Statistical Considerations and Software for Designing Sequential, Multiple Assignment, Randomized Trials (SMART) with a Survival Final Endpoint.

Sequential, multiple assignment, randomized trial (SMART) designs are appropriate for comparing adaptive treatment interventions, in which intermediate outcomes (called tailoring variables) guide subsequent treatment decisions for individual patients. Within a SMART design, patients may be re-randomized to subsequent treatments following the outcomes of their intermediate assessments. In this paper, we provide an overview of statistical considerations necessary to design and implement a two-stage SMART design with a binary tailoring variable and a survival final endpoint. A chronic lymphocytic leukemia trial with a final endpoint of progression-free survival is used as an example for the simulations to assess how design parameters, including, choice of randomization ratios for each stage of randomization, and response rates of the tailoring variable affect the statistical power. We assess the choice of weights from restricted re-randomization on data analyses and appropriate hazard rate assumptions. Specifically, for a given first-stage therapy and prior to the tailoring variable assessment, we assume equal hazard rates for all patients randomized to a treatment arm. After the tailoring variable assessment, individual hazard rates are assumed for each intervention path. Simulation studies demonstrate that the response rate of the binary tailoring variable impacts power as it directly impacts the distribution of patients. We also confirm that when the first stage randomization is 1:1, it is not necessary to consider the first stage randomization ratio when applying the weights. We provide an R-shiny application for obtaining power for a given sample size for SMART designs.

Partial Least Squares, Experimental Design, and Near-Infrared Spectrophotometry for the Remote Quantification of Nitric Acid Concentration and Temperature.

Near-infrared spectrophotometry and partial least squares regression (PLSR) were evaluated to create a pleasantly simple yet effective approach for measuring HNO3 concentration with varying temperature levels. A training set, which covered HNO3 concentrations (0.1-8 M) and temperature (10-40 °C), was selected using a D-optimal design to minimize the number of samples required in the calibration set for PLSR analysis. The top D-optimal-selected PLSR models had root mean squared error of prediction values of 1.4% for HNO3 and 4.0% for temperature. The PLSR models built from spectra collected on static samples were validated against flow tests including HNO3 concentration and temperature gradients to test abnormal conditions (e.g., bubbles) and the model performance between sample points in the factor space. Based on cross-validation and prediction modeling statistics, the designed near-infrared absorption approach can provide remote, quantitative analysis of HNO3 concentration and temperature for production-oriented applications in facilities where laser safety challenges would inhibit the implementation of other optical techniques (e.g., Raman spectroscopy) and in which space, time, and/or resources are constrained. The experimental design approach effectively minimized the number of samples in the training set and maintained or improved PLSR model performance, which makes the described chemometric approach more amenable to nuclear field applications.

Initial results of a phase II trial of 18F-DOPA PET-guided re-irradiation for recurrent high-grade glioma.

PURPOSE: In-field high-grade glioma (HGG) recurrence is a common challenge with limited treatment options, including re-irradiation. The radiotracer 3,4-dihydroxy-6-[18F]-fluoro-L-phenylalanine (18F-DOPA) crosses the blood brain barrier and demonstrates high uptake in tumor, but low uptake in normal tissue. This study investigated whether 18F-DOPA positron emission tomography (PET) and MRI guided re-irradiation for recurrent HGG may improve progression free survival (PFS). METHODS: Adults with recurrent or progressive HGG previously treated with radiation were eligible. The primary endpoint was a 20% improvement from the historical control PFS at 3 months (PFS3) of 20% with systemic therapy alone. Re-RT dose was 35 Gy in 10 fractions. The target volume was MRI T1 contrast-enhancement defined tumor plus 18F-DOPA PET defined tumor. RESULTS: Twenty patients completed treatment per protocol. Diagnosis was most commonly glioblastoma, IDH-wildtype (60%). MRI-defined volumes were expanded by a median 43% (0-436%) by utilizing 18F-DOPA PET. PFS3 was 85% (95% CI 63.2-95.8%), meeting the primary endpoint of PFS3 ≥ 40%. With 9.7 months median follow-up, 17 (85%) had progressed and 15 (75%) had died. Median OS from re-RT was 8.8 months. Failure following re-RT was within both the MRI and PET tumor volumes in 75%, MRI only in 13%, PET only in 0%, and neither in 13%. Four (20%) patients experienced grade 3 toxicity, including CNS necrosis (n = 2, both asymptomatic with bevacizumab initiation for radiographic findings), seizures (n = 1), fatigue (n = 1), and nausea (n = 1). No grade 4-5 toxicities were observed. CONCLUSION: 18F-DOPA PET-guided re-irradiation for progressive high-grade glioma appears safe and promising for further investigation.

