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We report the case of a patient with dextrocardia and situs inversus totalis associated with obstructive coronariopathy in the anterior and posterior descending arteries, right coronary artery, first diagonal branch and left marginal branch. The patient underwent coronary artery bypass grafting surgery. This surgery has been rarely reported in literature and we found only one similar case in the national medical literature. The myocardial revascularization was carried out with the right mammary artery for the anterior descending artery. The saphenous vein anastomosed the aorta to the right coronary artery, left marginal branch, fist diagonal branch and posterior descending artery. The surgery was performed with extracorporeal circulation. [ABSTRACT FROM AUTHOR]

Despite the power of path sampling strategies in enabling simulations of rare events, such strategies have not reached their full potential. A common challenge that remains is the identification of a progress coordinate that captures the slow relevant motions of a rare event. Here we have developed a weighted ensemble (WE) path sampling strategy that exploits reinforcement learning to automatically identify an effective progress coordinate among a set of potential coordinates during a simulation. We apply our WE strategy with reinforcement learning to three benchmark systems: (i) an egg carton-shaped toy potential, (ii) an S-shaped toy potential, and (iii) a dimer of the HIV-1 capsid protein (C-terminal domain). To enable rapid testing of the latter system at the atomic level, we employed discrete-state synthetic molecular dynamics trajectories using a generative, fine-grained Markov state model that was based on extensive conventional simulations. Our results demonstrate that using concepts from reinforcement learning with a weighted ensemble of trajectories automatically identifies relevant progress co-ordinates among multiple candidates at a given time during a simulation. Due to the rigorous weighting of trajectories, the simulations maintain rigorous kinetics.

Background: Effective therapeutics for severe acute respiratory syndrome CoronaVirus-2 (SARS-CoV-2) infection are evolving. Under Emergency Use Authorization, COVID-19 convalescent plasma (CCP) was widely used in individuals hospitalized for COVID-19, but few randomized controlled trials supported its efficacy to limit respiratory failure or death., Methods: VA CoronavirUs Research and Efficacy Studies-1 (VA CURES-1) was a double-blind, multi-site, placebo-controlled, randomized clinical trial evaluating the efficacy and safety of CCP with conventional therapy in hospitalized Veterans with SARS-CoV-2 infection and early respiratory compromise (requirement for oxygen). Participants (planned sample size 702) were randomized 1:1 to receive CCP with high titer neutralizing activity or 0.9% saline, stratified by site and age (≥65 versus <65 years old). Participants were followed daily during initial hospitalization and at Days 15, 22 and 28., Outcomes: The composite primary outcome was acute hypoxemic respiratory failure or all-cause death by Day 28. Secondary outcomes by day 28 included time-to-recovery, clinical severity, mortality, rehospitalization for COVID-19, and adverse events. Serial respiratory and blood samples were collected for safety, virologic and immunologic analyses and future studies. Key variables in predicting the success of CURES-1 were: (1) enrollment early in the course of severe infection; (2) use of plasma with high neutralizing activity; (3) reliance on unambiguous, clinically meaningful outcomes. CURES-1 was terminated for futility due to perceived inability to enroll in the lull between the Alpha and Delta waves of the SARS CoV-2 epidemic., Conclusions: VA CURES-1 was a large multi-site trial designed to provide conclusive information about the efficacy of CCP in well-characterized patients at risk for progression of COVID-19. It utilized a rigorous study design with relevant initial timing, quality of product and outcomes., Trial Registration: ClinicalTrials.gov Identifier: NCT04539275., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Primary cervical ganglioneuroblastoma is rare and reports of its subtypes are limited. This case series describes two pediatric patients with the nodular subtype of primary cervical ganglioneuroblastoma with lymphatic spread. Clinical course, diagnosis, and management of this rare tumor are discussed with emphasis on the importance of including neuroblastic tumors in the differential diagnosis of pediatric neck masses. We also report the use of nerve monitoring of the recurrent laryngeal nerve as a surrogate for the vagus nerve during a pediatric neck dissection., (Copyright © 2021. Published by Elsevier B.V.)

