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Targeted therapies tend to have biomarker defined subgroups that derive differential efficacy from treatments. This article corrects three prevailing oversights in stratified analyses comparing treatments in randomized controlled trials (RCTs) with binary and time-to-event outcomes: 1.Using efficacy measures such as odds ratio (OR) and hazard ratio (HR) can make a prognostic biomarker appear predictive, targeting wrong patients, because the inference is affected by a confounding/covert factor even with ignorable treatment assignment in an RCT. As shown analytically and with real immunotherapy patient level data, OR and HR cannot meet the causal Estimand requirement of ICH E9R1. 2.Mixing efficacy in subgroups by prevalence, the prevailing practice, can give misleading results also, for any efficacy measured as a ratio. However, mixing relative response (RR) and ratio of median (RoM) survival times by the prognostic effect, the confounding/covert factor hiding in plain sight, will give causal inference in an RCT. 3.Effects in subgroups should not be mixed on the logarithmic scale, because it creates an artificial Estimand for the whole population which changes depending on how the population is divided into subgroups. Current computer package implementations contain all these oversights. Probabilities, including survival curve probabilities, naturally average within each treatment arm by prevalence. The subgroup mixable estimation (SME) principle fixes the oversights by first averaging probabilities (not their logarithms) within each treatment arm, then computing simultaneous confidence intervals for ratio efficacy in subgroups and their mixtures based on rigorous mathematical derivation, to finally provide causal inference in the form of apps.

Aims To evaluate the safety, pharmacokinetics and pharmacodynamics of single- and multiple-rising doses (MRDs) of BI 705564 and establish proof of mechanism. Methods BI 705564 was studied in 2 placebo-controlled, Phase I clinical trials testing single-rising doses (1-160 mg) and MRDs (1-80 mg) of BI 705564 over 14 days in healthy male volunteers. Blood samples were analysed for BI 705564 plasma concentration, Bruton's tyrosine kinase (BTK) target occupancy (TO) and CD69 expression in B cells stimulated ex vivo. A substudy was conducted in allergic, otherwise healthy, MRD participants. Safety was assessed in both studies. Results All doses of BI 705564 were well tolerated. Geometric mean BI 705564 plasma terminal half-life ranged from 10.1 to 16.9 hours across tested doses, with no relevant accumulation after multiple dosing. Doses ≥20 mg resulted in ≥85% average TO that was maintained for ≥48 hours after single-dose administration. Functional effects of BTK signalling were demonstrated by dose-dependent inhibition of CD69 expression. In allergic participants, BI 705564 treatment showed a trend in wheal size reduction in a skin prick test and complete inhibition of basophil activation. Mild bleeding-related adverse events were observed with BI 705564; bleeding time increased in 1/12 participants (8.3%) who received placebo vs 26/48 (54.2%) treated with BI 705564. Conclusion BI 705564 showed efficient target engagement through durable TO and inhibition of ex vivo B-cell activation, and proof of mechanism through effects on allergic skin responses. Mild bleeding-related adverse events were probably related to inhibition of platelet aggregation by BTK inhibition.

Despite its extensive application in practice, the Metropolis-Hastings sampler can suffer from slow mixing and, in turn, statistical inefficiency. We introduce a modification to the Metropolis-Hast...

The diagnosis of Alzheimer's disease (AD) at early stage is urgent for the clinical treatment. However, the methods of detecting multiple AD related markers with noninvasive sampling are still limited, which hinders their wide applications among potential patients. Here, we present a microfluidic chip with capture arrays to isolate and analyze immunomagnetic beads conjugated with AD salivary biomarkers. Through the design of a three-stage microfluidic capture array, magnetic beads combined with different biomarkers can captured at corresponding sections for high-resolution characterization. Finite element simulation was used to validate the capture efficiency. The lactoferrin with concentration comparable to AD patients was effectively analyzed using the fabricated microfluidic chip. These results indicate the proposed platform to be a potential non-invasive method to detect multiple AD markers by one-time injection of saliva samples with high sensitivity.

