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Long-term effects of angiotensin-converting enzyme inhibition and metabolic control in hypertensive type 2 diabetic patients. In hypertensive type 2 diabetic patients, treatment with angiotensin-converting enzyme (ACE) inhibitors is associated with a lower incidence of cardiovascular events than those treated with calcium channel-blocking agents. However, the long-term renal effects of ACE inhibitors in these patients remain inconclusive. In 1989, we commenced a placebo-controlled, double-blind, randomized study to examine the anti-albuminuric effects of enalapril versus nifedipine (slow release) in 102 hypertensive, type 2 diabetic patients. These patients have been followed up for a mean trial duration of 5.5 ± 2.2 years. We examined the determinants, including the effect of ACE inhibition on clinical outcomes in these patients. After a six-week placebo-controlled, run-in period, 52 patients were randomized double-blind to receive nifedipine (slow release) and 50 patients to receive enalapril. After the one-year analysis, which confirmed the superior anti-albuminuric effects of enalapril (-54%) over nifedipine (+11%), all patients were continued on their previously assigned treatment with informed consent. They were subdivided into normoalbuminuric (N = 43), microalbuminuric (N = 34), and macroalbuminuric (N = 25) groups based on two of three 24-hour urinary albumin excretion (UAE) measurements during the run-in period. Renal function was shown by the 24-hour UAE, creatinine clearance (CCr), and the regression coefficient of the yearly plasma creatinine reciprocal (β-1/Cr). Clinical endpoints were defined as death, cardiovascular events, and/or renal events (need for renal replacement therapy or doubling of baseline plasma creatinine). In the whole group, patients treated with enalapril were more likely to revert to being normoalbuminuric (23.8 vs. 15.4%), and fewer of them developed macroalbuminuria (19.1 vs. 30.8%) compared with the nifedipine-treated patients (P < 0.05). In the microalbuminuric group, treatment with enalapril (N = 21) was associated with a 13.0% (P < 0.01) reduction in 24-hour UAE compared with a 17.3% increase in the nifedipine group (N = 13). In the macroalbuminuric patients, enalapril treatment (N = 11) was associated with stabilization compared with a decline in renal function in the nifedipine group, as shown by the β-1/Cr (0.65 ± 4.29 vs. -1.93 ± 2.35 1/μmol × 10-3, P < 0.05) after adjustment for baseline values. Compared with the normoalbuminuric and microalbuminuric patients, those with macroalbuminuria had the lowest mean CCr (75.5 ± 24.1 vs. 63.5 ± 21.3 vs. 41.9 ± 18.5 mL/min, P < 0.001) and the highest frequency of clinical events (4.7 vs. 5.9 vs. 52%, P < 0.001). On multivariate analysis, β-1/Cr (R2 = 0.195, P < 0.001) was independently associated with baseline HbA1c (β = -0.285, P = 0.004), whereas clinical outcomes (R2 = 0.176, P < 0.001) were independently related to the mean low-density lipoprotein cholesterol (β = 2.426, P = 0.018), high-density lipoprotein cholesterol (β = -8.797, P = 0.03), baseline UAE (β = 0.002, P = 0.04), and mean CCr during treatment (β = -0.211, P = 0.006). In this prospective cohort analysis involving 102 hypertensive, type 2 diabetic patients with varying degrees of albuminuria followed up for a mean duration of five years, we observed the importance of good metabolic and blood pressure control on the progression of albuminuria and renal function. Treatment with enalapril was associated with a greater reduction in albuminuria than with nifedipine in the entire patient group, and especially in those with microalbuminuria. In the macroalbuminuric patients, the rate of deterioration in renal function was also attenuated by treatment with enalapril.

As evidence becomes increasingly important in educational policy, it is essential to understand how research design might contribute to reported effect sizes in experiments evaluating educational programs. A total of 645 studies from 12 recent reviews of evaluations of preschool, reading, mathematics, and science programs were studied. Effect sizes were roughly twice as large for published articles, small-scale trials, and experimenter-made measures, compared to unpublished documents, large-scale studies, and independent measures, respectively. Effect sizes were significantly higher in quasiexperiments than in randomized experiments. Excluding tutoring studies, there were no significant differences in effect sizes between elementary and middle/high studies. Regression analyses found that effects of all factors maintained after controlling for all other factors. Explanations for the effects of methodological features on effect sizes are discussed, as are implications for evidence-based policy.