Compassion fatigue is the result of repeated vicarious trauma from caring for those who have suffered. Although not well-researched in pediatric nephrology to date, there is reason to believe that it is a real and sustained threat to the pediatric nephrology workforce. Interventions aimed at individuals, the profession, and the organizations in which pediatric nephrologists work can create spaces to discuss and ameliorate compassion fatigue. This will result in better care for patients, more stable pediatric nephrology divisions and a stronger, more resilient pediatric nephrology workforce., Competing Interests: The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Goldberg.)

Background: Although many large, randomized controlled trials (RCT) have been conducted on antibiotic therapy for patients with primary C. difficile infections (CDI), few RCTs have been performed for patients with recurrent CDI (rCDI). In addition, fecal microbial transplant (FMT) is neither FDA-approved or guideline-recommended for patients with pauci-rCDI (first or second recurrences). Therefore, a rigorous RCT of sufficient size was designed to determine the optimal treatment among three antibiotic regimens in current practice for treatment of pauci-rCDI., Methods: VA Cooperative Studies Program (CSP) #596 is a prospective, double-blind, multi-center clinical trial of veteran patients with pauci-rCDI comparing fidaxomicin (FDX) 200 mg twice daily for 10 days and vancomycin (VAN) 125 mg four times daily for 10 days followed by a 3-week vancomycin taper and pulse (VAN-T/P) regimen to a standard course of VAN 125 mg four times daily for 10 days. The primary endpoint is sustained clinical response at day 59, with sustained response measured as a diarrhea composite outcome (D-COM) that includes symptom resolution during treatment (before day 10) without recurrence of diarrhea or other clinically important outcomes through day 59., Discussion: CSP study 596 is designed to compare three current antibiotic treatments for recurrent CDI that are in clinical practice, but which lack high-quality evidence to support strong guideline recommendations. The design of the study which included a pilot phase initiated at six sites with expansion to 24 sites is described along with protocol modifications based on early trial experience and clinical realities including the COVID-19 pandemic., Trial Registration: This study is registered with clinicaltrials.gov (Identifier: NCT02667418)., (Published by Elsevier Inc.)

Background: Success in conducting clinical trials during the coronavirus disease of 2019 pandemic requires the ability to innovate and adapt. There are well-established procedures for the blinding of investigational agents, especially medications, in placebo-controlled randomized clinical trials within the Veterans Health Administration. However, these procedures, managed by research pharmacists, may not apply to investigational agents that are not exclusively managed by pharmacy, such as blood products, including coronavirus disease of 2019 convalescent plasma (plasma). In the absence of established blinding procedures, such studies require special design considerations to minimize uncertainty or bias., Methods: We describe the processes and procedures developed for blinding of plasma in "Veterans Affairs CoronavirUs Research and Efficacy Studies-1" as a prototypical study using this class of investigational therapeutic agents. Veterans Affairs CoronavirUs Research and Efficacy Studies-1 is an ongoing multicenter randomized clinical trial testing the efficacy of plasma added to conventional therapy for severe acute respiratory syndrome coronavirus-2 infection., Results: We report the design of procedures to supply investigational blood products or 0.9% normal saline (saline) control while ensuring the integrity of the blind. Key aspects include workflow considerations, physical blinding strategies, and methods for engaging stakeholders. These procedures leverage the well-established Veterans Affairs research pharmacist's research infrastructure, and Blood Bank Services, which is responsible for blood-based investigational products., Conclusion: By describing the methods used to deliver blood products in a blinded manner in Veterans Affairs CoronavirUs Research and Efficacy Studies-1, we strive both to educate and to increase awareness to improve the implementation of these biological therapeutics for future, high-quality research studies.

Dioxygenase enzymes are essential protein catalysts for the breakdown of catecholic rings, structural components of plant woody tissue. This powerful chemistry is used in nature to make antibiotics and other bioactive materials or degrade plant material, but we have a limited understanding of the breadth and depth of substrate space for these potent catalysts. Here we report steady-state and pre-steady-state kinetic analysis of dopamine derivatives substituted at the 6-position as substrates of L-DOPA dioxygenase, and an analysis of that activity as a function of the electron-withdrawing nature of the substituent. Steady-state and pre-steady-state kinetic data demonstrate the dopamines are impaired in binding and catalysis with respect to the cosubstrate molecular oxygen, which likely afforded spectroscopic observation of an early reaction intermediate, the semiquinone of dopamine. The reaction pathway of dopamine in the pre-steady state is consistent with a nonproductive mode of binding of oxygen at the active site. Despite these limitations, L-DOPA dioxygenase is capable of binding all of the dopamine derivatives and catalyzing multiple turnovers of ring cleavage for dopamine, 6-bromodopamine, 6-carboxydopamine, and 6-cyanodopamine. 6-Nitrodopamine was a single-turnover substrate. The variety of substrates accepted by the enzyme is consistent with an interplay of factors, including the capacity of the active site to bind large, negatively charged groups at the 6-position and the overall oxidizability of each catecholamine, and is indicative of the utility of extradiol cleavage in semisynthetic and bioremediation applications.

