Datopotamab Deruxtecan in Advanced or Metastatic HR+/HER2- and Triple-Negative Breast Cancer: Results From the Phase I TROPION-PanTumor01 Study.

PURPOSE: Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate consisting of a humanized antitrophoblast cell-surface antigen 2 (TROP2) monoclonal antibody linked to a potent, exatecan-derived topoisomerase I inhibitor payload via a plasma-stable, selectively cleavable linker. PATIENTS AND METHODS: TROPION-PanTumor01 (ClinicalTrials.gov identifier: NCT03401385) is a phase I, dose-escalation, and dose-expansion study evaluating Dato-DXd in patients with previously treated solid tumors. The primary study objective was to assess the safety and tolerability of Dato-DXd. Secondary objectives included evaluation of antitumor activity and pharmacokinetics. Results from patients with advanced/metastatic hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer (BC) or triple-negative BC (TNBC) are reported. RESULTS: At data cutoff (July 22, 2022), 85 patients (HR+/HER2- BC = 41, and TNBC = 44) had received Dato-DXd. The objective response rate by blinded independent central review was 26.8% (95% CI, 14.2 to 42.9) and 31.8% (95% CI, 18.6 to 47.6) for patients with HR+/HER2- BC and TNBC, respectively. The median duration of response was not evaluable in the HR+/HER2- BC cohort and 16.8 months in the TNBC cohort. The median progression-free survival in patients with HR+/HER2- BC and TNBC was 8.3 and 4.4 months, respectively. All-cause treatment-emergent adverse events (TEAEs; any grade, grade ≥3) were observed in 100% and 41.5% of patients with HR+/HER2- BC and 100% and 52.3% of patients with TNBC. Stomatitis was the most common TEAE (any grade, grade ≥3) in both HR+/HER2- BC (82.9%, 9.8%) and TNBC (72.7%, 11.4%) cohorts. CONCLUSION: In patients with heavily pretreated advanced HR+/HER2- BC and TNBC, Dato-DXd demonstrated promising clinical activity and a manageable safety profile. Dato-DXd is currently being evaluated in phase III studies.

The Prospective Natural History Study of Patients with Intractable Venous Malformation and Klippel-Trenaunay Syndrome to Guide Designing a Proof-of-Concept Clinical Trial for Novel Therapeutic Intervention.

Background: The natural history of venous malformation (VM) and Klippel-Trenaunay Syndrome (KTS) has not been quantitatively studied. To obtain benchmarks to guide designing clinical trials to assess safety and efficacy of novel drug candidates, the clinical course of the patients was followed for 6 months. Methods and Results: This is a multicenter prospective observational study evaluating the change rate in lesion volume from baseline with magnetic resonance images, as the primary endpoint. In addition, disease severities, performance status (PS), pain visual analog scale (VAS) score, quality of life (QoL), infections, and coagulation markers were also evaluated. Thirty-four patients (VM = 17, KTS = 17, 1-53 of age; median 15.9 years) with measurable lesion volume were analyzed. There was no statistically significant difference in the lesion volume between baseline and day 180, and the mean change rate (standard deviation) was 1.06 (0.28). There were no baseline characteristics that affected the change in lesion volume over 6 months. However, there were patients who showed more than 20% volume change and it was suggested that the lesion volume was largely impacted by local infection. There were no statistically significant changes in pain VAS score, severity, PS, QoL score, D-dimer, and platelet count over 6 months within all patients analyzed. Conclusion: The results showed the representative natural course of VM and KTS for a 6-month period with objective change of lesion volume and other factors, suggesting that it is scientifically reasonable to conduct a Phase 2 proof-of-concept study without a placebo arm, using the results of this study as the control. Clinical Trial Registration: NCT04285723, NCT04589650.

First-in-Human, Phase I Dose-Escalation and Dose-Expansion Study of Trophoblast Cell-Surface Antigen 2-Directed Antibody-Drug Conjugate Datopotamab Deruxtecan in Non-Small-Cell Lung Cancer: TROPION-PanTumor01.