This review examines the effectiveness of educational technology applications in improving the reading achievement of struggling readers in elementary schools. The review applies consistent inclusion standards to focus on studies that met high methodological standards. A total of 20 studies based on about 7,000 students in grades 1–6 were included in the final analysis. Findings indicate that educational technology applications produced a positive but small effect on the reading skills of struggling readers (ES = .14) in comparison with “business as usual” methods. Among four types of educational technology applications, small‐group integrated applications such as Read, Write & Type and the Lindamood Phoneme Sequence Program produced the largest effect sizes (ES = .32). These are tutorial educational technology applications that use small‐group interaction tightly integrated with reading curriculum. Supplementary models, such as Jostens and Lexia, had a larger number of studies (N = 12) and a more modest effect size (ES = .18). Comprehensive models, such as READ 180 and ReadAbout (ES = .04) and Fast ForWord (ES = .06), did not produce meaningful positive effect sizes. However, the results of these two categories of programs should be interpreted with extreme caution due to the small number of studies involved. More studies are required to validate the effectiveness of all technology applications. Policy implications are discussed. 本综述研究考查小学教育技术应用程序,在提高有阅读困难学生的阅读成绩方面的有效性。本综述研究使用一致的纳入考查标准,聚焦在达到高标准方法的研究项目。被纳入作最终研究分析的相关研究共20项,其研究对象都是小一至小六年级的学生,人数约7000名。调查结果显示,教育技术程序应用与其他”一切如常”的教学方法相比较下,在有阅读困难学生的阅读技巧方面,能产生一个积极但小规模的效应(效应值=.14)。在四种类型的教育技术应用程序中,以小组综合性的应用程序(例如「读、写与键入」和「Lindamood 音素序列教程」)所产生之效应为最大(效应值=.32)。这些都是使用小组式互动与阅读课程紧密综合起来的辅导教育技术应用程序。补充性的教育技术应用程序(例如Jostens和Lexia)有较多相关的研究(N = 12)和产生较小的效应(效应值=.18)。广泛性的教育技术应用程序,例如「阅读180」和「阅读有关」(效应值=.04)以及「快速拼读」(效应值=.06),并没有产生有意义的正面效应。然而,读者应十分谨慎去理解这两个类别的教育技术应用程序所得出的研究结果,因为这些结果只涉及少数量的研究项目。如要验证所有教育技术应用程序之有效性,则需考查更多的相关研究项目。本文结论部分讨论这综述研究结果对政策的启示。 Esta evaluación examina la eficacia de aplicaciones tecnológicas educativas para mejorar la lectura de estudiantes con dificultades en escuelas primarias. La evaluación emplea estándares consistentes de inclusión para enfocarse en estudios que satisficieron estándares metodológicos altos. Un total de 20 estudios basados en aproximadamente 7,000 estudiantes de primer a sexto grado fueron incluidos en el análisis final. Los resultados indican que las aplicaciones tecnológicas educativas produjeron un efecto positivo aunque pequeño en las habilidades lectoras de estudiantes con dificultades (ES = .14) comparado con los métodos de siempre. Entre cuatro tipos de aplicaciones tecnológicas educativas, aplicaciones integradas de grupos pequeños como los de Read, Wrtie & Type y el Lindamood Phoneme Sequence Program produjeron los efectos más notables (ES = .32). Estas son aplicaciones tecnológicas educacionales de tutoría que usan la interacción en grupos pequeños estrechamente integradas con el currículo de lectura. Había un mayor número de estudios (N = 12) de modelos suplementarios, como el de Jostens and Lexia, que mostraron un efecto más modesto (ES = .18). Modelos amplios, como READ 180 y ReadAbout (ES = .04) y Fast ForWord (ES = .06), no produjeron efectos positivos de importancia. Sin embargo, los resultados de estas dos categorías de programas deben ser interpretados con mucha precaución debido al número muy reducido de estudios involucrados. Se necesitan más estudios para convalidar la eficacia de todas las aplicaciones tecnológicas. Se discuten las implicaciones para las normas. تفحص هذه المراجعة فعالية تطبيقات التقنية التعليمية في تحسين إنجاز القراءة لدى القراء الضعفاء في المدارس الابتدائية. وتطبق هذه المراجعة معايير متضمنة متطابقة للتركيز على الدراسات التي حظت بمعايير منهجية عالية. وقد تم انضمام 20 دراسة مبنية على ما تقارب 7،000 طالباً في الصفوف الأول إلى السادس في التحليل النهائي. تشير النتائج إلى أن التطبيقات التقنية التعليمية أنتجت تأثيراً إيجابياً إنما صغيراً على مهارات القراءة لدى القراء الضعفاء (حجم التأثير = .14) بالمقارنة مع مناهج ((بقاء الأمور على حالها)). ومن بين الأنواع الأربعة من التطبيقات التقنية التعليمية، فإن التطبيقات المندمجة في مجموعات صغيرة مثل برنامج القراءة والكتابة والضرب على الآلة الكاتبة وبرنامج لندامود لتسلسل الصوتيات قد أنتجت أكبر أحجام التأثير (= .32). وتستخدم التطبيقات التقنية التعليمية هذه تفاعلات في مجموعات صغيرة مندمجة اندماجاً مُحكَماً مع منهاج القراءة بينما تمتعت النماذج التكميلية مثل جونستن وليكزيا بعدد أكبر من الدراسات (عدد = 12) وكان حجم تأثيرها أكثر تواضعاً (= .18). غير أن النماذج الشمولية مثل قراءة 180 وريد أبوت (حجم تأثيرهما = .04) وفاست فورورد (حجم تأثيره = .06) لم تنتج أحجام تأثير إيجابية ذات المعنى. بيد أن نتائج هذين الصنفين من النماذج ينبغي أن يتم تفسيرها مع حذر شديد بسبب عدد دراساتها الضئيل. ومن ثم فأنه يتطلب إتمام أكبر عدد من الدراسات لإثبات فعالية كل التطبيقات التقنية. ونناقش دلالة السياسة. Aвтopы пpeдлaгaют oбзop эффeктивнocти paзличныx кoмпьютepизиpoвaнныx мeтoдoв oбyчeния чтeнию, пpeднaзнaчeнныx для paбoты c yчeникaми нaчaльнoй шкoлы, кoтopыe иcпытывaют тpyднocти в чтeнии. Meтoды и пpoгpaммы включaлиcь в oбзop пo eдиным cтpoгим кpитepиям, и вce oни cooтвeтcтвyют выcoким мeтoдичecким cтaндapтaм. B oбщeй cлoжнocти oцeнивaютcя 20 иccлeдoвaний, ocнoвaнныx нa пpoвepкe пpиблизитeльнo 7000 yчaщиxcя c пepвoгo пo шecтoй клacc. Peзyльтaты cвидeтeльcтвyют o тoм, чтo – пo cpaвнeнию дeтьми из кoнтpoльнoй гpyппы, кoтopыx oбyчaли oбычным oбpaзoм, – “ocoбыe пoдxoды” oкaзывaют пoзитивнoe, нo нecyщecтвeннoe влияниe нa нaвыки дeтeй, иcпытывaющиx пpoблeмы c чтeниeм (ES =.14). Cpeди чeтыpex типoв пpoгpaмм c пpимeнeниeм кoмпьютepныx тexнoлoгий нaибoлee эффeктивными (ES =.32) oкaзaлиcь тe, гдe дeти тpeниpyютcя в мaлыx гpyппax в тoчнoм cooтвeтcтвии c yчeбным плaнoм пo чтeнию: Read, Write & Type (Пpoчти, зaпиши и нaпeчaтaй) и Lindamood Phoneme Sequence Program (Фoнeмaтичecкaя пpoгpaммa Пaтpишии Линдaмyд). Бoльшee чиcлo иccлeдoвaний (N = 12) были пocвящeны вcпoмoгaтeльным yчeбным мoдeлям, тaким кaк, нaпpимep, Jostens и Lexia. Иx эффeктивнocть oкaзaлacь cкpoмнee (ES =.18). Кoмплeкcныe мoдeли дaли eщe мeньший пoлoжитeльный эффeкт: READ 180 и ReadAbout (ES =.04) и Fast ForWord (ES =.06), нo вocпpинимaть эти peзyльтaты cлeдyeт кpaйнe ocтopoжнo, тaк кaк иccлeдoвaний пo ним мaлo. Для yтoчнeния эффeктивнocти вcex тexнoлoгий нeoбxoдимo пpoвecти дoпoлнитeльныe иccлeдoвaния. B кoнцe oбзopa oбcyждaeтcя знaчeниe пoлyчeнныx дaнныx для oбpaзoвaтeльнoй пoлитики. Cette revue de question s'intéresse aux applications de technologie pédagogique qui visent à améliorer la lecture des enfants en difficulté en lecture à l’école élémentaire. Cette revue exige des normes de haut niveau méthodologique pour l'inclusion des travaux dans le corpus. Nous avons inclus finalement dans l'analyse un total de 20 études comportant environ 7000 élèves du CP à la 6e. Les résultats montrent que les applications de technologie pédagogique ont un effet positif mais petit sur les compétences en lecture des mauvais lecteurs (ES = .14) en comparaison avec les méthodes tout venant. Parmi les quatre types d'applications de technologie pédagogique, les applications avec petits groupes intégrés, comme celle de Read, Write & Type et le Programme de séquence phonémique de Lindamood, produit les effets les plus massifs (ES = .32). Il s'agit d'applications de technologie pédagogique recourant à une interaction en petit groupe étroitement liée au programme de lecture. Des modèles supplémentaires, comme celui de Jostens et Lexia, comptent un grand nombre d’études (N = 12) et un effet de taille plus modeste (ES = .18). Les modèles compréhensifs, comme READ 180 et ReadAbout (ES = .04) et Fast ForWord (ES = .06), ne produisent pas d'effet ayant une taille significative. Toutefois, il faut interpréter les résultats de ces deux catégories de programme avec une très grande précaution compte tenu du petit nombre d’études concernées. Il est nécessaire de disposer de davantage d’études pour valider l'efficacité de toutes les applications technologiques. La discussion porte sur les implications politiques.

Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies.

This review synthesizes research on English reading outcomes of all types of programs for Spanish-dominant English language learners (ELLs) in elementary schools. It is divided into two major sections. One focuses on studies of language of instruction and one on reading approaches for ELLs holding constant language of instruction. A total of 13 qualifying studies met the inclusion criteria for language of instruction. Though the overall findings indicate a positive effect (effect size = .21) in favor of bilingual education, the largest and longest term evaluations, including the only multiyear randomized evaluation of transitional bilingual education, did not find any differences in outcomes by the end of elementary school for children who were either taught in Spanish and transitioned to English or taught only in English. The review also identified whole-school and whole-class interventions with good evidence of effectiveness for ELLs, including Success for All, cooperative learning, Direct Instruction, and ELLA. Programs that use phonetic small group or one-to-one tutoring have also shown positive effects for struggling ELL readers. What is in common across the most promising interventions is their use of extensive professional development, coaching, and cooperative learning. The findings support a conclusion increasingly being made by researchers and policymakers concerned with optimal outcomes for ELLs and other language minority students: Quality of instruction is more important than language of instruction.

Many common illnesses, for reasons that have not been identified, differentially affect men and women. For instance, the autoimmune diseases systemic lupus erythematosus (SLE) and Sjögren’s syndrome affect nine times more women than men 1 , whereas schizophrenia affects men with greater frequency and severity relative to women 2 . All three illnesses have their strongest common genetic associations in the major histocompatibility complex (MHC) locus, an association that in SLE and Sjögren’s syndrome has long been thought to arise from alleles of the human leukocyte antigen (HLA) genes at that locus 3 – 6 . Here we show that variation of the complement component 4 (C4) genes C4A and C4B , which are also at the MHC locus and have been linked to increased risk for schizophrenia 7 , generates 7-fold variation in risk for SLE and 16-fold variation in risk for Sjögren’s syndrome among individuals with common C4 genotypes, with C4A protecting more strongly than C4B in both illnesses. The same alleles that increase risk for schizophrenia greatly reduce risk for SLE and Sjögren’s syndrome. In all three illnesses, C4 alleles act more strongly in men than in women: common combinations of C4A and C4B generated 14-fold variation in risk for SLE, 31-fold variation in risk for Sjögren’s syndrome, and 1.7-fold variation in schizophrenia risk among men (versus 6-fold, 15-fold and 1.26-fold variation in risk among women, respectively). At a protein level, both C4 and its effector C3 were present at higher levels in cerebrospinal fluid and plasma 8 , 9 in men than in women among adults aged between 20 and 50 years, corresponding to the ages of differential disease vulnerability. Sex differences in complement protein levels may help to explain the more potent effects of C4 alleles in men, women’s greater risk of SLE and Sjögren’s syndrome and men’s greater vulnerability to schizophrenia. These results implicate the complement system as a source of sexual dimorphism in vulnerability to diverse illnesses. Sexual dimorphism in genetic vulnerability to schizophrenia, systemic lupus erythematosus and Sjögren’s syndrome is linked to differential protein abundance from alleles of complement component 4.

