Search

Catalytic RNAs (ribozymes) were central to early stages of life on earth. The first ribozymes probably emerged in the presence of prebiotically generated peptides because amino acids can be generated under abiotic conditions, and amino acids can oligomerize into peptides under prebiotically plausible conditions. Here we tested whether the presence of prebiotically plausible peptides could have aided the emergence of ribozymes, by an in vitro selection of self-triphosphorylation ribozymes from random sequence in the presence of ten different octapeptides. These peptides were composed of ten different, prebiotically plausible amino acids, each as mixture of d- and l-stereoisomers. After five rounds of selection and high throughput sequencing analysis, ten ribozymes that appeared most promising for peptide benefits were tested biochemically for possible benefits from each of the ten peptides. The strongest peptide benefit enhanced ribozyme activity by 2.6-fold, similar to the effect from an increase in the pH by one-half unit. Four arbitrarily chosen ribozymes from a previous selection without peptides showed no significant change in their activity in the presence of the ten peptides. Therefore, the used prebiotically plausible peptides - peptides without evolutionarily optimized sequence, without cationic or aromatic side chains - did not provide a strong benefit for the emergence of ribozyme activity. This finding stands in contrast to previously identified polycationic peptides, conjugates between peptides and polyaromatic hydrocarbons, and modern mRNA encoded proteins, all of which can strongly increase ribozyme function. The results are discussed in the context of origins of life.

Early stages of life likely employed catalytic RNAs (ribozymes) in many functions that are today filled by proteins. However, the earliest life forms must have emerged from heterogenous chemical mixtures, which included amino acids, short peptides, and many other compounds. Here we explored whether the presence of short peptides can help the emergence of catalytic RNAs. To do this, we conducted an in vitro selection for catalytic RNAs from randomized sequence in the presence of ten different peptides with a prebiotically plausible length of eight amino acids. This in vitro selection generated dozens of ribozymes, one of them with ∼900-fold higher activity in the presence of one specific peptide. Unexpectedly, the beneficial peptide had retained its N-terminal Fmoc protection group, and this group was required to benefit ribozyme activity. The same, or higher benefit resulted from peptide conjugates with prebiotically plausible polyaromatic hydrocarbons (PAHs) such as fluorene and naphthalene. This shows that PAH-peptide conjugates can act as potent cofactors to enhance ribozyme activity. The results are discussed in the context of the origin of life.

INTRODUCTION: Children and adolescents often do not receive mental healthcare when they need it. By 2021, the complex impact of the COVID-19 pandemic, structural racism, inequality in access to healthcare, and a growing shortage of mental health providers led to a national emergency in child and adolescent mental health in the United States. The need for effective, accessible treatment is more pressing than ever. Interdisciplinary, team-based pediatric integrated mental healthcare has been shown to be efficacious, accessible, and cost-effective. METHODS: In response to the youth mental health crisis, Rady Childrens Hospital-San Diegos Transforming Mental Health Initiative aimed to increase early identification of mental illness and improve access to effective treatment for children and adolescents. A stakeholder engagement process was established with affiliated pediatric clinics, community mental health organizations, and existing pediatric integrated care programs, leading to the development of the Primary Care Mental Health Integration program and drawing from established models of integrated care: Primary Care Behavioral Health and Collaborative Care. RESULTS: As of 2023, the Primary Care Mental Health Integration program established integrated care teams in 10 primary care clinics across San Diego and Riverside counties in California. Measurement-based care has been implemented and preliminary results indicate that patient response to therapy has resulted in a 44% reduction in anxiety symptoms and a 62% decrease in depression symptoms. The program works toward fiscal sustainability via fee-for-service reimbursement and more comprehensive payor contracts. The impact on patients, primary care provider satisfaction, measurement-based care, funding strategies, as well as challenges faced and changes made will be discussed using the lens of the Reach, Effectiveness, Adoption, Implementation and Maintenance framework. DISCUSSION: Preliminary results suggest that the Primary Care Mental Health Integration is a highly collaborative integrated care model that identifies the needs of children and adolescents and delivers brief, evidence informed treatment. The successful integration of this model into 10 primary care clinics over 3 years has laid the groundwork for future program expansion. This model of care can play a role addressing youth mental health and increasing access to care. Challenges, successes, and lessons learned will be reviewed.

