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Whether ambulance transport patterns are optimized to match children to high-readiness emergency departments (EDs) and the resulting effect on survival are unknown. We quantified the number of children transported by 9-1-1 emergency medical services (EMS) to high-readiness EDs, additional children within 30 minutes of a high-readiness ED, and the estimated effect on survival.This was a cross-sectional study using data from the National EMS Information System for 5,461 EMS agencies in 28 states from 1/1/2012 through 12/31/2019, matched to the 2013 National Pediatric Readiness Project assessment of ED pediatric readiness. We performed a geospatial analysis of children 0 to 17 years requiring 9-1-1 EMS transport to acute care hospitals, including day-, time-, and traffic-adjusted estimates for driving times to all EDs within 30 minutes of the scene. We categorized receiving hospitals by quartile of ED pediatric readiness using the weighted Pediatric Readiness Score (wPRS, range 0-100) and defined a high-risk subgroup of children as a proxy for admission. We used published estimates for the survival benefit of high readiness EDs to estimate the number of lives saved.There were 808,536 children transported by EMS, of whom 253,541 (31.4%) were high-risk. Among the 2,261 receiving hospitals, the median wPRS was 70 (IQR 57-85, range 26-100) and the median number of receiving hospitals within 30 minutes was 4 per child (IQR 2-11, range 1 to 53). Among all children, 411,685 (50.9%) were taken to EDs in the highest quartile of pediatric readiness, and 180,547 (22.3%) children transported to lower readiness EDs were within 30 minutes of a high readiness ED. Findings were similar among high-risk children. Based on high-risk children, we estimated that 3,050 pediatric lives were saved by transport to high-readiness EDs and an additional 1,719 lives could have been saved by shifting transports to high readiness EDs within 30 minutes.Approximately half of children transported by EMS were taken to high-readiness EDs and an additional one quarter could have been transported to such an ED, with measurable effect on survival.

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.

Traditionally, in biomedical animal research, laboratory rodents are individually examined in test apparatuses outside their home cages at selected time points. However, the outcome of such tests can be influenced by the novel environment, the time of day, separation from the social group, or the presence of an experimenter. Moreover, valuable information may be missed when the animals are only monitored in short periods. These issues can be overcome by longitudinal monitoring mice and rats in their home cages. To shed light on the development of home cage monitoring (HCM) and the current state of the art, a systematic review was carried out on 521 publications retrieved through PubMed and Web of Science. Both the absolute (∼ ×26) and relative (∼ ×7) number of HCM-related publications increased from 1974 to 2020. In both mice and rats, there was a clear bias towards males and individually housed animals, but during the past decade (2011–2020), an increasing number of studies used both sexes and group housing. More than 70 % of the studies did not involve a disease model, but the percentage of studies using disease models increased since the 2000s. In most studies, animals were kept for short (up to 4 weeks) length periods in the HCM systems; intermediate length periods (4–12 weeks) increased in frequency in the years between 2011 and 2020. Before the 2000s, HCM techniques were predominantly applied for less than 12 hours, while 24-hour measurements have been more frequently since the 2000s. The systematic review demonstrated that manual monitoring is decreasing but still relevant. Until (and including) the 1990s, most techniques were applied manually but have been progressively replaced by automation since the 2000s. Independent of the publication year, the main behavioral parameters measured were locomotor activity, feeding, and social behaviors; the main physiological parameters were heart rate and electrocardiography. External appearance-related parameters were rarely examined in the home cages. Due to technological progress and application of artificial intelligence, more refined and detailed behavioral parameters could be investigated in the home cage in recent times.Over the period covered in this study, techniques for HCM of mice and rats has improved considerably. This development is ongoing and further progress and validation of HCM systems will extend the applications to allow for continuous, longitudinal, non-invasive monitoring of an increasing range of parameters in group-housed small rodents in their home cages.

Enhanced crosslinking and immunoprecipitation (eCLIP) sequencing is a powerful method for transcriptome-wide detection of binding sites of RNA-binding proteins (RBPs). However, identified crosslink sites can profoundly deviate from experimentally established functional elements of even well-studied RBPs. Current peak-calling strategies result in low replication and high false-positive rates. Here, we present the R/Bioconductor packageDEWSeqthat makes full use of replicate information and size-matched input controls. We benchmarkedDEWSeqon 107 RBPs for which both eCLIP data and RNA sequence motifs are available and were able to more than double the number of motif-containing binding regions relative to standard eCLIP processing (2.3-fold median). The improvement not only relates to the number of binding sites (e.g., 3.1-fold of known motifs for RBFOX2), but also their subcellular localisation (e.g., 1.9-fold of mitochondrial genes for FASTKD2) and structural targets (e.g., 2.2-fold increase of stem-loop regions for SLBP). DEWSeq therefore shows promise as an improved processing method for eCLIP protein–RNA interaction data.

