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Extreme weather events have significant adverse costs for individuals, firms, communities, regional, and national economies. Extreme Event Attribution (EEA), a methodology that examines the degree to which anthropogenic greenhouse gas emissions had changed the occurrence of specific extreme weather events, allows us to quantify the climate-change-induced component of these costs. We use EEA to aggregate the global economic damage from extreme weather events that is attributable to anthropogenic climate change. For that, we collect data from all available attribution studies which estimate the Fraction of Attributable Risk (FAR) for extreme events, and combine these FAR estimates with data on the socio-economic costs of these events. With extrapolation for missing data, we then arrive at our benchmark estimates. We find that US$ 143 billion per year, of the costs of extreme events during the last twenty years, is attributable to anthropogenic climatic change. This EEA-based method for calculating the costs of climate change from extreme weather differs fundamentally from other approaches to climate cost estimation. Those other approaches use macroeconomic modelling embedded within climate models in various types of Integrated Assessment Models (IAM). As we show, our research is not directly comparable, but it does provide a new form of evidence that suggests that most IAMs are substantially under-estimating the current economic costs of climate change. Given some of the data deficiencies we identify in terms of temporal and spatial coverage, the purpose here is not to produce a definitive quantification, but rather to sketch a path towards a more comprehensive and reliable estimation. As better EEA studies and more thorough and exhaustive economic costs estimates for extreme events become available over time, and the method is refined, the precision of this approach's estimates will increase in tandem.

Background The dissemination of MBLs compromises effective use of many β-lactams in the treatment of patients with life-threatening bacterial infections. Predicted global increases in the prevalence of MBL-producing carbapenem-resistant Enterobacterales (CRE) are being realized, yielding infections that are untreatable with existing therapies including newly approved β-lactam/β-lactamase inhibitor combinations. Developing MBL inhibitors (MBLIs) now is essential to address the growing threat that MBL-producing CRE pose to patients. Methods A novel MBLI series was assessed by susceptibility testing and time–kill assays. Target activity and selectivity was evaluated using bacterial NDM, VIM and IMP enzyme assays and human matrix metallopeptidase enzyme assays, respectively, and cytotoxicity was assessed in HepG2 cells. In vivo efficacy of meropenem/MBLI combinations was evaluated in a mouse thigh infection model using an NDM-1-producing Escherichia coli strain. Results Combination of MBLIs with carbapenems reduced MICs for NDM/IMP/VIM-producing Enterobacterales by up to 128-fold compared with the carbapenems alone. Supplementation of meropenem with the promising compound 272 reduced the MIC90 from 128 to 0.25 mg/L in a panel of MBL-producing CRE clinical isolates (n = 115). Compound 272 restored the bactericidal activity of meropenem and was non-cytotoxic, potentiating the antimicrobial action of meropenem through specific inhibition of NDM, IMP and VIM. In vivo efficacy was achieved in a mouse thigh infection model with meropenem/272 dosed subcutaneously. Conclusions We have developed a series of rationally designed MBLIs that restore activity of carbapenems against NDM/IMP/VIM-producing Enterobacterales. This series warrants further development towards a novel combination therapy that combats antibiotic-resistant organisms, which pose a critical threat to human health.

This meta-analysis systematically reviewed the most up-to-date literature to determine the effectiveness of reading interventions on measures of word and pseudoword reading, reading comprehension, ...

There is an increasingly urgent and unmet medical need for novel antibiotic drugs that tackle infections caused by multidrug-resistant (MDR) pathogens. Novel bacterial type II topoisomerase inhibitors (NBTIs) are of high interest due to limited cross-resistance with fluoroquinolones, however analogues with Gram-negative activity often suffer from hERG channel inhibition. A novel series of bicyclic-oxazolidinone inhibitors of bacterial type II topoisomerase were identified which display potent broad-spectrum anti-bacterial activity, including against MDR strains, along with an encouraging in vitro safety profile. In vivo proof of concept was achieved in a A. baumannii mouse thigh infection model.