Assessments of scientific reasoning that capture the intertwining aspects of conceptual, procedural and epistemic knowledge are often associated with intensive qualitative analyses of student responses to open-ended questions, work products, interviews, discourse and classroom observations. While such analyses provide evaluations of students' reasoning skills, they are not scalable. The purpose of this study is to develop a three-tiered multiple-choice assessment to measure students' reasoning about biological phenomena and to understand the affordances and limitations of such an assessment. To validate the assessment and to understand what the assessment measures, qualitative and quantitative data were collected and analyzed, including read-aloud, focus group interviews and analysis of large sample data sets. These data served to validate our three-tiered assessment called the Assessment of Biological Reasoning (ABR) consisting of 10 question sets focused on core biological concepts. Further examination of our data suggests that students' reasoning is intertwined in such a way that procedural and epistemic knowledge is reliant on and given meaning by conceptual knowledge, an idea that pushes against the conceptualization that the latter forms of knowledge construction are more broadly applicable across disciplines.

Women and girls, particularly women and girls of color, remain underrepresented in STEM disciplines. This underrepresentation begins as early as late elementary school age. Educators, particularly those in informal STEM education, can help address gender inequity in STEM by understanding how research can be translated into actionable strategies. This article summarizes research on gender equitable practices for middle school girls in the last decade and addresses the disconnect between research and practice by presenting the findings in a way that educators can immediately act on. The research falls into six strategies that have demonstrated positive influences on gender inequity in STEM education: (1) connecting STEM experiences to girls' lives; (2) supporting girls as they investigate questions and solve problems using STEM practices; (3) empowering girls to embrace struggle, overcome challenges, and increase self-confidence in STEM; (4) encouraging girls to identify and challenge STEM stereotypes; (5) emphasizing that STEM is collaborative, social, and community-oriented; (6) providing opportunities for girls to interact with and learn from diverse STEM role models. Our review highlights that each of these strategies are important to developing positive STEM identities in girls, particularly girls of color, which can help them to bridge the STEM gender and racial gap.

Background We sought to determine recurrent stroke predictors among patients with embolic strokes of undetermined source (ESUS). Methods and Results We applied Cox proportional hazards models to identify clinical features associated with recurrent stroke among participants enrolled in RE-SPECT ESUS (Randomized, Double-Blind, Evaluation in Secondary Stroke Prevention Comparing the Efficacy and Safety of the Oral Thrombin Inhibitor Dabigatran Etexilate Versus Acetylsalicylic Acid in Patients With Embolic Stroke of Undetermined Source) trial, an international clinical trial evaluating dabigatran versus aspirin for patients with ESUS. During a median follow-up of 19 months, 384 of 5390 participants had recurrent stroke (annual rate, 4.5%). Multivariable models revealed that stroke or transient ischemic attack before the index event (hazard ratio [HR], 2.27 [95% CI, 1.83-2.82]), creatinine clearance

Background Increasing arterial stiffness is a prominent feature of the aging cardiovascular system. Arterial stiffening leads to fundamental alterations in central hemodynamics with widespread detrimental implications for organ function resulting in significant morbidity and death, and specific therapies to address the underlying age‐related structural arterial remodeling remain elusive. The present study investigates the potential of the recently clinically available dual angiotensin receptor–neprilysin inhibitor (ARNI) sacubitril/valsartan (LCZ696) to counteract age‐related arterial fibrotic remodeling and stiffening in 1‐year‐old mice. Methods and Results Treatment of in 1‐year‐old mice with ARNI (sacubitril/valsartan), in contrast to angiotensin receptor blocker monotherapy (valsartan) and vehicle treatment (controls), significantly decreases structural aortic stiffness (as measured by in vivo pulse‐wave velocity and ex vivo aortic pressure myography). This phenomenon appears, at least partly, independent of (indirect) blood pressure effects and may be related to a direct antifibrotic interference with aortic smooth muscle cell collagen production. Furthermore, we find aortic remodeling and destiffening due to ARNI treatment to be associated with improved parameters of cardiac diastolic function in aged mice. Conclusions This study provides preclinical mechanistic evidence indicating that ARNI‐based interventions may counteract age‐related arterial stiffening and may therefore be further investigated as a promising strategy to improve cardiovascular outcomes in the elderly.

