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A primary goal of neuroscience is to understand the relationship between the brain and behavior. While magnetic resonance imaging (MRI) examines brain structure and function under controlled conditions, digital phenotyping via portable automatic devices (PAD) quantifies behavior in real‐world settings. Combining these two technologies may bridge the gap between brain imaging, physiology, and real‐time behavior, enhancing the generalizability of laboratory and clinical findings. However, the use of MRI and data from PADs outside the MRI scanner remains underexplored. Herein, we present a Preferred Reporting Items for Systematic Reviews and Meta‐Analysis systematic literature review that identifies and analyzes the current state of research on the integration of brain MRI and PADs. PubMed and Scopus were automatically searched using keywords covering various MRI techniques and PADs. Abstracts were screened to only include articles that collected MRI brain data and PAD data outside the laboratory environment. Full‐text screening was then conducted to ensure included articles combined quantitative data from MRI with data from PADs, yielding 94 selected papers for a total of N = 14,778 subjects. Results were reported as cross‐frequency tables between brain imaging and behavior sampling methods and patterns were identified through network analysis. Furthermore, brain maps reported in the studies were synthesized according to the measurement modalities that were used. Results demonstrate the feasibility of integrating MRI and PADs across various study designs, patient and control populations, and age groups. The majority of published literature combines functional, T1‐weighted, and diffusion weighted MRI with physical activity sensors, ecological momentary assessment via PADs, and sleep. The literature further highlights specific brain regions frequently correlated with distinct MRI‐PAD combinations. These combinations enable in‐depth studies on how physiology, brain function and behavior influence each other. Our review highlights the potential for constructing brain–behavior models that extend beyond the scanner and into real‐world contexts. [ABSTRACT FROM AUTHOR]

The recent benefit–risk framework (BRF) developed by the Food and Drug Administration (FDA) is intended to improve the clarity and consistency in communicating the reasoning behind the FDA's decisions, acting as an important advancement in US drug regulation. In the PDUFA VI implementation plan, the FDA states that it will continue to explore more structured or quantitative decision analysis approaches; however, it restricts their use within the current BRF that is purely qualitative. By contrast, European regulators and researchers have been long exploring the use of quantitative decision analysis approaches for evaluating drug benefit–risk balance. In this paper, we show how quantitative modelling, backed by decision theory, could complement and extend the FDA's BRF to better support the appraisal of evidence and improve decision outcomes. After providing relevant scientific definitions for benefit–risk assessment and describing the FDA and European Medicines Agency (EMA) frameworks, we explain the components of and differences between qualitative and quantitative approaches. We present lessons learned from the EMA experience with the use of quantitative modelling and we provide evidence of its benefits, illustrated by a real case study that helped to resolve differences of judgements among EMA regulators. [ABSTRACT FROM AUTHOR]

Data Monitoring Committees (DMCs) are an integral part of clinical drug development. Their use has evolved along with changing study designs and regulatory expectations, which has associated statistical and ethical implications. Although there is guidance from the different regulatory agencies, there are opportunities to bring more consistency to address practical issues of establishing and operating a DMC. Challenging issues include defining the scope of DMC decisions, the regulatory requirements and expectations, the perceived independence of DMCs, the specific focus primarily on safety, etc. Wider use of adaptive clinical trial designs in recent years introduce additional challenges in terms of trial governance and the complexity of DMC activities. A panel comprised of clinical and statistical experts from across academia, industry, and regulatory agencies shared their experience and thoughts on the importance of these aspects and offered perspectives on the future of the DMCs. This paper documents the thinking from the panel session at the CEN‐ISBS conference held in Vienna, Austria, 2017. [ABSTRACT FROM AUTHOR]

Abstract: The record high 42 model accuracy estimation methods were tested in CASP12. The paper presents results of the assessment of these methods in the whole‐model and per‐residue accuracy modes. Scores from four different model evaluation packages were used as the “ground truth” for assessing accuracy of methods' estimates. They include a rigid‐body score—GDT_TS, and three local‐structure based scores—LDDT, CAD and SphereGrinder. The ability of methods to identify best models from among several available, predict model's absolute accuracy score, distinguish between good and bad models, predict accuracy of the coordinate error self‐estimates, and discriminate between reliable and unreliable regions in the models was assessed. Single‐model methods advanced to the point where they are better than clustering methods in picking the best models from decoy sets. On the other hand, consensus methods, taking advantage of the availability of large number of models for the same target protein, are still better in distinguishing between good and bad models and predicting local accuracy of models. The best accuracy estimation methods were shown to perform better with respect to the frozen in time reference clustering method and the results of the best method in the corresponding class of methods from the previous CASP. Top performing single‐model methods were shown to do better than all but three CASP12 tertiary structure predictors when evaluated as model selectors. [ABSTRACT FROM AUTHOR]