INTRODUCTION: Rotavirus is one of the most common pathogens causing diarrhea in children

Antigen‐specific B‐cell responses require endosomal trafficking to regulate antigen uptake and presentation to helper T cells, and to control expression and signaling of immune receptors. However, the molecular composition of B‐cell endosomal trafficking pathways and their specific roles in B‐cell responses have not been systematically investigated. Here, we report high‐throughput identification of genes regulating B‐cell receptor (BCR)‐mediated antigen internalization using genome‐wide functional screens. We show that antigen internalization depends both on constitutive, clathrin‐mediated endocytosis and on antigen‐induced, clathrin‐independent endocytosis mediated by endophilin A2. Although endophilin A2‐mediated endocytosis is dispensable for antigen presentation, it is selectively required for metabolic support of B‐cell proliferation, in part through regulation of iron uptake. Consequently, endophilin A2‐deficient mice show defects in GC B‐cell responses and production of high‐affinity IgG. The requirement for endophilin A2 highlights a unique importance of clathrin‐independent intracellular trafficking in GC B‐cell clonal expansion and antibody responses., A genome‐wide screen reveals a new clathrin‐independent mechanism of antigen uptake in B lymphocytes. The pathway is regulated by endophilin A2, a protein essential for germinal centre expansion and antibody responses.

Globally the rates of breastfeeding duration are extremely low and postnatal mental health issues are common. As a result, it is important to examine the emotions that underlie these matters. Across two studies (one correlational study N = 160 and one experimental study N = 118), we examined participants’ experiences of shame and guilt when feeding their baby, and the relationship between these emotions with breastfeeding behaviors and internalized stigma. We also examined the psychosocial factors that predict internalized stigma, and whether shame and guilt mediate these relationships. We focused on three factors that have been shown to be associated with internalized stigma in other domains: self-esteem and social support (Study 1), as well as self-efficacy (Study 2). Multiple regression revealed that experienced guilt uniquely predicted a shorter duration of exclusive breastfeeding (Study 1). Higher self-efficacy (Study 2), self-esteem, and perceived social support (Study 1) predicted lower internalized stigma of feeding choice. We found that shame was a mediator for the self-esteem and internalized stigma relationship (Study 1), while guilt was a mediator for the self-efficacy and internalized stigma relationship (Study 2). Our findings highlight the importance of experienced shame and guilt in mothers’ infant feeding experiences. The current results can inform future research and the design of interventions to improve breastfeeding rates and reduce feelings of stigma.

OBJECTIVES Functional hypothalamic amenorrhoea (FHA) is a common cause of amenorrhoea, but diagnosis can be challenging. The aim of this study was to investigate the clinical and biochemical features of FHA, compared to that of polycystic ovarian syndrome (PCOS) and assess the diagnostic performance of the different parameters for differentiating the two conditions. DESIGN AND PATIENTS This was a retrospective observational study. We analysed clinical and biochemical parameters of women diagnosed with FHA and PCOS following specialist assessment at the reproductive endocrine gynaecology clinic, St Mary's Hospital. RESULTS Compared with PCOS, women with FHA had significantly lower body mass index (BMI; 20.1 ± 2.9 vs. 31.1 ± 7.8 kg/m2 ; p

SummaryIgE antibodies protect against toxins and parasites, however, they also mediate allergic reactions. In contrast to other antibody isotypes, B cells switched to IgE respond transiently and do not give rise to long-lived plasma cells (PCs) or memory B cells. Although the intrinsic differences of IgE+ B cells have been linked to signaling by the IgE-B cell receptor (BCR), the molecular pathways controlling their behavior remain poorly understood. Here we employ whole-genome CRISPR screening to identify genes regulating IgE+ B cell proliferation, survival and differentiation into PCs. We show that IgE+ B cells are selectively suppressed by the IgE-BCR signaling to intracellular calcium, which inhibits PC differentiation and limits their lifespan after differentiation. Consequently, manipulation of calcium signaling in vivo enhances IgE+ PC responses. Insights from this pathway shed new light on the self-limiting character of IgE responses and open new avenues to eliminate IgE+ PCs in allergy.

