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Early experience with food influences taste preference in adulthood. How gustatory experience influences development of taste preferences and refinement of cortical circuits has not been investigated. Here we exposed weanling mice to an array of tastants and determined the effects on the preference for sweet in adulthood. We demonstrate an experience-dependent shift in sucrose preference persisting several weeks following the termination of exposure. A shift in sucrose palatability, altered neural responsiveness to sucrose, and inhibitory synaptic plasticity in the gustatory portion of the insular cortex (GC) were also induced. The modulation of sweet preference occurred within a restricted developmental window, but restoration of the capacity for inhibitory plasticity in adult GC reactivated the sensitivity of sucrose preference to taste experience. Our results establish a fundamental link between gustatory experience, sweet-preference, inhibitory plasticity, and cortical circuit function, and highlight the importance of early life experience in setting taste preferences.

Accuracy of hemoglobin (Hb) measured by arterial blood gas (ABG) analyzer is considered inferior to laboratory (lab) measurements as it could overestimate Hb levels.The study aims to compare Hb measured using ABG versus conventional lab method at the time of major blood loss and in the preoperative and immediate postoperative periods.It was a prospective, nonrandomized observational study conducted in a tertiary care center.The study was conducted in 24 patients undergoing major head-and-neck surgeries. Simultaneous blood samples were sent for Hb measurement by ABG analysis and lab method at induction of anesthesia, when intraoperative blood loss exceeded maximum allowable blood loss, and in the immediate postoperative period.Chi-square test, independent sample'sMean Hb values obtained by both techniques were significantly different at all time points. Hb obtained by ABG analysis was significantly higher than lab value preoperatively (12.78 ± 2.51 vs. 12.05 ± 2.2,Hb measured by ABG analysis was significantly higher than that measured by lab method at the time of major blood loss, preoperatively, and at the immediate postoperative period in patients undergoing major head-and-neck surgeries, with a good correlation of values obtained by both the techniques.

Acute disseminated encephalomyelitis (ADEM) affects the central nervous system (CNS) via a rapid and auto-immune process. It has been associated to viral and bacterial infections, as well as after immunization. Since the beginning of the SARS-CoV-2 (COVID-19) pandemic, reports of COVID 19 infection have been linked to ADEM. We present a case of an 11-year-old female with neurological symptoms during the acute phase of her COVID-19 illness, with MRI changes and positive Myelin Oligodendrocyte Glycoprotein (MOG) antibodies, with clinical presentation consistent of ADEM.

Dementia is often characterized as being caused by one of several major diseases, such as Alzheimer's disease (AD), cerebrovascular disease, Lewy body disease, or a frontotemporal degeneration. Failure to acknowledge that more than one entity may be present precludes attempts to understand interactive relationships. The clinicopathological studies of dementia demonstrate that multiple pathologic processes often coexist.How overlapping pathologic findings affect the diagnosis and treatment of clinical AD and other dementia phenotypes was the topic taken up by the Alzheimer's Association's Research Roundtable in October 2014. This review will cover the neuropathologic basis of dementia, provide clinical perspectives on multiple pathologies, and discuss therapeutics and biomarkers targeting overlapping pathologies and how these issues impact clinical trials.High prevalence of multiple pathologic findings among individuals with clinical diagnosis of AD suggests that new treatment strategies may be needed to effectively treat AD and other dementing illnesses.

Author(s): Touchon, J; Rosenbaum, J; Aisen, P; Andrieu, S; Carrillo, MC; Ceccaldi, M; Dartiques, J-F; Feldman, H; Gabelle, A; Isaac, M; Fitten, LJ; Sperling, RA; Vellas, B; Tariot, P; Weiner, M

Neuronal fate determination and maturation requires an intricate interplay between genetic programs and environmental signals. However, disentangling the roles of intrinsic vs. extrinsic mechanisms that regulate this differentiation process is a conundrum for all developmental neurobiologists. This issue is magnified for GABAergic interneurons, an incredibly heterogeneous cell population that is born from transient embryonic structures and undergo a protracted migratory phase to disperse throughout the telencephalon. To explore how different brain environments affect interneuron fate and maturation, we developed a protocol for harvesting fluorescently labeled immature interneuron precursors from specific brain regions in newborn mice (P0-P2). At this age, interneuron migration is nearly complete and these cells are residing in their final resting environments with relatively little synaptic integration. Following collection of single cell solutions via flow cytometry, these interneuron precursors are transplanted into P0-P2 wildtype postnatal pups. By performing both homotopic (e.g., cortex-to-cortex) or heterotopic (e.g., cortex-to-hippocampus) transplantations, one can assess how challenging immature interneurons in new brain environments affects their fate, maturation, and circuit integration. Brains can be harvested in adult mice and assayed with a wide variety of posthoc analysis on grafted cells, including immunohistochemical, electrophysiological and transcriptional profiling. This general approach provides investigators with a strategy to assay how distinct brain environments can influence numerous aspects of neuron development and identify if specific neuronal characteristics are primarily driven by hardwired genetic programs or environmental cues.