ASL-LEX is a publicly available, large-scale lexical database for American Sign Language (ASL). We report on the expanded database (ASL-LEX 2.0) that contains 2,723 ASL signs. For each sign, ASL-LEX now includes a more detailed phonological description, phonological density and complexity measures, frequency ratings (from deaf signers), iconicity ratings (from hearing non-signers and deaf signers), transparency ("guessability") ratings (from non-signers), sign and videoclip durations, lexical class, and more. We document the steps used to create ASL-LEX 2.0 and describe the distributional characteristics for sign properties across the lexicon and examine the relationships among lexical and phonological properties of signs. Correlation analyses revealed that frequent signs were less iconic and phonologically simpler than infrequent signs and iconic signs tended to be phonologically simpler than less iconic signs. The complete ASL-LEX dataset and supplementary materials are available at https://osf.io/zpha4/ and an interactive visualization of the entire lexicon can be accessed on the ASL-LEX page: http://asl-lex.org/., (© The Author(s) 2021. Published by Oxford University Press.)

In this article, I review the ethical issues that arise in the allocation of deceased-donor organs to children and young adults. By analyzing the public media cases of Sarah Murnaghan, Amelia Rivera, and Riley Hancey, I assess whether public appeals to challenge inclusion and exclusion criteria for organ transplantation are ethical and under which circumstances. The issues of pediatric allocation with limited evidence and candidacy affected by factors such as intellectual disability and marijuana use are specifically discussed. Finally, I suggest that ethical public advocacy can coexist with well-evidenced transplant allocation if and when certain conditions (morally defensible criteria, expert evidence, nonprioritization of the poster child, and greater advocacy for organ transplantation in general) are met., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The author has indicated she has no potential conflicts of interest to disclose., (Copyright © 2020 by the American Academy of Pediatrics.)

Despite the fact that type III collagen is the second most abundant collagen type in the body, its contribution to the physiologic maintenance and repair of skeletal tissues remains poorly understood. This study queried the role of type III collagen in the structure and biomechanical functions of two structurally distinctive tissues in the knee joint, type II collagen-rich articular cartilage and type I collagen-dominated meniscus. Integrating outcomes from atomic force microscopy-based nanomechanical tests, collagen fibril nanostructural analysis, collagen cross-link analysis and histology, we elucidated the impact of type III collagen haplodeficiency on the morphology, nanostructure and biomechanical properties of articular cartilage and meniscus in Col3a1 +/- mice. Reduction of type III collagen leads to increased heterogeneity and mean thickness of collagen fibril diameter, as well as reduced modulus in both tissues, and these effects became more pronounced with skeletal maturation. These data suggest a crucial role of type III collagen in mediating fibril assembly and biomechanical functions of both articular cartilage and meniscus during post-natal growth. In articular cartilage, type III collagen has a marked contribution to the micromechanics of the pericellular matrix, indicating a potential role in mediating the early stage of type II collagen fibrillogenesis and chondrocyte mechanotransduction. In both tissues, reduction of type III collagen leads to decrease in tissue modulus despite the increase in collagen cross-linking. This suggests that the disruption of matrix structure due to type III collagen deficiency outweighs the stiffening of collagen fibrils by increased cross-linking, leading to a net negative impact on tissue modulus. Collectively, this study is the first to highlight the crucial structural role of type III collagen in both articular cartilage and meniscus extracellular matrices. We expect these results to expand our understanding of type III collagen across various tissue types, and to uncover critical molecular components of the microniche for regenerative strategies targeting articular cartilage and meniscus repair., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The original supplementary information included with this article contained several minor errors. Corrected Supplementary Information accompanies this corrigendum.