In contrast to other antibody isotypes, B cells switched to IgE respond transiently and do not give rise to long-lived plasma cells (PCs) or memory B cells. To better understand IgE-BCR-mediated control of IgE responses, we developed whole-genome CRISPR screening that enabled comparison of IgE

MotivationDrug repositioning allows expedited discovery of new applications for existing compounds, but re-screening vast compound libraries is often prohibitively expensive. “Connectivity mapping” is a process that links drugs to diseases by identifying compounds whose impact on expression in a collection of cells reverses the disease’s impact on expression in disease-relevant tissues. The high throughput LINCS project has expanded the universe of compounds and cell types for which data are available, but even with this effort, many potentially clinically useful combinations are missing. To evaluate the possibility of repurposing drugs this way despite missing data, we compared collaborative filtering with either neighborhood-based or SVD imputation methods to two naive approaches via cross-validation.ResultsMethods were evaluated for their ability to predict drug connectivity despite missing data. Predictions improved when cell type was taken into account. Neighborhood-based collaborative filtering was the most successful method, with the best improvements in non-immortalized primary cells. We also explored which classes of compounds are most and least reliant on cell type for accurate imputation, and we identified connections between related compounds even when many were not measured in the relevant cells. We conclude that even for cells in which drug responses have not been fully characterized, it is possible to identify unassayed drugs that reverse in those cells the expression signatures observed in disease.Contactdonna.slonim@tufts.edu

A narrative support group was run for teenage girls with a first episode of psychosis and a history of bullying. Semi-structured interviews were used to evaluate the impact and effectiveness of this type of therapeutic approach.

The purpose of this replication study was to examine the impact of the Teacher Study Group (TSG) professional development in vocabulary on first-grade teachers' knowledge of vocabulary instruction and observed teaching practice, and on students' vocabulary knowledge. Sixty-two schools from 16 districts in four states were randomly assigned to treatment and control conditions. A total of 182 first-grade teachers and their 1,811 students formed the sample. Treatment teachers received the TSG professional development from October to March. Teachers in the business-as-usual control condition received school/district professional development. A multilevel analysis was conducted to detect impacts. Significant impacts were found for teacher knowledge and observed teaching practice. No impacts were found at the student level.

RNA-binding proteins of the ZFP36 family are best known for inhibiting the expression of cytokines through binding to AU-rich elements in the 3' untranslated region and promoting mRNA decay. Here we identified an indispensable role for ZFP36L1 as the regulator of a post-transcriptional hub that determined the identity of marginal-zone B cells by promoting their proper localization and survival. ZFP36L1 controlled a gene-expression program related to signaling, cell adhesion and locomotion; it achieved this in part by limiting expression of the transcription factors KLF2 and IRF8, which are known to enforce the follicular B cell phenotype. These mechanisms emphasize the importance of integrating transcriptional and post-transcriptional processes by RNA-binding proteins for maintaining cellular identity among closely related cell types.

Background Decomposing a protein-protein interaction network (PPI network) into non-overlapping clusters or communities, sometimes called “network modules,” is an important way to explore functional roles of sets of genes. When the method to accomplish this decomposition is solely based on purely graph-theoretic measures of the interconnection structure of the network, this is often called unsupervised clustering or community detection. In this study, we compare unsupervised computational methods for decomposing a PPI network into non-overlapping modules. A method is preferred if it results in a large proportion of nodes being assigned to functionally meaningful modules, as measured by functional enrichment over terms from the Gene Ontology (GO). Results We compare the performance of three popular community detection algorithms with the same algorithms run after the network is pre-processed by removing and reweighting based on the diffusion state distance (DSD) between pairs of nodes in the network. We call this “detangling” the network. In almost all cases, we find that detangling the network based on the DSD distance reweighting provides more meaningful clusters. Conclusions Re-embedding using the DSD distance metric, before applying standard community detection algorithms, can assist in uncovering GO functionally enriched clusters in the yeast PPI network.