PURPOSE: This first-in-human, dose-escalation and dose-expansion study evaluated the safety, tolerability, and antitumor activity of datopotamab deruxtecan (Dato-DXd), a novel trophoblast cell-surface antigen 2 (TROP2)-directed antibody-drug conjugate in solid tumors, including advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Adults with locally advanced/metastatic NSCLC received 0.27-10 mg/kg Dato-DXd once every 3 weeks during escalation or 4, 6, or 8 mg/kg Dato-DXd once every 3 weeks during expansion. Primary end points were safety and tolerability. Secondary end points included objective response rate (ORR), survival, and pharmacokinetics. RESULTS: Two hundred ten patients received Dato-DXd, including 180 in the 4-8 mg/kg dose-expansion cohorts. This population had a median of three prior lines of therapy. The maximum tolerated dose was 8 mg/kg once every 3 weeks; the recommended dose for further development was 6 mg/kg once every 3 weeks. In patients receiving 6 mg/kg (n = 50), median duration on study, including follow-up, and median exposure were 13.3 and 3.5 months, respectively. The most frequent any-grade treatment-emergent adverse events (TEAEs) were nausea (64%), stomatitis (60%), and alopecia (42%). Grade ≥3 TEAEs and treatment-related AEs occurred in 54% and 26% of patients, respectively. Interstitial lung disease adjudicated as drug-related (two grade 2 and one grade 4) occurred in three of 50 patients (6%). The ORR was 26% (95% CI, 14.6 to 40.3), and median duration of response was 10.5 months; median progression-free survival and overall survival were 6.9 months (95% CI, 2.7 to 8.8 months) and 11.4 months (95% CI, 7.1 to 20.6 months), respectively. Responses occurred regardless of TROP2 expression. CONCLUSION: Promising antitumor activity and a manageable safety profile were seen with Dato-DXd in heavily pretreated patients with advanced NSCLC. Further investigation as first-line combination therapy in advanced NSCLC and as monotherapy in the second-line setting and beyond is ongoing.

Thoracic spine hemangioma causing rapidly progressive myelopathy and mimicking a malignant tumor: A case report.

Vertebral hemangiomas are common benign tumors that are mostly asymptomatic and are discovered incidentally. Only 0.9-1.2% of all vertebral hemangiomas, termed aggressive vertebral hemangiomas, expand to cause pain and neural compression. We present an extremely rare case of a 49-year-old woman who had an aggressive vertebral hemangioma of the thoracic spine that caused rapidly progressive myelopathy with remarkable irregular extraosseous bone proliferation, which mimicked a malignant vertebral tumor. In this case, despite the lesion's hostile appearance during imaging, the pathological diagnosis was benign and symptom-based surgical treatment with posterior decompression and stabilization provided good clinical outcomes during the postoperative 18 months follow-up period. In this case, despite the use of standard imaging modalities (radiograph, CT, and MRI), making a preoperative imaging diagnosis of an aggressive vertebral hemangioma was difficult, and although aggressive vertebral hemangiomas with atypical radiological features are rare, they should be considered as a differential diagnosis.

Evaluation of Potential Drug-Drug Interaction Risk of Pexidartinib With Substrates of Cytochrome P450 and P-Glycoprotein.

Pexidartinib is approved for treatment of adults with symptomatic tenosynovial giant cell tumor. In vitro data showed pexidartinib's potential to inhibit and induce cytochrome P450 (CYP) 3A, inhibit CYP2C9, CYP2C19 and P-glycoprotein (P-gp). Herein, 2 open-label, single-sequence, crossover studies evaluated the drug-drug interaction potential of pexidartinib on CYP enzymes (CYP2C9, CYP2C19, and CYP3A) and P-gp. Thirty-two subjects received single oral doses of midazolam (CYP3A substrate) and tolbutamide (CYP2C9 substrate) alone and after single and multiple oral doses of pexidartinib. Twenty subjects received single oral doses of omeprazole (CYP2C19 substrate) and digoxin (P-gp substrate) alone or with pexidartinib. Analysis of variance was conducted to determine the effect of pexidartinib on various substrates' pharmacokinetics. No drug-drug interaction was concluded if the 90% confidence interval of the ratio of test to reference was within the range 80% to 125%. Coadministration of single and multiple doses of pexidartinib resulted in 21% and 52% decreases, respectively, in the area under the plasma concentration-time curve from time zero to the last measurable time point (AUClast ) of midazolam, whereas AUClast values of tolbutamide increased 15% and 36%, respectively. Omeprazole exposure decreased on concurrent administration with pexidartinib, the metabolite-to-parent ratio was similar following omeprazole administration alone vs coadministration with pexidartinib; pexidartinib did not affect CYP2C19-mediated metabolism. Maximum plasma concentrations of digoxin slightly increased (32%) with pexidartinib coadministration; no significant effect on digoxin AUClast . These results indicate that pexidartinib is a moderate inducer of CYP3A and a weak inhibitor of CYP2C9 and does not significantly affect CYP2C19-mediated metabolism or P-gp transport.