Em 2009, ocorreu uma pandemia do virus Influenza A H1N1. Por conta da capacidade de disseminacao do virus, o mesmo foi alvo de preocupacao por toda a sociedade. Com isso, observou-se a importância de profissionais de saude capacitados para realizacao de diagnostico e tratamento oportunos bem como medidas de prevencao e controle da epidemia. O objetivo e avaliar o conhecimento de profissionais da saude sobre a Influenza H1N1. A pesquisa teve como publico-alvo profissionais da saude de um hospital geral do municipio do Rio de Janeiro, referencia durante a epidemia de 2009. Aplicou-se um questionario durante a campanha de vacinacao destinada a este grupo, realizada pelo Nucleo de Epidemiologia do hospital. De 1710 vacinados, 462 participaram da pesquisa. A media de idade foi de 38,9 anos (DP ± 11,96), sendo 61,5% do sexo feminino e 33,3% do sexo masculino. Em relacao a categoria funcional, 25,5% eram medicos, 39,6% enfermeiros e 34,6% da categoria “outros”. Na autoavaliacao do conhecimento sobre a doenca, 45% classificaram seus conhecimentos sobre a doenca como Muito Bom ou Bom. As pontuacoes medias obtidas dos conhecimentos sobre fatores de risco mostram um bom desempenho dos medicos, com media de 6,17 (± 2,9) acertos, quando o maximo seriam 10. Os resultados apontam que o conhecimento demonstrado pelos profissionais de saude e insuficiente. Este grupo tem papel fundamental de enfrentar provavel segunda onda causada por este virus. Assim, sao importantes acoes continuas de educacao e informacao direcionadas a este publico, bem como subsidio ao seu planejamento e organizacao.

Parkinson’s disease is a complex heterogeneous disorder with urgent need for disease-modifying therapies. Progress in successful therapeutic approaches for PD will require an unprecedented level of collaboration. At a workshop hosted by Parkinson’s UK and co-organized by Critical Path Institute’s (C-Path) Coalition Against Major Diseases (CAMD) Consortiums, investigators from industry, academia, government and regulatory agencies agreed on the need for sharing of data to enable future success. Government agencies included EMA, FDA, NINDS/NIH and IMI (Innovative Medicines Initiative). Emerging discoveries in new biomarkers and genetic endophenotypes are contributing to our understanding of the underlying pathophysiology of PD. In parallel there is growing recognition that early intervention will be key for successful treatments aimed at disease modification. At present, there is a lack of a comprehensive understanding of disease progression and the many factors that contribute to disease progression heterogeneity. Novel therapeutic targets and trial designs that incorporate existing and new biomarkers to evaluate drug effects independently and in combination are required. The integration of robust clinical data sets is viewed as a powerful approach to hasten medical discovery and therapies, as is being realized across diverse disease conditions employing big data analytics for healthcare. The application of lessons learned from parallel efforts is critical to identify barriers and enable a viable path forward. A roadmap is presented for a regulatory, academic, industry and advocacy driven integrated initiative that aims to facilitate and streamline new drug trials and registrations in Parkinson’s disease.

Our objectives are to describe the procedure for qualification advice and opinion from EU regulators on the use of novel methodologies in drug development, the key stakeholders involved and the evidence requirements for qualification opinion. We present a case study of the request from the Coalition Against Major Disease (CAMD) Consortium of the Critical Path (C-Path) Institute for EU regulators׳ qualification opinion on the use of low hippocampal volume as a biomarker for population enrichment in clinical trials of novel drugs in Alzheimer׳s disease (AD). We discuss the main concerns from the regulators, data analysis requests and guidance during the qualification. EU regulators concluded that low hippocampal volume, measured by vMRI and considered as a dichotomized variable (low volume or not), appears to help enriching recruitment into clinical trials aimed at studying drugs that potentially slow the progression of the pre-dementia stage of AD. The biomarker qualification procedure is a dynamic process in which pharmaceutical companies and research consortia can submit further data to update the qualifications and improve the predictive value of the biomarkers.

Failures in trials for Alzheimer’s disease (AD) may be attributable to inadequate dosing, population selection, drug inefficacy, or insufficient design optimization. The Coalition Against Major Diseases (CAMD) was formed in 2008 to develop drug development tools (DDT) to expedite drug development for AD and Parkinson’s disease.(1) CAMD led a process that successfully advanced a clinical trial simulation (CTS) tool for AD through the formal regulatory review process at the US Food and Drug Administration (FDA) and European Medicines Agency (EMA).

Objectives There is a pressing need for drug development in pediatric ulcerative colitis (UC). Lack of scientific consensus on efficacy endpoints and disease outcome assessments presents a hurdle for global drug development in pediatric UC. Scientists from 4 regulatory agencies convened an International Inflammatory Bowel Disease Working Group (i-IBD Working Group) to harmonize present thinking about various aspects of drug development in pediatric UC globally. Methods The i-IBD Working Group was convened in 2012 by scientists from the US Food and Drug Administration, European Medicines Agency, Health Canada, and the Pharmaceuticals and Medical Devices Agency of Japan. The members of this group considered reasons for differences in their acceptance of efficacy endpoints and disease activity indices used in pediatric UC, reviewed the available literature, and developed consensus opinions regarding approaches for evaluating outcomes in pediatric UC trials. Results There is lack of harmonization in using efficacy endpoint and outcome assessments including disease activity indices to assess clinical benefit in pediatric UC trials. Many disease activity indices have been developed, but their biometric properties, such as responsiveness, reliability, and validity, have not been properly validated. Biomarkers, such as fecal calprotectin and lactoferrin, are being investigated for their potential as noninvasive surrogate endpoints in UC. Conclusions Consensus on the efficacy endpoints, disease activity indices, and outcome assessments is needed for globalization of pediatric UC trials. The i-IBD Working Group offers several perspectives to facilitate harmonization across regions. The development of noninvasive biomarkers as reliable surrogate endpoints needs to be explored further.