Background Decomposing a protein-protein interaction network (PPI network) into non-overlapping clusters or communities, sometimes called “network modules,” is an important way to explore functional roles of sets of genes. When the method to accomplish this decomposition is solely based on purely graph-theoretic measures of the interconnection structure of the network, this is often called unsupervised clustering or community detection. In this study, we compare unsupervised computational methods for decomposing a PPI network into non-overlapping modules. A method is preferred if it results in a large proportion of nodes being assigned to functionally meaningful modules, as measured by functional enrichment over terms from the Gene Ontology (GO). Results We compare the performance of three popular community detection algorithms with the same algorithms run after the network is pre-processed by removing and reweighting based on the diffusion state distance (DSD) between pairs of nodes in the network. We call this “detangling” the network. In almost all cases, we find that detangling the network based on the DSD distance reweighting provides more meaningful clusters. Conclusions Re-embedding using the DSD distance metric, before applying standard community detection algorithms, can assist in uncovering GO functionally enriched clusters in the yeast PPI network.

Summary Sequence-specific RNA binding proteins (RBP) are important regulators of the immune response. RBP modulate gene expression by regulating splicing, polyadenylation, localization, translation and decay of target mRNAs. Increasing evidence suggests that RBP play critical roles in the development, activation and function of lymphocyte populations in the immune system. This review will discuss the post-transcriptional regulation of gene expression by RBP during lymphocyte development, with particular focus on the Tristetraprolin family of RBP.

Introduction The importance of the antitumor activity of some antimicrobial peptides (AMPs) is being increasingly recognized. The antimicrobial peptide, tachyplesin, has been shown to exhibit anticancer properties and a linear, cysteine deleted analogue (CDT), was found to retain its antibacterial function. Objectives The objective was to test CDT and related analogues against normal mammalian, bacterial, and cancer cells to determine their effectiveness and then utilize specific assays to determine a possible mechanism of action. Methods We used sequence reversal and D-amino acids to synthesize four CDT analogues by solid phase peptide synthesis. A number of assays were used including liposome dye-leakage, antibacterial activity against both Gram-positive and Gram-negative bacterial strains, hemolytic assays, methyl thiazolyl tetrazolium (MTT), and apoptosis to examine their effectiveness as both AMPs and anti-cancer peptides (ACPs). We then tested the analogues for their ability to inhibit proliferation of the human lung cancer cell line, A549. Results We found that D-CDT exhibited the best bactericidal properties of those tested and was not damaging to red blood cells. Both D-CDT and reverse D-CDT showed a dose-dependent reduction of cell viability. However, D-CDT was most effective with an IC50 of 9.814 μM, a value 9-fold lower than that calculated for reverse D-CDT (90.16 μM). Apoptosis does not appear to be a mechanism by which D-CDT exerts its anticancer properties since > 100 μM was required to increase activation of caspase 3. Moreover, the ERK1/2 pathway is also unlikely since only a modest (20%) decrease of activity was observed with > 100 μM D-CDT. However, D-CDT was found to operate via a hyaluronan (HA)-dependent mechanism as pretreatment of the cells with hyaluronidase decreased the cytotoxic effects of D-CDT on A549 cells and increased its IC50 29-fold to 283.9 μM. Conclusion D-CDT is both an effective AMP and ACP, and likely exerts its anticancer effects through both membranolytic as well as an HA-mediated mechanism.