Three-dimensional (3D) cell migrations are regulated by force interactions between cells and a 3D extracellular matrix (ECM). Mapping the 3D traction force generated by cells on the surrounding ECM with controlled confinement and contact area will be useful in understanding cell migration. In this study, double-sided micropost arrays were fabricated. The cell traction force was mapped by microposts on the top and bottom of opposing surfaces with a controlled separating distance to create different confinements. The density of micropost arrays was modified to investigate the effect of cell contact area on 3D traction force development. Using MC3T3-E1 osteoblastic cells, the leading traction force was found to increase with additional contact surface on the top. Summing force vectors on both surfaces, a large force imbalance was found from the leading to trailing regions for fast migrating cells. With 10 μm separation and densely arranged microposts, the traction force on the top surface was the largest at 28.6 ± 2.5 nN with the highest migration speed of 0.61 ± 0.07 μm min−1. Decreasing the density of the top micropost arrays resulted in a reduced traction force on the top and lower migration speed. With 15 μm separation, the cell traction force on the top and migration speed further decreased simultaneously. These results revealed traction force development on 3D ECM with varied degrees of confinement and contact area, which is important in regulating 3D cell migration.

7042 Background: Ivosidenib (IVO) is a potent oral targeted inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1). IVO plus azacitidine (AZA) significantly improved event-free survival (EFS), overall survival and complete remission + partial hematologic recovery rates compared with placebo (PBO) + AZA, in patients (pts) with newly diagnosed IDH1-mutant acute myeloid leukemia (AML) in the Phase 3 AGILE trial (NCT03173248). Here we report blood count recovery results from the AGILE trial. Methods: Pts were randomized 1:1 to IVO 500 mg QD + AZA 75 mg/m2 SC or IV for 7 days in 28-day cycles (n = 72), or PBO+AZA (n = 74). Red blood cell (RBC)/platelet transfusion history were assessed at screening and follow-up. Bone marrow (BM) and peripheral blood samples were obtained at screening, and during weeks 9, 17, 25, 33, 41, 53, and every 24 weeks thereafter, and at end of treatment and during EFS follow up. Samples were analyzed at each local site according to ICSH guidelines. Results: In the IVO+AZA and PBO+AZA arms, 4.2% and 5.5% of pts, respectively, received concomitant granulocyte colony-stimulating factor. Hemoglobin levels steadily increased from baseline at a similar rate in both treatment arms. Mean platelet count recovered from baseline values in the IVO+AZA and PBO+AZA arms (71.0 and 92.6 x 109/L, respectively) as early as week 9 of treatment (171.1 and 155.1 x 109/L, respectively) and continued to steadily increase thereafter in the treated population. In pts receiving IVO+AZA, mean neutrophil counts rapidly increased from baseline (0.99 x 109/L) to week 2 (2.05 x 109/L) and week 5 (4.07 x 109/L), and then generally stabilized to within the normal range to study end (last available cycle value; ̃2.0 x 109/L). Mean neutrophil counts initially declined with PBO+AZA before slowly recovering to near-normal levels after 36-40 weeks. The increased blood counts were accompanied by a rapid decrease in the mean BM blast percentage from 54.8% at baseline to 12.0% and 7.2% at week 9 and 17, respectively, in IVO+AZA treated patients and were maintained for 149 weeks. The decline in BM blasts was slower in the PBO+AZA arm (53.7%, 34.6% and 19.6% at baseline, week 9 and week 17, respectively). Among patients who were RBC/platelet transfusion-dependent at baseline (̃54.0% in both groups), 46.2% in the IVO+AZA group achieved RBC/platelet transfusion independence compared with 17.5% in the PBO+AZA arm (1-sided p = 0.0032). Additionally, fewer adverse events of febrile neutropenia (28.2% vs 34.2%) and infections (28.2% vs 49.3%) were reported in the IVO+AZA arm compared to the PBO+AZA arm. Conclusions: IVO+AZA demonstrated a significant clinical benefit compared with PBO+AZA and this sub-analysis demonstrated a rapidly improved recovery of blood counts and a reduced dependence on RBC and/or platelet transfusion. Moreover, rates of febrile neutropenia and infections were reduced with IVO+AZA. Clinical trial information: NCT03173248.