Benjamin Neale and colleagues report the LD Score regression method, used to distinguish the relative contributions of confounding bias and polygenicity to inflated test statistics in GWAS. They apply their method to summary statistics from GWAS for over 30 phenotypes, confirm that polygenicity accounts for the majority of inflation in test statistics and demonstrate use of this method as a correction factor. Both polygenicity (many small genetic effects) and confounding biases, such as cryptic relatedness and population stratification, can yield an inflated distribution of test statistics in genome-wide association studies (GWAS). However, current methods cannot distinguish between inflation from a true polygenic signal and bias. We have developed an approach, LD Score regression, that quantifies the contribution of each by examining the relationship between test statistics and linkage disequilibrium (LD). The LD Score regression intercept can be used to estimate a more powerful and accurate correction factor than genomic control. We find strong evidence that polygenicity accounts for the majority of the inflation in test statistics in many GWAS of large sample size.

Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia. Schizophrenia is a highly heritable genetic disorder, however, identification of specific genetic risk variants has proven difficult because of its complex polygenic nature—a large multi-stage genome-wide association study identifies 128 independent associations in over 100 loci (83 of which are new); key findings include identification of genes involved in glutamergic neurotransmission and support for a link between the immune system and schizophrenia. The genetics of schizophrenia Although schizophrenia is a highly heritable disorder, its complex polygenic nature has impeded attempts to establish its genetic basis. This paper reports a genome-wide association study of more than 36,000 schizophrenia patients and 100,000 controls. The study identifies 128 independent associations in 108 loci, 83 of them new. Among them are many genes involved in glutamatergic neurotransmission, highlighting a potential therapeutic avenue. In addition, the results provide support for the hypothesized link between the immune system and schizophrenia.

Transcriptomic imputation approaches combine eQTL reference panels with large-scale genotype data in order to test associations between disease and gene expression. These genic associations could elucidate signals in complex genome-wide association study (GWAS) loci and may disentangle the role of different tissues in disease development. We used the largest eQTL reference panel for the dorso-lateral prefrontal cortex (DLPFC) to create a set of gene expression predictors and demonstrate their utility. We applied DLPFC and 12 GTEx-brain predictors to 40,299 schizophrenia cases and 65,264 matched controls for a large transcriptomic imputation study of schizophrenia. We identified 413 genic associations across 13 brain regions. Stepwise conditioning identified 67 non-MHC genes, of which 14 did not fall within previous GWAS loci. We identified 36 significantly enriched pathways, including hexosaminidase-A deficiency, and multiple porphyric disorder pathways. We investigated developmental expression patterns among the 67 non-MHC genes and identified specific groups of pre- and postnatal expression. This study uses gene expression predictors for the dorsolateral prefrontal cortex and other brain regions to perform a transcriptomic imputation analysis of schizophrenia, identifying 413 genic associations across 13 brain regions and 36 significantly enriched pathways.

Based on the discovery by the Resilience Project (Chen R. et al. Nat Biotechnol 34:531–538, 2016) of rare variants that confer resistance to Mendelian disease, and protective alleles for some complex diseases, we posited the existence of genetic variants that promote resilience to highly heritable polygenic disorders1,0 such as schizophrenia. Resilience has been traditionally viewed as a psychological construct, although our use of the term resilience refers to a different construct that directly relates to the Resilience Project, namely: heritable variation that promotes resistance to disease by reducing the penetrance of risk loci, wherein resilience and risk loci operate orthogonal to one another. In this study, we established a procedure to identify unaffected individuals with relatively high polygenic risk for schizophrenia, and contrasted them with risk-matched schizophrenia cases to generate the first known “polygenic resilience score” that represents the additive contributions to SZ resistance by variants that are distinct from risk loci. The resilience score was derived from data compiled by the Psychiatric Genomics Consortium, and replicated in three independent samples. This work establishes a generalizable framework for finding resilience variants for any complex, heritable disorder.