ASL-LEX is a lexical database that catalogues information about nearly 1,000 signs in American Sign Language (ASL). It includes the following information: subjective frequency ratings from 25-31 deaf signers, iconicity ratings from 21-37 hearing non-signers, videoclip duration, sign length (onset and offset), grammatical class, and whether the sign is initialized, a fingerspelled loan sign, or a compound. Information about English translations is available for a subset of signs (e.g., alternate translations, translation consistency). In addition, phonological properties (sign type, selected fingers, flexion, major and minor location, and movement) were coded and used to generate sub-lexical frequency and neighborhood density estimates. ASL-LEX is intended for use by researchers, educators, and students who are interested in the properties of the ASL lexicon. An interactive website where the database can be browsed and downloaded is available at http://asl-lex.org .

Amid growing efforts to advance the replacement, reduction, and refinement of the use of animals in research, there is a growing recognition that in vitro testing of medical devices can be more effective, both in terms of cost and time, and also more reliable than in vivo testing. Although the technological landscape has evolved rapidly in support of these concepts, regulatory acceptance of alternative testing methods has not kept pace. Despite the acceptance by regulators of some in vitro tests (cytotoxicity, gene toxicity, and some hemocompatibility assays), many toxicity tests still rely on animals (irritation, sensitization, acute toxicity, reproductive/developmental toxicity), even where other industrial sectors have already abandoned them. Bringing about change will require a paradigm shift in current approaches to testing - and a concerted effort to generate better data on risks to human health from exposure to leachable chemicals from medical devices, and to boost confidence in the use of alternative methods to test devices. To help advance these ideas, stir debate about best practices, and coalesce around a roadmap forward, the JHU-Center for Alternatives to Animal Testing (CAAT) hosted a symposium believed to be the first gathering dedicated to the topic of in vitro testing of medical devices. Industry representatives, academics, and regulators in attendance presented evidence to support the unique strengths and challenges associated with the approaches currently in use as well as new methods under development, and drew next steps to push the field forward from their presentations and discussion.

Purpose: The study's purpose was to delineate the genetic mutations that cause classic nonketotic hyperglycinemia (NKH)., Methods: Genetic results, parental phase, ethnic origin, and gender data were collected from subjects suspected to have classic NKH. Mutations were compared with those in the existing literature and to the population frequency from the Exome Aggregation Consortium (ExAC) database., Results: In 578 families, genetic analyses identified 410 unique mutations, including 246 novel mutations. 80% of subjects had mutations in GLDC. Missense mutations were noted in 52% of all GLDC alleles, most private. Missense mutations were 1.5 times as likely to be pathogenic in the carboxy terminal of GLDC than in the amino-terminal part. Intragenic copy-number variations (CNVs) in GLDC were noted in 140 subjects, with biallelic CNVs present in 39 subjects. The position and frequency of the breakpoint for CNVs correlated with intron size and presence of Alu elements. Missense mutations, most often recurring, were the most common type of disease-causing mutation in AMT. Sequencing and CNV analysis identified biallelic pathogenic mutations in 98% of subjects. Based on genotype, 15% of subjects had an attenuated phenotype. The frequency of NKH is estimated at 1:76,000., Conclusion: The 484 unique mutations now known in classic NKH provide a valuable overview for the development of genotype-based therapies.Genet Med 19 1, 104-111.

The paper examines the relationship between farm animal welfare, industrial farm animal production, and human health consequences. The data suggest that when the animal welfare of land-based farm animals is compromised, there are resulting significant negative human health consequences due to environmental degradation, the use of non-therapeutic levels of antibiotics for growth promotion, and the consequences of intensification. This paper accepts that even if meat and fish consumption is reduced, meat and fish will be part of the diet of the future. Industrial production modified from the current intensified systems will still be required to feed the world in 2050 and beyond. This paper identifies the concept of sustainable intensification and suggests that if farm animal welfare is improved, many of the human health consequences of intensified industrial production can be eliminated or reduced. In water-based farm animal production, many new systems are resulting in a product that actually protects the environment and can be done at industrial levels without the use of antibiotics.

