Reading instruction in first-grade classrooms: Do basals control teachers?

This study describes first-grade teachers beliefs and practices about reading instruction. Drawing from interview and observational data, 16 teachers from four districts were placed on a continuum from skills-based to literature-based in relationship to their use of the basal. Only 2 teachers were found to rely solely on the basal, while 3 teachers enhanced the basal with literature, and 4 teachers used only literature in their reading instruction. Six teachers enhanced their basal use with additional skills and 1 teacher relied on skills only in her reading instruction. This diversity\u27 of teaching beliefs and practices was corroborated by questionnaire data from a larger sample of teachers. Next, a framework developed by Belenky, Clinchy, Goldberger, and Tarule (1986) was used to categorize teachers\u27 ways of knowing. The findings showed 1 teacher to be a silent knower, 6 were received knowers, 1 was a subjective knower, 7 were procedural knowers, and 1 was a connected knower. Results challenge Shannon\u27s (1987) hypothesis that basals deskill teachers while supporting Sosniak and Stodolskv\u27s (1993) view that teachers are more autonomous in their use of textbook materials

Application of the relationship between pharmacokinetics and pharmacodynamics in drug development and therapeutic equivalence::a PEARRL review

Objectives: The objective of this review is to provide an overview of PK/PD models, focusing on drug-specific PK/PD models and highlighting their value-added in drug development and regulatory decision-making. Key findings: Many PK/PD models, with varying degrees of complexity and physiological understanding, have been developed to evaluate the safety and efficacy of drug products. In special populations (e.g. pediatrics), in cases where there is genetic polymorphism and in other instances where therapeutic outcomes are not well described solely by PK metrics, the implementation of PK/PD models is crucial to assure the desired clinical outcome. Since dissociation between the pharmacokinetic and pharmacodynamic profiles is often observed, it is proposed that physiologically-based pharmacokinetic (PBPK) and PK/PD models be given more weight by regulatory authorities when assessing the therapeutic equivalence of drug products. Summary: Modeling and simulation approaches already play an important role in drug development. While slowly moving away from “one-size fits all” PK methodologies to assess therapeutic outcomes, further work is required to increase confidence in PK/PD models in translatability and prediction of various clinical scenarios to encourage more widespread implementation in regulatory decision-making

THE IMPACT OF FOOD INTAKE ON THE LUMINAL ENVIRONMENT AND PERFORMANCE OF ORAL DRUG PRODUCTS WITH A VIEW TO IN VITRO AND IN SILICO SIMULATIONS: A PEARRL REVIEW

Objective: Using the type of meal and dosing conditions suggested by regulatory agencies as a basis, this review has two specific objectives. First, to summarize our understanding on the impact of food intake on luminal environment and drug product performance. Second, to summarize the usefulness and limitations of available in vitro and in silico methodologies for the evaluation of drug products performance after food intake. Key findings: Characterization of the luminal environment and studies evaluating product performance in the lumen, under conditions suggested by regulatory agencies for simulating the fed state, are limited. Various in vitro methodologies have been proposed for evaluating drug product performance in the fed state but systematic validation is lacking. Physiologically based pharmacokinetic (PBPK) modelling approaches require the use of in vitro biorelevant data and, to date, have been used primarily for investigating the mechanisms via which an already observed food effect is mediated. Conclusion: Better understanding of the impact of changes induced by the meal administration conditions suggested by regulatory agencies on the luminal fate of the drug product is needed. Relevant information will be useful for optimizing the in vitro test methods, and increasing the usefulness of PBPK modelling methodologies

So What\u27s New in the New Basals? A Focus on First Grade

The authors examine the first grade materials in five new basal programs submitted for the 1993 Texas state adoption. These series are compared with program materials currently in use in the state (Copyright 1986/1987). The analysis focuses on features of the pupil texts(e.g., total number of words, number of unique words, readability levels, literary quality) and features of the teachers\u27 editions (e.g., program design, organization, tone). Results of the analysis indicate substantial changes in the more recent series.The findings are interpreted in terms of historical trends as well as recent developments in the literature-based and whole language movements.Implications for future research are identified that relate to the study of the implementation and effects of these new programs

Temporal order of RNase IIIb and loss-of-function mutations during development determines phenotype in DICER1 syndrome: a unique variant of the two-hit tumor suppression model [v1; ref status: approved with reservations 1, http://f1000r.es/5l9]