This chapter focuses on a key test of rational choice in CV studies: do estimates of WTP for environmental amenities derived from split-sample (external) tests in CV studies increase as the amount of the good (or the number of goods) increases (i.e., as scope increases), and, if so, are the WTP estimates “adequately†responsive to scope? For the 111 studies of environmental non-use and mixed use/non-use environmental amenities in our study, after fractional allocation of mixed results and appropriate weighting of studies based on common underlying data, more studies fail (54 percent of the total) than pass (46 percent). Contrary to expectations, the percentage of studies failing scope has increased over time: over the 1987–2001 period, 49 percent of the studies failed a scope test vs 59 percent for the 2001–2016 period. We also find that even the scope tests that “pass†often do not exhibit “adequate†scope sensitivity. For the 21 studies that lend themselves to appropriate quantitative analysis, nine have scope elasticities less than 0.10 and 12 have scope elasticities less than 0.2; only three have scope elasticities above 0.5. The high frequency of no or limited scope elasticities documented in this study suggests that warm glow is an important element of measured WTP for non-use environmental amenities.

The novel bacterial topoisomerase inhibitor class is an investigational type of antibacterial inhibitor of DNA gyrase and topoisomerase IV that does not have cross-resistance with the quinolones. Here, we report the evaluation of the in vitro properties of a new series of this type of small molecule. Exemplar compounds selectively and potently inhibited the catalytic activities of Escherichia coli DNA gyrase and topoisomerase IV but did not block the DNA breakage-reunion step. Compounds showed broad-spectrum inhibitory activity against a wide range of Gram-positive and Gram-negative pathogens, including biodefence microorganisms and Mycobacterium tuberculosis . No cross-resistance with fluoroquinolone-resistant Staphylococcus aureus and E. coli isolates was observed. Measured MIC 90 values were 4 and 8 μg/ml against a panel of contemporary multidrug-resistant isolates of Acinetobacter baumannii and E. coli , respectively. In addition, representative compounds exhibited greater antibacterial potency than the quinolones against obligate anaerobic species. Spontaneous mutation rates were low, with frequencies of resistance typically −8 against E. coli and A. baumannii at concentrations equivalent to 4-fold the MIC. Compound-resistant E. coli mutants that were isolated following serial passage were characterized by whole-genome sequencing and carried a single Arg38Leu amino acid substitution in the GyrA subunit of DNA gyrase. Preliminary in vitro safety data indicate that the series shows a promising therapeutic index and potential for low human ether-a-go-go-related gene (hERG) inhibition (50% inhibitory concentration [IC 50 ], >100 μM). In summary, the compounds' distinct mechanism of action relative to the fluoroquinolones, whole-cell potency, low potential for resistance development, and favorable in vitro safety profile warrant their continued investigation as potential broad-spectrum antibacterial agents.

Many people with a terminal diagnosis experience anxiety and require emotional support. Anxiety is characterised by various symptoms, including apprehension, worry, difficulty in concentrating, irritability, panic, fear and restlessness. For some people, the anxiety becomes excessive and persistent and has a significant impact on their quality of life. In advanced disease, symptoms of anxiety can be difficult to differentiate from symptoms of physical disease. Therefore, anxiety states are often undiagnosed in palliative care patients. This article describes the case of a 72-year-old woman with ovarian cancer who was admitted to the author’s hospice following a period of worsening anxiety, breathlessness and pain. The aim of the article is to show how a holistic assessment can successfully address anxiety at the end of life. However, it is recommended that formal assessments of psychological wellbeing are also required for patients with significant psychological needs to evaluate the effectiveness of the interventions and approaches used. For the purposes of confidentiality, all names have been changed and potentially identifying details omitted ([Nursing and Midwifery Council, 2008][1]). Conflicts of interest: none [1]: #ref-33

Decomposing a protein-protein interaction network (PPI network) into non-overlapping clusters or communities, sometimes called "network modules," is an important way to explore functional roles of sets of genes. When the method to accomplish this decomposition is solely based on purely graph-theoretic measures of the interconnection structure of the network, this is often called unsupervised clustering or community detection. In this study, we compare unsupervised computational methods for decomposing a PPI network into non-overlapping modules. A method is preferred if it results in a large proportion of nodes being assigned to functionally meaningful modules, as measured by functional enrichment over terms from the Gene Ontology (GO).We compare the performance of three popular community detection algorithms with the same algorithms run after the network is pre-processed by removing and reweighting based on the diffusion state distance (DSD) between pairs of nodes in the network. We call this "detangling" the network. In almost all cases, we find that detangling the network based on the DSD distance reweighting provides more meaningful clusters.Re-embedding using the DSD distance metric, before applying standard community detection algorithms, can assist in uncovering GO functionally enriched clusters in the yeast PPI network.