Science reforms in national K-12 science education standards position engineering as a discipline that can be productively integrated into science curricula. This integrated approach presents science as foundational to engineering and engineering as a tool to contextualize and reinforce science ideas such that students come to develop understandings about the natural and engineered worlds. To better understand if integrating engineering into science classrooms achieves the promise described in national reforms, we explored how elementary school students came to understand what is expected of them when asked to engage in an integrated science and engineering unit and whether their understandings represent epistemologically productive ways of integrating the doing of science and engineering. For this purpose, we examined video recordings, transcripts, and classroom artifacts of tasks from a 9-week unit contextualized in an engineering challenge in which students engaged in activities to explore, design, and build simple circuits devices to develop explanations of energy movement in a circuit. Our findings suggest that an integrated approach may be more problematic than promising; while at times students took up integrated tasks as opportunities to wonder about, question, and explore materials that sparked their interest, their framing of the tasks did not align with the vision for integration called for in current reform documents.

IntroductionChildren and adolescents often do not receive mental healthcare when they need it. By 2021, the complex impact of the COVID-19 pandemic, structural racism, inequality in access to healthcare, and a growing shortage of mental health providers led to a national emergency in child and adolescent mental health in the United States. The need for effective, accessible treatment is more pressing than ever. Interdisciplinary, team-based pediatric integrated mental healthcare has been shown to be efficacious, accessible, and cost-effective.MethodsIn response to the youth mental health crisis, Rady Children’s Hospital-San Diego’s Transforming Mental Health Initiative aimed to increase early identification of mental illness and improve access to effective treatment for children and adolescents. A stakeholder engagement process was established with affiliated pediatric clinics, community mental health organizations, and existing pediatric integrated care programs, leading to the development of the Primary Care Mental Health Integration program and drawing from established models of integrated care: Primary Care Behavioral Health and Collaborative Care.ResultsAs of 2023, the Primary Care Mental Health Integration program established integrated care teams in 10 primary care clinics across San Diego and Riverside counties in California. Measurement-based care has been implemented and preliminary results indicate that patient response to therapy has resulted in a 44% reduction in anxiety symptoms and a 62% decrease in depression symptoms. The program works toward fiscal sustainability via fee-for-service reimbursement and more comprehensive payor contracts. The impact on patients, primary care provider satisfaction, measurement-based care, funding strategies, as well as challenges faced and changes made will be discussed using the lens of the Reach, Effectiveness, Adoption, Implementation and Maintenance framework.DiscussionPreliminary results suggest that the Primary Care Mental Health Integration is a highly collaborative integrated care model that identifies the needs of children and adolescents and delivers brief, evidence informed treatment. The successful integration of this model into 10 primary care clinics over 3 years has laid the groundwork for future program expansion. This model of care can play a role addressing youth mental health and increasing access to care. Challenges, successes, and lessons learned will be reviewed.