Objectives To facilitate global drug development, the International Pediatric Inflammatory Bowel Disease Working Group (i-IBD Working Group) discussed data extrapolation, trial design, and pharmacokinetic (PK) considerations for drugs intended to treat pediatric ulcerative colitis (UC), and considered possible approaches toward harmonized drug development. Methods Representatives from the US Food and Drug Administration, European Medicines Agency, Health Canada, and the Pharmaceuticals and Medical Devices Agency of Japan convened monthly to explore existing regulatory approaches, reviewed the results of a literature search, and provided perspectives on pediatric UC drug development based on the available medical literature. Results Although pediatric UC, when compared with UC in adults, has a similar disease progression and response to intervention, the similarity of the exposure-response relation has not been adequately established. Consequently, clinical endpoints should be selected to optimally assess efficacy in children. The inclusion of a placebo control in pediatric trials to assure assay sensitivity may be appropriate under limited circumstances. In clinical studies, although the drug under investigation could provide possible direct benefit, placebo treatment should present no more than a minor increase over minimal risk to children with UC. Conclusions Partial extrapolation of efficacy from informative adult studies may be appropriate. Placebo-controlled efficacy trials are scientifically and ethically appropriate for pediatric UC given appropriate patient selection and the use of early escape. Clinical studies in pediatric UC may include initial dose-finding studies and exposure-response modeling followed by an efficacy and safety study to further explore the exposure-response relation.

Precompetitive collaborations have been successful in several disease areas and industries. Such collaborations are critical to address the gaps and challenges in therapeutic development for chronic neurodegenerative diseases. On November 5, 2012, members of the scientific community, advocates, regulators, industry, and government officials met at the US Food and Drug Administration to develop tools to expedite drug development and maximize the potential for success in future drug trials for Alzheimer disease and Parkinson disease. The meeting established that multiple collaborative approaches are essential for accelerating drug development. Such approaches include precompetitive data sharing, regulatory qualification of biomarkers and clinical outcome assessments, implementation of data standards, and development of quantitative drug disease trial models. While challenges to collaboration among industry partners are formidable, they are not insurmountable. The Coalition Against Major Diseases (CAMD) has several positive examples to highlight. This review represents proceedings from CAMD's annual conference and discusses the key themes that are being advanced by the Critical Path Institute.

A clinician-reported outcome (ClinRO) assessment is a type of clinical outcome assessment (COA). ClinRO assessments, like all COAs (patient-reported, observer-reported, or performance outcome assessments), are used to 1) measure patients' health status and 2) define end points that can be interpreted as treatment benefits of medical interventions on how patients feel, function, or survive in clinical trials. Like other COAs, ClinRO assessments can be influenced by human choices, judgment, or motivation. A ClinRO assessment is conducted and reported by a trained health care professional and requires specialized professional training to evaluate the patient's health status. This is the second of two reports by the ISPOR Clinical Outcomes Assessment-Emerging Good Practices for Outcomes Research Task Force. The first report provided an overview of COAs including definitions important for an understanding of COA measurement practices. This report focuses specifically on issues related to ClinRO assessments. In this report, we define three types of ClinRO assessments (readings, ratings, and clinician global assessments) and describe emerging good measurement practices in their development and evaluation. The good measurement practices include 1) defining the context of use; 2) identifying the concept of interest measured; 3) defining the intended treatment benefit on how patients feel, function, or survive reflected by the ClinRO assessment and evaluating the relationship between that intended treatment benefit and the concept of interest; 4) documenting content validity; 5) evaluating other measurement properties once content validity is established (including intra- and inter-rater reliability); 6) defining study objectives and end point(s) objectives, and defining study end points and placing study end points within the hierarchy of end points; 7) establishing interpretability in trial results; and 8) evaluating operational considerations for the implementation of ClinRO assessments used as end points in clinical trials. Applying good measurement practices to ClinRO assessment development and evaluation will lead to more efficient and accurate measurement of treatment effects. This is important beyond regulatory approval in that it provides evidence for the uptake of new interventions into clinical practice and provides justification to payers for reimbursement on the basis of the clearly demonstrated added value of the new intervention.

© 2010 Elsevier Ltd. All rights reserved, The development of disease-modifying treatments for Alzheimer's disease requires innovative trials with large numbers of subjects and long observation periods. The use of blood, cerebrospinal fluid or neuroimaging biomarkers is critical for the demonstration of disease-modifying therapy effects on the brain. Suitable biomarkers are those which reflect the progression of AD related molecular mechanisms and neuropathology, including amyloidogenic processing and aggregation, hyperphosphorylation, accumulation of tau and neurofibrillary tangles, progressive functional, metabolic and structural decline, leading to neurodegeneration, loss of brain tissue and cognitive symptoms. Biomarkers should be used throughout clinical trial phases I–III of AD drug development. They can be used to enhance inclusion and exclusion criteria, or as baseline predictors to increase the statistical power of trials. Validated and qualified biomarkers may be used as outcome measures to detect treatment effects in pivotal clinical trials. Finally, biomarkers can be used to identify adverse effects. Questions regarding which biomarkers should be used in clinical trials, and how, are currently far from resolved. The Oxford Task Force continues and expands the work of our previous international expert task forces on disease-modifying trials and on endpoints for Alzheimer's disease clinical trials. The aim of this initiative was to bring together a selected number of key international opinion leaders and experts from academia, regulatory agencies and industry to condense the current knowledge and state of the art regarding the best use of biological markers in Alzheimer's disease therapy trials and to propose practical recommendations for the planning of future AD trials., GW was partly funded by the NIHR Biomedical Research Center Programme, Oxford, UK.

Alzheimer's disease (AD) is among the most significant health care burdens. Disappointing results from clinical trials in late-stage AD persons combined with hopeful results from trials in persons with early-stage suggest that research in the preclinical stage of AD is necessary to define an optimal therapeutic success window. We review the justification for conducting trials in the preclinical stage and highlight novel ethical challenges that arise and are related to determining appropriate risk-benefit ratios and disclosing individuals' biomarker status. We propose that to conduct clinical trials with these participants, we need to improve public understanding of AD using unified vocabulary, resolve the acceptable risk-benefit ratio in asymptomatic participants, and disclose or not biomarker status with attention to study type (observational studies vs clinical trials). Overcoming these challenges will justify clinical trials in preclinical AD at the societal level and aid to the development of societal and legal support for trial participants. The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no 115736, resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007–2013) and EFPIA companies' in kind contribution.