Biotechnology and nanotechnology provide a growing number of innovator-driven complex drug products and their copy versions. Biologics exemplify one category of complex drugs, but there are also nonbiological complex drug products, including many nanomedicines, such as iron-carbohydrate complexes, drug-carrying liposomes or emulsions, and glatiramoids. In this white paper, which stems from a 1-day conference at the New York Academy of Sciences, we discuss regulatory frameworks in use worldwide (e.g., the U.S. Food and Drug Administration, the European Medicines Agency, the World Health Organization) to approve these complex drug products and their follow-on versions. One of the key questions remains how to assess equivalence of these complex products. We identify a number of points for which consensus was found among the stakeholders who were present: scientists from innovator and generic/follow-on companies, academia, and regulatory bodies from different parts of the world. A number of topics requiring follow-up were identified: (1) assessment of critical attributes to establish equivalence for follow-on versions, (2) the need to publish scientific findings in the public domain to further progress in the field, (3) the necessity to develop worldwide consensus regarding nomenclature and labeling of these complex products, and (4) regulatory actions when substandard complex drug products are identified. [ABSTRACT FROM AUTHOR]

Objective: There is reason to believe that introversion may relate to different patterns of negative and positive experiences in everyday life ("hassles" and "uplifts"), but there is little evidence for this based on reports made in daily life as events occur. We thus extend the literature by using data from ecological momentary assessments to examine whether introversion is associated with either the frequency or intensity of hassles and uplifts. Method: Participants (N = 242) were community‐dwelling adults (63% Black, 24% Hispanic; ages 25‐65; 65% women) who completed baseline measures of personality and mental health, followed by reports of hassles and uplifts 5x/day for 14 days. We present associations between introversion and hassles/uplifts both with and without controlling for mood‐related factors (neuroticism, recent symptoms of depression, and anxiety). Results: Introversion was associated with reporting less frequent and less enjoyable uplifts, but not with overall hassle frequency or unpleasantness; exploratory analyses suggest associations with specific types of hassles. Conclusions: Our results expand understanding of the role of introversion in everyday experiences, suggesting an overall association between introversion and uplifts (but not hassles, broadly) in daily life. Better understanding of such connections may inform future research to determine mechanisms by which introversion relates to health. [ABSTRACT FROM AUTHOR]

MXene can be used to create bifunctional materials for supercapacitors and electromagnetic wave absorbers by logical composition arrangement and microstructure design. The layered structure, high electrical conductivity, high capacitance, mechanical strength, and flexibility of Ti3C2Tx MXene all make it ideal for use as flexible energy storage devices and electromagnetic wave absorbers. In this study, MXene was innovatively intercalated with g‐C3N4 and CNTs to produce MXCN/CNTs ternary hybrid film. The restacking is successfully avoided, and the layer spacing is increased. Meanwhile, g‐C3N4 makes the interlayer charge density increase, and CNTs establish the interlayer conducting network, both of which greatly improve the charge transfer efficiency. These ternary hybrid films exhibit superior performance for both supercapacitor electrodes and electromagnetic wave absorbers. The specific capacitance of MXCN/CNTs electrode reaches 477.4 F/g at 1 A/g. The energy density of flexible symmetrical all‐solid supercapacitor achieves 25.28 Wh/Kg at 449.99 W/Kg. When bent 180°, the electrochemical performance remains constant. The MXCN/CNTs composites also show excellent electromagnetic wave absorption (EMA) performance. It achieves an optimized absorption intensity of −43.44 dB at 2.6 mm and shows an extremely wide effective absorption bandwidth (EAB) of 8.94 GHz. This work enhances the application studies of Ti3C2Tx MXene‐based composite materials as multifunctional materials. [ABSTRACT FROM AUTHOR]