WNK (With no Lysine [K]) kinases have critical roles in the maintenance of ion homeostasis and the regulation of cell volume. Their overactivation leads to pseudohypoaldosteronism type II (Gordon syndrome) characterized by hyperkalemia and high blood pressure. More recently, WNK family members have been shown to be required for the development of the nervous system in mice, zebrafish, and flies, and the cardiovascular system of mice and fish. Furthermore, human WNK2 and Drosophila Wnk modulate canonical Wnt signaling. In addition to a well-conserved kinase domain, animal WNKs have a large, poorly conserved C-terminal domain whose function has been largely mysterious. In most but not all cases, WNKs bind and activate downstream kinases OSR1/SPAK, which in turn regulate the activity of various ion transporters and channels. Here, we show that Drosophila Wnk regulates Wnt signaling and cell size during the development of the wing in a manner dependent on Fray, the fly homolog of OSR1/SPAK. We show that the only canonical RF(X)V/I motif of Wnk, thought to be essential for WNK interactions with OSR1/SPAK, is required to interact with Fray in vitro. However, this motif is unexpectedly dispensable for Fray-dependent Wnk functions in vivo during fly development and fluid secretion in the Malpighian (renal) tubules. In contrast, a structure function analysis of Wnk revealed that the less-conserved C-terminus of Wnk, that recently has been shown to promote phase transitions in cell culture, is required for viability in vivo. Our data thus provide novel insights into unexpected in vivo roles of specific WNK domains.

Abstract Background The prevalence of diabetes mellitus has risen considerably and currently affects more than 422 million people worldwide. Cardiovascular diseases including myocardial infarction and heart failure represent the major cause of death in type 2 diabetes (T2D). Diabetes patients exhibit accelerated aortic stiffening which is an independent predictor of cardiovascular disease and mortality. We recently showed that aortic stiffness precedes hypertension in a mouse model of diabetes (db/db mice), making aortic stiffness an early contributor to cardiovascular disease development. Elucidating how aortic stiffening develops is a pressing need in order to halt the pathophysiological process at an early time point. Methods To assess EndMT occurrence, we performed co-immunofluorescence staining of an endothelial marker (CD31) with mesenchymal markers (α-SMA/S100A4) in aortic sections from db/db mice. Moreover, we performed qRT-PCR to analyze mRNA expression of EndMT transcription factors in aortic sections of db/db mice and diabetic patients. To identify the underlying mechanism by which EndMT contributes to aortic stiffening, we used aortas from db/db mice and diabetic patients in combination with high glucose-treated human umbilical vein endothelial cells (HUVECs) as an in vitro model of diabetes-associated EndMT. Results We demonstrate robust CD31/α-SMA and CD31/S100A4 co-localization in aortic sections of db/db mice which was almost absent in control mice. Moreover, we demonstrate a significant upregulation of EndMT transcription factors in aortic sections of db/db mice and diabetic patients. As underlying regulator, we identified miR-132-3p as the most significantly downregulated miR in the micronome of db/db mice and high glucose-treated HUVECs. Indeed, miR-132-3p was also significantly downregulated in aortic tissue from diabetic patients. We identified Kruppel-like factor 7 (KLF7) as a target of miR-132-3p and show a significant upregulation of KLF7 in aortic sections of db/db mice and diabetic patients as well as in high glucose-treated HUVECs. We further demonstrate that miR-132-3p overexpression and KLF7 downregulation ameliorates EndMT in high glucose-treated HUVECs. Conclusions We demonstrate for the first time that EndMT contributes to aortic stiffening in T2D. We identified miR-132-3p and KLF7 as novel EndMT regulators in this context. Altogether, this gives us new insights in the development of aortic stiffening in T2D.

Background Nerve cross-sectional area (CSA) reference values in high-resolution ultrasound for children and adolescents are influenced by demographic and anthropometric factors such as age, height and weight. Objectives The influence of hand volume as an additional morphometric factor was evaluated and nerve echogenicity was analyzed in a prospective cross-sectional study. Methods CSA were measured in 30 healthy children and adolescents from 2 to 17 years in the median, ulnar, radial, tibial, peroneal and sural nerves. Height, weight, age, handedness and gender were recorded, the volume of the hands was measured using the water displacement method. The intra-nerve CSA variability (INV), left/right ratios and absolute differences were calculated. Age groups were compared by the Kruskal-Wallis test. The influence of demographic factors was analyzed using Spearman correlation and multiple linear regression. Echogenicity and fraction of black were determined for each nerve segment. Results Nerve CSA values were consistently lower than those reported for adults and correlated in all measured nerve sites with age, height, weight and hand volume. Weight showed the highest correlation coefficient (R = .95) with the best fitting model predicting CSA. Correlation coefficients were higher in a linear than in a logarithmic model. Ratios were stable, the absolute differences increased with age and were significantly different between age groups. Most nerves showed a mixed or hypoechogenic pattern in echogenicity analysis, hyperechogenicity is less frequently observed. Conclusions Nerve CSA in children and adolescents is lower than in adults and increases proportionally during growth with a constant INV and left/right ratio in different age groups. Weight and age are predominant anthropometric factors predicting nerve size. Hand volume is correlated with nerve size, but does not predict CSA independently. Echogenicity can provide additional information on nerve structure.