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.

Photothermal spectroscopy is a promising technique for monitoring gas concentrations. We provide an approach to signal enhancement relying upon the ratio between excitation frequency and gas flow velocity. Our statements are supported experimentally and theoretically.

Breast cancer is a heterogeneous disease classified into four main subtypes with different clinical outcomes, such as patient survival, prognosis, and relapse. Current genetic tests for the differential diagnosis of BC subtypes showed a poor reproducibility. Therefore, an early and correct diagnosis of molecular subtypes is one of the challenges in the clinic. In the present study, we identified differentially expressed genes, long non-coding RNAs and RNA binding proteins for each BC subtype from a public dataset applying bioinformatics algorithms. In addition, we investigated their interactions and we proposed interacting biomarkers as potential signature specific for each BC subtype. We found a network of only 2 RBPs (RBM20 and PCDH20) and 2 genes (HOXB3 and RASSF7) for luminal A, a network of 21 RBPs and 53 genes for luminal B, a HER2-specific network of 14 RBPs and 30 genes, and a network of 54 RBPs and 302 genes for basal BC. We validated the signature considering their expression levels on an independent dataset evaluating their ability to classify the different molecular subtypes with a machine learning approach. Overall, we achieved good performances of classification with an accuracy >0.80. In addition, we found some interesting novel prognostic biomarkers such as RASSF7 for luminal A, DCTPP1 for luminal B, DHRS11, KLC3, NAGS, and TMEM98 for HER2, and ABHD14A and ADSSL1 for basal. The findings could provide preliminary evidence to identify putative new prognostic biomarkers and therapeutic targets for individual breast cancer subtypes. The research leading to these results has been supported by European Research Council grant agreements RIBOMYLOME (309545) and ASTRA (855923), and the European Union’s Horizon 2020 research and innovation programme grant agreements IASIS (727658), DeepRNA (793135), and INFORE (825080). We would like to thank for the financial support the project Grant SysBioNet, Italian Roadmap Research Infrastructures 2012.

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.

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.

Photothermal spectroscopy (PTS) is a promising sensing technique for the measurement of gases and aerosols. PTS systems using a Fabry–Pérot interferometer (FPI) are considered particularly promising owing to their robustness and potential for miniaturization. However, limited information is available on viable procedures for signal improvement through parameter tuning. In our work, we use an FPI-based PTS configuration, in which the excitation laser irradiates the target collinearly to the flowing gas. We demonstrate that the generated thermal wave, and thus the signal intensity, is significantly affected by the ratio between excitation modulation frequency and gas flow velocity towards another. We provide an analytical model that predicts the signal intensity with particular considerations of these two parameter settings and validate the findings experimentally. The results reveal the existence of an optimal working regime, depending on the modulation frequency and flow velocity.

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.

The authors put forward an interesting response to detractors of black box algorithms. According to the authors, what is of ethical relevance for medical artificial intelligence is not so much their transparency, but rather their reliability as a process capable of producing accurate and trustworthy results. The implications of this view are twofold. First, it is permissible to implement a black box algorithm in clinical settings, provided the algorithm’s epistemic authority is tempered by physician expertise and consideration of patient autonomy. Second, physicians are not expected to possess exhaustive knowledge or understanding of the algorithmic computation by which they verify or augment their medical opinions. The potential of these algorithms to improve diagnostic and procedural accuracy alongside the quality of patient decision-making is undoubtedly a boon to modern medicine, but blind deference to them is neither feasible nor responsible, as several logistical and ethical quagmires noted by the authors still remain inherent in algorithmic software. I concur …

We present a concept for a miniaturizable black carbon monitor based on a fiber-coupled Fabry-Pérot interferometer. By means of photothermal excitation, we reach a limit of detection as low as 13 µg/m³.

