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Background: This Site Feasibility Task Force convened to assess the complex and burdensome process of site feasibility in clinical trials. The objective was to create mutual understanding of challenges and provide suggestions for improving collaboration among sponsors, contract research organizations (CROs), and sites. Methods: The task force was composed of representatives from sponsors, CROs and sites (43 % Sites, 20 % Site Networks, 10 % Small/mid-size sponsors, 10 % Small/mid-size CROs, 10 % Large sponsors, 7 % Large CROs). The group collaborated to define the scope of the problem, identify challenges in the current process, and provide suggestions for improving the process. Results: The group found there is a need for better differentiation between the three main stages of feasibility, and the four sub-phases of Site Feasibility. The discussion brought to light emerging trends like early initiation of Site Feasibility and premature engagement of sites by CROs. To fully explain these challenges, the group analyzed the current practices and documented their downstream impact on clinical trial execution for all stakeholders. A list of best practices emerged naturally from this analysis. These findings are aggregated into short and actionable best practice guides. Conclusion: The task force suggests practical changes for the feasibility process and raises awareness of emerging trends and their associated risks. This awareness can begin to drive change in the site feasibility process, although industry-wide transformation will require new levels of collaboration, data standardization and automation tools. The potential benefits of evolving this process are significant and meaningful for more efficient and successful clinical trials.

Abstract Over the last ten years, there has been considerable progress in using digital behavioral phenotypes, captured passively and continuously from smartphones and wearable devices, to infer depressive mood. However, most digital phenotype studies suffer from poor replicability, often fail to detect clinically relevant events, and use measures of depression that are not validated or suitable for collecting large and longitudinal data. Here, we report high-quality longitudinal validated assessments of depressive mood from computerized adaptive testing paired with continuous digital assessments of behavior from smartphone sensors for up to 40 weeks on 183 individuals experiencing mild to severe symptoms of depression. We apply a combination of cubic spline interpolation and idiographic models to generate individualized predictions of future mood from the digital behavioral phenotypes, achieving high prediction accuracy of depression severity up to three weeks in advance (R 2 ≥ 80%) and a 65.7% reduction in the prediction error over a baseline model which predicts future mood based on past depression severity alone. Finally, our study verified the feasibility of obtaining high-quality longitudinal assessments of mood from a clinical population and predicting symptom severity weeks in advance using passively collected digital behavioral data. Our results indicate the possibility of expanding the repertoire of patient-specific behavioral measures to enable future psychiatric research.

Abstract Y-box binding protein 1 (YBX1 or YB1) is a therapeutically relevant oncoprotein capable of RNA and DNA binding and mediating protein–protein interactions that drive proliferation, stemness, and resistance to platinum-based therapies. Given our previously published findings, the potential for YB1-driven cisplatin resistance in medulloblastoma (MB), and the limited studies exploring YB1-DNA repair protein interactions, we chose to investigate the role of YB1 in mediating radiation resistance in MB. MB, the most common pediatric malignant brain tumor, is treated with surgical resection, cranio-spinal radiation, and platinum-based chemotherapy, and could potentially benefit from YB1 inhibition. The role of YB1 in the response of MB to ionizing radiation (IR) has not yet been studied but remains relevant for determining potential anti-tumor synergy of YB1 inhibition with standard radiation therapy. We have previously shown that YB1 drives proliferation of cerebellar granular neural precursor cells (CGNPs) and murine Sonic Hedgehog (SHH) group MB cells. While others have demonstrated a link between YB1 and homologous recombination protein binding, functional and therapeutic implications remain unclear, particularly following IR-induced damage. Here we show that depleting YB1 in both SHH and Group 3 MB results not only in reduced proliferation but also synergizes with radiation due to differential response dynamics. YB1 silencing through shRNA followed by IR drives a predominantly NHEJ-dependent repair mechanism, leading to faster γH2AX resolution, premature cell cycle re-entry, checkpoint bypass, reduced proliferation, and increased senescence. These findings show that depleting YB1 in combination with radiation sensitizes SHH and Group 3 MB cells to radiation.

Abstract Objective: Compare the real-world impact of fidaxomicin (FDX) and vancomycin (VAN) on Clostridioides difficile infection (CDI) recurrence in a high-risk patient population. Design: A retrospective, matched-cohort study evaluating hospitalized patients with CDI from January 1, 2016, to November 1, 2022, within a tertiary academic medical center. Patients: Adult patients with at least 1 prior CDI case who received either FDX or VAN for non-fulminant CDI while admitted, and had at least 1 additional risk factor for recurrence. Risk factors included age >70, solid organ or bone marrow transplant recipients, broad-spectrum antibiotic use within 30 days, or receipt of chemotherapy/immune-modulating agents within 30 days of admission. FDX and VAN patients were matched according to risk factors. Results: A total of 415 patient admissions were identified. After the exclusion of 92 patients for fulminant CDI, diarrhea from another cause, or use of VAN taper therapy, and 15 unmatched patients, 308 patient admissions were included (68 FDX and 240 VAN patients). There were no significant differences in 4-week recurrence (26% vs 23%; OR 1.1; P = .51), 90-day CDI readmission (29% vs 23%; P = .65), or 90-day all-cause readmission (54% vs 53%; P = .91). There was a significant 17% decrease in 90-day mortality associated with the use of FDX (OR .3; P = .04). Conclusions: In a real-world high-risk patient population, the use of FDX compared to oral VAN did not result in decreased CDI recurrence within 4 weeks or fewer hospital readmissions within 90 days. Further research is needed to better assess the value of FDX in this patient population.