Grapheme-color and lexical-color synesthesia, the association of colors with letters and words, respectively, are some of the most commonly studied forms of synesthesia, yet relatively little is known about how synesthesia arises from and interfaces with the reading process. To date, synesthetic experiences in reading have only been reported in relation to a word's graphemes and meaning. We present a case study of WBL, a 21-year old male who experiences synesthetic colors for letters and words. Over 3 months, we obtained nearly 3000 color judgments for visually presented monomorphemic, prefixed, suffixed, and compound words as well as judgments for pseudocompound words (e.g., carpet), and nonwords. In Experiment 1, we show that word color is nearly always determined by the color of the first letter. Furthermore, WBL reported two separate colors for prefixed and compound words approximately 14% of the time, with the additional color determined by the first letter of the second morpheme. In Experiment 2, we further investigated how various morphological factors influenced WBL's percepts using the compound norms of Juhasz, Lai, and Woodcock (2014). In a logistic regression analysis of color judgments for nearly 400 compounds, we observed that the likelihood that WBL would perceive a compound as bearing 1 lexical color or 2 lexical colors was influenced by a variety of factors including stem frequency, compound frequency, and the relationship between the meaning of the compound and the meaning of its stems. This constitutes the first study reporting an effect of morphological structure in synesthesia and demonstrates that synesthetic colors result from a complex interaction of perceptual, graphemic, morphological, and semantic factors., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Current evidence suggests that there is a difference between the representations of multimorphemic words in production and perception. In perception, it is widely believed that both whole-word and root representations exist, while in production there is little evidence for whole-word representations. The present investigation demonstrates that whole-word and root frequency independently predict the duration of words suffixed with -ing, -ed, and -s, which reveals that both root and word representations play a role in the production of inflected English words. In a second line of analysis, we find that the number of inflected phonological neighbours independently predicts the duration of monomorphemic words, which extends these results and suggests that whole-word representations exist at the lexical level. Together these results suggest that both root and word representations of inflected words are stored in the lexicon and are relevant for the production of both monomorphemic and multimorphemic words.

Phonological theories differ as to whether phonological knowledge is abstract (e.g., phonemic), concrete (e.g., exemplar-based), or some combination of the two. The abstractness/concreteness of phonological knowledge was examined by analyzing the process of /r/-sandhi in two corpora of spoken English. Two predictions of exemplar-based theories were examined: the extent to which a word manifests a particular sound pattern like /r/-deletion should be influenced by (1) its lexical frequency and (2) its distribution in the language with respect to the sound pattern's conditioning environment. Lexical frequency was found to influence /r/-sandhi in a corpus of rhotic American English but not in a corpus of predominantly non-rhotic British English. No effect of a word's long-term distribution was found in either corpus. These results support theories proposing that phonological knowledge is both word-specific and abstract and indicate that speakers do not store all phonetic detail that is in principle available to them. The factors that may favor the use of word-specific versus abstract representations are discussed.

Research has shown that priming one's racial identity can alter a biracial individuals' social behavior, but can such priming also influence their speech? Language is often used as a marker of one's social group membership and studies have shown that social context can affect the style of language that a person chooses to use, but this work has yet to be extended to the biracial population. Audio clips were extracted from a previous study involving biracial Black/White participants who had either their Black or White racial identity primed. Condition-blind coders rated Black-primed biracial participants as sounding significantly more Black and White-primed biracial participants as sounding significantly more White, both when listening to whole (Study 1a) and thin-sliced (Study 1b) clips. Further linguistic analyses (Studies 2a-c) were inconclusive regarding the features that differed between the two groups. Future directions regarding the need to investigate the intersections between social identity priming and language behavior with a biracial lens are discussed.

Previous research has shown that listeners can tell the difference between phonemically identical onsets of monomorphemic words (e.g., cap and captain) using acoustic cues (Davis, Marslen-Wilson, & Gaskell, 2002). This study investigates whether this finding extends to multimorphemic words, asking whether listeners can use phonetic information to distinguish unsuffixed from suffixed words before they differ phonemically (e.g., clue vs. clueless). We report 4 experiments investigating this issue using forced-choice identification and mouse-tracking tasks. We find that listeners are in fact able to distinguish mono- and multimorphemic words using only subphonemic information. Our experiments reveal that duration information alone is sufficient to make this discrimination and that listeners make use of an abstract rule that relates duration to morphological structure. The implications of these results for theories of morphological processing are discussed.

