling for body size, females exhibited significantly larger heart weight and heart width when compared with males. Wild females also had an increased heart height when compared with wild males, and this was not observed in any other strain. Females sampled in saltwater showed significantly larger heart height with rounder hearts, than saltwater males. Collectively, these results demonstrate an additive basis of growth and, despite a strong influence of domestication on growth, no clear evidence of changes in heart or liver morphology associated with domestication was identified.

BackgroundGreater anticholinergic burden (ACB) increases the risk of mortality in older individuals, yet the strength of this association varies between studies. One possible explanation for this variance is the use of different approaches to quantify ACB. This systematic review (PROSPERO number CRD42019115918) assessed the prognostic utility of ACB-specific measures on mortality in older individuals.MethodsMultiple cross-disciplinary databases were searched from 2006–2018. Observational studies assessing the association between ACB and mortality utilizing ≥1 ACB measure, involving persons aged ≥65 years were included. Screening and data extraction were performed by two independent reviewers, with disagreements resolved by a third independent reviewer. Risk of bias and quality of evidence were assessed using Quality in Prognosis Studies (QUIPS) and Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) criteria. Meta-analysis was conducted where appropriate.ResultsOf 19,224 titles, 20 articles describing 18 cohort studies involving 498,056 older individuals were eligible. Eight anticholinergic-specific measures were identified; the Anticholinergic Cognitive Burden Scale (ACBS, n=9) and Anticholinergic Risk scale (ARS, n=8) were most frequently reported. The evidence base was of poor quality, with moderate to high risk of bias. Meta-analysis showed increased mortality risk.ConclusionsThere was a modest association between some ACB measures and mortality, with most evidence derived from the ACBS. Studies comparing different measures within the same population were lacking. Analysis was limited by poor generalizability between studies, specifically regarding heterogeneity in methodology and reporting, as well as high risk of bias for most studies in the evidence base.

Abstract Australia has one of the worst extinction rates of any nation, yet there has been little assessment of the effect of its flagship environmental legislation, the Environment Protection and Biodiversity Conservation Act 1999 (EPBC Act), to prevent species extinction. By coupling remotely sensed forest and woodland data with the distributions of 1,638 terrestrial threatened species, terrestrial migratory species, and threatened ecological communities, we quantified the loss of potential habitat and communities since the EPBC Act came into force in 2000. We found that over 7.7 million ha of potential habitat and communities were cleared in the period 2000–2017. Of this clearing, over 93% was not referred to the Federal Government for assessment, meaning the loss was not scrutinized under the EPBC Act. While 1,390 (84%) species suffered loss, Mount Cooper striped skink, Keighery's macarthuria, and Southern black‐throated finch lost 25, 23, and 10% of potential habitat, respectively. Iconic Australian species, such as koala, also lost ~1 million ha (2.3%) of potential habitat. Our analysis showed that the EPBC Act is ineffective at protecting potential habitat for terrestrial threatened species, terrestrial migratory species, or threatened ecological communities. We recommend that when scientifically determinable, critical habitat is demarcated for listed species and communities, which provides absolute protection that is enforced, monitored, and investigated by the regulator. Without a fundamental change in how environmental law is enforced, Australia faces an increasing extinction rate.

Long Interspersed Nuclear Element-1 (LINE-1, L1) constitutes a family of autonomous, self-replicating genetic elements known as retrotransposons. Although most are inactive, copious L1 sequences populate the human genome. L1s proliferate in a ‘copy-and-paste’ fashion through an RNA intermediate; a full-length L1 transcript is ~6,000 nucleotides long and functions as a bicistronic mRNA that encodes and assembles in cis with two main polypeptides, ORF1p and ORF2p, forming a ribonucleoprotein (RNP); L1 RNPs also interact with a wide range of host factors in positive and negative regulatory capacities. The following protocol describes an approach to affinity enrich ectopically expressed L1 RNPs and, using RNases, release the fraction of protein that depends upon the presence of intact RNA for retention in the immobilized macromolecules.