KDR genetic predictor of toxicities induced by sorafenib and regorafenib.

No biomarkers are available to predict toxicities induced by VEGFR TKIs. This study aimed to identify markers of toxicities induced by these drugs using a discovery-validation approach. The discovery set included 140 sorafenib-treated cancer patients (TARGET study) genotyped for SNPs in 56 genes. The most significant SNPs associated with grade ≥2 hypertension, diarrhea, dermatologic toxicities, and composite toxicity (any one of the toxicities) were tested for association with grade ≥2 toxicity in a validation set of 201 sorafenib-treated patients (Alliance/CALGB 80802). The validated SNP was tested for association with grade ≥2 toxicity in 107 (LCCC 1029) and 82 (Italian cohort) regorafenib-treated patients. SNP-toxicity associations were evaluated using logistic regression, and a meta-analysis between the studies was performed by inverse variance. Variant rs4864950 in KDR increased the risk of grade ≥2 composite toxicity in TARGET, Alliance/CALGB 80802, and the Italian cohort (meta-analysis p = 6.79 × 10-4, OR = 2.01, 95% CI 1.34-3.01). We identified a predictor of toxicities induced by VEGFR TKIs. CLINICALTRIALS.GOV IDENTIFIER: NCT00073307 (TARGET), NCT01015833 (Alliance/CALGB 80802), and NCT01298570 (LCCC 1029).

Association of Adiponectin and Vitamin D With Tumor Infiltrating Lymphocytes and Survival in Stage III Colon Cancer.

Background: Adipocyte-derived adiponectin may play a role in the host inflammatory response to cancer. We examined the association of plasma adiponectin with the density of tumor-infiltrating lymphocytes (TILs) in colon cancers and with vitamin D, clinicopathological features, and patient survival. Methods: Plasma adiponectin and 25-hydroxyvitamin D [25(OH)D] were analyzed by radioimmunoassay in 600 patients with stage III colon cancer who received FOLFOX-based adjuvant chemotherapy (NCCTG N0147 [Alliance]). TIL densities were determined in histopathological sections. Associations with disease-free survival (DFS), time to recurrence, and overall survival were evaluated by multivariable Cox regression adjusting for potential confounders (ie, body mass index, race, TILs, and N stage). All statistical tests were 2-sided. Results: We found a statistically significant reduction in adiponectin, but not 25(OH)D, levels in tumors with high vs low TIL densities (median = 6845 vs 8984 ng/mL; P = .04). A statistically significant reduction in adiponectin was also observed in obese (body mass index >30 kg/m2) vs nonobese patients (median = 6608 vs 12 351 ng/mL; P < .001), in men vs women (median = 8185 vs 11 567 ng/mL; P < .001), in Blacks vs Whites or Asians (median = 6412 vs 8847 vs 7858 ng/mL; P < .03), and in those with fewer lymph node metastases (N1 vs N2: median = 7768 vs 9253 ng/mL; P = .01). Insufficiency of 25(OH)D (<30 ng/mL) was detected in 291 (48.5%) patients. In multivariable analyses, neither adiponectin nor 25(OH)D were associated with a statistically significant difference in DFS, overall survival , or time to recurrence in models adjusted for potential confounders. We found a statistically significant association of TILs with prognosis, yet no such interaction was observed for the association of adiponectin with TILs for DFS. Conclusions: Lower circulating adiponectin levels were associated with a statistically significant increase in TIL densities in colon cancers, indicating an enhanced antitumor immune response. In contrast to TILs, neither adiponectin nor 25(OH)D was independently prognostic.