The discovery of 3C 273 in 1963, and the emergence of the Kerr solution shortly thereafter, precipitated the current era in astrophysics focused on using black holes to explain active galactic nuclei (AGN). But while partial success was achieved in separately explaining the bright nuclei of some AGN via thin disks, as well as powerful jets with thick disks, the combination of both powerful jets in an AGN with a bright nucleus, such as in 3C 273, remained elusive. Although numerical simulations have taken center stage in the last 25 years, they have struggled to produce the conditions that explain them. This is because radiatively efficient disks have proved a challenge to simulate. Radio quasars have thus been the least understood objects in high energy astrophysics. But recent simulations have begun to change this. We explore this milestone in light of scale-invariance and show that transitory jets, possibly related to the jets seen in these recent simulations, as some have proposed, cannot explain radio quasars. We then provide a road map for a resolution., Comment: 9 pages

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.

With protein structure prediction recently getting a seismic boost in accuracy, hopes are also up to better predict unstructured protein regions that can adopt diverse conformations. CAID, a community effort to revive systematic benchmarking, should help.

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.

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.

Sensors for the reliable measurement of trace gases are of high interest. A compact and robust fiber-coupled Fabry-PErot interferometer is employed in photothermal spectroscopy to measure nitrogen dioxide concentrations at the ppb level.

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]

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

Recent work by Chang has shown that even at the very earliest stages of second language (L2) acquisition, the phonetic implementation of speakers’ native English phoneme categories is slightly modified by contact with L2 Korean, which is referred to as “phonetic drift.” This study investigates whether rapid phonetic drift generalizes to another pairing of languages. We examined naïve American English learners of French, who were recorded producing both American English and French vowels after one and six weeks of a study abroad program in Paris. In addition, the Study Abroad group is compared with proficient American English L1 speakers of French who have been residents of Paris for at least five years, to investigate the impact of long-term use of an L2 on the vowel categories of L1. Whereas the Study Abroad group showed no evidence of phonetic drift after six weeks, the Paris Residents’ American English vowel space shifted along F1 and several English vowels demonstrated clear movement toward French monolingual norms. A closer look at the high vowels provides insight into how phonetic categories are influenced both by drift and by a pressure to keep vowel categories distinct between the languages. The results are also discussed with respect to potential effects of the size of the vowel inventory and the amount of input required to cause phonetic drift.

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.

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

We present a novel method to determine the resonance frequency and Q factor of a quartz tuning fork (QTF) in quartz-enhanced photoacoustic spectroscopy (QEPAS) in a few seconds. A CHIRP modulates a laser diode.

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.)

This study was undertaken to investigate potential drugdrug interactions between the sodium glucose cotransporter 2 inhibitor empagliflozin and simvastatin.In this open-label, randomized crossover trial, healthy volunteers (median (range) age 36.5 (20 - 50) years) received 3 single-dose treatments: 25 mg empagliflozin (n = 18), 40 mg simvastatin (n = 17), and 25 mg empagliflozin with 40 mg simvastatin (n = 18).Based on standard criteria, simvastatin had no effect on empagliflozin area under the plasma concentration-time curve (AUC(0-∞), adjusted geometric mean ratio (GMR): 102.05; 90% CI: 98.90 - 105.29) or maximum plasma concentration (C(max), GMR: 109.49; 90% CI: 96.91 - 123.69). There were only minor deviations in simvastatin AUC(0-∞) (GMR: 101.26; 90% CI: 80.06 - 128.07) and C(max) (GMR: 97.18; 90% CI: 76.30 - 123.77) when co-administered with empagliflozin. Empagliflozin had no effect on AUC(0-∞) (GMR: 104.87; 90% CI: 90.09 - 122.07) or C(max) (GMR: 97.27; 90% CI: 84.90 - 111.44) of simvastatin acid, the active metabolite of simvastatin. Adverse events (AEs) were reported for 6 subjects on empagliflozin, 4 on simvastatin, and 5 on co-administered treatment. No serious AEs or investigator-defined drug-related AEs were reported.No relevant drug-drug interaction was observed, and pharmacokinetic results suggest that no dose adjustments for either drug are necessary when empagliflozin and simvastatin are co-administered. Empagliflozin was well tolerated when administered alone or in combination with simvastatin.