Randomized, Double-Blind, Single-Dose, Placebo-Controlled Crossover Study to Evaluate the Effects of Esaxerenone on QTc Interval in Healthy Subjects.

This phase 1 single-center, single-dose, double-dummy, placebo-controlled, 4-period and 4-sequence crossover study assessed the potential of esaxerenone, a novel nonsteroidal mineralocorticoid receptor blocker used to treat hypertension, to affect cardiac repolarization. In this double-blind study, 55 subjects were randomized to single doses of 10 mg esaxerenone (therapeutic dose), 40 mg esaxerenone (supratherapeutic dose), 400 mg moxifloxacin, or placebo. Serial electrocardiograms and pharmacokinetics (PK) were obtained over 24 and 168 hours, respectively. The primary end point was Fridericia-corrected QT interval (QTcF). Secondary end points included safety and PK. Assay sensitivity was confirmed as the lower limit of 90% confidence interval (90%CIs) for placebo-corrected change from baseline QTcF (∆∆QTcF) for moxifloxacin was >5 milliseconds at the prespecified times; mean ∆∆QTcF was 12.5 milliseconds at 3 and 4 hours postdose. The upper 90%CI limits of ∆∆QTcF were ≤0 milliseconds at all times for both doses of esaxerenone. No concentration-QTc relationship was identified. Therefore, esaxerenone had no potential to inhibit cardiac repolarization. No deaths or serious adverse events (AEs) occurred; 1 subject discontinued the study because of a treatment-emergent AE unrelated to esaxerenone. This clinical evaluation showed that esaxerenone has no QTc prolongation potential.

Negative viscosity of liquid crystals in the presence of turbulence: Conductivity dependence, phase diagram, and self-oscillation.

Recently, we reported the discovery of enormous negative viscosity of a nematic liquid crystal in the presence of turbulence induced by ac electric fields, which enabled us to observe unique phenomena related to the negative viscosity, such as spontaneous shear flow, hysteresis in flow curves, and self-oscillation [Orihara et al., Phys. Rev. E 99, 012701 (2019)10.1103/PhysRevE.99.012701]. In the present paper, we report the rheological properties of another nematic liquid crystal, which is a homologue of the previous one. The properties of the present liquid crystal are strongly dependent on electrical conductivity. Three samples with different conductivities were prepared by changing the amount of an ionic dopant. It was found that the lowest-conductivity sample without dopant shows no negative viscosity whereas the other ion-doped samples exhibit negative viscosity with strong dependence on the frequency of the ac electric field, consistent with microscopic observations. Phase diagrams of the negative- and positive-viscosity states in the amplitude and frequency plane are constructed to show the conductivity effect. Furthermore, we propose a model to reproduce another type of self-oscillation found in the present study.

Safety and Pharmacokinetics of DS-1040 Drug-Drug Interactions With Aspirin, Clopidogrel, and Enoxaparin.

DS-1040, a novel low-molecular-weight inhibitor of activated thrombin-activatable fibrinolysis inhibitor, is under development for the treatment of thromboembolic diseases including venous thromboembolism and acute ischemic stroke. Here we describe the results of 3 studies that evaluated the safety and tolerability of DS-1040 along with the effect on DS-1040 pharmacokinetic (PK) parameters, when dosed alone or when coadministered with aspirin (NCT02071004), clopidogrel (NCT02560688), or enoxaparin in healthy subjects. Concomitant administration of single-dose DS-1040 with multiple-dose aspirin, multiple-dose clopidogrel, or single-dose enoxaparin, consistent with clinically relevant dose regimens, was safe and well tolerated with no serious treatment-emergent adverse events (TEAEs), TEAEs leading to discontinuation, bleeding-related TEAEs, and no significant changes in coagulation parameters. DS-1040 did not prolong bleeding time when administered concomitantly with aspirin or clopidogrel. In the aspirin study, DS-1040 PK was evaluated following the concomitant administration with multiple-dose aspirin, where the plasma DS-1040 exposure (peak plasma concentration [Cmax ] and area under the concentration-time curve [AUCinf ]) was to be similar to the data previously published in the first-in-human study of DS-1040 in healthy subjects. The PK parameters of DS-1040 coadministered with clopidogrel were similar to those of DS-1040 alone, with small increases in geometric means for Cmax (7%) and AUClast (9%). When coadministered with enoxaparin, the PK parameters of DS-1040 were not affected (1.1% and 1.5% decreases in geometric means for Cmax and AUClast , respectively). Therefore, concomitant administration of DS-1040 and clopidogrel or enoxaparin did not demonstrate PK drug-drug interactions.

