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BI 695501 is an FDA-approved biosimilar to adalimumab reference product (RP). VOLTAIRE-X was a randomized clinical trial to assess outcomes with a biosimilar monoclonal antibody in line with the FDA requirements for designation as an 'interchangeable' biosimilar.The aim of this study was to assess whether multiple switches between adalimumab RP and BI 695501 lead to equivalent pharmacokinetics and a similar safety and immunogenicity profile compared with continuous adalimumab RP.We conducted a phase III, double-blind, randomized controlled trial between July 19, 2017, and April 16, 2019. There were 49 investigational sites across Europe and North America. Of 323 screened patients with moderate-to-severe chronic plaque psoriasis, 259 were treated with adalimumab RP during the run-in period. Of these, 118 and 120 were randomized to the continuous or switching arms, respectively. Interventions consisted of a run-in period with adalimumab RP 80 mg subcutaneously (SC) on Day 1, then 40 mg SC every other week (EOW) Weeks 2-12. Patients were then randomized to receive adalimumab RP 40 mg EOW Weeks 14-48 (continuous arm) or BI 695501 40 mg Weeks 14 and 16, adalimumab RP 40 mg Weeks 18 and 20, and BI 695501 40 mg EOW Weeks 22 to 48 (switching arm); all interventions were given SC. Primary endpoints were pharmacokinetics parameters, area under the plasma concentration-time curve (AUC238 patients (mean [standard deviation] age 44.9 [13.8]; 66.0% male) were treated in the switching (n = 118) or continuous arms (n = 120). Adjusted mean CPharmacokinetic equivalence was demonstrated, with highly similar efficacy and immunogenicity, and comparable safety observed in patients with chronic plaque psoriasis who received either adalimumab RP continuously or who switched between adalimumab RP and BI 695501.ClinicalTrials.gov: NCT03210259 (registered July 2017); Eudract.ema.europa.eu: 2016-002254-20.

For the clinical development of a new drug, the determination of dose-proportionality is an essential part of the pharmacokinetic evaluations, which may provide early indications of non-linear pharmacokinetics and may help to identify sub-populations with divergent clearances. Prior to making any conclusions regarding dose-proportionality, the goodness-of-fit of the model must be assessed to evaluate the model performance. We propose the use of simulation-based visual predictive checks to improve the validity of dose-proportionality conclusions for complex designs. We provide an illustrative example and include a table to facilitate review by regulatory authorities.

Bioethicists today are taking a greater role in the design and implementation of emerging technologies by “embedding” within the development teams and providing their direct guidance and recommendations. Ideally, these collaborations allow ethical considerations to be addressed in an active, iterative, and ongoing process through regular exchanges between ethicists and members of the technological development team. In this article, we discuss a challenge to this embedded ethics approach—namely, that bioethical guidance, even if embraced by the development team in theory, is not easily actionable in situ. Many of the ethical problems at issue in emerging technologies are associated with preexisting structural, socioeconomic, and political factors, making compliance with ethical recommendations sometimes less a matter of choice and more a matter of feasibility (at least at the local level in which an embedded bioethicist operates). Moreover, incentive structures within these systemic factors maintain them against reform efforts. We recommend that embedded bioethicists utilize principles from behavioral science (such as behavioral economics) to better understand and account for these incentive structures so as to encourage ethically responsible uptake of technological innovations.

MicroRNA expression is important for gene regulation and deregulated microRNA expression is often observed in disease such as cancer. The processing of primary microRNA transcripts is an important regulatory step in microRNA biogenesis. Due to low expression level and association with chromatin primary microRNAs are challenging to study in clinical samples where input material is limited.Here, we present a high-sensitivity targeted method to determine processing efficiency of several hundred primary microRNAs from total RNA using as little as 500 thousand Illumina HiSeq sequencing reads. We validate the method using RNA from HeLa cells and show the applicability to clinical samples by analyzing RNA from normal liver and hepatocellular carcinoma.We identify 24 primary microRNAs with significant changes in processing efficiency from normal liver to hepatocellular carcinoma, among those the highly expressed miRNA-122 and miRNA-21, demonstrating that differential processing of primary microRNAs is occurring and could be involved in disease. With our method presented here we provide means to study pri-miRNA processing in disease from clinical samples.