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

A drug is defined as highly variable if its intra-individual coefficient of variation (CV) is greater than or equal to 30%. In such a case, bioequivalence may be assessed by means of methods that take the (high) variability into account. The Scaled Average Bioequivalence (SABE) approach is such a procedure and represents the recommendations of FDA. The aim of this investigation is to compare the performance characteristics of classical group sequential designs (GSD) and fixed design settings for three-period crossover bioequivalence studies with highly variable drugs, where the SABE procedure is utilized. Monte Carlo simulations were performed to assess type I error rate, power, and average sample size for GSDs with Pocock’s and O’Brien-Fleming’s stopping rules and various timings of the interim analysis and for fixed design settings. Based on our investigated scenarios, the GSDs show comparable properties with regard to power and type I error rate as compared to the corresponding fixed designs. However, due to an advantage in average sample size, the most appealing design is Pocock’s approach with interim analysis after 50% information fraction. Due to their favorable performance characteristics, two-stage GSDs are an appealing alternative to fixed sample designs when assessing bioequivalence in highly variable drugs.

Photoacoustic spectroscopy (PAS) is a well-established methodology for selectively sensing gaseous components. We present a design framework for a PAS sensor concept based on an open path detection geometry. The main purpose of the framework is the optimization of the open sensor geometry in harsh environments regarding flow speed and external noise. A first design study of a NO 2 sensor including the technical realization was carried out. Good qualitative agreement of simulation and experiment was achieved, resulting in a theoretical limit of detection for NO 2 as low as 5 ppm and providing a valid basis for future design optimizations for a multitude of analytes.

ObjectivePaediatric resuscitation is highly stressful, technically challenging and infrequently performed by paramedics. Length-based equipment selection, weight-based medication dosing and less familiar paediatric clinical scenarios create high cognitive load. Our project aimed to decrease cognitive load and increase paramedic comfort by providing standardised paediatric resuscitation cards across an entire Emergency Medical Services (EMS) system.MethodsAfter 2 years of collaboration between EMS and regional paediatric subspecialists, we created and implemented a novel set of length-based, colour-coded cards: Medic One Pediatric (MOPed) cards. MOPed cards standardise the approach to paediatric scenarios, such as rapid sequence intubation (RSI), seizure management and cardiac arrest. We standardised drug concentrations across all five EMS agencies to allow for volume-based dosing, removing medication calculations, simplifying the process of medication administration and potentially decreasing both calculation error and time to intervention. We consolidated medications on MOPed cards to the 12 most commonly used in Paediatric Advanced Life Support scenarios. We surveyed 240 EMS personnel before and after implementation to determine use and effect on paramedic comfort.ResultsAfter 12 months of implementation, 97% of respondents reported using the new cards as their primary reference, and 94% reported improved speed and accuracy of medication administration. Specifically, RSI medication administration received the greatest improvement in comfort (p=0.001). Additionally, paramedics increased the use of MOPed cards when selecting endotracheal tubes: 45% of the respondents had done so by 6 months, and 60% had done so after 12 months of implementation (p=0.01).ConclusionsMOPed cards were well adopted across a large EMS system, with improvement in paramedic comfort in managing some paediatric resuscitation scenarios.

Sensors for the reliable measurement of nitrogen dioxide concentrations are of high interest due the adverse health effects of this pollutant. This work employs photothermal spectroscopy to measure nitrogen dioxide concentrations at the parts per billion level. Absorption induced temperature changes are detected by means of a fiber-coupled Fabry&ndash, P&eacute, rot interferometer. The small size of the interferometer enables small detection volumes, paving the way for miniaturized sensing concepts as well as fast response times, demonstrated down to 3 s. A normalized noise equivalent absorption of 7.5 &times, 10 &minus, 8 cm&minus, 1W/ Hz is achieved. Additionally, due to the rigid structure of the interferometer, the sensitivity to mechanical vibrations is shown to be minor.