Children with multiple comorbidities, including neurodevelopmental delay, can develop end-stage kidney disease (ESKD). When and if these children should be eligible for kidney transplantation is an area of debate within the pediatric nephrology community and the public. Discussions focus on expected survival and quality of life posttransplant, as well as resource allocation decisions, as donor kidneys remain a limited resource. This paper focuses on the evidence available regarding outcomes in this population and the ethical issues that should be considered. The authors offer a framework for transplant teams evaluating children with comorbidities for kidney transplant, focusing on the benefits and burdens that transplantation can be expected to achieve.

PSYCHOLINGUISTIC THEORIES HAVE PREDOMINANTLY BEEN BUILT UPON DATA FROM SPOKEN LANGUAGE, WHICH LEAVES OPEN THE QUESTION: How many of the conclusions truly reflect language-general principles as opposed to modality-specific ones? We take a step toward answering this question in the domain of lexical access in recognition by asking whether a single cognitive architecture might explain diverse behavioral patterns in signed and spoken language. Chen and Mirman (2012) presented a computational model of word processing that unified opposite effects of neighborhood density in speech production, perception, and written word recognition. Neighborhood density effects in sign language also vary depending on whether the neighbors share the same handshape or location. We present a spreading activation architecture that borrows the principles proposed by Chen and Mirman (2012), and show that if this architecture is elaborated to incorporate relatively minor facts about either (1) the time course of sign perception or (2) the frequency of sub-lexical units in sign languages, it produces data that match the experimental findings from sign languages. This work serves as a proof of concept that a single cognitive architecture could underlie both sign and word recognition.

The aim of this study was to evaluate the influence of multiple factors on bacterial contamination in 213 ejaculates from four boar studs. Semen contamination by aerobic mesophiles increased in ejaculates where the preputial fluid flowed into the collection container, collection glove was dirty, preputial hair was long (>1.0 cm), the collection lasted >7 min and boars were older than 18 months. An increase in coliforms occurred when preputial fluid dripped into the collection container, collections lasted >7 min or when penis escaped during collection. Semen contamination increased when two or more factors related to hygiene (poor hygiene of the boar, dirty preputial ostium, large preputial diverticulum, long preputial hair, dirty gloves, preputial liquid trickling from the hand of the technician into the semen container and penis escaping) were present. A vigilant protocol of collection must be followed to minimize bacterial contamination, especially avoiding dripping of preputial liquid into the semen container., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Morphological and phonological processes are tightly interrelated in spoken production. During processing, morphological processes must combine the phonological content of individual morphemes to produce a phonological representation that is suitable for driving phonological processing. Further, morpheme assembly frequently causes changes in a word's phonological well-formedness that must be addressed by the phonology. We report the case of an aphasic individual (WRG) who exhibits an impairment at the morpho-phonological interface. WRG was tested on his ability to produce phonologically complex sequences (specifically, coda clusters of varying sonority) in heteromorphemic and tautomorphemic environments. WRG made phonological errors that reduced coda sonority complexity in multimorphemic words (e.g., passed→[pæstıd]) but not in monomorphemic words (e.g., past). WRG also made similar insertion errors to repair stress clash in multimorphemic environments, confirming his sensitivity to cross-morpheme well-formedness. We propose that this pattern of performance is the result of an intact phonological grammar acting over the phonological content of morphemic representations that were weakly joined because of brain damage. WRG may constitute the first case of a morpho-phonological impairment-these results suggest that the processes that combine morphemes constitute a crucial component of morpho-phonological processing., (Copyright © 2013 Elsevier B.V. All rights reserved.)

The role that in vitro systems can play in toxicological risk assessment is determined by the appropriateness of the chosen methods, with respect to the way in which in vitro data can be extrapolated to the in vivo situation. This report presents the results of a workshop aimed at better defining the use of in vitro-derived biomarkers of toxicity (BoT) and determining the place these data can have in human risk assessment. As a result, a conceptual framework is presented for the incorporation of in vitro-derived toxicity data into the risk assessment process. The selection of BoT takes into account that they need to distinguish adverse and adaptive changes in cells. The framework defines the place of in vitro systems in the context of data on exposure, structural and physico-chemical properties, and toxicodynamic and biokinetic modeling. It outlines the determination of a proper point-of-departure (PoD) for in vitro-in vivo extrapolation, allowing implementation in risk assessment procedures. A BoT will need to take into account both the dynamics and the kinetics of the compound in the in vitro systems. For the implementation of the proposed framework it will be necessary to collect and collate data from existing literature and new in vitro test systems, as well as to categorize biomarkers of toxicity and their relation to pathways-of-toxicity. Moreover, data selection and integration need to be driven by their usefulness in a quantitative in vitro-in vivo extrapolation (QIVIVE).