Interferon lambdas (IFN{lambda}) (also known as type III IFNs) are critical cytokines that combat infection predominantly at barrier tissues, such as the lung, liver and gastrointestinal tract. Humans have four IFN{lambda}s (1-4) where IFN{lambda}1-3 show [~]80-95% homology and IFN{lambda}4 is the most divergent displaying only [~]30% sequence identity. Variants in IFN{lambda}4 in humans are associated with the outcome of infection, such as with hepatitis C virus. However, how IFN{lambda}4 variants impact cytokine signalling in other tissues and how well this is conserved is largely unknown. In this study we address whether differences in antiviral signalling exist between IFN{lambda}4 variants in human hepatocyte and intestinal cells, comparing them to IFN{lambda}3. We demonstrate that compared to IFN{lambda}3, wild-type human IFN{lambda}4 induces a signalling response with distinct magnitudes and kinetics, which is modified by naturally-occurring variants P70S and K154E in both cell types. IFN{lambda}4s distinct antiviral response was more rapid yet transient compared to IFN{lambda}1 and 3. Additionally, divergent antiviral kinetics were also observed using non-human primate IFN{lambda}s and cell lines. Furthermore, an IFN{lambda}4-like receptor-interacting interface failed to alter IFN{lambda}1s kinetics. Together our data provide further evidence that major functional differences exist within the IFN{lambda} gene family. These results highlight the possible tissue specialisation of IFN{lambda}s and encourage further investigation of the divergent, non-redundant activities of IFN{lambda}4 and other IFN{lambda}s. Contribution to the FieldViral infections remain major causes of death and disease in humans and other animals. Interferons (IFNs) are a diverse group of host signalling proteins that can induce a potent antiviral state in cells and are intimately involved in the outcome of infection. Genetic variants within one IFN (interferon lambda 4, IFN{lambda}4) are associated with the outcome of hepatitis C infection in humans. However, how IFN{lambda}4 functions - and how natural variants affect its activity - remains poorly understood. Comparing how the antiviral activity changes over time following stimulation with different IFN{lambda}s, we identified that IFN{lambda}4 induces a more rapid antiviral state compared to other IFN{lambda}s in liver and intestinal cells. Importantly, this response was conserved within human variants and between humans and non-human primates (chimpanzee and Rhesus macaque). Our results shed light on the unique functions of the divergent IFN{lambda}4 protein.

Listeners make assumptions about speaker gender identity (GI), sexual orientation (SO), or gender expression (GE) from speech (Tripp and Munson, 2021). Researchers have identified correlations between acoustic cues such as center of gravity (COG) of /s/ and perceived speaker’s identity. In this study, I investigate how a multitude of acoustic features combine to influence nuanced perception of GI, SO, and GE in speech. In an online study, 197 listeners rated the speech of 66 speakers of American English for perceived GI, SO, and GE. Acoustic measures for f0, vowel formants and dispersion, segment durations, fricative spectra, and creaky voice were correlated with these judgments using analyses such as random forests and PCA. The results indicate that ensembles of acoustic features, including well-known features such as f0 and COG of /s/ but also creaky voice and diphthong formants, contribute to the perception of GI, SO, and GE such that common perceived social categories emerge. I discuss the complex interactions of acoustic cues that describe the ways in which listeners construct a speaker’s identity along traditional binaries such masculine or feminine as well as outside those binaries for queer identities.

Background The IL-36 pathway plays a key role in the pathogenesis of generalized pustular psoriasis (GPP). In a proof-of-concept clinical trial, treatment with spesolimab, an anti-IL-36 receptor antibody, resulted in rapid skin and pustular clearance in patients presenting with GPP flares. Objective To compare the molecular profiles of lesional and non-lesional skin from patients with GPP or palmoplantar pustulosis (PPP) with skin from healthy volunteers, and to investigate the molecular changes after spesolimab treatment in the skin and blood of patients with GPP flares. Methods Pre- and post-treatment skin and blood samples were collected from patients with GPP who participated in a single-arm, Phase I study (n = 7). Skin biopsies from patients with PPP (n = 8) and healthy volunteers (n = 16) were obtained for comparison at baseline. Biomarkers were assessed by RNA sequencing, histopathology and immunohistochemistry. Results In GPP and PPP lesions, 1287 transcripts were commonly up- or downregulated. Selected transcripts from the IL-36 signalling pathway were upregulated in untreated GPP and PPP lesions. In patients with GPP, IL-36 pathway-related signatures, T helper (Th)1/Th17 and innate inflammation signalling, neutrophilic mediators and keratinocyte-driven inflammation pathways, were downregulated by spesolimab as early as Week 1. Spesolimab also decreased related serum biomarkers and cell populations in the skin lesions from patients with GPP, including CD3+ T, CD11c+, IL-36γ+ cells and lipocalin-2-expressing cells. Conclusion In patients with GPP, spesolimab showed rapid modulation of commonly dysregulated molecular pathways in GPP and PPP, which may be associated with improved clinical outcomes.

RNA-binding proteins (RBPs) are crucial factors of post-transcriptional gene regulation and their modes of action are intensely investigated. At the center of attention are RNA motifs that guide where RBPs bind. However, sequence motifs are often poor predictors of RBP-RNA interactions in vivo. It is hence believed that many RBPs recognize RNAs as complexes, to increase specificity and regulatory possibilities. To probe the potential for complex formation among RBPs, we assembled a library of 978 mammalian RBPs and used rec-Y2H matrix screening to detect direct interactions between RBPs, sampling > 600 K interactions. We discovered 1994 new interactions and demonstrate that interacting RBPs bind RNAs adjacently in vivo. We further find that the mRNA binding region and motif preferences of RBPs deviate, depending on their adjacently binding interaction partners. Finally, we reveal novel RBP interaction networks among major RNA processing steps and show that splicing impairing RBP mutations observed in cancer rewire spliceosomal interaction networks. The dataset we provide will be a valuable resource for understanding the combinatorial interactions of RBPs with RNAs and the resulting regulatory outcomes., Spanish Ministry of Economy and Competitiveness (MINECO) [BFU2017-85361-P, BFU2014-54278-P, BFU2015-62550-ERC]; Spanish Ministry of Economy and Competitiveness to the EMBL partnership, ‘Centro de Excelencia Severo Ochoa’ [SEV-2012–0208 and SEV‐2015‐0533]; Spanish Ministry of Science and Innovation-State Research Agency (AEI), through the ‘Severo Ochoa Programme for Centres of Excellence in R&D’ [SEV-2015-0533 and CEX2019-000902-S]; CERCA Programme/Generalitat de Catalunya; European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie [793135 to B.L.]. Funding for open access charge: Ministerio de Economía y Competitividad.