A bio-hybrid odor-guided autonomous palm-sized air vehicle.

Biohybrid systems integrate living materials with synthetic devices, exploiting their respective advantages to solve challenging engineering problems. One challenge of critical importance to society is detecting and localizing airborne volatile chemicals. Many flying animals depend their ability to detect and locate the source of aerial chemical plumes for finding mates and food sources. A robot with comparable capability could reduce human hazard and drastically improve performance on tasks such as locating disaster survivors, hazardous gas leaks, incipient fires, or explosives. Three advances are needed before they can rival their biological counterparts: (1) a chemical sensor with a much faster response time that nevertheless satisfies the size, weight, and power constraints of flight, (2) a design, sensor suite, and control system that allows it to move toward the source of a plume fully autonomously while navigating obstacles, and (3) the ability to detect the plume with high specificity and sensitivity among the assortment of chemicals that invariably exist in the air. Here we address the first two, introducing a human-safe palm-sized air vehicle equipped with the odor-sensing antenna of an insect, the first odor-sensing biohybrid robot system to fly. Using this sensor along with a suite of additional navigational sensors, as well as passive wind fins, our robot orients upwind and navigates autonomously toward the source of airborne plumes. Our robot is the first flying biohybrid system to successfully perform odor localization in a confined space, and it is able to do so while detecting and avoiding obstacles in its flight path. We show that insect antennae respond more quickly than metal oxide gas sensors, enabling odor localization at an improved speed over previous flying robots. By using the insect antennae, we anticipate a feasible path toward improved chemical specificity and sensitivity by leveraging recent advances in gene editing.

Correction: A laser-microfabricated electrohydrodynamic thruster for centimeter-scale aerial robots.

[This corrects the article DOI: 10.1371/journal.pone.0231362.].

A laser-microfabricated electrohydrodynamic thruster for centimeter-scale aerial robots.

To date, insect scale robots capable of controlled flight have used flapping-wings for generating lift, but this requires a complex and failure-prone mechanism. A simpler alternative is electrohydrodynamic (EHD) thrust, which requires no moving mechanical parts. In EHD, corona discharge generates a flow of ions in an electric field between two electrodes; the high-velocity ions transfer their kinetic energy to neutral air molecules through collisions, accelerating the gas and creating thrust. We introduce a fabrication process for EHD thruster based on 355 nm laser micromachining, which potentially allows for greater materials selection, such as fiber-based composites, than is possible with semiconductor-based lithographic processing. Our four-thruster device measures 1.8 × 2.5 cm and is composed of steel emitters and a lightweight carbon fiber mesh. We measured the electrical current and thrust of each thruster of our four-thruster design, showing agreement with the Townsend relation. The peak thrust of our device, at 5.2 kV, was measured to be 3.03 times its 37 mg (363.0 µN) mass using a precision balance. In free flight, we demonstrated liftoff at 4.6 kV.

Inattentiveness and Language Abilities in Preschoolers: A Latent Profile Analysis.

Growing evidence suggests that early symptoms of inattentiveness may affect the language development and academic success of young children. In the present study, we examined the extent to which profiles of inattentiveness and language could be discerned within a heterogeneous group of preschoolers attending early childhood special education programs (n = 461). Based on parent-reported observations of children's symptoms of inattentiveness and direct assessments of children's language skills (grammar, vocabulary, and narrative ability), three distinct profiles were identified. The three groups, representing levels of severity (at risk, almost average, above average), differed not only by their end of year performance, but also with respect to which their abilities changed over the course of the academic year. Children in the poorest performing profile had poorer mean scores in the spring of their preschool year on all measures, but exhibited patterns of gain that exceeded or equaled their peers in higher-performing groups, in the domains of vocabulary and grammar. Examination of subsequent kindergarten reading skills suggested that profile differences remained consistent. Findings underscore the associations between early symptoms of inattentiveness and language difficulties, and further indicate that these relations extend to the acquisition of early reading skills. Future research is needed to corroborate these findings with more robust measures of attention, and to understand the long-term associations between inattentiveness, language and literacy, and potential effects on these associations from early intervention.