A measure of treatment effect is needed to assess the utility of any novel intervention in acute stroke. For a potentially disabling condition such as stroke, outcomes of interest should include some measure of functional recovery. There are many functional outcome assessments that can be used after stroke. In this narrative review, we discuss exemplars of assessments that describe impairment, activity, participation, and quality of life. We will consider the psychometric properties of assessment scales in the context of stroke trials, focusing on validity, reliability, responsiveness, and feasibility. We will consider approaches to the analysis of functional outcome measures, including novel statistical approaches. Finally, we will discuss how advances in audiovisual and information technology could further improve outcome assessment in trials.

Background and purposeThe modified Rankin Scale (mRS) was designed to measure poststroke recovery but is often used to describe pre-stroke disability. We sought to evaluate three aspects of pre-stroke mRS: validity as a measure of pre-stroke disability; prognostic accuracy and association of pre-stroke mRS scores, and process of care.MethodsWe used data from a large, UK clinical registry. For analysis of validity, we compared pre-stroke mRS against other markers of pre-stroke function (age, comorbidity index, care needs). For analysis of prognostic accuracy, we described univariable and multivariable models comparing pre-stroke mRS and other prognostic variables against a variety of outcomes (early and late mortality, length of stay, institutionalization, incident complications). Finally, we described association of pre-stroke mRS and components of evidence-based stroke care (early neuroimaging, admission to stroke unit, assessment of swallow).ResultsWe analyzed data of 2,491 stroke patients. Concurrent validity analyses suggested statistically significant, but modest correlations between pre-stroke mRS and chosen variables (rho >0.40; p

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Full completion of cognitive screening tests can be problematic in the context of a stroke. Our aim was to examine the completion of various brief cognitive screens and explore reasons for untestability. Data were collected from consecutive stroke admissions (May 2016−August 2018). The cognitive assessment was attempted during the first week of admission. Patients were classified as partially untestable (≥1 test item was incomplete) and fully untestable (where assessment was not attempted, and/or no questions answered). We assessed univariate and multivariate associations of test completion with: age (years), sex, stroke severity (National Institutes of Health Stroke Scale (NIHSS)), stroke classification, pre-morbid disability (modified Rankin Scale (mRS)), previous stroke and previous dementia diagnosis. Of 703 patients admitted (mean age: 69.4), 119 (17%) were classified as fully untestable and 58 (8%) were partially untestable. The 4A-test had 100% completion and the clock-draw task had the lowest completion (533/703, 76%). Independent associations with fully untestable status had a higher NIHSS score (odds ratio (OR): 1.18, 95% CI: 1.11−1.26), higher pre-morbid mRS (OR: 1.28, 95% CI: 1.02−1.60) and pre-stroke dementia (OR: 3.35, 95% CI: 1.53−7.32). Overall, a quarter of patients were classified as untestable on the cognitive assessment, with test incompletion related to stroke and non-stroke factors. Clinicians and researchers would benefit from guidance on how to make the best use of incomplete test data.

Six calves were immunized with schistosomula of Schistosoma bovis irradiated at 3 or 20 Kilorad (Krad) and three calves were kept as controls. Twenty four weeks post immunization, three calves (one from the 20 Krad and two from the 3 Krad group) were challenged with normal cercaria of S. bovis. The immune response was monitored by agar gel immunodiffusion (AGID) and the Enzyme Linked Immunosorbent Assay (ELISA) using adult worm antigen. Using AGID, precipitin lines were observed only with sera from challenged animals. Using ELISA, the immune response of the vaccinated calves was first detected by 2-3 weeks, peaking by 6-8 weeks post vaccination. The immune response of the three challenged calves was elevated by 2 weeks post challenge, peaking at 8-10 weeks post challenge and remained high throughout the experimental period. This study suggests that ELISA could be used for diagnosis of bovine schistosomiasis.