e19024 Background: Ivosidenib (IVO) is a potent, targeted inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1) that is approved for acute myeloid leukemia (AML). IVO plus azacitidine (AZA) demonstrated clinical benefit compared with placebo (PBO) and AZA in the AGILE study (NCT03173248), and here we report the impact of IVO+AZA versus PBO+AZA on health-related quality of life (HRQoL). Methods: In the double-blind, PBO-controlled phase 3 AGILE study, patients (pts) were randomized 1:1 to IVO 500 mg QD + AZA 75 mg/m2 SC or IV for 7 days in 28-day cycles, or PBO+AZA. HRQoL was a secondary endpoint assessed using two validated questionnaires: the European Organisation of Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) and the EuroQol 5-dimension 5-level questionnaire (EQ-5D-5L). Questionnaires were administered pre-dose on cycle (C) 1 Day (D) 1, on C1D15, C2D1, C2D15, and on D1 of every odd cycle thereafter until the end of treatment. Score change from baseline across visits for all subscales of EORTC QLQ-C30 was analyzed with mixed models. A 10-point threshold in EORTC QLQ-C30 subscale score was used to evaluate clinically meaningful changes from baseline or differences between arms. Two-sided nominal p-values are reported. Results: At baseline, 69 and 68 pts out of 72 receiving IVO+AZA completed the EORTC QLQ-C30 and EQ-5D-5L, respectively, and 66 pts out of 74 receiving PBO+AZA completed both. Mean baseline HRQoL scores were similar between treatment arms. There was an initial decline in HRQoL (EORTC QLQ-C30 global health status [GHS/QoL]) in both arms for ̃4 months, consistent with time to response, and which was generally not clinically meaningful. IVO+AZA was associated with preserved or improved HRQoL compared to baseline for most subscales of the EORTC QLQ-C30 from C5 to C19 (after which no PBO+AZA HRQoL data were available), and at most timepoints for EQ-5D-5L VAS scores and index values. EORTC QLQ-C30 subscales with clinically meaningful improvements from baseline at most timepoints from C5 to C19 in the IVO+AZA arm included GHS/QoL, fatigue, pain and appetite loss. In contrast, there were few clinically meaningful improvements from baseline in PBO+AZA pts. GHS/QoL scores were significantly improved (p≤0.05) for IVO+AZA versus PBO+AZA at C2D1, C2D15, C7 and C9, and differences were clinically meaningful at C2D1 (10.2 point difference), C2D15 (10.1), C7 (12.6), C9 (22.6), C13 (14.9), C15 (15.4) and C19 (19.2). Likewise, improvements in EORTC QLQ-C30 fatigue, appetite loss, nausea and vomiting, diarrhea, cognitive functioning and social functioning favored IVO+AZA over PBO+AZA at multiple timepoints. Conclusions: Data from the AGILE study show that patients with mIDH1 AML receiving treatment with IVO+AZA tended to report maintenance or improved HRQoL from cycle 5 through to cycle 19 compared with PBO+AZA. Clinical trial information: NCT03173248.

A wideband THz H-plane dielectric horn antenna based on silicon (Si) technology is proposed in this paper. The antenna can be integrated with the planar structure circuit and the dielectric ridge waveguide. To fabricate the proposed antenna, the deep reactive ion etching high-resistivity Si fabrication process is used. The size of the proposed antenna is $3.13 \times 4 \times 0.1$ mm3. The operating frequency of the antenna ranges from 750 to 1000 GHz, which corresponds to a fractional impedance bandwidth of 28.6%. The antenna has a narrow beamwidth in the H-plane and a high gain. To test this antenna, the characterization of the metal waveguide diagonal horn for measurement is analyzed. Then the non-contact measurement method is applied to measure the designed dielectric horn. The simulated radiation efficiency of the antenna is higher than 80% while the measured gain of the antenna is larger than 8 dBi. Measured H-plane radiation patterns from the proposed antenna are presented and show reasonable agreement with the simulated results.

For pediatric drug development, the clinical effectiveness of the study medication for the adult population has already been demonstrated. Given the fact that it is usually not feasible to enroll a large number of pediatric patients, appropriately leveraging historical adult data into pediatric evaluation may be critical to success of pediatric drug development. In this manuscript, we propose a new empirical Bayesian approach, profile Bayesian estimation, to dynamically borrow adult information to the evaluation of treatment effect in pediatric patients. The new approach demonstrates an attractive balance between type I error control and power gain under the transfer-ability assumption that the pediatric treatment effect size may differ from the adult treatment effect size. The decision making boundary mimics the real-world practice in pediatric drug development. In addition, the posterior mean of the proposed empirical profile Bayesian is an unbiased estimator of the true pediatric treatment effect. We compare our approach to robust mixture prior with prior weight for informative borrowing set to 0.5 or 0.9, regular Bayesian approach, and frequentist for both type I error and power.