Amplitude Sensing below the Zero-Point Fluctuations with a Two-Dimensional Trapped-Ion Mechanical Oscillator.

We present a technique to measure the amplitude of a center-of-mass (c.m.) motion of a two-dimensional ion crystal of ∼100 ions. By sensing motion at frequencies far from the c.m. resonance frequency, we experimentally determine the technique's measurement imprecision. We resolve amplitudes as small as 50 pm, 40 times smaller than the c.m. mode zero-point fluctuations. The technique employs a spin-dependent, optical-dipole force to couple the mechanical oscillation to the electron spins of the trapped ions, enabling a measurement of one quadrature of the c.m. motion through a readout of the spin state. We demonstrate sensitivity limits set by spin projection noise and spin decoherence due to off-resonant light scattering. When performed on resonance with the c.m. mode frequency, the technique demonstrated here can enable the detection of extremely weak forces (<1 yN) and electric fields (<1 nV/m), providing an opportunity to probe quantum sensing limits and search for physics beyond the standard model.

Short-term morbidity in transdiaphragmatic cardiophrenic lymph node resection for advanced stage gynecologic cancer.

Ovarian cancer is commonly diagnosed at an advanced stage, with disease involving the upper abdomen. The finding of enlarged cardiophrenic lymph nodes (CPLNs) on pre-operative imaging often indicates the presence of malignant spread to the mediastinum. Surgical resection of CPLN through a transdiaphragmatic approach can help to achieve cytoreduction to no gross residual. A retrospective chart review was conducted on all patients who underwent transdiaphragmatic cardiophrenic lymph node resection from 8/1/11 through 2/1/15. All relevant pre-, intra-, and post-operative characteristics and findings were recorded. A brief description of the surgical technique is included for reference. Eleven patients were identified who had undergone transdiaphragmatic resection of cardiophrenic lymph nodes. Malignancy was identified in 18/21 (86%) of total lymph nodes submitted. The median number of post-operative days was 7. The overall post-operative morbidity associated with CPLN resection was low, with the most common finding being a small pleural effusion present on chest x-ray between POD# 3-5 (55%). Transdiaphragmatic CPLN resection is a feasible procedure with relatively minor short-term post-operative morbidities that can be used to achieve cytoreduction to no gross residual disease.

The effects of display size on performance.

We examined the systematic effects of display size on task performance as derived from a standard perceptual and cognitive test battery. Specifically, three experiments examined the influence of varying viewing conditions on response speed, response accuracy and subjective workload at four differing screen sizes under three different levels of time pressure. Results indicated a ubiquitous effect for time pressure on all facets of response while display size effects were contingent upon the nature of the viewing condition. Thus, performance decrement and workload elevation were evident only with the smallest display size under the two most restrictive levels of time pressure. This outcome generates a lower boundary threshold for display screen size for this order of task demand. Extrapolations to the design and implementation of all display sizes and forms of cognitive and psychomotor demand are considered.

Genetic association of impulsivity in young adults: a multivariate study.

Impulsivity is a heritable, multifaceted construct with clinically relevant links to multiple psychopathologies. We assessed impulsivity in young adult (N~2100) participants in a longitudinal study, using self-report questionnaires and computer-based behavioral tasks. Analysis was restricted to the subset (N=426) who underwent genotyping. Multivariate association between impulsivity measures and single-nucleotide polymorphism data was implemented using parallel independent component analysis (Para-ICA). Pathways associated with multiple genes in components that correlated significantly with impulsivity phenotypes were then identified using a pathway enrichment analysis. Para-ICA revealed two significantly correlated genotype-phenotype component pairs. One impulsivity component included the reward responsiveness subscale and behavioral inhibition scale of the Behavioral-Inhibition System/Behavioral-Activation System scale, and the second impulsivity component included the non-planning subscale of the Barratt Impulsiveness Scale and the Experiential Discounting Task. Pathway analysis identified processes related to neurogenesis, nervous system signal generation/amplification, neurotransmission and immune response. We identified various genes and gene regulatory pathways associated with empirically derived impulsivity components. Our study suggests that gene networks implicated previously in brain development, neurotransmission and immune response are related to impulsive tendencies and behaviors.