Many students must take remedial or developmental mathematics coursework to gain skills and knowledge necessary to satisfy college-level quantitative literacy requirements; however, large numbers of those students struggle to complete such coursework and are consequently unable to graduate. This issue implies the need to reform developmental mathematics curricula, and modern developmental mathematics curriculum standards have been used as a basis reforming developmental mathematics curricula and programs at a number of community colleges and universities. We report an analysis of developmental mathematics assessment practices based on a large dataset, and how assessment practices indicate alignment with reform-oriented curriculum standards. We conclude with suggestions for improving developmental mathematics curricula.

Learning analytics is an emerging discipline and, as such, benefits from new tools and methodological approaches. This work reviews and summarizes our workshop on microgenetic data analysis techniques using R, held at the second annual Learning Analytics Summer Institute in Cambridge, Massachusetts, on 30 June 2014. Specifically, this paper introduces educational researchers to our experience using data analysis techniques with the RStudio development environment to analyze temporal records of 52 elementary students' affective and behavioural responses to a digital learning environment. In the RStudio development environment, we used methods such as hierarchical clustering and sequential pattern mining. We also used RStudio to create effective data visualizations of our complex data. The scope of the workshop, and this paper, assumes little prior knowledge of the R programming language, and thus, covers everything from data import and cleanup to advanced microgenetic analysis techniques. Additionally, readers will be introduced to software setup, R data types, and visualizations. This paper not only adds to the toolbox for learning analytics researchers (particularly when analyzing time series data), but also shares our experience interpreting a unique and complex dataset.

Teaching mathematics has long required the use of technology due many powerful affordances. More recently, education technology has been developed to support personalized learning through the use of adaptive learning systems. Through the use of educational technology in online learning, there is great potential for improving students' mathematics achievement. In this article, we report the results of an evaluation study, where 11 online mathematics educational technology products were distributed to close to 200,000 K-12 students and their teachers in the state of Utah to supplement classroom instruction. While only ten percent of students used the products at the recommended level over the course of the 2014-15 school year, there were six products where an educationally meaningful impact on mathematics achievement was found. While teachers responded positively, a third of teachers reported lack of access to technology as a barrier. We are already seeing improved usage during the second year of the project due to modifications to the expectations for schools based on what was learned from the first year of implementation.

My goal in crafting homework in calculus is twofold: to provide scaffolding for students to develop a theoretical understanding of calculus concepts and to incorporate good mathematical exposition, including justification and proof when appropriate. I achieve these goals by creating weekly homework sets that students work on in groups of three or four, beginning in class and finishing outside of class. In this paper, we explore examples of homework questions that promote abstract thought and the details necessary to implement this system in a calculus class. We discuss the ways in which group assignments invalidate solutions found online and ease the grading burden for the instructor. We mention possible pitfalls of this approach as well as ways in which to avoid them. Finally, we discuss student attitudes and feedback on this particular method of homework.

Advances in educational neuroscience have made it possible for researchers to conduct studies that observe concurrent behavioral (i.e., task performance) and neural (i.e., brain activation) responses to naturalistic educational activities. Such studies are important because they help educators, clinicians, and researchers to better understand the etiology of both typical and atypical math processing. Because of its ease of use and robust tolerance of movement, functional near-infrared spectroscopy (fNIRS) provides a brain-imaging platform that is optimally suited for such studies. To that end, the focus of the current research is to use fNIRS to help better understand the neural signatures associated with real-world math learning activities. For example, the computer game "Refraction" was designed as a fun and engaging method to improve fraction knowledge in children. Data collected in previous studies have identified significant correlations between Refraction play and improvements in fraction knowledge. Here we provide the results of a pilot study that describes participants' cortical activations in response to Refraction play. As hypothesized, Refraction play resulted in increases in parietal cortical activations at levels above those measured during spatial-specific activities. Moreover, our results were similar to another fNIRS study by Dresler et al. ("J Neural Transm" 116(12): 1689-1700, 2009), where children read Arabic numeral addition equations compared to written equations. Our results provide a valuable proof-of-concept for the use of Refraction within a large-scale fNIRS-based longitudinal study of fraction learning.