On FRAME's 40th anniversary, I had the opportunity to examine FRAME and CAAT's missions as closely linked to those of their universities. The roles of education, research and service are key, both to the universities and to our two centres. By examining the current programmes, and identifying the needs of the future, the research activities, policy studies and training, it becomes clear that the Three Rs of alternatives contribute significantly to our respective universities' missions., (2009 FRAME.)

Although considerable progress has been made in determining the cognitive architecture of spelling, less is known about the serial-order mechanism of spelling: the process(es) involved in producing each letter in the proper order. In this study, we investigate compound chaining as a theory of the serial-order mechanism of spelling. Chaining theories posit that the retrieval from memory of each element in a sequence is dependent upon the retrieval of previous elements. We examine this issue by comparing the performance of simple recurrent networks (a class of neural networks that we show can operate by chaining) with that of two individuals with acquired dysgraphia affecting the serial-order mechanism of spelling-the graphemic buffer. We compare their performance in terms of the effects of serial position, the effect of length on overall letter accuracy, and the effect of length on the accuracy of specific positions within the word. We find that the networks produce significantly different patterns of performance from those of the dysgraphics, indicating that compound chaining is not an appropriate theory of the serial-order mechanism of spelling.

Current U.S. legislation restricts reimbursement for organ transplantation for nondocumented residents, which makes it difficult for many immigrants, including children, to access the transplants they need. In this article, we offer moral, economic, and legal reasons that nondocumented immigrants deserve the same access to kidney transplantation as do legal residents. We argue that the current reasoning for such a ban is based on unjustified fears and unsupported assumptions, which are not a solid basis for determining eligibility for lifesaving therapy for the neediest members of our society.

To address the growing need for scientifically valid and humane alternatives to developmental neurotoxicity testing (DNT), we propose that basic research scientists in developmental neurobiology be brought together with mechanistic toxicologists and policy analysts to develop the science and policy for DNT alternatives that are based on evolutionarily conserved mechanisms of neurodevelopment. In this article we briefly review in vitro and other alternative models and present our rationale for proposing that resources be focused on adapting alternative simple organism systems for DNT. We recognize that alternatives to DNT will not completely replace a DNT paradigm that involves in vivo testing in mammals. However, we believe that alternatives will be of great value in prioritizing chemicals and in identifying mechanisms of developmental neurotoxicity, which in turn will be useful in refining and reducing in vivo mammalian tests for exposures most likely to be hazardous to the developing human nervous system.

There are a number of national and international efforts designed to screen chemicals for toxicity. Although the emphasis in terms of the specific chemicals is different, e.g. endocrine disruptors, children's health, High Production Volume (HPV), the European Registration, Evaluation and Authorisation of Chemicals (REACH) programme, the purpose is the same. Each is intended to evaluate the potential toxicity of chemicals to humans and, in some cases, to the environment. How best can these tasks be accomplished? The first need is to provide a realistic prioritisation of which chemicals need to be evaluated. Once identified, a defined decision-tree approach with an emphasis on short-term in vitro assays and new genomic technologies offers the greatest promise. The more practical matter of screening the chemicals would be by using a tiered decision-tree approach. Common features of the approach would be the use of three tiers. The first tier would be a screening/prioritisation tier, the second would provide an initial characterisation of toxicity, and the third would discern mode of action/biological activity. The intent of this approach is to provide a concept that will allow decisions to be made as to which chemicals need to be tested, provide some idea as to their toxicity and finally mode of action, and at the same time, taking into account the Three Rs, reduction, refinement and replacement. Thus, specific batteries of tests are not discussed, as these would need to be tailored to the specific chemicals of concern, e.g. endocrine disruptors, HPV. Neither are regulatory requirements factored into the concept, but the data that would be gathered should consider the possibility of eventual submission of the data obtained by in vitro and other non-traditional approaches by regulatory authorities.