Aim: Use of immunomodulating therapeutics for immune‐mediated inflammatory diseases may cause disease‐drug‐drug interactions (DDDIs) by reversing inflammation‐driven alterations in the metabolic capacity of cytochrome P450 enzymes. European Medicine Agency (EMA) and US Food and Drug Administration (FDA) guidelines from 2007 recommend that the DDDI potential of therapeutic proteins should be assessed. This systematic analysis aimed to characterize the available DDDI trials with immunomodulatory drugs, experimental evidence for a DDDI risk and reported DDDI risk information in FDA/EMA approved drug labelling. Method: For this systematic review, the EMA list of European Public Assessment Reports of human medicine was used to select immunomodulating monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs) marketed after 2007 at risk for a DDDI. Selected drugs were included in PubMed and Embase searches to extract reported interaction studies. The Summary of Product Characteristics (SPCs) and the United States Prescribing Information (USPIs) were subsequently used for analysis of DDDI risk descriptions. Results: Clinical interaction studies to evaluate DDDI risks were performed for 12 of the 24 mAbs (50%) and for none of the TKIs. Four studies identified a DDDI risk, of which three were studies with interleukin‐6 (IL‐6) neutralizing mAbs. Based on (non)clinical data, a DDDI risk was reported in 32% of the SPCs and in 60% of the USPIs. The EMA/FDA documentation aligned with the DDDI risk potential in 35% of the 20 cases. Conclusion: This systematic review reinforces that the risk for DDDI by immunomodulating drugs is target‐ and disease‐specific. Drug labelling information designates the greatest DDDI risk to mAbs that neutralize the effects of IL‐6, Tumor Necrosis Factor alfa (TNF‐α) and interleukin‐1 bèta (IL‐1β) in diseases with systemic inflammation. [ABSTRACT FROM AUTHOR]

Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease and is usually diagnosed in childhood, especially in the first decade of life. Paediatric FMF is characterized by a protean clinical expression and a variable therapeutic response, which can make its medical management very challenging. However, even if long‐term complications of untreated FMF (e.g. amyloidosis and related organ damage) are less frequent in children compared to adults, they are not uncommon. Colchicine is the mainstay of the therapy in paediatric FMF; however, if children develop colchicine intolerance and/or resistance, biologics, particularly interleukin‐1 antagonists, must be considered. Other conventional or biological therapeutic options do not currently have appropriate evidence‐based support, except for some specific clinical presentations (e.g., arthritis). In this review, we discuss the biological basis and the clinical evidence for the current pharmacological treatment options available for paediatric FMF. [ABSTRACT FROM AUTHOR]

Aims: Dose adjustment for drugs eliminated by the kidneys generally assume a linear relationship between renal drug clearance (CLR) and glomerular filtration rate (GFR). This assumption may not hold for drugs that undergo extensive tubular secretion where nonlinearity in drug handling is expected. The aim of this study is to determine if renal drug study designs recommended by the European Medicines Agency (EMA) and Food and Drug Administration (FDA) could distinguish linear from nonlinear renal drug handling. Methods: In this simulation and estimation study, the study designs based on the EMA and FDA guidelines for Phase I renal drug studies were evaluated for their ability to discriminate a linear from a nonlinear relationship between CLR and GFR. The number of subjects for each simulated study ranged from 4 to 960. Power, relative standard error and bias were calculated. Results: Study designs under the EMA and FDA guidelines required ≥8 and ≥48 subjects, respectively, to achieve ≥80% power to discriminate a linear from nonlinear relationship between CLR and GFR. The relative standard error of estimated parameters were 13–37 and 17–44% for the designs with 24 subjects under the EMA and FDA guidelines, respectively. The bias in parameter estimates under the EMA designs were not evident, however, they were biased (13–21%) under the FDA designs. Conclusion: The EMA design was found to require fewer subjects (n = 8) compared to the FDA (n = 48) to discriminate linear from nonlinear drug renal handling at ≥80% study power while both the designs perform poorly for the parameter precision. [ABSTRACT FROM AUTHOR]

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Ecological momentary assessment (EMA) has been shown to be a valid and sensitive measure of treatment effects in obsessive‐compulsive disorder (OCD). As part of a clinical trial, this EMA study deals with a comparison of two treatment conditions, that is, cognitive restructuring (CR) and detached mindfulness (DM). EMA data from n = 39 OCD patients were available from a randomized clinical trial on the effectiveness of CR and DM. Smartphone‐based EMA sampling spread over 4 days each before and after treatment, with 10 random prompts per day and a 2‐week intervention of either CR or DM. We tracked CR strategies (e.g., questioning an appraisal by re‐evaluating risk), DM strategies (e.g., allowing one's thoughts to come and go), and application of newly learned strategies during Post‐Treatment EMA. Although there was a trend towards DM strategies being applied more often during Pre‐Treatment EMA than CR strategies, we did not find differences during Post‐Treatment EMA between CR and DM regarding frequency or difficulty of application and experienced relief. As expected, we found a clear pre‐post increase for all CR and DM behaviours except for one DM item. However, we did not find a treatment‐specific increase of CR and DM behaviours; that is, both interventions equally well promoted a seemingly general treatment effect. Despite the ecological validity of EMA, however, social desirability effects cannot be ruled out, so that this conclusion must be handled cautiously. Further research is needed to replicate and generalize our results. [ABSTRACT FROM AUTHOR]