First-in-Human Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of an Oral Formulation of DS-1040, an Inhibitor of the Activated Form of Thrombin-Activatable Fibrinolysis Inhibitor, in Healthy Subjects.

DS-1040, a low-molecular-weight imidazole derivative, inhibits the enzymatic activity of thrombin-activatable fibrinolysis inhibitor (TAFIa), enhancing endogenous tissue plasminogen activator-triggered fibrinolysis. This first-in-human, randomized, placebo-controlled, phase 1 study evaluated the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of an oral formulation of DS-1040. Healthy adults (aged 20-45 years; N = 56) were randomized 3:1 to receive DS-1040 orally administered as single ascending doses (50, 100, 200, or 400 mg) or placebo, or DS-1040 multiple ascending doses (100 mg once daily, 200 mg once daily, or 150 mg twice daily) or placebo for 14 days. Safety, PK, and PD parameters were assessed. All doses of DS-1040 were well tolerated; no serious/severe adverse events (AEs) or discontinuations due to AEs occurred. DS-1040 had no effect on coagulation parameters, and no treatment-related trends in the bleeding time were observed. DS-1040 exposure (peak concentration and area under the concentration-time curve) increased in a dose-proportional manner across the single-dose range. With multiple doses, steady state was achieved by day 7 with minimal accumulation (mean accumulation ratio 1.15-1.25), and the PK was time-independent. After 72 hours, approximately 10% of the DS-1040 400-mg single dose was recovered in urine as intact parent drug. The mean terminal half-life ranged from 17.2 to 24.9 hours, which was similar to previous intravenous administration data. Dose-dependent inhibition of total TAFIa activity was observed following single and multiple doses of oral DS-1040. The safety and PK/PD profiles of oral DS-1040 in healthy subjects support further clinical development.

Negative viscosity of a liquid crystal in the presence of turbulence.

We report on the discovery of enormous negative viscosity in a nematic liquid crystal in the presence of turbulence induced by electric fields. As the negative viscosity in this system is so large, we are able to observe several phenomena originating from it. For example, we observe a spontaneous shear flow that rotates the upper disk of a rheometer, as well as the reversal of the rotational direction upon applying an external torque in the opposite direction. Hysteresis loops are also observed in the shear-stress-shear-rate curves, which is reminiscent of those seen for ferromagnetic and ferroelectric materials. The similarities between the phenomena observed for our system and ferroic materials are comprehensively demonstrated, although the two systems are fundamentally different in that the former is out of equilibrium. We elucidate the origin of the negative viscosity and propose a simple model that reproduces the phenomena observed in this active fluid.

Investigation of the Lewis acidic behaviour of an oxygen-bridged planarized triphenylborane toward amines and the properties of their Lewis acid-base adducts.

Lewis acid behavior of an oxygen-bridged triphenylborane (1) to amines and the properties of Lewis acid-base adducts of 1 with amines have been investigated. UV-vis titration and 11B NMR experiments showed the formation of Lewis acid-base adducts of 1 with pyridine, DMAP, quinuclidine, and DABCO, respectively (1·amine). X-ray crystallographic analysis revealed that the planar shape of 1 was converted to a bowl shape by the formation of 1·amine. Interestingly, 1·quinuclidine, 12·DABCO, and 1·DABCO exhibited dual emissions. Excitation spectra and photoluminescence decay time measurements suggest that the dual emissions were ascribed to two excited species, i.e., [1·amine]* and [1]* generated by photodissociation in the excited states.

Single- and multiple-dose escalation study to assess pharmacokinetics, pharmacodynamics and safety of oral esaxerenone in healthy Japanese subjects.