The use of placebo in clinical trials, and, related to this, ethical and feasibility aspects, are often debated. However, regulatory authorities must ensure that only new drugs with a positive benefit/risk would be granted a marketing authorization. It is therefore not surprising that they often put forward the need for placebo control in clinical trials in an area where many trials fail, and assay sensitivity is not self-evident. To illustrate the complexity that regulatory authorities encounter when faced with the registration dossier of products in the main psychiatric therapeutic areas, Major Depressive Disorder (MDD) and schizophrenia, the trial outcome for products receiving an opinion in the EU during the past 15 years were reviewed.European Public Assessment Reports and registration files.A total of 45 studies qualified for analysis. For the indication MDD 38% of the studies (10/26) were recorded as failed, and another 15% (4/26) as negative. For schizophrenia, these figures were 16% (3/19) and 11% (2/19). Further exploration of the trials in MDD revealed an inconsistent pattern in terms of magnitude of placebo- and drug-mediated response (i.e. similar studies with consistent placebo response provided different treatment outcomes).From a regulatory perspective the dilemma of a priori exclusion of the placebo arm in clinical trials in the domains of depression or schizophrenia cannot be solved at this time as long as factors influencing trial variability are not better identified or understood. This counts in particular for MDD where the added drug effect is not consistent across trials with almost identical inclusion criteria. Unfortunately, this trend has not changed over the past 15 years. However, all efforts should be taken to optimize the clinical development of drugs in the psychiatric domain, and improve the intrinsic quality of the clinical trials in order to allow for a different viewpoint.

BACKGROUND: Various statistical methods have been used for data analysis in alcohol treatment studies. Trajectory analyses can better capture differences in treatment effects and may provide insight on the optimal duration of future clinical trials and grace periods. This improves on the limitation of commonly used parametric (e.g., linear) methods that cannot capture nonlinear temporal trends in the data. METHODS: We propose an exploratory approach, using more flexible smoothing mixed effects models, more accurately to characterize the temporal patterns of the drinking data. We estimated the trajectories of the treatment arms for data sets from 2 sources: a multisite topiramate study, and the Combined Pharmacotherapies (acamprosate and naltrexone) and Behavioral Interventions study. RESULTS: Our methods illustrate that drinking outcomes of both the topiramate and placebo arms declined over the entire course of the trial but with a greater rate of decline for the topiramate arm. By the point-wise confidence intervals, the heavy drinking probabilities for the topiramate arm might differ from those of the placebo arm as early as week 2. Furthermore, the heavy drinking probabilities of both arms seemed to stabilize at the end of the study. Overall, naltrexone was better than placebo in reducing drinking over time yet was not different from placebo for subjects receiving the combination of a brief medical management and an intensive combined behavioral intervention. CONCLUSIONS: The estimated trajectory plots clearly showed nonlinear temporal trends of the treatment with different medications on drinking outcomes and offered more detailed interpretation of the results. This trajectory analysis approach is proposed as a valid exploratory method for evaluating efficacy in pharmacotherapy trials in alcoholism. Language: en

The European Medicines Agency (EMA) in London is responsible for the Regulatory review of new medicinal products for Marketing Authorisation, through which pharmaceutical companies may obtain first Marketing Authorisation and subsequent Variations valid throughout the EU and EFTA. The qualification opinion of novel methodologies is a new procedure where applicants can obtain scientific advice on new methodologies for regulatory clinical trials of efficacy of new compounds. It will help benefit/risk assessment of the CHMP. The definition of prodromal AD is acceptable. The "Dubois Criteria" as criteria to define the population must be validated in full at the time of the submission of the dossiers. Including a positive CSF biomarker profile is considered predictive for the evaluation of the AD-dementia type. However, although high CSF tau and low CSF Aβ42 are predictive of Alzheimer's disease, the criterion "positive CSF tau/Aβ42 ratio" is not well defined. The qualification of biomarkers in the pre-dementia stage of Alzheimer's disease will allow better inclusion criteria of patients in pre-dementia trials in which the benefit/risk is higher for treatment with these novel compounds.

Child and adolescent psychiatry is a relatively young field and the recognition, classification, and treatment of disorders in children and adolescents lag behind those in adults. In recent years there is an increasing awareness of the differences between children and adults in psychopathology and pharmacology. Related to this new paediatric regulations have been introduced. This article reviews the regulatory and legislative measures that were adopted in the EU in 2007 and the subsequent impact of these measures on the field of paediatric psychopharmacology. The consequences of the paediatric regulation in the EU are reflected in several domains: regulatory, research aimed at drug development and clinical practices. In the regulatory domain, the consequences include: new paediatric indications, inclusion of special (class) warnings, specification of dose regimens, and information on safety specific to children and adolescents, and development of new medicinal formulations. The paediatric regulation leads to timely development of paediatric friendly formulations and better quality of the clinical evidence. In clinical practices, an increased awareness of the uniqueness of paediatric pharmacology is emerging among medical professionals, and subsequent improvement of medical care (i.e. correct doses, appropriate formulation, monitoring for expected adverse events). In addition, clinical guidelines will have to be revised more frequently in order to integrate the recently acquired knowledge. The new regulations stimulate transparency and discussions between academia, pharmaceutical industry, and regulators. The purpose is to optimize clinical research and obtain evidence for paediatric psychopharmacology, thereby providing adequate support for treatment.