Computing fields are foundational to most STEM disciplines and the only STEM discipline to show a consistent decline in women's representation since 1990, making it an important field for STEM educators to study. The explanation for the underrepresentation of women and girls in computing is twofold: a sense that they do not fit within the stereotypes associated with computing and a lack of access to computer games and technologies beginning at an early age (Richard, 2016). Informal coding education programs are uniquely situated to counter these hurdles because they can offer additional resources and time for engagement in specially designed activities developed around best practices to improve girls coding identities (National Research Council [NRC], 2009). We draw upon research by Calabrese Barton et al. (2013) and Carlone and Johnson's (2007) research as a lens by which to examine girls' coding identity work in an informal coding education setting--a concept not currently defined in the science education research literature. In this paper, we describe the coding identity trajectories of three middle school girls who participated in a coding camp: Lilly, Victoria, and Beth. Our results provide a conceptual framework that will guide future research on coding identity that better encompasses the role of recognition by educators and peers on youth's coding identity development. This framework can be used to guide broader science education identity research, particularly as it applies to informal STEM education settings that work to engage students, especially girls, across the STEM spectrum.

Background: Prior to the conduct of the Head Position in Stroke Trial (HeadPoST), an international survey ( n = 128) revealed equipoise for selection of head position in acute ischemic stroke. Objectives: We aimed to determine whether equipoise exists for head position in spontaneous hyperacute intracerebral hemorrhage (ICH) patients following HeadPoST. Design: This is an international, web-distributed survey focused on head positioning in hyperacute ICH patients. Methods: A survey was constructed to examine clinicians’ beliefs and practices associated with head positioning of hyperacute ICH patients. Survey items were developed with content experts, piloted, and then refined before distributing through stroke listservs, social media, and purposive snowball sampling. Data were analyzed using descriptive statistics and χ 2 test. Results: We received 181 responses representing 13 countries on four continents: 38% advanced practice providers, 32% bedside nurses, and 30% physicians; overall, participants had median 7 [interquartile range (IQR) = 3–12] years stroke experience with a median of 100 (IQR = 37.5–200) ICH admissions managed annually. Participants disagreed that HeadPoST provided ‘definitive evidence’ for head position in ICH and agreed that their ‘written admission orders include 30-degree head positioning’, with 54% citing hospital policies for this head position in hyperacute ICH. Participants were unsure whether head positioning alone could influence ICH longitudinal outcomes. Use of serial proximal clinical and technology measures during the head positioning intervention were identified by 82% as the most appropriate endpoints for future ICH head positioning trials. Conclusion: Interdisciplinary providers remain unconvinced by HeadPoST results that head position does not matter in hyperacute ICH. Future trials examining the proximal effects of head positioning on clinical stability in hyperacute ICH are warranted.

Objective: Health sciences librarians frequently engage in scholarly publication, both with other librarians undertaking intradisciplinary scholarship, and increasingly as members of research teams centered in other disciplines. We sought to assess the emotional and institutional context of authorship among health sciences librarians, including emotions experienced during authorship negotiation, the frequency with which authorship is denied, and the correlation of perceived support from supervisors and the research community with the number of publications produced. Methods: 342 medical and health sciences librarians took an online survey of 47 questions regarding emotions experienced when asking for authorship, denial of authorship, if they have been given authorship without asking, and the extent to which they felt supported to conduct research in their current job. Results: Authorship negotiation creates varied and complex emotions among librarians. The emotions reported differed when negotiating authorship with librarian colleagues and when negotiating authorship with professionals in another field. Negative emotions were reported when asking either type of colleague for authorship. Respondents reported feeling mostly supported and encouraged by their supervisors, research communities, and workplaces. Nearly one quarter (24.4%) of respondents reported being denied authorship by colleagues outside of their departments. Perceived research appreciation and support by the research community is correlated with the total number of articles or publications produced by librarians. Conclusions: Authorship negotiation among health sciences librarians involves complex and frequently negative emotions. Denial of authorship is frequently reported. Institutional and professional support appear to be critical to publication among health sciences librarians.