RNA-binding proteins (RBPs) are crucial factors of post-transcriptional gene regulation and their modes of action are intensely investigated. At the center of attention are RNA motifs that guide where RBPs bind. However, sequence motifs are often poor predictors of RBP-RNA interactions in vivo. It is hence believed that many RBPs recognize RNAs as complexes, to increase specificity and regulatory possibilities. To probe the potential for complex formation among RBPs, we assembled a library of 978 mammalian RBPs and used rec-Y2H screening to detect direct interactions between RBPs, sampling > 600 K interactions. We discovered 1994 new interactions and demonstrate that interacting RBPs bind RNAs adjacently in vivo. We further find that the mRNA binding region and motif preferences of RBPs can deviate, depending on their adjacently binding interaction partners. Finally, we reveal novel RBP interaction networks among major RNA processing steps and show that splicing impairing RBP mutations observed in cancer rewire spliceosomal interaction networks.Graphical abstract

This work describes the latest design, calibration and application of a near-infrared laser diode-based photoacoustic (PA) hygrometer developed for total water content measurement in simulated atmospheric freezing precipitation and high ice water content conditions with relevance in fundamental icing research, aviation testing, and certification. The single-wavelength and single-pass PA absorption cell is calibrated for molar water vapor fractions with a two-pressure humidity generator integrated into the instrument. Laboratory calibration showed an estimated measurement accuracy better than 3.3 % in the water vapor mole fraction range of 510–12 360 ppm (5 % from 250–21 200 ppm) with a theoretical limit of detection (3σ) of 3.2 ppm. The hygrometer is examined in combination with a basic isokinetic evaporator probe (IKP) and sampling system designed for icing wind tunnel applications, for which a general description of total condensed water content (CWC) measurements and uncertainties are presented. Despite the current limitation of the IKP to a hydrometeor mass flux below 90 gm-2s-1, a CWC measurement accuracy better than 20 % is achieved by the instrument above a CWC of 0.14 g m−3 in cold air (−30 ∘C) with suitable background humidity measurement. Results of a comparison to the Cranfield University IKP instrument in freezing drizzle and rain show a CWC agreement of the two instruments within 20 %, which demonstrates the potential of PA hygrometers for water content measurement in atmospheric icing conditions.

Ewing sarcoma/peripheral primitive neuroectodermal tumor (ES/pPNET) is a malignant small round cell sarcoma commonly occurring among children, adolescents, and adults. We report a rare case of ES/pPNET arising from the lung in a 49-year-old woman. She was found to have a mass in the right lung on a screening imaging study for her BRCA2 mutation. A lobectomy was performed and the mass had histological, immunohistochemical, and molecular features of ES/pPNET. Few cases of primary pulmonary Ewing sarcoma have been reported.

Introduction Serotonin syndrome is caused by an accumulation of serotonin in the body from drug interactions or overdose of serotonergic medications, including commonly used antidepressants. Symptoms can be life-threatening and encompass both neurologic and cardiovascular toxicity, including agitation, seizure, tachycardia, rhabdomyolysis, and hyperthermia. Methods This simulation case was developed for pediatric emergency medicine fellows and emergency medicine residents in the pediatric emergency department and can be altered to accommodate other learners. The case involved a 16-year-old male, represented by a low- or high-fidelity manikin, who presented with altered mental status/agitation after an overdose of antidepressant medication. The team of learners was required to perform a primary and a secondary assessment; manage airway, breathing, and circulation; and recognize and initiate treatment for serotonin syndrome. The patient had a seizure resulting in airway compromise requiring advanced airway support, as well as developed rhabdomyolysis requiring aggressive fluid hydration. We created a debriefing guide and a participant evaluation form. Results Fifty-seven participants across five institutions completed this simulation, which included residents, fellows, faculty, and students. The scenario was rated by participants using a 5-point Likert scale and was generally well received. Participants rated the simulation case as effective in learning how to both recognize (M = 4.9) and manage (M = 4.8) serotonin syndrome. Discussion This pediatric emergency simulation scenario can be tailored for a range of learner backgrounds and simulation environments. We used the participant evaluation form to improve future iterations of the simulation.