Background The small molecule BI 705564 is a highly selective, covalent and potent inhibitor (B cell CD69 activation IC50=2.2 nM) of the Brutons tyrosine kinase (BTK). BTK plays a critical role in the differentiation and function of B cells and myeloid cell lineages and may play a major role in autoimmune diseases. Blocking the BTK pathways may be a promising new treatment of autoimmune diseases like SLE. Methods BI 705564 has been studied in 43 male healthy volunteers (HV) in a single-blinded, partially randomized, placebo-controlled trial testing single rising doses from 10 to 160 mg. In a double-blinded, randomized, placebo-controlled study BI 705564 was administered to 50 male HV at doses from 10 to 80 mg once daily for 14 days. Blood samples were analyzed for BI 705564 plasma concentrations, BTK target occupancy (TO) and CD69 expression in B cells stimulated ex-vivo with anti-IgD. Results All doses of BI 705564 were well-tolerated in both studies. There were no serious adverse events (AEs) and reported AEs were mainly of mild intensity and not dose-limiting. There was no difference in the total number of subjects with AEs (combined data from both trials) between BI 705564 [28/75 (37.3%)] and placebo [8/18 (44.4%)] and no dose-relationship of AEs. The most frequently reported AE was headache (BI 705564: 8.0% vs placebo: 5.6%, combined data). There was no difference in the occurrence of infections (BI 705564: 6.5% vs placebo: 11.1%) or gastrointestinal disorders (BI 705564: 13.3% vs. placebo 11.1%) in both studies (combined data). There were no relevant drug-related changes in vital signs, ECGs and standard safety laboratory tests. Analysis of BI 705564 plasma exposures showed a terminal half-life between 5.7 and 14.2 hour with no relevant accumulation after multiple dosing. Doses of 20 mg and above resulted in an average TO 85% which is expected to result in clinical efficacy based on preclinical studies. After a single dose administration, TO was maintained for at least 48 hour consistent with the mechanism of a covalent irreversible inhibitor. Functional effects on BTK signalling were demonstrated by dose-dependent inhibition up to 100% of CD69 expression on anti-IgD stimulated B cells. Conclusions BI 705564 was well-tolerated in healthy subjects after single and multiple doses. The favorable clinical safety profile and the high potential based on pre-clinical studies and effects on CD69 support further investigation of BI 705564 in patients with autoimmune diseases like SLE. Funding Source(s): This study was funded by Boehringer Ingelheim.

Understanding cell migration in a 3D microenvironment is essential as most cells encounter complex 3D extracellular matrix (ECM) in vivo. Although interactions between cells and ECM have been studied previously on 2D surfaces, cell migration studies in 3D environment are still limited. To investigate cell migration under various degrees of confinements and coating conditions, 3D platforms with micropost arrays and controlled fibronectin (FN) protein coating were developed. MC3T3-E1 cells spread and contacted the top surface of microposts if FN was coated on top. When FN was coated all over the microposts, cells were trapped between microposts with 3 μm spacing and barely moved. As the spacing between microposts increased from 3 to 5 μm, cells became elongated with limited cell movement of 0.18 μm/min, slower than the cell migration speed of 0.40 μm/min when cells moved on top. When cells were trapped in between the microposts, cell nuclei were distorted and actin filaments formed along the sidewalls of microposts. With the addition of a top cover to introduce cell confinement, the cell migration speed was 0.23 and 0.84 μm/min when the channel height was reduced from 20 to 10 μm, respectively. Cell traction force was monitored at on the top and bottom microposts with 10 μm channel height. These results show that the MC3T3-E1 cell morphology, migration speed, and movement position were affected by surface coating and physical confinement, which will provide significant insights for in vivo cell migration within a 3D ECM.