AIMS: To characterize the pharmacokinetics, pharmacodynamics and safety of esaxerenone, a mineralocorticoid receptor antagonist, in healthy adult Japanese men. METHODS: Double-blind, placebo-controlled, sequential, dose-escalation studies were conducted in subjects randomized to receive oral once-daily esaxerenone (ranges: 5-200 mg [single-dose]; 10-100 mg over 10 days [multiple-dose]) or placebo under fasting conditions. Plasma concentrations were analysed by liquid chromatograph-tandem mass spectrometry. Pharmacokinetic parameters were determined by noncompartment analysis. Plasma/urine levels of pharmacodynamic biomarkers for mineralocorticoid receptor activity were evaluated. RESULTS: In total, 48/48 and 39/40 subjects completed the single- and multiple-dose studies, respectively. Exposures were generally dose-proportional. The tmax , t1/2 and CL/F remained unchanged, independent of dose; the respective ranges were 1.5-4.0 h, 22.3-25.1 h, and 4.0-5.2 l h-1 (multiple-dose study). Vz /F ranged from 136.5 to 283.7 l in the multiple-dose study, and exposure reached steady state by day 4. The mean observed accumulation ratio, by dose, ranged from 1.36-1.98. The urinary Na+ /K+ ratio increased after single-dose administration; however, its relationship to the doses tested remains unclear. Plasma renin activity, active renin concentration and aldosterone concentration increased dose-dependently. Although blood potassium levels increased dose-dependently in the multiple-dose study (reaching a maximum mean ± standard deviation of 4.63 ± 0.354 mmol l-1 in the 100-mg group), no safety/tolerability-related problems were detected in either study. CONCLUSIONS: Exposure levels in healthy adults receiving esaxerenone were generally dose-proportional. Dose-dependent changes in plasma pharmacodynamic biomarkers for the mineralocorticoid receptor were identified during multiple-dose treatment and support the pharmacological activity of esaxerenone. No important safety concerns were identified.

Tunable two-dimensional polarization grating using a self-organized micropixelated liquid crystal structure.

Utilization of the self-organizing nature of soft materials is promising for fabricating micro- and nano-structures, which can be applied for optics. Because of the high birefringence, liquid crystals are especially suitable for optoelectronic applications such as beam steering and polarization conversion. On the other hand, most self-organized patterns in liquid crystals are one-dimensional and there are only a few examples of two dimensional systems. Here we study the light diffraction from a micro-pixelated pattern of a nematic liquid crystal which is formed by self-organization of topological defects. We demonstrate that the system works as a tunable two dimensional optical grating, which splits the incident laser beam and changes the polarization property. The intensity can be controlled by electrical voltages, which cause extinction of the zeroth-order beam. The polarization properties depend on the location of spots. The numerical calculation and the theoretical analysis not only support the experimental results but also unveil the uniqueness of the pixelated structure.

A phase 1 study comparing the proposed biosimilar BS-503a with bevacizumab in healthy male volunteers.

This is a randomized, double-blind, single-dose, parallel group phase 1 study to assess pharmacokinetic similarity, safety, and tolerability of BS-503a, a proposed bevacizumab biosimilar. A total of 114 male healthy subjects were randomized (1:1) to receive a single 3 mg/kg intravenous dose of either BS-503a or bevacizumab (Avastin®). Pharmacokinetic (PK) blood samples were collected up to Day 78, and serum drug concentrations were measured using a validated enzyme-linked immunosorbent assay. Pharmacokinetic similarity was evaluated using area under the serum concentration-time curve from zero to infinity (AUC inf) as a primary PK parameter, and maximum serum concentration (Cmax) and area under the serum concentration-time curve from zero to the last measurable time (AUC last) as secondary PK parameters. The 90% confidence intervals (CIs) of geometric mean ratio of AUC inf ranged 0.980-1.105, which met the predefined criteria of 0.80-1.25. The 90% CIs of geometric mean ratios for Cmax and AUC last were 1.009-1.125 and 0.982-1.096, respectively, falling into the same criteria. At least one drug-related treatment emergent adverse event occurred in 18 and 21 subjects treated with BS-503a and bevacizumab, respectively. The most common adverse events were headache, epistaxis, and rhinorrhea. Most adverse events were mild or moderate; however, one drug-related serious adverse event of duodenal ulcer perforation was reported by a subject 47 days after treatment of BS-503a. In conclusion, BS-503a was demonstrated to have highly similar PK to bevacizumab and adverse events observed were consistent with those observed for bevacizumab.