Photoacoustic spectroscopy is a highly sensitive technique, well suited for and used in applications targeting the accurate measurement of water vapor in a wide range of concentrations. This work demonstrates the nonlinear photoacoustic response obtained for water vapor in air at typical atmospheric concentration levels, which is a result of the resonant vibrational coupling of water and oxygen. Relevant processes in the relaxation path of water in a mixture with air, excited with near-infrared radiation, are identified and a physical model for the acoustic signal measured with a resonant photoacoustic cell is presented. The model is valid for modulation frequencies typical for conventional and quartz-enhanced photoacoustic spectroscopy and provides a simplified means of calibration for photoacoustic water vapor sensors. Estimated values for comprised model coefficients are evaluated from photoacoustic measurements of water vapor in synthetic air. Furthermore, it is shown experimentally that the process of vibrational excitation of nitrogen is of negligible importance in the relaxation path of water vapor and thus insignificant in the photoacoustic heat production in atmospheric measurement environments.

Tumor cells exhibit a resistance-associated secretory phenotype involving extracellular vesicles (EVs) and heat shock proteins (HSPs). This response occurs in response to cell stress and cancer therapeutics. HSPs are stress-responsive molecular chaperones promoting proper protein folding, while also being released from cells with EVs as well as in free form as alarmins. We have here investigated the secretory phenotype of castration-resistant prostate cancer (CRPC) cells using proteome analysis. We have also examined the roles of the key co-chaperone CDC37 in stressome release, epithelial-to-mesenchymal transition (EMT), and tumor progression. A number of HSP family members and their common receptor CD91/LRP1 were enriched at high levels in CRPC cell-derived EVs among over 700 other protein species. The small EVs (30 to 200 nm in size, potentially exosomes) were released even in a non-heated condition from the prostate cancer cells, whereas EMT-coupled release of EVs (200 to 500 nm, likely ectosomes) with associated HSP90α was increased after heat shock stress (HSS). Lactate dehydrogenase, a marker of membrane leakage/damage of cells, was also released upon HSS from the prostate cancer cells. During this stress response, intracellular CDC37 was also transcriptionally inducible by heat shock factor 1, and knockdown of CDC37 decreased EMT-coupled release of EVs. Triple knockdown of CDC37, HSP90α, and HSP90β was required for efficient reduction of the chaperone trio and to reduce tumorigenicity of the CRPC cells in vivo. Taken together, the data indicated that CDC37 and HSP90 are essential for stressome release and for tumorigenesis in resistant cancer.

Bacterial infections have been on the rise world-wide in recent years and have a considerable impact on human well-being in terms of attributable deaths and disability-adjusted life years. Yet many mechanisms underlying bacterial pathogenesis are still poorly understood. Here, we introduce the BacFITBase database for the systematic characterization of bacterial proteins relevant for host infection aimed to enable the identification of new antibiotic targets. BacFITBase is manually curated and contains more than 90 000 entries with information on the contribution of individual genes to bacterial fitness under in vivo infection conditions in a range of host species. The data were collected from 15 different studies in which transposon mutagenesis was performed, including top-priority pathogens such as Acinetobacter baumannii and Campylobacter jejuni, for both of which increasing antibiotic resistance has been reported. Overall, BacFITBase includes information on 15 pathogenic bacteria and 5 host vertebrates across 10 different tissues. It is freely available at www.tartaglialab.com/bacfitbase. This study was supported by the Spanish Ministerio de Ciencia, Innovación y Universidades [SAF2015-72518-EXP, SAF2017-82158-R, RYC-2012-09999]; European Research Council [RIBOMYLOME_309545]; European Union's Horizon 2020 Research and Innovation Programme [727658, IASIS]; Spanish Ministry of Economy and Competitiveness [BFU2014-55054-P, BFU2017-86970-P]; Spanish Ministry of Economy and Competitiveness; ‘Centro de Excelencia Severo Ochoa 2013–2017’; CERCA Programme of the Generalitat de Catalunya; European Union's Horizon 2020 Research and Innovation Programme, Marie Sklodowska-Curie Individual Fellowship [793135, ‘DeepRNA’ to B.L.]; European Society of Clinical Microbiology and Infectious Diseases, Research Grant 2016 (ESCMID). Funding for open access charge: Spanish Ministerio de Ciencia, Innovación y Universidades [SAF2017-82158-R]

Despite antibiotic resistance being a matter of growing concern worldwide, the bacterial mechanisms of pathogenesis remain underexplored, restraining our ability to develop new antimicrobials. The rise of high-throughput sequencing technology has made available a massive amount of transcriptomic data that could help elucidate the mechanisms underlying bacterial infection. Here, we introduce the DualSeqDB database, a resource that helps the identification of gene transcriptional changes in both pathogenic bacteria and their natural hosts upon infection. DualSeqDB comprises nearly 300 000 entries from eight different studies, with information on bacterial and host differential gene expression under in vivo and in vitro conditions. Expression data values were calculated entirely from raw data and analyzed through a standardized pipeline to ensure consistency between different studies. It includes information on seven different strains of pathogenic bacteria and a variety of cell types and tissues in Homo sapiens, Mus musculus and Macaca fascicularis at different time points. We envisage that DualSeqDB can help the research community in the systematic characterization of genes involved in host infection and help the development and tailoring of new molecules against infectious diseases. DualSeqDB is freely available at http://www.tartaglialab.com/dualseq. Ministerio de Ciencia, Innovación y Universidades [SAF2015-72518-EXP, SAF2017-82158-R, BFU2017-86970-P and RYC-2012-09999]; European Research Council [RIBOMYLOME 309545]; Horizon 2020—Research and Innovation Framework Programme [727658, 793135 to B.L.]; Ministry of Economy and Competitiveness [BFU2017-86970-P]; Centro de Excelencia Severo Ochoa 2013–2017; Generalitat de Catalunya; European Society of Clinical Microbiology and Infectious Diseases Research Grant 2016. Funding for open access charge: Ministerio de Ciencia, Innovación y Universidades [BFU2017-86970-P].