When choosing a medicine two aspects determine the balance between benefit and harm (risk–benefit), matching the medicine to the individual and the choice of dose. Knowing the relationship between dose and response allows a calculation of the dose that causes 50% of the maximal effect, the ED50. Rational drug dosing depends on defining the ratio of the dose to the ED50. The ED50 of each drug has two scales, whether the effect measured is for efficacy, or safety. Quantifying efficacy is comparatively straightforward. A fall in blood pressure, combined with a statistical and clinically significant reduction in cardiovascular events, might justify the efficacy of an antihypertensive. Measuring a drug's effect on safety is more complex, as this is so often a subjective assessment of a collection of adverse events. Though a science‐based therapeutic window defined from in vitro efficacy and safety dose response curves is reassuring, this review discusses how to translate this into dose‐dependent risk–benefit based on clinical trial data. Some of the limitations of our knowledge about the choice of dose that optimizes an individual's risk–benefit, or whether no drug is a better option, are discussed. It is important to define these limitations when educating the consumer/patient about the clinical pharmacology that justifies their treatment dose options. [ABSTRACT FROM AUTHOR]

Mobile cognitive testing may be used to help characterize subtle deficits at the earliest stages of cognitive decline. Despite growing interest in this approach, comprehensive information concerning its feasibility and validity has been lacking in elderly samples. Over a one-week period, this study applied mobile cognitive tests of semantic memory, episodic memory and executive functioning in a cohort of 114 elderly non-demented community residents. While the study acceptance rate was moderate (66%), the majority of recruited individuals met minimal compliance thresholds and responded to an average of 82% of the repeated daily assessments. Missing data did not increase over the course of the study, but practice effects were observed for several test scores. However, even when controlling for practice effects, traditional neuropsychological tests were significantly associated with mobile cognitive test scores. In particular, the Isaacs Set Test was associated with mobile assessments of semantic memory ( γ = 0.084, t = 5.598, p < 0.001), the Grober and Buschke with mobile assessments of episodic memory ( γ = 0.069, t = 3.156, p < 0.01, and the Weschler symbol coding with mobile assessments of executive functioning ( γ = 0.168, t = 4.562, p < 0.001). Mobile cognitive testing in the elderly may provide complementary and potentially more sensitive data relative to traditional neuropsychological assessment. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Aim In 2006, Omnitrope (by Sandoz) was the first approved biosimilar in Europe. To date, 21 biosimilars for seven different biologics are on the market. The present study compared the clinical trials undertaken to obtain market authorization. Methods We summarized the findings of a comprehensive review of all clinical trials up to market authorization of approved biosimilars, using the European public assessment reports (EPARs) published by the European Medicines Agency (EMA). The features compared were, among others, the number of patients enrolled, the number of trials, the types of trial design, choice of endpoints and equivalence margins for pharmacokinetic (PK)/pharmacodynamic (PD) and phase III trials. Results The variability between the clinical development strategies is high. Some differences are explainable by the characteristics of the product; if, for example, the PD marker can be assumed to predict the clinical outcome, no efficacy trials might be necessary. However, even for products with the same reference product, the sample size, endpoints and statistical models are not always the same. Conclusions There seems to be flexibility for sponsors regarding the decision as to how best to prove biosimilarity. [ABSTRACT FROM AUTHOR]