This article discusses the effectiveness of a cognitive behavioural therapy (CBT) group for clients with a first episode of psychosis, who were also experiencing comorbid symptoms of anxiety. Clients of 18–35 years of age who reported anxiety symptoms, either as a direct or indirect result of psychotic symptoms, were invited to attend a 12-week CBT-based group. The effectiveness of the intervention was evaluated at screening and 3-month follow-up with the Depression, Anxiety and Stress Scale (DASS-21) ( Lovibond and Lovibond, 2004 ). The results showed a statistically significant improvement in symptoms (depression, p=0.06; anxiety, p=0.05; stress, p=.014), sustainable at 3-month follow-up. The authors concluded that a CBT group for people with a first episode of psychosis that focuses on the management of anxiety can be an effective and viable means of reducing levels of anxiety and associated stress and depression. This model is recommended for use by community mental health teams.

* Disproportionality of English learners in special education has been a longstanding (Dunn, 1968) and ongoing (Ford, 2012) concern for almost half a century. The Council for Children with Behavioral Disorders (Skiba, Albrecht, & Losen, 2012) noted that, "despite court challenges, abundant research, and policy initiatives, racial and ethnic disproportionality [including English learners] persists as a critical and unresolved problem in the field" (p. 2). The topic has played a large role in the history of behavior disorders; however, the focus has often been on disproportionate representation of African Americans (Skiba, PoloniStaudinger, Callini, Simmons, & Feggins-Azziz, 2006).In contrast, a paucity of research has specifically examined disproportionality of English learners with emotional and/or behavioral disorders (EBD; Artiles, Bal, Trent, & Thorius, 2012). Although English learners currently represent approximately 21% of all students in U.S. schools (Aud et al., 2010), little is known about their representation in the EBD category. Donovan and Cross (2002) reported that English learners were generally underrepresented in the EBD category based on their synthesis of research conducted in the last century (prior to the year 2001). However, no study has examined patterns in the current century. To address this gap, we examined representation statistics of English learners with EBD in the post-No Child Left Behind (NCLB) education era (2002 to the present) to (a) identify the extent of disproportionality in the EBD category; (b) determine whether disproportionality was variable across educational contexts, be they individual schools, school districts, or state; and (c) compare the results for students with EBD with those for students with learning disabilities (LD).Disproportionality in Special EducationDisproportionality refers to "the extent to which membership in a given group affects the probability of being placed in a specific disability category" (Oswald, Coutinho, Best, & Singh, 1999, p. 198). For example, we would say that representation of English learners is disproportionately high if the probability of English learners being identified as having a LD is significantly greater than the expected probability given census statistics. Overall, findings from research examining disproportionality for culturally diverse students, including English learners, provide mixed signals and inconsistent findings. The picture is particularly murky when one combines results across many decades and many categories of disability and varying ethnic groups. Then, the picture appears mixed and often contradictory (Chinn & Hughes, 1987; Hopstock & Stephenson, 2003; Hosp & Reschly, 2003; Oswald et al., 1999; Sullivan, 2011).Two National Research Council (NRC) reports on disproportionality, separated by two decades (Donovan & Cross, 2002; Heller, Holtzman, & Messick, 1982), found some evidence of overrepresentation of both culturally diverse and English learners in special education. Although they differed in their conclusions and inferences drawn from the data, both expert syntheses concluded that overrepresentation was not consistent across all disability categories or ethnic minorities. Furthermore, patterns of disproportionality appeared mediated by educational context (school, district, state) in some unspecified fashion.Early litigation (Larry P v. Riles 1972/1974/ 1979/1984) cited test bias against English learners as a possible cause of disproportionality in special education. Later research focused on professional practices, including teacher bias (Riccio, Ochoa, Garza, & Nero, 2003) and all aspects of the assessment process (Loe & Miranda, 2002) as possible causes. Others contend that disproportionality may be a function of poverty, not just English learner status (Hosp & Reschly, 2003; MacMillan & Reschly, 1998; Oswald, Coutinho, Best, & Nguyen, 2001 ). …