BI 695501 has shown similar efficacy, safety, and immunogenicity to the adalimumab reference product, Humira®. We present two phase 1 studies comparing the pharmacokinetics, safety, and immunogenicity of BI 695501 delivered via autoinjector (AI) vs. prefilled syringe (PFS). Both trials were randomized, open-label, parallel-group studies undertaken in subjects aged ≥ 18–65 years. VOLTAIRE®-AI (NCT02606903) recruited healthy, Caucasian, male, non-athletic volunteers with BMI ≥ 18 to ≤ 30 kg/m2. VOLTAIRE®-TAI (NCT02899338) recruited healthy men and women with BMI > 17.5 to

This Phase I trial (INVICTAN®-1) evaluated three-way bioequivalence and safety of BI 695502 a bevacizumab biosimilar candidate, and reference product bevacizumab from two sources (US-approved Avastin®, Genentech; EU-approved Avastin, Roche).Healthy male subjects (N = 91) were randomized 1:1:1 to receive a single intravenous infusion of 1 mg/kg of BI 695502 or US- or EU-approved Avastin. An interim analysis was planned when ~50% of subjects were evaluable for the primary end point to determine if the prespecified criteria for bioequivalence were achieved; if demonstrated, the study could be stopped early. The primary end point was area under the concentration-time curve (AUC) of the analyte in plasma from time zero extrapolated to infinity (AUCThe interim analysis demonstrated three-way bioequivalence for all comparisons. The confidence intervals around the geometric mean ratios of the primary and secondary PK parameters were within the predefined acceptance ranges. Study drugs were well tolerated with no clinically relevant differences in safety.BI 695502 and US- and EU-approved Avastin showed three-way bioequivalence with similar safety profile.NCT01608087.

Aims Idarucizumab, a humanized monoclonal anti-dabigatran antibody fragment, is effective in emergency reversal of dabigatran anticoagulation. Pre-existing and treatment-emergent anti-idarucizumab antibodies (antidrug antibodies; ADA) may affect the safety and efficacy of idarucizumab. This analysis characterized the pre-existing and treatment-emergent ADA and assessed their impact on the pharmacokinetics and pharmacodynamics (PK/PD) of idarucizumab. Methods Data were pooled from three Phase I, randomized, double-blind idarucizumab studies in healthy Caucasian subjects; elderly, renally impaired subjects; and healthy Japanese subjects. In plasma sampled before and after idarucizumab dosing, ADA were detected and titrated using a validated electrochemiluminescence method. ADA epitope specificities were examined using idarucizumab and two structurally related molecules. Idarucizumab PK/PD data were compared for subjects with and without pre-existing ADA. Results Pre-existing ADA were found in 33 out of 283 individuals (11.7%), seven of whom had intermittent ADA. Titres of pre-existing and treatment-emergent ADA were low, estimated equivalent to

This Phase I study (VOLTAIRE®-PK) aimed to evaluate three-way pharmacokinetic similarity (bioequivalence), safety, and immunogenicity of BI 695501 (a Humira® [adalimumab] biosimilar candidate) compared with US- and EU-approved Humira in healthy male subjects.Subjects (N = 327) were randomized 1:1:1 to receive one 40-mg subcutaneous dose of BI 695501, US- or EU-approved Humira; safety was assessed for 70 days. Bioequivalence was evaluated using the average bioequivalence method to test if the 90% confidence intervals (CIs) of the geometric means (BI 695501 vs US- and EU-approved Humira) for the primary end points were within prespecified acceptance ranges (80-125%). Immunogenicity was assessed using a sensitive bridging method.Bioequivalence between BI 695501 and US- and EU-approved Humira was demonstrated with the 90% CIs of the ratios of all primary end points: CThree-way bioequivalence of BI 695501 to US- and EU-approved Humira was demonstrated; safety and immunogenicity results of the three study drugs were also similar.2013-003722-84 (EudraCT) and NCT02045979.

Aims Bioequivalence (BE) trials aim to demonstrate that the 90% confidence interval of the T/R-ratio of the pharmacokinetic metrics between two formulations (test [T] and reference [R]) of a drug is fully included in the acceptance interval [0.80, 1.25]. Traditionally, the sample size of BE trials is based on a power calculation based on the intrasubject variability coefficient of variation (CV) and the T/R-ratio of the metrics. Since the exact value of the T/R-ratio is not known prior to the trial, it is often assumed that the difference between the treatments does not exceed 5%. Hence, uncertainty about the T/R-ratio is expressed by using a fixed value for the sample size calculation. We propose to characterise the uncertainty about the T/R-ratio by a (normal) distribution for the log(T/R-ratio), with an assumed mean of log θ = 0.00 (i.e. θ = 1.00) and a standard deviation σu , which quantifies the uncertainty. Evaluating this distribution leads to the statistical assurance of the BE trial. Methods The assurance of a clinical trial can be derived by integrating the power over the distribution of the input parameters, in this case, the assumed distribution of the log(T/R)-ratio. Because it is an average power, the assurance can be interpreted as a measure of the probability of success that does not depend on a specific assumed value for the log(T/R)-ratio. The relationship between power and assurance will be analysed by comparing the numerical outcomes. Results Using the assurance concept, values of the standard deviation for the distribution of potential log(T/R)-ratios can be chosen to reflect the magnitude of uncertainty. For most practical cases (i.e. when 0.95 ≤ θ ≤ 1.05), the sample size is not, or only slightly, changed when σ = |log(θ)|. Conclusion The advantage of deriving the assurance for BE trials is that uncertainty is directly expressed as a parameter of variability.