Abstract Introduction Based on demographical trends and the expected worldwide increase in the number of individuals with atrial fibrillation, the rate of patients who are on oral anticoagulation therapy for secondary prevention of stroke rises continuously. Despite correct drug intake and good adherence to the respective medication, recurrent ischemic stroke still occurs in ~ 3% of patients. The question how to deal with such patients with regard to intravenous thrombolysis with rt-PA within the 4.5 h time window is of great relevance for daily clinical routine. However, international guidelines can be considered heterogenous or do even lack recommendations on this topic especially in light of available reversal agents. Therefore, we provide this SOP. Comments Beyond the identification of acute stroke patients on oral anticoagulation therapy, the type of medication, time since last intake, renal function and laboratory exams as well as the availability of reversal agents have to be considered before rt-PA application and potential endovascular therapy. Treatment on a Stroke Unit or Neuro-ICU is certainly recommended in any of those patients. Conclusions This standardized operating procedure was designed to guide stroke physicians through questions on eligibility for rt-PA treatment in patients with acute ischemic stroke who are on approved oral anticoagulation therapy thereby increasing the number of patients benefitting from thrombolysis and minimizing door-to-needle times.

This research, a descriptive qualitative analysis of self-defined serious illness goals, expands the knowledge of what goals are important beyond the physical-making existing disease-specific guidelines more holistic. Integration of goals of care discussions and documentation is standard for quality palliative care but not consistently executed into general and specialty practice. Over 14 months, lay health-care workers (care guides) provided monthly supportive visits for 160 patients with advanced heart failure, cancer, and dementia expected to die in 2 to 3 years. Care guides explored what was most important to patients and documented their self-defined goals on a medical record flow sheet. Using definitions of an expanded set of whole-person domains adapted from the National Consensus Project (NCP) Clinical Practice Guidelines for Quality Palliative Care, 999 goals and their associated plans were deductively coded and examined. Four themes were identified-medical, nonmedical, multiple, and global. Forty percent of goals were coded into the medical domain; 40% were coded to nonmedical domains-social (9%), ethical (7%), family (6%), financial/legal (5%), psychological (5%), housing (3%), legacy/bereavement (3%), spiritual (1%), and end-of-life care (1%). Sixteen percent of the goals were complex and reflected a mix of medical and nonmedical domains, "multiple" goals. The remaining goals (4%) were too global to attribute to an NCP domain. Self-defined serious illness goals express experiences beyond physical health and extend into all aspects of whole person. It is feasible to elicit and record serious illness goals. This approach to goals can support meaningful person-centered care, decision-making, and planning that accords with individual preferences of late life.

Abstract Due to a steeply growing number of energy assets, the increasingly decentralized and segmented energy sector fuels the potential for new digital use cases. In this paper, we focus our attention on the application field of asset logging, which addresses the collection, documentation, and usage of relevant asset data for direct or later verification. We identified a number of promising use cases that so far have not been implemented; supposedly due to the lack of a suitable technical infrastructure. Besides the high degree of complexity associated with various stakeholders and the diversity of assets involved, the main challenge we found in asset logging use cases is to guarantee the tamper-resistance and integrity of the stored data while meeting scalability, addressing cost requirements, and protecting sensitive data. Against this backdrop, we present a blockchain-based platform and argue that it can meet all identified requirements. Our proposed technical solution hierarchically aggregates data in Merkle trees and leverages Merkle proofs for the efficient and privacy-preserving verification of data integrity, thereby ensuring scalability even for highly frequent data logging. By connecting all stakeholders and assets involved on the platform through bilateral and authenticated communication channels and adding a blockchain as a shared foundation of trust, we implement a wide range of asset logging use cases and provide the basis for leveraging platform effects in future use cases that build on verifiable data. Along with the technical aspects of our solution, we discuss the challenges of its practical implementation in the energy sector and the next steps for testing in a regulatory sandbox approach.