In the UK, widespread national variation in the funding and provision of end-of-life care services has led to an independent Palliative Care Funding Review being commissioned, the aim of which is to create a transparent funding system, with better outcomes for patients and value for the NHS. The Review’s proposed national per-patient funding model is currently being piloted. This article provides a critical analysis of the model, with a particular focus on its likely impact on family members caring for adults approaching the end of life. It outlines some of the challenges faced by family carers and discusses the importance of meeting their needs within the UK’s current social, economic and political context. It discusses how the Review’s proposals are likely to meet or neglect particular needs of family carers. It is argued that, although the Review promotes holistic care and support for family carers, there do not appear to be clear funding mechanisms for the provision of such support. As a result, variations in the provision of supportive services for family carers are likely to continue, with potentially significant policy implications. Conflicts of interest: none

To date, 27 states and the District of Columbia have passed laws easing marijuana control. This paper examines the relationship between the legalization of medical marijuana, depenalization of possession, and the incidence of non-drug crime. Using state panel data from 1970 to 2012, results show evidence of 4–12 % reductions in robberies, larcenies, and burglaries due to the legalization of medical marijuana, but that depenalization has little effect and may instead increase crime rates. These effects are supported by null results for crimes unrelated to the cannabis market and are consistent with the supply-side effects of medicinal use that are absent from depenalization laws as well as existing evidence on the substitution between marijuana and alcohol. The findings contribute new evidence to the complex debate surrounding marijuana policy and the war on drugs.

This article presents evidence from a large-scale randomized controlled trial of the effects of four supplemental reading comprehension curricula (Project CRISS, ReadAbout, Read for Real, and Reading for Knowledge) on students’ understanding of informational text. Across 2 school years, the study included 10 school districts, more than 200 schools, and more than 10,000 fifth-grade students. Schools interested in implementing 1 of the 4 supplemental curricula were randomly assigned to 1 of 4 treatment groups or to a control group. The impact analyses in the study's first year revealed a statistically significant negative impact of Reading for Knowledge on students’ reading comprehension scores and no other significant impacts. The impact of ReadAbout was positive and significant in the study's second year among teachers with 1 year of experience using the intervention.

This article describes key findings from contemporary research on screening for early primary grade students in the area of mathematics. Existing studies were used to illustrate the constructs most worth measuring and the diverse strategies that researchers used to study potential measures. The authors discussed the strengths and weaknesses of assessing a few key proficiencies (as is often done in early reading) versus a more full-scale battery, and described the importance of going beyond merely reporting predictive validity correlation coefficients to examining the classification accuracy, specificity, and sensitivity of screening measures.