Pleuropulmonary blastoma (PPB) is the most frequent pediatric lung tumor and often the first indication of a pleiotropic cancer predisposition, DICER1 syndrome, comprising a range of other individually rare, benign and malignant tumors of childhood and early adulthood. The genetics of DICER1-associated tumorigenesis are unusual in that tumors typically bear neomorphic missense mutations at one of five specific “hotspot” codons within the RNase IIIb domain of DICER 1, combined with complete loss of function (LOF) in the other allele. We analyzed a cohort of 124 PPB children for predisposing DICER1 mutations and sought correlations with clinical phenotypes. Over 70% have inherited or de novo germline LOF mutations, most of which truncate the DICER1 open reading frame. We identified a minority of patients who have no germline mutation, but are instead mosaic for predisposing DICER1 mutations. Mosaicism for RNase IIIb domain hotspot mutations defines a special category of DICER1 syndrome patients, clinically distinguished from those with germline or mosaic LOF mutations by earlier onsets and numerous discrete foci of neoplastic disease involving multiple syndromic organ sites. A final category of patients lack predisposing germline or mosaic mutations and have disease limited to a single PPB tumor bearing tumor-specific RNase IIIb and LOF mutations. We propose that acquisition of a neomorphic RNase IIIb domain mutation is the rate limiting event in DICER1-associated tumorigenesis, and that distinct clinical phenotypes associated with mutational categories reflect the temporal order in which LOF and RNase IIIb domain mutations are acquired during development

The use of PBPK/PD to establish clinically relevant dissolution specifications for zolpidem immediate release tablets

Background: Zolpidem is a non-benzodiazepine hypnotic agent which has been shown to be effective in inducing and maintaining sleep in adults and is one of the most frequently prescribed hypnotics in the world. For drugs that are used to treat sleeping disorders, the time to reach the maximum concentration (Tmax) of the drug in plasma is important to achieving a fast onset of action and this must be maintained when switching from one product to another. Objectives: The main objective of the present work was to create a PBPK/PD model for zolpidem and establish a clinically relevant “safe space” for dissolution of zolpidem from the commercial immediate release (IR) formulation. A second objective was to analyze literature pharmacokinetic data to verify the negative food effect ascribed to zolpidem and consider its ramifications in terms of the “safe space” for dissolution. Methods: Using dissolution, pharmacokinetic and pharmacodynamic data, an integrated PBPK/PD model for immediate release zolpidem tablets was constructed in Simcyp®. This model was used to identify the clinically relevant dissolution specifications necessary to ensure efficacy. Results: According to the simulations, as long as 85% of the drug is released in 45 minutes or less, the impact on the PK and PD profiles of zolpidem would be minimal. According to the FDA, the drug has to dissolve from the test and reference products at a similar rate and to an extent of 85% in not more than 30 minutes to pass bioequivalence via the BCS-biowaiver test. Thus, the BCS-biowaiver specifications are somewhat more stringent than the “safe space” based on the PBPK/PD model. Published data from fasted and fed state pharmacokinetic studies suggest but do not prove a negative food effect of zolpidem. Conclusions: A PBPK/PD model indicates that current BCS biowaiver criteria are more restrictive for immediate release zolpidem tablets than they need to be. In view of the close relationship between PK and PD, it remains advisable to avoid taking zolpidem tablets with or immediately after a meal, as indicated by the Stilnox® labeling

How the biotin–streptavidin interaction was made even stronger: investigation via crystallography and a chimaeric tetramer

The interaction between SA (streptavidin) and biotin is one of the strongest non-covalent interactions in Nature. SA is a widely used tool and a paradigm for protein–ligand interactions. We previously developed a SA mutant, termed Tr (traptavidin), possessing a 10-fold lower off-rate for biotin, with increased mechanical and thermal stability. In the present study, we determined the crystal structures of apo-Tr and biotin–Tr at 1.5 Å resolution. In apo-SA the loop (L3/4), near biotin's valeryl tail, is typically disordered and open, but closes upon biotin binding. In contrast, L3/4 was shut in both apo-Tr and biotin–Tr. The reduced flexibility of L3/4 and decreased conformational change on biotin binding provide an explanation for Tr's reduced biotin off- and on-rates. L3/4 includes Ser45, which forms a hydrogen bond to biotin consistently in Tr, but erratically in SA. Reduced breakage of the biotin–Ser45 hydrogen bond in Tr is likely to inhibit the initiating event in biotin's dissociation pathway. We generated a Tr with a single biotin-binding site rather than four, which showed a simi-larly low off-rate, demonstrating that Tr's low off-rate was governed by intrasubunit effects. Understanding the structural features of this tenacious interaction may assist the design of even stronger affinity tags and inhibitors

Nevirapine and Efavirenz Elicit Different Changes in Lipid Profiles in Antiretroviral- Therapy-Naive Patients Infected with HIV-1