Protein-RNA interactions are implicated in a number of physiological roles as well as diseases, with molecular mechanisms ranging from defects in RNA splicing, localization and translation to the formation of aggregates. Currently, ∼1400 human proteins have experimental evidence of RNA-binding activity. However, only ∼250 of these proteins currently have experimental data on their target RNAs from various sequencing-based methods such as eCLIP. To bridge this gap, we used an established, computationally expensive protein-RNA interaction prediction method, catRAPID, to populate a large database, RNAct. RNAct allows easy lookup of known and predicted interactions and enables global views of the human, mouse and yeast protein-RNA interactomes, expanding them in a genome-wide manner far beyond experimental data (http://rnact.crg.eu). European Research Council [RIBOMYLOME_309545]; European Union's Horizon 2020 research and innovation programme [727658, IASIS]; Spanish Ministry of Economy and Competitiveness [BFU2014-55054-P, BFU2017-86970-P]; Spanish Ministry of Economy and Competitiveness; ‘Centro de Excelencia Severo Ochoa 2013-2017’; CERCA Programme of the Generalitat de Catalunya; Marie Sklodowska-Curie Individual Fellowship from the European Union's Horizon 2020 research and innovation programme (793135, ‘DeepRNA’ to B.L.). Funding for open access charge: European Research Council [RIBOMYLOME_309545], European Union [793135].

Objectives This study was conducted to investigate the effect of food and coadministration of omeprazole on the relative bioavailability (BA) of faldaprevir (FDV). Methods Fifteen healthy participants participated in this open-label, randomized, three-way cross-over study. Faldaprevir was administered as a 240 mg single dose during fasting state, following intake of a high-fat breakfast, or following omeprazole 40 mg q.d. dosing for 5 days. PK samples were collected on the day of faldaprevir administration. Key findings We found geometric mean (gMean) AUC0–∞ values for faldaprevir of 48 200, 37 900 and 36 000 ng h/ml under the fed, fasted and omeprazole coadministration conditions respectively. Similarly, gMean Cmax values for faldaprevir were 2600, 2030, 1920 ng/ml under the same respective conditions. The adjusted gMean ratio between the fed and fasted condition was approximately 120% for both AUC0–∞ and Cmax, while the ratio of omeprazole coadministration to fasted condition was approximately 94%. Faldaprevir was safe and well tolerated in the study. Conclusions Administration of a single dose of 240 mg faldaprevir after high-fat breakfast led to a modest, clinically irrelevant increase in faldaprevir exposure, while coadministration of omeprazole did not influence faldaprevir exposure.

Graphical abstract, Highlights • NO2 trace gas detection by means of bare fork quartz enhanced photoacoustic spectroscopy (QEPAS). • The dependency of the photoacoustic signal on environmental conditions was discussed and investigated. • Acoustic filters were designed to decrease noise and delay drift to allow longer averaging times. • A noise analysis was performed., Increasing awareness of the adverse health effects of air pollution leads to a demand of low-cost sensors for the measurement of pollutants such as NO2. However, commercially available low-cost sensors lack accuracy and long-term stability, and suffer from cross-sensitivity to other gases. These drawbacks can be overcome by the method of quartz-enhanced photoacoustic spectroscopy (QEPAS). In QEPAS modulated light is absorbed by the NO2 molecules, which results in the production of a sound wave. The sound wave is detected by resonance of a quartz tuning fork, which results in a measurable electric signal. Due to the small size of the tuning forks, the gas sensing element can be smaller than 1 cm3. We present the first bare fork QEPAS setup for the ppb-level detection of NO2, which is ideally suited for environmental trace gas detection without the need of using micro-resonators. Micro-resonators are commonly used to amplify photoacoustic signals. However, micro-resonators have different dependencies on environmental conditions than tuning forks, which makes them difficult to operate in changing conditions. In contrast, our bare fork QEPAS setup is more robust and easily adopted by the use of a low-cost temperature and humidity sensor. By using acoustic filters the integration time could be increased to offer higher sensitivity at a continuous flow rate of 200 std cm3 min−1. The 1σ noise equivalent concentration is determined to 21 ppb NO2 in synthetic air for 120 s measurement time, allowing detection which satisfies international health and safety standards thresholds.