Background Cell-free RNA in amniotic fluid supernatant reflects developmental changes in gene expression in the living fetus, which includes genes that are specific to the central nervous system. Although it has been previously shown that central nervous system–specific transcripts are present in amniotic fluid supernatant, it is not known whether changes in the amniotic fluid supernatant transcriptome reflect the specific pathophysiologic condition of fetal central nervous system disorders. In myelomeningocele, there is open communication between the central nervous system and amniotic fluid. Objectives The purpose of this study was to identify molecular pathophysiologic changes and novel disease mechanisms that are specific to myelomeningocele by the analysis of amniotic fluid supernatant cell-free RNA in fetuses with open myelomeningocele. Study Design Amniotic fluid supernatant was collected from 10 pregnant women at the time of the open myelomeningocele repair in the second trimester (24.5±1.0 weeks); 10 archived amniotic fluid supernatant from sex and gestational age–matched euploid fetuses without myelomeningocele were used as controls (20.9±0.9 weeks). Differentially regulated gene expression patterns were analyzed with the use of human genome expression arrays. Results Fetuses with myelomeningocele had 284 differentially regulated genes (176 up- and 108 down-regulated) in amniotic fluid supernatant. Known genes that were associated with myelomeningocele ( PRICKLE2 , GLI3 , RAB2 3, HES1 , FOLR1 ) and novel dysregulated genes were identified in association with neurodevelopment and neuronal regeneration (up-regulated, GAP4 3 and ZEB1 ) or axonal growth and guidance (down-regulated, ACAP1 ). Pathway analysis demonstrated a significant contribution of inflammation to disease and a broad influence of Wnt signaling pathways ( Wnt1 , Wnt5A , ITPR1 ). Conclusion Transcriptomic analyses of living fetuses with myelomeningocele with the use of amniotic fluid supernatant cell-free RNA demonstrated differential regulation of specific genes and molecular pathways relevant to this central nervous system disorder, which resulted in a new understanding of pathophysiologic changes. The data also suggested the importance of pathways that involve secondary disease, such as inflammation, in myelomeningocele. These newly identified pathways may lead to hypotheses that can test novel therapeutic targets as adjuncts to fetal surgical repair.

In recent years, there has been increasing attention to the importance of interagency collaboration for improving community well-being, environmental and public health, and educational outcomes. This article uses a mixed-methods approach including network analysis to examine the changes in interagency collaboration in one site funded by the Safe Schools/Healthy Students Initiative (SS/HS). Results of the evaluation demonstrated that although intraproject collaboration peaked in the middle of the grant and began to decline during the last year, interagency collaborations continued to grow during the last year of the grant. These results illustrate how network data can easily be collected and used to assess the development of interagency relationships.

Seven narrative and systematic reviews published since 2000 and focusing on self-determination for individuals with disabilities are reviewed in this narrative metasynthesis. The authors distinguish their work from other metasynthesis work by calling it a narrative metasynthesis because they include both narrative reviews and meta-analyses in this metasynthesis. These seven reviews focused on different disability groups, different intervention curricular and instructional techniques, and different outcomes. Findings were relatively consistent with multicomponent self-determination interventions demonstrating greater positive effects than single-component interventions and self-determination and academic productivity outcomes showing greater positive effects than academic quality outcomes. Theoretical, empirical, and methodological findings and implications are discussed.

This article describes the outcomes of Project LINK, a Safe Schools/Healthy Students grantee in Larimer County, Colorado. The study analyzed the influence of policies and administrative support on the implementation of programs as well as on risk and protective factors predictive of violent behaviors and drug and alcohol use. Results showed increased feelings of safety in comparison to the rest of the state and changes in risk and protective factors by school level. Results also indicate that leadership support and enforcement of policies are associated with successful adoption, implementation, and positive behavioral outcomes.

The phosphatidylinositol-3-kinase (PI3K) pathway has an essential role in signal transduction, where it is required for a number of different cellular processes including proliferation, differentiation, development, migration and growth. In the immune system, PI3K regulates inflammation by controlling the activation and recruitment of leukocytes. The generation of conditional knockout mice has allowed the study of PI3K isoforms specifically in B and T lymphocytes, and demonstrates the importance of intact signalling in their development and function. PI3K signalling must be tightly regulated in lymphocytes as excessive PI3K can lead to autoimmunity, immunodeficiency or cancer, whilst diminished signalling can result in developmental defects and immunodeficiency. Recent advances in the understanding of PI3K signalling have hastened the application of isoform-specific PI3K inhibitors, which are currently undergoing clinical trials. This review will focus on the p110δ catalytic subunit of the class 1A family of PI3K, and its role in the development and activation of B lymphocytes through various downstream effectors.