BACKGROUND: Patients infected with HIV-1 initiating antiretroviral therapy (ART) containing a non-nucleoside reverse transcriptase inhibitor (NNRTI) show presumably fewer atherogenic lipid changes than those initiating most ARTs containing a protease inhibitor. We analysed whether lipid changes differed between the two most commonly used NNRTIs, nevirapine (NVP) and efavirenz (EFV). METHODS AND FINDINGS: Prospective analysis of lipids and lipoproteins was performed in patients enrolled in the NVP and EFV treatment groups of the 2NN study who remained on allocated treatment during 48 wk of follow-up. Patients were allocated to NVP (n = 417), or EFV (n = 289) in combination with stavudine and lamivudine. The primary endpoint was percentage change over 48 wk in high-density lipoprotein cholesterol (HDL-c), total cholesterol (TC), TC:HDL-c ratio, non-HDL-c, low-density lipoprotein cholesterol, and triglycerides. The increase of HDL-c was significantly larger for patients receiving NVP (42.5%) than for patients receiving EFV (33.7%; p = 0.036), while the increase in TC was lower (26.9% and 31.1%, respectively; p = 0.073), resulting in a decrease of the TC:HDL-c ratio for patients receiving NVP (−4.1%) and an increase for patients receiving EFV (+5.9%; p < 0.001). The increase of non-HDL-c was smaller for patients receiving NVP (24.7%) than for patients receiving EFV (33.6%; p = 0.007), as were the increases of triglycerides (20.1% and 49.0%, respectively; p < 0.001) and low-density lipoprotein cholesterol (35.0% and 40.0%, respectively; p = 0.378). These differences remained, or even increased, after adjusting for changes in HIV-1 RNA and CD4+ cell levels, indicating an effect of the drugs on lipids over and above that which may be explained by suppression of HIV-1 infection. The increases in HDL-c were of the same order of magnitude as those seen with the use of the investigational HDL-c-increasing drugs. CONCLUSION: NVP-containing ART shows larger increases in HDL-c and decreases in TC:HDL-c ratio than an EFV-containing regimen. Based on these findings, protease-inhibitor-sparing regimens based on non-nucleoside reverse transcriptase inhibitor, particularly those containing NVP, may be expected to result in a reduced risk of coronary heart disease

Erlotinib or gefitinib for the treatment of relapsed platinum pretreated non-small cell lung cancer and ovarian cancer: a systematic review

BACKGROUND: Platinum-based chemotherapy is the standard of care for ovarian cancer and non-small cell lung cancer (NSCLC). However, resistance to platinum agents invariably develops. Targeted therapies, such as tyrosine kinase inhibitors (TKIs), have great potential here as they exert their anti-tumour effect via alternative mechanisms to platinum-based drugs and as such may remain unaffected by emergent resistance to platinum. METHODS: A systematic review was conducted to investigate whether two EGFR-TKIs, erlotinib and gefitinib, have efficacy in the platinum-resistance setting. Preclinical studies of platinum-resistant cancer cell lines, which had been subsequently treated with EGFR-TKIs, were sought to establish proof-of-concept. Clinical trials reporting administration of EGFR-TKIs to ovarian cancer and NSCLC patients relapsed after therapy with platinum drugs were investigated to determine sensitivity of these cohorts to EGFR-TKI treatment. The role of EGFR mutation, copy number and protein expression on response to EGFR-TKIs after failure of platinum chemotherapy were also investigated. RESULTS: Preclinical models of platinum-resistant cancer were found which display a spectrum of cross-resistance profiles to EGFR-TKIs. Sensitivity to EGFR-TKIs is dependent on the activation of the EGFR pathway or EGFR interacting proteins such as HER-2. EGFR-TKIs show favourable response rates in platinum-pretreated NSCLC, 11.14% and 15.25% for 150mg/day erlotinib and 250mg/day gefitinib, respectively. These response rates significantly improve in patients of Asian descent (28.3% and 29.17%, respectively) and patients with EGFR activation mutations (41.6% and 63.89%, respectively) or increased copy number (33.3% and 45.45%, respectively). Gefitinib significantly outperformed erlotinib and should therefore be the EGFR-TKI of choice in platinum-pretreated relapsed NSCLC. In contrast, response rates are very poor to both erlotinib and gefitinib in platinum pretreated ovarian cancer, 0-5.9% and they should not be used in this cohort of patients. Preclinical models demonstrate that, while cross resistance can occur between platinums and EGFR-TKIs, there is not a generalised cross-resistance phenotype. Erlotinib and gefitinib are suitable for the treatment of platinum-pretreated NSCLC, particularly in patients with EGFR mutations or increases in copy number. Unfortunately, the high rates of EGFR protein overexpression in ovarian cancer are not translating to a clinically useful therapeutic target for EGFR-TKIs; EGFR mutations are rare in ovarian cancer. Newer TKIs may improve response rates in these cohorts and future clinical trials need to collect tumour biopsies from all patients to ensure the success of personalised chemotherapy