Controlling free flight of a robotic fly using an onboard vision sensor inspired by insect ocelli.

Scaling a flying robot down to the size of a fly or bee requires advances in manufacturing, sensing and control, and will provide insights into mechanisms used by their biological counterparts. Controlled flight at this scale has previously required external cameras to provide the feedback to regulate the continuous corrective manoeuvres necessary to keep the unstable robot from tumbling. One stabilization mechanism used by flying insects may be to sense the horizon or Sun using the ocelli, a set of three light sensors distinct from the compound eyes. Here, we present an ocelli-inspired visual sensor and use it to stabilize a fly-sized robot. We propose a feedback controller that applies torque in proportion to the angular velocity of the source of light estimated by the ocelli. We demonstrate theoretically and empirically that this is sufficient to stabilize the robot's upright orientation. This constitutes the first known use of onboard sensors at this scale. Dipteran flies use halteres to provide gyroscopic velocity feedback, but it is unknown how other insects such as honeybees stabilize flight without these sensory organs. Our results, using a vehicle of similar size and dynamics to the honeybee, suggest how the ocelli could serve this role.

Transgene delivery to endothelial cultures derived from porcine carotid artery ex vivo.

Carotid artery disease is a widespread cause of morbidity and mortality. Porcine models of vascular disease are well established in vivo, but existing endothelial systems in vitro (e.g. human umbilical vein endothelial cells, rat aortic endothelial cultures) poorly reflect carotid endothelium. A reliable in vitro assay would improve design of in vivo experiments and allow reduction and refinement of animal use. This study aimed (1) to develop ex vivo endothelial cultures from porcine carotid and (2) to test whether these were suitable for lentivector-mediated transgene delivery. Surplus carotid arteries were harvested from young adult female Large White pigs within 10 min post-mortem. Small sectors of carotid artery wall (approximately 4 mm×4 mm squares) were immobilised in a stable gel matrix. Cultures were exposed to HIV-derived lentivector (LV) encoding a reporter transgene or the equivalent integration-deficient vector (IDLV). After 7-14 days in vitro, cultures were fixed and labelled histochemically. Thread-like multicellular outgrowths were observed that were positive for endothelial cell markers (CD31, VEGFR2, von Willebrand factor). A minority of cells co-labelled for smooth muscle markers. Sensitivity to cytotoxic agents (paclitaxel, cycloheximide, staurosporine) was comparable to that in cell cultures, indicating that the gel matrix permits diffusive access of small pharmacological molecules. Transgene-expressing cells were more abundant following exposure to LV than IDLV (4.7, 0.1% of cells, respectively). In conclusion, ex vivo adult porcine carotid artery produced endothelial cell outgrowths that were effectively transduced by LV. This system will facilitate translation of novel therapies to clinical trials, with reduction and refinement of in vivo experiments.

Controlled flight of a biologically inspired, insect-scale robot.

Flies are among the most agile flying creatures on Earth. To mimic this aerial prowess in a similarly sized robot requires tiny, high-efficiency mechanical components that pose miniaturization challenges governed by force-scaling laws, suggesting unconventional solutions for propulsion, actuation, and manufacturing. To this end, we developed high-power-density piezoelectric flight muscles and a manufacturing methodology capable of rapidly prototyping articulated, flexure-based sub-millimeter mechanisms. We built an 80-milligram, insect-scale, flapping-wing robot modeled loosely on the morphology of flies. Using a modular approach to flight control that relies on limited information about the robot's dynamics, we demonstrated tethered but unconstrained stable hovering and basic controlled flight maneuvers. The result validates a sufficient suite of innovations for achieving artificial, insect-like flight.