Persistent olmesartan-based blood pressure-lowering effects on morning hypertension in Asians: the HONEST study.

Using data from the large-scale HONEST (Home blood pressure measurement with Olmesartan Naive patients to Establish Standard Target blood pressure) study, we investigated the characteristics of the effects of olmesartan-based treatment on morning hypertension in Asian hypertensive patients. Specifically, we investigated the relationship between baseline blood pressure (BP) and BP reduction after 16 weeks by linear regression analyses; determinants of BP reduction were also investigated. For both morning home BP (MHBP) and clinic BP (CBP), reduced systolic BP (SBP) after 16 weeks was associated with baseline SBP (P<0.001). The slope of the regression lines was similar for morning home SBP (MHSBP) (-0.744) and clinic SBP (-0.735). Although sex, concomitant diabetes mellitus and concomitant hepatic disease significantly influence the relationship between BP reduction and baseline BP for MHSBP, none were deemed clinically relevant. In conclusion, olmesartan-based treatment robustly reduced baseline high MHBP, similar to CBP, and the effect was associated with baseline BP but unaffected by patient background factors.

Effects of blood pressure on renal and cardiovascular outcomes in Asian patients with type 2 diabetes and overt nephropathy: a post hoc analysis (ORIENT-blood pressure).

BACKGROUND: Blood pressure (BP) control may have different effects on cardiovascular (CV) and renal outcomes in diabetes. We examined the impact of systolic BP (SBP) on renal and CV outcomes in a post hoc analysis in the Olmesartan Reducing Incidence of Endstage Renal Disease in Diabetic Nephropathy Trial. METHODS: We stratified mean follow-up SBP into three categories (≤130, 131-140 and >140 mmHg) and used a Cox regression model to estimate the hazard ratio (HR, 95% confidence interval) for the outcomes. The composite renal outcome was doubling of serum creatinine, end-stage renal disease and all-cause death. The composite CV outcome included CV death, nonfatal stroke, nonfatal myocardial infarction, hospitalization for unstable angina or heart failure, revascularization and lower extremity amputation. We also compared the slope of estimated glomerular filtration rate (eGFR) in all three groups. RESULTS: After a mean follow-up period of 3.2 years, the follow-up SBP was linearly associated with risk of renal outcomes in all 566 patients. In patients with heavy proteinuria (≥1 g/gCr), a follow-up SBP > 130 mmHg was associated with an HR of 2.33 (1.62-3.36) for renal outcomes with referent to SBP ≤ 130 mmHg. In patients without history of CV disease, a follow-up SBP > 140 mmHg was associated with an HR of 2.04 (1.23-3.40) for CV outcomes with referent to SBP < 140 mmHg. The median (interquartile range) slopes of eGFR were -3.27 (-6.90, -1.63), -4.53 (-8.08, -2.29) and -7.13 (-10.90, -3.99) dL/mg/year in patients with SBP ≤ 130, 131-140 and > 140 mmHg, respectively (P = 0.008 between ≤130 and 131-140, P < 0.001 between ≤ 130 and > 140 mmHg). CONCLUSION: In Asian type 2 diabetic patients with chronic kidney disease and heavy proteinuria, reduction of SBP ≤ 130 mmHg was associated with greater renoprotection than cardioprotection. However, our results emphasize the need to individualize BP targets in type 2 diabetes.

Differences between clinic blood pressure and morning home blood pressure, as shown by Bland-Altman plots, in a large observational study (HONEST study).

When interpreting home blood pressure (BP) measurements in hypertensive patients, differences between clinic and home BP should be noted. To investigate the differences between clinic and morning home BP in hypertensive patients, we analyzed clinic systolic BP (CSBP) and morning home systolic BP (MHSBP) data from the large-scale observational HONEST (Home BP measurement with Olmesartan Naive patients to Establish Standard Target blood pressure) study (n=21 340), using BP measurements obtained before starting olmesartan administration. We generated Bland-Altman plots, with the horizontal axis representing mean CSBP and MHSBP ([CSBP+MHSBP]/2) and the vertical axis representing the difference between CSBP and MHSBP (CSBP-MHSBP). We also did simulation experiments to explore factors affecting the results of the Bland-Altman plots. The difference between CSBP and MHSBP increased as the mean of the two values increased, and when the mean of CSBP and MHSBP was close to 140 mm Hg, the difference was theoretically 0 in average, although large interindividual BP variability existed in this BP range. Results were unaffected by factors such as previous antihypertensive treatment, age and concomitant diabetes or chronic kidney disease. Bland-Altman plots generated from simulated data of normal distribution showed that the slope of the regression line sloped upward, consistent with the results of the HONEST study, when the interindividual BP variability of MHSBP was less than that of CSBP. In conclusion, differences between mean CSBP and MHSBP may be caused by large interindividual variability in CSBP. Therefore, the differences between MHSBP and CSBP may vary between patient groups, which should be noted in the management of hypertension.