A low-loss dielectric microstrip line (DML) integrated circuit based on silicon (Si) technology is proposed for THz applications in this paper. Using the DML, a coupler and a crossover are designed. In the proposed technology, all THz passive components are made of high-resistivity silicon on insulator (SOI) wafer. To fabricate the proposed transmission line and its components, we developed a high-precision fabrication process for the SOI wafer. A non-contact measurement technology is used to test the fabricated samples. The measured loss per wavelength of DML ranges from 0.0082 to 0.042 dB/λ over 750–925 GHz. The measured isolation of the crossover is 25.45 ± 5.54 dB, and the measured coupler factor of the coupler is –13.22 ± 3.23 dB.

The cosmic web plays a major role in the formation and evolution of galaxies and defines, to a large extent, their properties. However, the relation between galaxies and environment is still not well understood. Here we present a machine learning approach to study imprints of environmental effects on the mass assembly of haloes. We present a galaxy-LSS machine learning classifier based on galaxy properties sensitive to the environment. We then use the classifier to assess the relevance of each property. Correlations between galaxy properties and their cosmic environment can be used to predict galaxy membership to void/wall or filament/cluster with an accuracy of $93\%$. Our study unveils environmental information encoded in properties of haloes not normally considered directly dependent on the cosmic environment such as merger history and complexity. Understanding the physical mechanism by which the cosmic web is imprinted in a halo can lead to significant improvements in galaxy formation models. This is accomplished by extracting features from galaxy properties and merger trees, computing feature scores for each feature and then applying support vector machine to different feature sets. To this end, we have discovered that the shape and depth of the merger tree, formation time and density of the galaxy are strongly associated with the cosmic environment. We describe a significant improvement in the original classification algorithm by performing LU decomposition of the distance matrix computed by the feature vectors and then using the output of the decomposition as input vectors for support vector machine., Comment: Accepted for publication in MNRAS

INTRODUCTION: Continuous development of cell traction force can regulate cell migration on various extracellular matrixes in vivo. However, the topographical effect on traction force is still not fully understood. METHODS: Micropost sensors with parallel guiding gratings were fabricated in polydimethylsiloxane to track the cell traction force during topographical guidance in real time. The force distributions along MC3T3-E1 mouse osteoblasts were captured every minute. The traction force in the leading, middle, and trailing regions was monitored during forward and reversed cell migration. RESULTS: The traction force showed periodic changes during cell migration when the cell changed from elongated to contracted shape. For cell migration without guiding pattern, the leading region showed the largest traction force among the three regions, typically 5.8 ± 0.8 nanonewton (nN) when the cell contracted and 7.1 ± 0.5 nN when it elongated. During guided cell migration, a lower traction force was obtained. When a cell contracted, the trailing traction force was 4.1 ± 0.4 for non-guided migration and 2.2 ± 0.2 nN for guided migration. As a cell became elongated, the trailing traction force was 6.0 ± 0.5 nN during non-guided migration and 4.8 ± 0.3 nN under guidance. When a cell reversed its migration direction, the magnitudes of the traction force from the leading to the trailing regions also flipped. CONCLUSION: The cell traction force is continuously influenced by topographical guidance, which determines cell migration speed and direction. These results of cell traction force development on various topographies could lead to better cell migration control using topotaxis. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12195-017-0514-7) contains supplementary material, which is available to authorized users.

In this paper, four types of silicon based THz dielectric waveguide are introduced. The silicon based THz dielectric waveguides are all fabricated by DRIE technology. The losses of these dielectric waveguides are very low.

In this paper, dielectric ribbon waveguides (DRWs) are designed to work at 750–1000 GHz. In this frequency band, the Deep Reactive Ion Etching (DRIE) of high resistivity silicon fabrication process is selected to fabricate the DRW. Our experiments show that the average attenuation constant of DRW is merely 0.107dB/mm at 750–1000GHz. Good agreements between the measured and simulated results are observed.

A compact multilayer substrate integrated waveguide (SIW) balun bandpass filter is proposed. A 180° reverse phase characteristic between the input/output ports can be easily achieved by the middle metal-ground of the SIW power divider. Four inductive posts are added to the multilayer SIW power divider to realise a passband. Good in-band balance performance (amplitude and phase imbalance are less than 0.35°dB and 2°) over the passband are achieved for the balun bandpass filter.