The European Medicines Agency (EMA) qualification process is a new, voluntary, scientific pathway leading to either a Committee for Medicinal Products for Human Use (CHMP) opinion or a Scientific Advice on innovative methods or drug development tools: (i) CHMP Qualification Opinion on the acceptability of a specific use of the proposed method, based on the assessment of submitted data and (ii) CHMP Qualification Advice on future protocols and methods for further method development towards qualification, based on the evaluation of the scientific rationale and on preliminary data submitted. The qualification procedure was established as a response to the drug development bottlenecks and inefficiencies, but also to the availability of new methodologies, not yet integrated in the drug development and clinical management paradigm. The qualification process addresses innovative methods developed by consortia, networks, public/private partnerships, learned societies or pharmaceutical industry. It is expected to facilitate communication between the scientific community and the regulators and to address challenges with the development and use of medicines. In this article, we will present an overview of the process and the up to now scientific advice working party (SAWP) experience.

In this paper we investigate mortality in short-term placebo-controlled trials conducted to demonstrate efficacy and safety of atypical antipsychotic drugs for the treatment of schizophrenic patients in the acute phase of illness. Arguments are provided, why short-term placebo-controlled studies are required. This is an integrated analysis of results from randomized placebo-controlled trials conducted pre-licensing for risperidone, olanzapine, quetiapine IR, ziprasidone, risperidone consta, aripiprazole, paliperidone, and quetiapine XR. Information was retrieved from study publications, EPAR, and from the FDA SBA, all in the public domain. 7553 patients were randomized in the remaining 23 short-term acute phase clinical trials. 2/5738 patients died after having been randomized to an active treatment. 5/1815 died in the placebo group. The crude odds-ratio for an increased death risk with placebo treatment is 7.92 (95% confidence interval (1.45 to 40.87), two sided P=0.0134). Death narratives show: (i) both deaths in active treatment groups occurred during randomized treatment period, (ii) two deaths in the placebo group of a trial in the elderly were observed in patients with severe co-morbidities not usually included in a randomized trial, and (iii) two further deaths in the placebo groups occurred 9 and 23 days after the end of the randomized treatment period. Under these circumstances the crude odds-ratio for an increased risk of death for patient with placebo as compared to active treatment is 1.58 (95% confidence interval (0.14-17.45), two sided P=0.71). Confidence intervals are generally wide indicating a still limited knowledge about a potential increase in mortality with placebo treatment. Unless, however, society is willing to take the risk that ineffective drugs are licensed and cause undetected harm thereafter, or is willing to restrict licensing to drugs that are superior to current treatments, short-term placebo-controlled trials in the acute phase of schizophrenia are necessary. Measures are proposed to minimize risks.

An outcome assessment, the patient assessment used in an endpoint, is the measuring instrument that provides a rating or score (categorical or continuous) that is intended to represent some aspect of the patient’s health status. Outcome assessments are used to define efficacy endpoints when developing a therapy for a disease or condition. Most efficacy endpoints are based on specified clinical assessments of patients. When clinical assessments are used as clinical trial outcomes, they are called clinical outcome assessments (COAs). COAs include any assessment that may be influenced by human choices, judgment, or motivation. COAs must be well-defined and possess adequate measurement properties to demonstrate (directly or indirectly) the benefits of a treatment. In contrast, a biomarker assessment is one that is subject to little, if any, patient motivational or rater judgmental influence. This is the first of two reports by the ISPOR Clinical Outcomes Assessment – Emerging Good Practices for Outcomes Research Task Force. This report provides foundational definitions important for an understanding of COA measurement principles. The foundation provided in this report includes what it means to demonstrate a beneficial effect, how assessments of patients relate to the objective of showing a treatment’s benefit, and how these assessments are used in clinical trial endpoints. In addition, this report describes intrinsic attributes of patient assessments and clinical trial factors that can affect the properties of the measurements. These factors should be considered when developing or refining assessments. These considerations will aid investigators designing trials in their choice of using an existing assessment or developing a new outcome assessment. Although the focus of this report is on the development of a new COA to define endpoints in a clinical trial, these principles may be applied more generally. A critical element in appraising or developing a COA is to describe the treatment’s intended benefit as an effect on a clearly identified aspect of how a patient feels or functions. This aspect must have importance to the patient and be part of the patient’s typical life. This meaningful health aspect can be measured directly or measured indirectly when it is impractical to evaluate it directly or when it is difficult to measure. For indirect measurement, a concept of interest (COI) can be identified. The COI must be related to how a patient feels or functions. Procedures are then developed to measure the COI. The relationship of these measurements with how a patient feels or functions in the intended setting and manner of use of the COA (the context of use) could then be defined. A COA has identifiable attributes or characteristics that affect the measurement properties of the COA when used in endpoints. One of these features is whether judgment can influence the measurement, and if so, whose judgment. This attribute defines four categories of COAs: patient reported outcomes, clinician reported outcomes, observer reported outcomes, and performance outcomes. A full description as well as explanation of other important COA features is included in this report. The information in this report should aid in the development, refinement, and standardization of COAs, and, ultimately, improve their measurement properties.

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As neurologists and neuroscientists, we are trained to evaluate disorders of the nervous system by thinking systematically. Clinically, we think in terms of cognition, behavior, motor function, sensation, balance and co-ordination, and autonomic system function. But when we assess symptoms of neurological disorders for the purpose of drug development, we tend to create disease-specific outcome measures, often using a variety of methods to assess the same types of dysfunction in overlapping, related disorders. To begin to explore the potential to simplify and harmonize the assessment of dysfunction across neurological disorders, a symposium, entitled, "Commonalities in the Development of Outcome Measures in Neurology" was held at the 16th annual meeting of the American Society for Experimental NeuroTherapeutics (ASENT), in February 2014. This paper summarizes the presentations at the symposium. The authors hope that readers will begin to view Clinical Outcome Assessment (COA) development in a new light. We hope that in presenting this material, we will stimulate discussions and collaborations across disease areas to develop common concepts of neurological COA development and construction.