My paper will focus on those events happening within the United States during the last year. The issue of including or excluding rats, birds and mice from inclusion under the Animal Welfare Act has been a difficult battle for both those that wish to exclude them and those that wish to include these animals under this legislation. As of the writing of this abstract, the Senate, which originally intended to include rats, birds and mice under the Animal Welfare Act, has passed an amendment which will permanently exclude their listing under this Act. During the last several years it has become clear that refinement, as one of the 3Rs, has and will become the most important set of activities to add humanness to animal experimentation. It is clear that refinement approaches provide the opportunity to possibly eliminate or significantly minimize any pain or distress in animal protocol. My presentation will focus on CAAT's (http://caat.jhsph.edu) activities in this important area. Understanding potential health hazards to environmental industrial chemicals has become a major focus of activity both in the US, Europe and Japan. These programs offer the first opportunity to provide information, in the public domain, on these chemicals. One of the consequences, however, is the potential requirement for large numbers of animals. In the presentation, I will focus on two approaches to significantly including the 3Rs in these important programs. Although it is common practice in Japan to recognize contributions of laboratory animals through a day of memorialization, this has not been the case in the United States. During the last year, several activities have been initiated to begin to institutionalize memorial services for animals used in research. As the host institution of Altweb (http://altweb.jhsph.edu), the alternative web site internationally, current statistics and accomplishments will be provided on its worldwide utilization.

The TestSmart program was developed in response to the High Production Volume Chemical Challenge, a voluntary initiative under which chemical producers provide basic toxicity data on chemicals produced in greater than one million pounds annually. Specifically, under the Challenge, chemical producers will generate data as needed to complete the Screening Information Data Set (SIDS), as defined by the Organization for Economic Cooperation and Development (OECD). The TestSmart program is a collaborative effort of the Johns Hopkins Center for Alternatives to Animal Testing, the Environmental Defense Fund, Carnegie-Mellon University, and the University of Pittsburgh. The goal of the TestSmart program is to provide a humane and efficient approach to collecting SIDS data. The program has two objectives, one immediate and the other more long term. The immediate objective has been to make recommendations to reduce the number of animals used in collecting SIDS data under the Challenge. This was accomplished, through a group process, by examining the current status of alternative methods for SIDS endpoints and by providing an assessment of the "state of readiness" of current and potential future alternatives. The long-term objective is to provide a model for other programs to follow the TestSmart concept of a more efficient and humane approach to obtain toxicological data of interest to regulators and the public., (Copyright 2001 Academic Press.)

The effects of pH and PEG 400 on the stoichiometry, conformation, and stability of the magnesium-oxytetracycline (Mg+2-OTC) complex were evaluated. Circular dichroism (CD) and HPLC were used to investigate Mg+2-OTC complex formation and determine the stability of the complexes formed. The stoichiometry of the complex was determined to be a 1:1 molar ratio of Mg+2 to OTC regardless of changes in pH, in the range 7-10, and regardless of the percentage of polyethylene glycol (PEG) 400 in solution. CD showed that the conformation assumed by Mg+2-OTC complex is sensitive to changes in pH, however, little to no effect was found when the PEG 400 concentration was varied. PEG 400 was found to effect the magnitude of complexation as evident by the dependence of CD peak intensity on the cosolvent concentration in solution. The Job's method confirmed that the formation of this complex increased with increasing PEG 400 concentration and was most favored at pH 8. HPLC analyses of OTC solutions at pH 9 revealed the formation of multiple degradation products after storage at 50 degrees C. The incidence and magnitude of OTC degradation products were reduced in the presence of Mg+2 and PEG 400. Despite the HPLC results of maintained OTC stability in magnesium-complexed solutions over time, visual inspection showed these solutions to have darkened, indicating that an oxidative process is responsible for initial degradation of OTC. Therefore, the need for additional measures (i.e., antioxidants) was established to ensure the long-term stability of OTC in solution.

Conceptually, irritant contact dermatitis (irritation) and allergic contact dermatitis (ACD) in man should provide the ideal platforms to launch in vitro toxicology into the pantheon of in vitro testing assays. In theory, irritant dermatitis has been considered by most a simple area of cutaneous biology, whereas ACD is a complex area of biology. However, both result in responses that are reasonably stereotypical and well characterized. The biology of the underlying mechanisms is becoming characterized and will thus allow development of mechanistically based in vitro assays that will be scientifically validated and thus acceptable to regulatory agencies.