Arbitrary waveform generator for quantum information processing with trapped ions.

Atomic ions confined in multi-electrode traps have been proposed as a basis for scalable quantum information processing. This scheme involves transporting ions between spatially distinct locations by use of time-varying electric potentials combined with laser or microwave pulses for quantum logic in specific locations. We report the development of a fast multi-channel arbitrary waveform generator for applying the time-varying electric potentials used for transport and for shaping quantum logic pulses. The generator is based on a field-programmable gate array controlled ensemble of 16-bit digital-to-analog converters with an update frequency of 50 MHz and an output range of ±10 V. The update rate of the waveform generator is much faster than relevant motional frequencies of the confined ions in our experiments, allowing diabatic control of the ion motion. Numerous pre-loaded sets of time-varying voltages can be selected with 40 ns latency conditioned on real-time signals. Here we describe the device and demonstrate some of its uses in ion-based quantum information experiments, including speed-up of ion transport and the shaping of laser and microwave pulses.

Laser based accelerator for ultracold atoms.

We present our first results on our implementation of a laser based accelerator for ultracold atoms. Atoms cooled to a temperature of 420 nK are confined and accelerated by means of laser tweezer beams, and the atomic scattering is directly observed in laser absorption imaging. The optical collider has been characterized using 87Rb atoms in the |F=2, m(F)=2] state, but the scheme is not restricted to atoms in any particular magnetic substates and can readily be extended to other atomic species as well.

Immunohistochemical study of human costotransverse joints: A preliminary investigation.

The human costotransverse joint (CTJ) is the articulation between the posterior tubercle of the ribs with the first through tenth costal facet of the thoracic transverse processes. While the CTJ is well defined anatomically and considered a synovial joint, the human CTJ as a pain generating structure is controversial and not supported from a histological perspective. The objective of the present study was to investigate the histological pain producing properties of CTJ capsule tissue. Ten micron cross-sections at each level (1-10) were stained with H & E or immunostained with antisera against Substance P (SP), calcitonin-gene-related peptide (CGRP), and neuropeptide Y (NPY). Immunoreactivity was confirmed for SP, CGRP, and NPY within the CTJ tissue samples of two unembalmed male cadavers. The presence of previously mentioned neuropeptides suggests that human CTJ is capable of producing pain through somatic and autonomic nervous systems. Therefore, clinicians should consider the CTJ as a differential diagnostic possibility when examining and treating painful thoracic conditions.

Reliability of the VmaxST portable metabolic measurement system.

The purpose of this study was to evaluate the reliability of the VmaxST portable metabolic measurement system. Forty-five healthy adults (age = 25.7 +/- 5.9 yr; height = 171.8 +/- 9.1 cm; weight = 69.6 +/- 12.8 kg; VO2peak) = 40.7 ml/kg/min; percent fat = 21.7 +/- 11.0) performed two separate and identical exercise routines on different days consisting of treadmill walking at 2.0 mph (53.6 m/min), 3.0 mph (80.5 m/min), and 4.0 mph (107.3 m/min) and running at 6.0 mph (160.9 m/min). VE and gas exchange were measured continuously breath-to-breath. A random effects model on log-transformed data yielded coefficients of variation (CV) and intraclass correlation coefficients (ICC) for VO2 and VE of 5.2 - 7.6 %, and 0.77 - 0.92, respectively, for all walking and running trials. For VCO2, CVs were higher (10 - 12 %) and ICCs lower (0.70 - 0.81). Ordinary least squares regression between the individual difference scores and the individual mean scores for VE, VO2 and VCO2, respectively, indicated no systematic bias (all p > 0.05). Bland-Altman analysis also illustrated no systematic bias between repeated measurements. The VmaxST provides reliable measurements of VO2 and VE during walking and running eliciting VE and VO2 at least up to approximately 56 and 2.2 l/min, respectively. The system appears to be less reliable for measuring VCO2.