OBJETIVOS: Estimar o risco da transmissão materno-infantil (TMI) do HIV no município de Santos e avaliar o efeito da introdução de medidas preventivas na transmissão vertical do HIV, tais como: utilização de AZT pela gestante, durante o pré-natal, trabalho de parto e parto, uso de AZT pelo recém-nascido; substituição do aleitamento natural pelo artificial e indicação de cesárea. MÉTODOS: Trata-se de um estudo de coorte. Os dados foram coletados dos prontuários das gestantes e das crianças nos serviços de referência para o atendimento de pessoas vivendo com HIV/Aids. Para estimar o risco de transmissão materno-infantil do HIV, dividiu-se o número de mães cujos filhos adquiriram o vírus por transmissão vertical pelo número de mães incluídas no estudo. Para estimar o risco de TMI associado aos fatores investigados, calcularam-se os riscos relativos com intervalos de confiança de 95% (IC 95%), considerando a ocorrência de transmissão como variável dependente e os outros fatores (idade materna, realização de pré-natal, uso de AZT oral, uso de AZT xarope, idade gestacional e amamentação) como variáveis independentes. Para controlar o possível efeito confundidor de algumas variáveis, foi realizada análise estratificada pela técnica de Mantel-Haenszel. RESULTADOS: A ocorrência da TMI do HIV foi estabelecida em 144 crianças. Quatorze delas foram classificadas como infectadas; o risco de transmissão foi de 0,097 (IC 95%; 0,030-0,163). O risco de transmissão foi menor nas mulheres com menos de 30 anos de idade. Na análise univariada, o risco de transmissão materno-infantil do HIV esteve associado de modo estatisticamente significante com: idade materna, realização do pré-natal, uso de AZT oral, uso de AZT xarope, idade gestacional (Capurro) e amamentação. CONCLUSÃO: O presente trabalho mostrou que a implantação de medidas preventivas tem importância na prevenção da transmissão do HIV mãe-filho, com redução de quase 40% no risco desta transmissão comparada à encontrada anteriormente sem a utilização de medidas preventivas.

As neurologists and neuroscientists, we are trained to evaluate disorders of the nervous system by thinking systematically. Clinically, we think in terms of cognition, behavior, motor function, sensation, balance and co-ordination, and autonomic system function. But when we assess symptoms of neurological disorders for the purpose of drug development, we tend to create disease-specific outcome measures, often using a variety of methods to assess the same types of dysfunction in overlapping, related disorders. To begin to explore the potential to simplify and harmonize the assessment of dysfunction across neurological disorders, a symposium, entitled, "Commonalities in the Development of Outcome Measures in Neurology" was held at the 16th annual meeting of the American Society for Experimental NeuroTherapeutics (ASENT), in February 2014. This paper summarizes the presentations at the symposium. The authors hope that readers will begin to view Clinical Outcome Assessment (COA) development in a new light. We hope that in presenting this material, we will stimulate discussions and collaborations across disease areas to develop common concepts of neurological COA development and construction.

Our objectives are to describe the procedure for qualification advice and opinion from EU regulators on the use of novel methodologies in drug development, the key stakeholders involved and the evidence requirements for qualification opinion. We present a case study of the request from the Coalition Against Major Disease (CAMD) Consortium of the Critical Path (C-Path) Institute for EU regulators׳ qualification opinion on the use of low hippocampal volume as a biomarker for population enrichment in clinical trials of novel drugs in Alzheimer׳s disease (AD). We discuss the main concerns from the regulators, data analysis requests and guidance during the qualification. EU regulators concluded that low hippocampal volume, measured by vMRI and considered as a dichotomized variable (low volume or not), appears to help enriching recruitment into clinical trials aimed at studying drugs that potentially slow the progression of the pre-dementia stage of AD. The biomarker qualification procedure is a dynamic process in which pharmaceutical companies and research consortia can submit further data to update the qualifications and improve the predictive value of the biomarkers.

Several lines of evidence from Alzheimer's disease (AD) research continue to support the notion that the biological changes associated with AD are occurring possibly several decades before an individual will experience the cognitive and functional changes associated with the disease. The National Institute on Aging—Alzheimer's Association revised criteria for AD provided a framework for this new thinking. As a result of this growing understanding, several research efforts have launched or will be launching large secondary prevention trials in AD. These and other efforts have clearly demonstrated a need for better measures of cognitive and functional change in people with the earliest changes associated with AD. Recent draft guidance from the US Food and Drug Administration further elevated the importance of cognitive and functional assessments in early stage clinical trials by proposing that even in the pre-symptomatic stages of the disease, approval will be contingent on demonstrating clinical meaningfulness. The Alzheimer's Association's Research Roundtable addressed these issues at its fall meeting October 28–29, 2013, in Washington, D.C. The focus of the discussion included the need for improved cognitive and functional outcome measures for clinical of participants with preclinical AD and those diagnosed with Mild Cognitive Impairment due to AD.

Regulatory agencies have a key role in facilitating the development of new drugs for Alzheimer disease, particularly given the challenges associated with early intervention. Here, we highlight the strategies of the European Medicines Agency to help address such challenges.