IN BRIEF Women with type 2 diabetes are less likely to receive prescriptions for contraceptives despite the fact that diabetes is associated with an increased risk of maternal and fetal complications. In the largest case series to date examining use of the levonorgestrel-releasing intrauterine device (LNG-IUD) in women with type 2 diabetes, we demonstrate that the LNG-IUD is safe and effective and does not affect glycemic control in women with type 2 diabetes. In this study of 115 women under the age of 55 years with type 2 diabetes who had an LNG-IUD placed between 2007 and 2012, we found low rates of pregnancies, expulsions, and other complications in every age category and disease stratification. Thirty-nine patients had A1C data before and up to 2 years after placement, and there was no significant change in A1C (mean A1C decrease of 0.17, 95% CI –0.76 to 0.43). This study will enable evidence-based contraceptive counseling for women with type 2 diabetes.

Introduction BI 695501 has shown similar efficacy, safety, and immunogenicity to the adalimumab reference product, Humira®. We present two phase 1 studies comparing the pharmacokinetics, safety, and immunogenicity of BI 695501 delivered via autoinjector (AI) vs. prefilled syringe (PFS). Methods Both trials were randomized, open-label, parallel-group studies undertaken in subjects aged ≥ 18–65 years. VOLTAIRE®-AI (NCT02606903) recruited healthy, Caucasian, male, non-athletic volunteers with BMI ≥ 18 to ≤ 30 kg/m2. VOLTAIRE®-TAI (NCT02899338) recruited healthy men and women with BMI > 17.5 to

Ribonucleoprotein (RNP) granules are dense aggregations composed of RNA-binding proteins (RBPs) and a part of the transcriptome that is still uncharacterized. We performed a large-scale study of interaction networks and discovered that RBPs phase-separating in RNP granules share specific RNA partners with high structural content, long untranslated regions (UTRs) and nucleotide repeat expansions. Our analysis suggests that RNAs can promote formation of RNP granules by acting as scaffolds for protein assembly. To experimentally validate our findings, we investigated the scaffolding ability of CGG repeats contained in the 5’ UTR of FMR1 transcript implicated in Fragile X-associated Tremor / Ataxia Syndrome (FXTAS). Using a novel high-throughput approach we identified RBPs recruited by FMR1 5’ UTRs of different lengths. We employed human primary tissues as well as primate and mouse models of FXTAS to characterize protein sequestration in FMR1 aggregates and focused on a previously unreported partner, TRA2A, which induces impairment of splicing in genes linked to mental retardation and intellectual disability. SIGNIFICANCE Proteins and RNAs phase-separate into granules under physiological (ribosome assembly and shuttling through neurons) and pathological (Amyotrophic Lateral Sclerosis and Fragile X Tremor/Ataxia Syndrome) conditions. We report here that granule-forming proteins share more RNA targets than other proteins and form a dense network of interactions. RNAs interacting with granule-forming proteins have longer UTRs, are more structured and contain nucleotide repeats. Our study suggests that specific RNAs can act as the ‘glue’ of ribonucleoprotein assemblies. To experimentally validate the results of our analysis, we investigated how nucleotide repeats contained in the 5’ UTR of FMR1 are able to sequester proteins in intranuclear inclusions. We predicted protein interactions in silico, confirmed them in vitro and further characterized the ribonucleoprotein aggregates in vivo.

Short linear motifs (SLiMs) are protein binding modules that play major roles in almost all cellular processes. SLiMs are short, often highly degenerate, difficult to characterize and hard to detect. The eukaryotic linear motif (ELM) resource (elm.eu.org) is dedicated to SLiMs, consisting of a manually curated database of over 275 motif classes and over 3000 motif instances, and a pipeline to discover candidate SLiMs in protein sequences. For 15 years, ELM has been one of the major resources for motif research. In this database update, we present the latest additions to the database including 32 new motif classes, and new features including Uniprot and Reactome integration. Finally, to help provide cellular context, we present some biological insights about SLiMs in the cell cycle, as targets for bacterial pathogenicity and their functionality in the human kinome. Fil: Gouw, Marc. European Molecular Biology Laboratory Heidelberg; Alemania Fil: Michael, Sushama. European Molecular Biology Laboratory Heidelberg; Alemania Fil: Sámano Sánchez, Hugo. European Molecular Biology Laboratory Heidelberg; Alemania Fil: Kumar, Manjeet. European Molecular Biology Laboratory Heidelberg; Alemania Fil: Zeke, András. Hungarian Academy Of Sciences; Hungría Fil: Lang, Benjamin. European Molecular Biology Laboratory Heidelberg; Alemania Fil: Bely, Benoit. Wellcome Trust; Reino Unido Fil: Chemes, Lucia Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina Fil: Davey, Norman E. Universidad de Dublin; Irlanda Fil: Deng, Ziqi. European Molecular Biology Laboratory Heidelberg; Alemania Fil: Diella, Francesca. European Molecular Biology Laboratory Heidelberg; Alemania Fil: Gürth, Clara Marie. European Molecular Biology Laboratory Heidelberg; Alemania Fil: Huber, Ann Kathrin. European Molecular Biology Laboratory Heidelberg; Alemania Fil: Kleinsorg, Stefan. Universitat Heidelberg; Alemania Fil: Schlegel, Lara S.. Universitat Heidelberg; Alemania Fil: Palopoli, Nicolás. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Roey, Kim V. Universitat Heidelberg; Alemania Fil: Altenberg, Brigitte. European Molecular Biology Laboratory Heidelberg; Alemania Fil: Reményi, Attila. European Molecular Biology Laboratory Heidelberg; Alemania Fil: Dinkel, Holger. European Molecular Biology Laboratory Heidelberg; Alemania Fil: Gibson, Toby J.. European Molecular Biology Laboratory Heidelberg; Alemania