Although the consensus seems to be that high-school-level introductory engineering courses should focus on design, this creates a problem for teacher training. Traditionally, math and science teachers are trained to teach and assess factual knowledge and closed-ended problem-solving techniques specific to a particular discipline, which is unsuited for teaching design skills for open-ended problems that may involve multiple engineering disciplines. Instead, engineering teacher training should use the more fluid framework of adaptive expertise which values the ability to apply knowledge in innovative ways as well as recall facts and solve problems using conventional techniques. In this study, we examined a 6-week program to train math/science teachers to teach high school design engineering. For each curriculum unit, we had a pre-posttest to assess the teachers' factual knowledge and ability to solve typical problems (termed ''efficiency'') and their ability to apply their knowledge to reason through open-ended problems (termed ''innovation''). In addition, we conducted a pre-posttest to see whether teachers' attitudes and beliefs related to adaptive expertise changed over the course of the program.

The struggle with fraction learning in kindergarten through Grade 12 in the United States is a persistent problem and one of the major stumbling blocks to succeeding in higher mathematics. Research into this problem has identified several areas where students commonly struggle with fractions. While there are many theories of fraction learning, none of the research on these theories employs samples large enough to test theories at scale or nuanced enough to demonstrate how learning unfolds over time during instructional activities based on these theories. The work reported here uses learning analytics methods with fine-grained log data from an online fraction game to unpack how splitting (i.e. partitioning a whole into equal-sized parts) impacts learning. Study 1 demonstrated that playing the game significantly improved students' fraction understanding. In addition, a cluster analysis suggested that exploring splitting was beneficial. Study 2 replicated the learning results, and a cluster analysis showed that compared to early game play, later game play showed more optimal splitting strategies. In addition, in looking at the types of transitions that were possible between a student's early cluster categorization and later cluster categorization, we found that some types of transitions were more beneficial for learning than others.

In this paper, we present two studies examining how high school students learn to program in a mobile, social programming environment that we have developed and deployed ("IPRO"). IPRO is delivered, with an associated curriculum, as an iPod Touch app and is freely and publicly available. We find that the affordances of mobility and collaboration in IPRO deployed in a short enactment ([similarity]90 minutes) lead to improved performance on programming content targets, improved performance on computational content transfer targets, and improved attitudes towards programming and computer science more generally. (Contains 7 tables and 4 figures.)

The learning sciences community's interest in learning analytics (LA) has been growing steadily over the past several years. Three recent symposia on the theme (at the American Educational Research Association 2011 and 2012 annual conferences, and the International Conference of the Learning Sciences 2012), organized by Paulo Blikstein, led to the meeting of learning scientists working in this area and ultimately generated the proposal for this special issue. In the two years that the authors have worked on putting together this special issue, the task of writing an introduction has become both much simpler and significantly more difficult. On the one hand, many of the trends that are driving the increasing attention to LA--big data, the Cloud--have become so prominent that the authors can count on readers to have some familiarity with them. Thus, the authors of this article do not need to start at the beginning of the discussion of LA for the "Journal of the Learning Sciences" ("JLS") audience. On the other hand, the scope of the field and the potential applications have grown tremendously in this short time. The result is that, if anything, the authors feel that they have fallen further behind. Although the educational data mining and LA communities have produced a steady stream of interesting results, work in education has far to go in order to reap the benefits for student learning that, say, businesses have reaped in advertising. The purpose of this special issue is to provide a focal point for researchers in learning sciences to understand and discuss the potential of LA. It is the hope of these authors that the special issue can introduce the community to the possibilities of LA and frame discussions of the future role of LA in the learning sciences.

Many have suggested that tinkering plays a critical role in novices learning to program, and recent work in learning analytics (Baker & Yacef, 2009 Blikstein, 2011) allows us to describe new relationships in the process. Using learning analytics, we explore how students progress from exploration, through tinkering, to refinement, a pathway that we term EXTIRE. The work contributes to learning sciences by: showing empirical support for previously theorized processes; identifying a role of tinkering in novices' learning; and presenting a data-driven approach to creating process descriptions. Furthermore, our findings illuminate how tinkering can be a valuable approach for novices.