Nanotechnology-based and advanced therapy medicinal products are at the cutting edge of innovation in translational drug development, potentially offering new treatment approaches for diseases with limited or no therapeutic alternatives. Their development from the laboratory to the clinic poses specific scientific and regulatory challenges, and some debate has recently arisen about the adequacy of the current EU regulatory framework for the assessment of quality, safety and efficacy of these medicinal products.

Sarcopenia, the age-related skeletal muscle decline, is associated with relevant clinical and socioeconomic negative outcomes in older persons. The study of this phenomenon and the development of preventive/therapeutic strategies represent public health priorities. The present document reports the results of a recent meeting of the International Working Group on Sarcopenia (a task force consisting of geriatricians and scientists from academia and industry) held on June 7–8, 2011 in Toulouse (France). The meeting was specifically focused at gaining knowledge on the currently available biomarkers (functional, biological, or imaging-related) that could be utilized in clinical trials of sarcopenia and considered the most reliable and promising to evaluate age-related modifications of skeletal muscle. Specific recommendations about the assessment of aging skeletal muscle in older people and the optimal methodological design of studies on sarcopenia were also discussed and finalized. Although the study of skeletal muscle decline is still in a very preliminary phase, the potential great benefits derived from a better understanding and treatment of this condition should encourage research on sarcopenia. However, the reasonable uncertainties (derived from exploring a novel field and the exponential acceleration of scientific progress) require the adoption of a cautious and comprehensive approach to the subject.

Systemic lupus erythematosus juvenile (SLEJ) is a multi-systemic, chronic inflammatory disease, and with autoimmune features. Some clinical manifestations of this disease are similar to those found inAcquired Immunodeficiency Syndrome (AIDS). Coexistence of AIDS with SLEJ is rare, especially in the pediatric population, being described in the literature just 5 patients with congenital HIV infection who developed this rheumatological condition, presenting lupus nephritis as the initial manifestation. We report the case of a 14 year old patient, diagnosed with HIV infection at 8 months of age, with signs and symptoms of SLEJ. This report aims to describe a female patient with AIDS who developed SLE in its classic and forms, but has evolved satisfactorily

Child and adolescent psychiatry is a relatively young field and the recognition, classification, and treatment of disorders in children and adolescents lag behind those in adults. In recent years there is an increasing awareness of the differences between children and adults in psychopathology and pharmacology. Related to this new paediatric regulations have been introduced. This article reviews the regulatory and legislative measures that were adopted in the EU in 2007 and the subsequent impact of these measures on the field of paediatric psychopharmacology. The consequences of the paediatric regulation in the EU are reflected in several domains: regulatory, research aimed at drug development and clinical practices. In the regulatory domain, the consequences include: new paediatric indications, inclusion of special (class) warnings, specification of dose regimens, and information on safety specific to children and adolescents, and development of new medicinal formulations. The paediatric regulation leads to timely development of paediatric friendly formulations and better quality of the clinical evidence. In clinical practices, an increased awareness of the uniqueness of paediatric pharmacology is emerging among medical professionals, and subsequent improvement of medical care (i.e. correct doses, appropriate formulation, monitoring for expected adverse events). In addition, clinical guidelines will have to be revised more frequently in order to integrate the recently acquired knowledge. The new regulations stimulate transparency and discussions between academia, pharmaceutical industry, and regulators. The purpose is to optimize clinical research and obtain evidence for paediatric psychopharmacology, thereby providing adequate support for treatment.

Systemic lupus erythematosus juvenile (SLEJ) is a multi-systemic, chronic inflammatory disease, and with autoimmune features. Some clinical manifestations of this disease are similar to those found in Acquired Immunodeficiency Syndrome (AIDS). Coexistence of AIDS with SLEJ is rare, especially in the pediatric population, being described in the literature just 5 patients with congenital HIV infection who developed this rheumatological condition, presenting lupus nephritis as the initial manifestation. We report the case of a 14 year old patient, diagnosed with HIV infection at 8 months of age, with signs and symptoms of SLEJ. This report aims to describe a female patient with AIDS who developed SLE in its classic and forms, but has evolved satisfactorily.

To estimate the risk of mother-to-child transmission (MTCT) of HIV-1 and evaluate the effect of preventive methods on vertical transmission of HIV, such as: use of AZT by pregnant women during the prenatal period, labor and delivery; use of AZT in newborns; replacement of breastfeeding by formula; and indication of cesarean section.This was a cohort study. Data was collected from medical records of pregnant women and of children followed at reference health centers for HIV/AIDS patients. To estimate the risk of MTCT we divided the number of mothers whose children acquired the virus through vertical transmission by the total number of mothers included in the study; the relative risks were calculated with a CI=95%. Occurrence of transmission was regarded as a dependent variable, the other factors (maternal age, use of oral AZT and use of AZT syrup, gestational age and breastfeeding) were considered as independent variables. Mantel-Haenszel's techniques were used in this analysis to control the possible effect of some variables.The occurrence of HIV in MTCT was identified in 144 children. Fourteen were classified as infected. Risk of transmission was of 0.097 (95% CI; 0.030-0.163). The risk of HIV vertical transmission was smaller in women under thirty years of age when compared with older ones. In the univariate analysis, the MTCT risk was significantly associated with maternal age, prenatal care, use of oral AZT and use of AZT syrup, gestational age and breastfeeding.This study showed that the implementation of preventive measures is important in the prevention of mother-to-child transmission of HIV, providing a risk reduction of almost 40% when compared to that before use of these preventive measures.