Multicrystalline (multi-Si) photovoltaic (PV) technology is increasingly common throughout Australia and the developed world, as renewable energy technologies become viable electrical generation alternatives to coal and nuclear power. We have examined the cradle-to-grave life cycle of a 3kWp multi-Si PV system within Australia. The highest contribution of environmental impacts results from the usage of fossil fuel energy resources and their emissions at the pre-production and manufacturing stages. We analyze the impacts of multi-Si technology on ecosystem goods and services (EGS) and compared it with impacts resulting from coal power electricity. For 3kWp multi-Si system, coal, crude oil and iron ore were the critical resources consumed from the lithosphere while the public supply of water was consumed from the hydrosphere. For coal power electricity, coal and water were the resources most consumed from both the lithosphere and hydrosphere. However the resource consumption from coal power electricity is significantly larger than that of multi-Si PV. Coal power electricity is also responsible for much greater energy and exergy consumption compared to multi-Si PV. The main ecosystem disturbances resulting from the lifecycle of a 3kWp multi-Si unit affect supporting and regulating services though these disturbances are considerably lower than the services impacted from coal power electricity. The study concludes that similar analysis performed on another PV technology would provide a greater understanding to the Eco-LCA results for multi-Si PV technology, particularly with relation to exergy analysis.

We consider the non-interacting source-free Maxwell field, described both in terms of the vector potential and the field strength. Starting from the classical field theory on contractible globally hyperbolic spacetimes, we extend the classical field theory to general globally hyperbolic spacetimes in two ways to obtain a "universal" theory and a "reduced" theory. The quantum field theory in terms of the unital $*$-algebra of the smeared quantum field is then obtained by an application of a suitable quantisation functor. We show that the universal theories fail local covariance and dynamical locality owing to the possibility of having non-trivial radicals in the classical and non-trivial centres in the quantum case. The reduced theories are both locally covariant and dynamically local. These models provide new examples relevant to the discussion of how theories should be formulated so as to describe the same physics in all spacetimes., Comment: 27pp v3: Some comments added; minor corrections and typos fixed

Faldaprevir is a potent hepatitis C virus (HCV) NS3/4A protease inhibitor with negligible urinary excretion. We assessed the pharmacokinetics and safety of a single oral dose of faldaprevir (480 mg) in 32 HCV-negative subjects with renal impairment or normal renal function. Compared with subjects with normal renal function, the adjusted geometric mean ratios (90% confidence intervals in parentheses) for overall exposure area under the concentration-time curve from zero to infinity (AUC 0–∞ ) were 113.6% (41.6 to 310.2%), 178.3% (85.2 to 373.0%), and 169.2% (73.2 to 391.2%) for subjects with mild, moderate, and severe renal impairment, respectively. Overall, 5/8 (63%) subjects with normal renal function and 20/24 (83%) subjects with renal impairment reported adverse events, with gastrointestinal events being the most common. No severe or serious adverse events or deaths were reported. These results suggest that moderate or severe renal impairment can result in a modest increase in faldaprevir exposure. The increase in exposure may be related to decrease in the activity of the liver uptake transporter OATP1B1 as a result of renal impairment. Given this relatively slight increase in exposure, a dose adjustment in HCV patients with renal impairment is not warranted. (This study has been registered at ClinicalTrials.gov under registration number NCT01957657.)

Idarucizumab is a specific reversal agent that rapidly neutralizes dabigatran’s anticoagulant activity [(1–3)][1]. We investigated restoration of dabigatran anticoagulation 24 h after idarucizumab treatment and the safety and effectiveness of a second idarucizumab treatment. Six male and 6

1.1. Uncharacterized Protein Segments Are a Source of Functional Novelty Over the past decade, we have observed a massive increase in the amount of information describing protein sequences from a variety of organisms.1,2 While this may reflect the diversity in sequence space, and possibly also in function space,3 a large proportion of the sequences lacks any useful function annotation.4,5 Often these sequences are annotated as putative or hypothetical proteins, and for the majority their functions still remain unknown.6,7 Suggestions about potential protein function, primarily molecular function, often come from computational analysis of their sequences. For instance, homology detection allows for the transfer of information from well-characterized protein segments to those with similar sequences that lack annotation of molecular function.8−10 Other aspects of function, such as the biological processes proteins participate in, may come from genetic- and disease-association studies, expression and interaction network data, and comparative genomics approaches that investigate genomic context.11−17 Characterization of unannotated and uncharacterized protein segments is expected to lead to the discovery of novel functions as well as provide important insights into existing biological processes. In addition, it is likely to shed new light on molecular mechanisms of diseases that are not yet fully understood. Thus, uncharacterized protein segments are likely to be a large source of functional novelty relevant for discovering new biology.