Background In 2010, the European Medicines Agency (EMA) initiated a pilot project on parallel scientific advice with Health Technology Assessment bodies (HTABs) that allows manufacturers to receive simultaneous feedback from both the European Union (EU) regulators and HTABs on their development plans for medicines. Aims The present retrospective qualitative analysis aimed to explore how the parallel scientific advice system is working and levels of commonality between the EU regulators and HTABs, and among HTABs, when applicants obtain parallel scientific advice from both a regulatory and an HTA perspective. Methods We analysed the minutes of discussion meetings held at the EMA between 2010, when parallel advice was launched, and 1 May 2015, when the cutoff date for data extraction was set. The analysis was based on predefined criteria and conducted at two different levels of comparison: the answers of the HTABs vs. those of the regulators, and between the answers of the participating HTA agencies. Results The analysis was based on 31 procedures of parallel scientific advice. The level of full agreements was highest for questions on patient population (77%), while disagreements reached a peak for questions on the study comparator (30%). With regard to comparisons among HTABs, there was a high level of agreement for all domains. Conclusions There is evident commonality, in terms of evidence requirements between the EU regulators and participating HTABs, as well as among HTABs, on most aspects of clinical development. Indeed, regardless of the question content, the analysis showed that a high level of overall agreement was reached through the process of parallel scientific advice. [ABSTRACT FROM AUTHOR]

The article presents assessment of the model accuracy estimation methods participating in CASP11. The results of the assessment are expected to be useful to both—developers of the methods and users who way too often are presented with structural models without annotations of accuracy. The main emphasis is placed on the ability of techniques to identify the best models from among several available. Bivariate descriptive statistics and ROC analysis are used to additionally assess the overall correctness of the predicted model accuracy scores, the correlation between the predicted and observed accuracy of models, the effectiveness in distinguishing between good and bad models, the ability to discriminate between reliable and unreliable regions in models, and the accuracy of the coordinate error self-estimates. A rigid-body measure (GDT_TS) and three local-structure-based scores (LDDT, CADaa, and SphereGrinder) are used as reference measures for evaluating methods’ performance. Consensus methods, taking advantage of the availability of several models for the same target protein, perform well on the majority of tasks. Methods that predict accuracy on the basis of a single model perform comparably to consensus methods in picking the best models and in the estimation of how accurate is the local structure. More groups than in previous experiments submitted reasonable error estimates of their own models, most likely in response to a recommendation from CASP and the increasing demand from users. [ABSTRACT FROM AUTHOR]

Objective: Smartphone‐based ecological momentary assessment (EMA), or real‐time, repeated sampling of participants' states, behaviors, or experiences over time, is a promising approach to understanding obesity‐related behaviors in African‐American women—a population with the highest obesity prevalence. In this study, we explored participants' experiences with this methodology. Design and Sample: In this secondary analysis of data, 100 African‐American women participated in seven consecutive days of EMA data collection. Measures: Measures related to acceptability (technical challenges, daily burden, emotional responses, willingness to participate in future studies) and data quality (reporting accuracy, behavior reactivity, adherence), as well as demographics, were collected. Results: While there were few demographic differences, women who were unemployed, had the lowest educational levels, or had the lowest per capita income reported the greatest enjoyment with mobile technology‐based EMA, while at the same time reporting the highest levels of challenge with use of the equipment. Participants consistently indicated willingness to participate in future EMA studies and indicated that the study method was acceptable. EMA methodology produced data of sufficient quality. Conclusion: Findings suggest future studies using smartphone‐based EMA with African‐American women are feasible. [ABSTRACT FROM AUTHOR]

Aims Angiocentric glioma ( AG) is a rare, slow-growing tumour of the central nervous system. It is often associated with refractory epilepsy and occurs most commonly in children and young adults. We herein report nine cases of AG, including four with atypical histological findings. Methods The clinical data and clinicopathological findings of nine cases with AG histological features were described. Results All nine patients had a history of refractory epilepsy with a mean history of 4.4 years and a median age of 17.6 years at surgery. The AG lesions were located in the superficial cerebrocortical region. Histological examination of these cases revealed characteristic structural features of AG, including bipolar spindle-shaped cells with an angiocentric growth pattern. However, four cases also exhibited atypical histological features: one had astroblastoma-like characteristics, two had a distinct cystic region with an onion-like structure and myxoid changes, and the other one had a region involving many abnormal neurones reminiscent to ganglioglioma. All were positive for glial fibrillary acidic protein and vimentin. Eight cases were positive for epithelial membrane antigen ( EMA), with a dot-like staining pattern. A diffuse D2-40 staining was visible in these cases, with two having similar staining pattern to EMA. All cases were immunonegative for BRAF V600 E and isocitrate dehydrogenase-1 R132 H mutations. Conclusions Our results demonstrate that atypical histological features can be present in AG. A collection of more cases and further molecular analyses are required to confirm our findings. [ABSTRACT FROM AUTHOR]