Patients with type 2 diabetes (T2D) are threatened by excessive cardiovascular morbidity and mortality. While accelerated arterial stiffening may represent a critical mechanistic factor driving cardiovascular risk in T2D, specific therapies to contain the underlying diabetic arterial remodeling have been elusive. The present translational study investigates the role of microRNA-29b (miR-29b) as a driver and therapeutic target of diabetic aortic remodeling and stiffening. Using a murine model (db/db mice), as well as human aortic tissue samples, we find that diabetic aortic remodeling and stiffening is associated with medial fibrosis, as well as fragmentation of aortic elastic layers. miR-29b is significantly downregulated in T2D and miR-29b repression is sufficient to induce both aortic medial fibrosis and elastin breakdown through upregulation of its direct target genes COL1A1 and MMP2 thereby increasing aortic stiffness. Moreover, antioxidant treatment restores aortic miR-29b levels and counteracts diabetic aortic remodeling. Concluding, we identify miR-29b as a comprehensive—and therefore powerful—regulator of aortic remodeling and stiffening in T2D that moreover qualifies as a (redox-sensitive) target for therapeutic intervention.

The safety and efficacy of hyperacute reperfusion therapies in childhood stroke due to focal cerebral arteriopathy (FCA) with an infectious and inflammatory component is unknown. Lyme neuroborreliosis (LNB) is reported as a rare cause of childhood stroke. Intravenous thrombolysis (IVT) and endovascular therapy (EVT) have not been reported in LNB-associated stroke in children. We report two children with acute stroke associated with LNB who underwent hyperacute stroke treatment. A systematic review of the literature was performed to identify case reports of LNB-associated childhood stroke over the last 20 years. Patient 1 received IVT within 73 min after onset of acute hemiparesis and dysarthria; medulla oblongata infarctions were diagnosed on magnetic resonance imaging (MRI). Patient 2 received successful EVT 6.5 hr after onset of progressive tetraparesis, coma, and decerebrate posturing caused by basilar artery occlusion with bilateral pontomesencephalic infarctions. Both patients exhibited a lymphocytic cerebrospinal fluid (CSF) pleocytosis and elevated antibody index (AI) to Borrelia burgdorferi . Antibiotic treatment, steroids, and platelet inhibitors including tirofiban infusion in patient 2 were administered. No side effects were observed. On follow-up, patient 1 showed good recovery and patient 2 was asymptomatic. In the literature, 12 cases of LNB-associated childhood stroke were reported. LNB-associated infectious and inflammatory FCA is not a medical contraindication for reperfusion therapies in acute childhood stroke. Steroids are discussed controversially in inflammatory FCA due to LNB. Intensified antiplatelet regimes may be considered; secondary prophylaxis with acetyl-salicylic acid (ASA) is recommended because of a high risk of early stroke recurrence.

Background We sought to determine recurrent stroke predictors among patients with embolic strokes of undetermined source (ESUS). Methods and Results We applied Cox proportional hazards models to identify clinical features associated with recurrent stroke among participants enrolled in RE‐SPECT ESUS (Randomized, Double‐Blind, Evaluation in Secondary Stroke Prevention Comparing the Efficacy and Safety of the Oral Thrombin Inhibitor Dabigatran Etexilate Versus Acetylsalicylic Acid in Patients With Embolic Stroke of Undetermined Source) trial, an international clinical trial evaluating dabigatran versus aspirin for patients with ESUS. During a median follow‐up of 19 months, 384 of 5390 participants had recurrent stroke (annual rate, 4.5%). Multivariable models revealed that stroke or transient ischemic attack before the index event (hazard ratio [HR], 2.27 [95% CI, 1.83–2.82]), creatinine clearance