Direct visualization of spatiotemporal structure of self-assembled colloidal particles in electrohydrodynamic flow of a nematic liquid crystal.

Characterization of spatiotemporal dynamics is of vital importance to soft matter systems far from equilibrium. Using a confocal laser scanning microscopy, we directly reveal three-dimensional motion of surface-modified particles in the electrohydrodynamic convection of a nematic liquid crystal. Particularly, visualizing a caterpillar-like motion of a self-assembled colloidal chain demonstrates the mechanism of the persistent transport enabled by the elastic, electric, and hydrodynamic contributions. We also precisely show how the particles' trajectory is spatially modified by simply changing the surface boundary condition.

Home blood pressure and cardiovascular outcomes in patients during antihypertensive therapy: primary results of HONEST, a large-scale prospective, real-world observational study.

UNLABELLED: This study aimed to investigate the relationship between on-treatment morning home blood pressure (HBP) and incidence of cardiovascular events using data from the Home Blood Pressure Measurement With Olmesartan Naive Patients to Establish Standard Target Blood Pressure (HONEST) study, a prospective observational study of 21 591 outpatients with essential hypertension (mean age, 64.9 years; women, 50.6%) enrolled between 2009 and 2010 at clinics and hospitals in Japan. They received olmesartan-based treatment throughout. The primary end point was major cardiovascular events. After a mean follow-up period of 2.02 years, cardiovascular events occurred in 280 patients (incidence, 6.46/1000 patient-years). The risk for the primary end point was significantly higher in patients with on-treatment morning HBP ≥145 to <155 mm Hg (hazard ratio [HR], 1.83; 95% confidence interval [CI], 1.12-2.99) and ≥155 mm Hg (HR, 5.03; 95% CI, 3.05-8.31) than <125 mm Hg and with on-treatment clinic blood pressure ≥150 to <160 mm Hg (HR, 1.69; 95% CI, 1.10-2.60) and ≥160 mm Hg (HR, 4.38; 95% CI, 2.84-6.75) than <130 mm Hg. Morning HBP associated with minimum risk was 124 mm Hg by spline regression analysis. Cardiovascular risk was increased in patients with morning HBP ≥145 mm Hg and clinic blood pressure <130 mm Hg (HR, 2.47; 95% CI, 1.20-5.08) compared with morning HBP <125 mm Hg and clinic blood pressure <130 mm Hg. In conclusion, it is essential to control morning HBP to <145 mm Hg, even in patients with controlled clinic blood pressure. CLINICAL TRIAL REGISTRATION URL: http://www.umin.ac.jp/ctr/index.htm. UMIN Clinical Trials Registry, trial No. UMIN000002567.

A new proportion measure of the treatment effect captured by candidate surrogate endpoints.

The use of surrogate endpoints is expected to play an important role in the development of new drugs, as they can be used to reduce the sample size and/or duration of randomized clinical trials. Biostatistical researchers and practitioners have proposed various surrogacy measures; however, (i) most of these surrogacy measures often fall outside the range [0,1] without any assumptions, (ii) these surrogacy measures do not provide a cut-off value for judging a surrogacy level of candidate surrogate endpoints, and (iii) most surrogacy measures are highly variable; thus, the confidence intervals are often unacceptably wide. In order to solve problems (i) and (ii), we propose a new surrogacy measure, a proportion of the treatment effect captured by candidate surrogate endpoints (PCS), on the basis of the decomposition of the treatment effect into parts captured and non-captured by the candidate surrogate endpoints. In order to solve problem (iii), we propose an estimation method based on the half-range mode method with the bootstrap distribution of the estimated surrogacy measures. Finally, through numerical experiments and two empirical examples, we show that the PCS with the proposed estimation method overcomes these difficulties. The results of this paper contribute to the reliable evaluation of how much of the treatment effect is captured by candidate surrogate endpoints.