Summary Recent evidence indicates that specific RNAs promote the formation of ribonucleoprotein condensates by acting as scaffolds for RNA-binding proteins (RBPs). We systematically investigated RNA-RBP interaction networks to understand ribonucleoprotein assembly. We found that highly contacted RNAs are structured, have long UTRs, and contain nucleotide repeat expansions. Among the RNAs with such properties, we identified the FMR1 3′ UTR that harbors CGG expansions implicated in fragile X-associated tremor/ataxia syndrome (FXTAS). We studied FMR1 binding partners in silico and in vitro and prioritized the splicing regulator TRA2A for further characterization. In a FXTAS cellular model, we validated the TRA2A-FMR1 interaction and investigated implications of its sequestration at both transcriptomic and post-transcriptomic levels. We found that TRA2A co-aggregates with FMR1 in a FXTAS mouse model and in post-mortem human samples. Our integrative study identifies key components of ribonucleoprotein aggregates, providing links to neurodegenerative disease and allowing the discovery of therapeutic targets., Graphical Abstract, Highlights • Highly contacted granule RNAs are structured and contain long, repetitive UTRs • Mutations related with FXTAS increase FMR1 scaffolding propensity • TRA2A co-aggregates with FMR1 in FXTAS mouse model and in post-mortem human samples • TRA2 sequestration has both transcriptomic and post-transcriptomic implications, Cid-Samper et al. analyze protein-RNA networks and identify properties of RNA scaffolds within biological condensates. They find that CGG repeats in the 3′ UTR of FMR1 attract several proteins, including the splicing factor TRA2A that co-aggregates in fragile X-associated tremor/ataxia syndrome (FXTAS).

Summary Background Idarucizumab is a monoclonal antibody fragment that binds dabigatran with high affinity in a 1:1 molar ratio. We investigated the safety, tolerability, and efficacy of increasing doses of idarucizumab for the reversal of anticoagulant effects of dabigatran in a two-part phase 1 study (rising-dose assessment and dose-finding, proof-of-concept investigation). Here we present the results of the proof-of-concept part of the study. Methods In this randomised, placebo-controlled, double-blind, proof-of-concept phase 1 study, we enrolled healthy volunteers (aged 18–45 years) with a body-mass index of 18·5–29·9 kg/m 2 into one of four dose groups at SGS Life Sciences Clinical Research Services, Belgium. Participants were randomly assigned within groups in a 3:1 ratio to idarucizumab or placebo using a pseudorandom number generator and a supplied seed number. Participants and care providers were masked to treatment assignment. All participants received oral dabigatran etexilate 220 mg twice daily for 3 days and a final dose on day 4. Idarucizumab (1 g, 2 g, or 4 g 5-min infusion, or 5 g plus 2·5 g in two 5-min infusions given 1 h apart) was administered about 2 h after the final dabigatran etexilate dose. The primary endpoint was incidence of drug-related adverse events, analysed in all randomly assigned participants who received at least one dose of dabigatran etexilate. Reversal of diluted thrombin time (dTT), ecarin clotting time (ECT), activated partial thromboplastin time (aPTT), and thrombin time (TT) were secondary endpoints assessed by measuring the area under the effect curve from 2 h to 12 h (AUEC 2–12 ) after dabigatran etexilate ingestion on days 3 and 4. This trial is registered with ClinicalTrials.gov, number NCT01688830. Findings Between Feb 23, and Nov 29, 2013, 47 men completed this part of the study. 12 were enrolled into each of the 1 g, 2 g, or 5 g plus 2·5 g idarucizumab groups (nine to idarucizumab and three to placebo in each group), and 11 were enrolled into the 4 g idarucizumab group (eight to idarucizumab and three to placebo). Drug-related adverse events were all of mild intensity and reported in seven participants: one in the 1 g idarucizumab group (infusion site erythema and hot flushes), one in the 5 g plus 2·5 g idarucizumab group (epistaxis); one receiving placebo (infusion site haematoma), and four during dabigatran etexilate pretreatment (three haematuria and one epistaxis). Idarucizumab immediately and completely reversed dabigatran-induced anticoagulation in a dose-dependent manner; the mean ratio of day 4 AUEC 2–12 to day 3 AUEC 2–12 for dTT was 1·01 with placebo, 0·26 with 1 g idarucizumab (74% reduction), 0·06 with 2 g idarucizumab (94% reduction), 0·02 with 4 g idarucizumab (98% reduction), and 0·01 with 5 g plus 2·5 g idarucizumab (99% reduction). No serious or severe adverse events were reported, no adverse event led to discontinuation of treatment, and no clinically relevant difference in incidence of adverse events was noted between treatment groups. Interpretation These phase 1 results show that idarucizumab was associated with immediate, complete, and sustained reversal of dabigatran-induced anticoagulation in healthy men, and was well tolerated with no unexpected or clinically relevant safety concerns, supporting further testing. Further clinical studies are in progress. Funding Boehringer Ingelheim Pharma GmbH & Co KG.