Aim: The SAMe-TT2R2 score helps identify patients with atrial fibrillation (AF) likely to have poor anticoagulation control during anticoagulation with vitamin K antagonists (VKA) and those with scores >2 might be better managed with a target-specific oral anticoagulant (NOAC). We hypothesized that in clinical practice, VKAs may be prescribed less frequently to patients with AF and SAMe-TT2R2 scores >2 than to patients with lower scores. Methods and results: We analyzed the Phase III dataset of the Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF), a large, global, prospective global registry of patients with newly diagnosed AF and ≥1 stroke risk factor. We compared baseline clinical characteristics and antithrombotic prescriptions to determine the probability of the VKA prescription among anticoagulated patients with the baseline SAMe-TT2R2 score >2 and ≤ 2. Among 17,465 anticoagulated patients with AF, 4,828 (27.6%) patients were prescribed VKA and 12,637 (72.4%) patients an NOAC: 11,884 (68.0%) patients had SAMe-TT2R2 scores 0-2 and 5,581 (32.0%) patients had scores >2. The proportion of patients prescribed VKA was 28.0% among patients with SAMe-TT2R2 scores >2 and 27.5% in those with scores ≤2. Conclusions: The lack of a clear association between the SAMe-TT2R2 score and anticoagulant selection may be attributed to the relative efficacy and safety profiles between NOACs and VKAs as well as to the absence of trial evidence that an SAMe-TT2R2-guided strategy for the selection of the type of anticoagulation in NVAF patients has an impact on clinical outcomes of efficacy and safety. The latter hypothesis is currently being tested in a randomized controlled trial. Clinical trial registration: URL: https://www.clinicaltrials.gov//Unique identifier: NCT01937377, NCT01468701, and NCT01671007.

The Next Generation Science Standards support understanding of the nature of science as it is practiced and experienced in the real world through interconnected concepts to be imbedded within scientific practices and crosscutting concepts. This study explored how fourth and fifth grade elementary students' views of nature of science change when they engage in a technology-enhanced, scientific inquiry-oriented curriculum that takes place across formal and informal settings. Results suggest that student engagement in technology-enhanced inquiry activities that occur in informal and formal settings when supported through explicit instruction focused on metacognitive and social knowledge construction can improve elementary students' understanding of nature of science.

U.S. mathematics teachers face considerable pressures to keep up with pacing guides and to prepare students for standardized tests. At the same time, they are called upon to engage students in innovative exploratory activities and to incorporate new technologies into their lessons. These competing priorities pose considerable challenges. Against this backdrop, we investigated how middle-school mathematics teachers incorporated play into lessons involving interactive computer simulations (sims). The teachers used PhET sims in a variety of lessons. Following general guidelines for teaching with PhET sims, these lessons included a short period of play prior to more structured work with the sim. Our analysis of 15 mathematics lessons involving play led to the identification of four characteristics that distinguish the play phases of these lessons. Based on combinations of these characteristics, we identified three specific profiles of play, which lie at different points along a continuum of priorities from foregrounding students' ideas to keeping pace. We discuss the implications associated with each profile of the play phase, and we begin to articulate a theory that frames teaching with play as a matter of balancing divergent and convergent modes of activity.

Mathematics teachers are increasingly encouraged to incorporate computer-based technology in their classrooms, but these tools require strategic use in order to provide any substantive improvement to student understanding. This paper reports on how three middle-school mathematics teachers leveraged one particular tool, PhET interactive simulations (sims), quite differently. Using the perspective of instrumental orchestration, we describe five different sim and student roles that emerged in their lessons. These roles prompted different lesson orchestrations and varying opportunities for students to engage in the mathematics. Additionally, we present data from interviews with the teachers that document their beliefs about the affordances of PhET sims as we offer explanations for why each teacher orchestrated lessons differently. The interviews revealed each teacher's preferred role in the classroom, demonstrating how tension between certain roles may inhibit the orchestration of an effective sim-based lesson. We conclude by sharing implications for sim-based mathematics instruction and teacher professional development.