OBJETIVOS: Estimar o risco da transmissão materno-infantil (TMI) do HIV no município de Santos e avaliar o efeito da introdução de medidas preventivas na transmissão vertical do HIV, tais como: utilização de AZT pela gestante, durante o pré-natal, trabalho de parto e parto, uso de AZT pelo recém-nascido; substituição do aleitamento natural pelo artificial e indicação de cesárea. MÉTODOS: Trata-se de um estudo de coorte. Os dados foram coletados dos prontuários das gestantes e das crianças nos serviços de referência para o atendimento de pessoas vivendo com HIV/Aids. Para estimar o risco de transmissão materno-infantil do HIV, dividiu-se o número de mães cujos filhos adquiriram o vírus por transmissão vertical pelo número de mães incluídas no estudo. Para estimar o risco de TMI associado aos fatores investigados, calcularam-se os riscos relativos com intervalos de confiança de 95% (IC 95%), considerando a ocorrência de transmissão como variável dependente e os outros fatores (idade materna, realização de pré-natal, uso de AZT oral, uso de AZT xarope, idade gestacional e amamentação) como variáveis independentes. Para controlar o possível efeito confundidor de algumas variáveis, foi realizada análise estratificada pela técnica de Mantel-Haenszel. RESULTADOS: A ocorrência da TMI do HIV foi estabelecida em 144 crianças. Quatorze delas foram classificadas como infectadas; o risco de transmissão foi de 0,097 (IC 95%; 0,030-0,163). O risco de transmissão foi menor nas mulheres com menos de 30 anos de idade. Na análise univariada, o risco de transmissão materno-infantil do HIV esteve associado de modo estatisticamente significante com: idade materna, realização do pré-natal, uso de AZT oral, uso de AZT xarope, idade gestacional (Capurro) e amamentação. CONCLUSÃO: O presente trabalho mostrou que a implantação de medidas preventivas tem importância na prevenção da transmissão do HIV mãe-filho, com redução de quase 40% no risco desta transmissão comparada à encontrada anteriormente sem a utilização de medidas preventivas. OBJECTIVES: To estimate the risk of mother-to-child transmission (MTCT) of HIV-1 and evaluate the effect of preventive methods on vertical transmission of HIV, such as: use of AZT by pregnant women during the prenatal period, labor and delivery; use of AZT in newborns; replacement of breastfeeding by formula; and indication of cesarean section. METHODS: This was a cohort study. Data was collected from medical records of pregnant women and of children followed at reference health centers for HIV/AIDS patients. To estimate the risk of MTCT we divided the number of mothers whose children acquired the virus through vertical transmission by the total number of mothers included in the study; the relative risks were calculated with a CI=95%. Occurrence of transmission was regarded as a dependent variable, the other factors (maternal age, use of oral AZT and use of AZT syrup, gestational age and breastfeeding) were considered as independent variables. Mantel-Haenszel's techniques were used in this analysis to control the possible effect of some variables. RESULTS: The occurrence of HIV in MTCT was identified in 144 children. Fourteen were classified as infected. Risk of transmission was of 0.097 (95% CI; 0.030-0.163). The risk of HIV vertical transmission was smaller in women under thirty years of age when compared with older ones. In the univariate analysis, the MTCT risk was significantly associated with maternal age, prenatal care, use of oral AZT and use of AZT syrup, gestational age and breastfeeding. CONCLUSION: This study showed that the implementation of preventive measures is important in the prevention of mother-to-child transmission of HIV, providing a risk reduction of almost 40% when compared to that before use of these preventive measures.

O lúpus eritematoso sistêmico juvenil (LESJ) é uma doença inflamatória crônica, multissistêmica e autoimune. Algumas manifestações clínicas dessa condição são semelhantes às encontradas na síndrome da imunodeficiência adquirida (SIDA). A coexistência da SIDA com o LESJ é rara, especialmente na população pediátrica, sendo descritos na literatura pesquisada apenas cinco casos de pacientes com infecção congênita por HIV que desenvolveram essa enfermidade reumatológica, tendo como manifestação inicial a nefrite lúpica. Relata-se o caso de uma paciente de 14 anos, com diagnóstico de infecção pelo HIV aos 8 meses de idade, na qual se realizou diagnóstico de LESJ com base nos critérios diagnósticos do Colégio Americano de Reumatologia. Este relato tem a finalidade de descrever uma paciente com SIDA que, embora tenha desenvolvido LESJ em sua forma clássica e grave, evoluiu satisfatoriamenteSystemic lupus erythematosus juvenile (SLEJ) is a multi-systemic, chronic inflammatory disease, and with autoimmune features. Some clinical manifestations of this disease are similar to those found inAcquired Immunodeficiency Syndrome (AIDS). Coexistence of AIDS with SLEJ is rare, especially in the pediatric population, being described in the literature just 5 patients with congenital HIV infection who developed this rheumatological condition, presenting lupus nephritis as the initial manifestation. We report the case of a 14 year old patient, diagnosed with HIV infection at 8 months of age, with signs and symptoms of SLEJ. This report aims to describe a female patient with AIDS who developed SLE in its classic and forms, but has evolved satisfactorily

We propose to construct and deploy a one-meter, wide field camera for cosmological, science education and other studies and site it on the International Space Station’s Japanese Exposure Module (JEM). The SHOUT Telescope (for S_pace H_ands-O_n U_niverse T_elescope) is an inexpensive powerful instrument that will yield some of the most significant measurements in astrophysics. The detector would consist of a 15,000×15,000 pixel2 imaging CCD made of high-resistivity silicon, with quantum efficiency of approximately 50% at one micron. In addition, a single channel spectrograph is included for spectroscopy on any interesting photometric discoveries. Advances in graphite carbon mirrors and telescope construction enable an instrument weight of about 100–200 kg. Such a low-weight instrument could be placed on a mass-limited shuttle launch. This system would have a performance for finding point objects in a random field ∼100x of that of the Advanced Camera system on HST at a wavelength of one micron. It would fil...