Abstract Background Acquired hemophilia A is a disorder caused by autoantibodies against coagulation factor VIII that may present with severe bleeding. We report a rare case of acquired hemophilia A presenting with coexisting lupus anticoagulant. Case presentation An 81-year-old Caucasian female presented with large ecchymoses over the torso and extremities in the setting of an enoxaparin bridge to warfarin. Anticoagulation was held, but she continued to develop bruises with significant anemia and prolonged coagulation studies that failed to correct with mixing. Workup revealed factor VIII activity

Background Pre-exposure prophylaxis for COVID-19 with tixagevimab/cilgavimab (T/C) received Emergency Use Authorization (EUA) based on results of a clinical trial conducted prior to the emergence of the Omicron variant. The clinical effectiveness of T/C has not been well described in the Omicron era. We examined the incidence of symptomatic illness and hospitalizations among T/C recipients when Omicron accounted for virtually all local cases. Methods Through retrospective electronic medical record chart review, we identified patients who received T/C between January 1 –July 31, 2022 within our quaternary referral health system. We determined the incidence of symptomatic COVID-19 infections and hospitalizations due to or presumed to be caused by early Omicron variants before and after receiving T/C (pre-T/C and post-T/C). Chi square and Mann-Whitney Wilcoxon two-sample tests were used to examine differences between the characteristics of those who got COVID-19 before or after T/C prophylaxis, and rate ratios (RR) and 95% confidence intervals (CI) were calculated to assess differences in hospitalization rates for the two groups. Results Of 1295 T/C recipients, 105 (8.1%) developed symptomatic COVID-19 infection before receiving T/C, and 102 (7.9%) developed symptomatic disease after receiving it. Of the 105 patients who developed symptomatic infection pre-T/C, 26 (24.8%) were hospitalized, compared with six of the 102 patients (5.9%) who were diagnosed with COVID-19 post-T/C (RR = 0.24; 95% CI = 0.10–0.55; p = 0.0002). Seven of the 105 (6.7%) patients infected pre-T/C, but none of the 102 infected post-T/C required ICU care. No COVID-related deaths occurred in either group. The majority of COVID-19 cases among those infected pre-T/C treatment occurred during the Omicron BA.1 surge, while the majority of post-T/C cases occurred when Omicron BA.5 was predominant. In both groups, having at least one dose of vaccine strongly protected against hospitalization (pre-T/C group RR = 0.31, 95% CI = 0.17–0.57, p = 0.02; post-T/C group RR = 0.15; 95% CI = 0.03–0.94; p = 0.04). Conclusion We identified COVID-19 infections after T/C prophylaxis. Among patients who received T/C at our institution, COVID-19 Omicron cases occurring after T/C were one-fourth as likely to require hospitalization compared to those with Omicron prior to T/C. However, due to the presence of changing vaccine coverage, multiple therapies, and changing variants, the effectiveness of T/C in the Omicron era remains difficult to assess.

RAS mutations occur in a broad spectrum of human hematopoietic malignancies. Activating Ras mutations in blood cells leads to hematopoietic malignancies in mice. In murine hematopoietic stem cells (HSCs), mutant N-RasG12D activates Stat5 to dysregulate stem cell function. However, the underlying mechanism remains elusive. In this study, we demonstrate that Stat5 activation induced by a hyperactive Nras mutant, G12D, is dependent on Jak2 activity. Jak2 is activated in Nras mutant HSCs and progenitors (HSPCs), and inhibiting Jak2 with ruxolitinib significantly decreases Stat5 activation and HSPC hyper-proliferation in vivo in NrasG12D mice. Activation of Jak2-Stat5 is associated with downregulation of Socs2, an inhibitory effector of Jak2/Stat5. Restoration of Socs2 blocks NrasG12D HSC reconstitution in bone marrow transplant recipients. SOCS2 downregulation is also observed in human acute myeloid leukemia (AML) cells that carry RAS mutations. RAS mutant AML cells exhibited suppression of the enhancer active marker H3K27ac at the SOCS2 locus. Finally, restoration of SOCS2 in RAS mutant AML cells mitigated leukemic growth. Thus, we discovered a novel signaling feedback loop whereby hyperactive Ras signaling activates Jak2/Stat5 via suppression of Socs2.

Dissecting epigenetic mechanisms controlling early cardiac differentiation will provide insights into heart regeneration and heart disease treatment. SWI/SNF complexes remodel nucleosomes to regulate gene expression and play a key role in organogenesis. Here, we reported a unique function of BAF250a in regulating the physical interaction of OCT4 and β-CATENIN during cardiac lineage differentiation from human ESCs. BAF250a deletion greatly reduced the physical interaction between OCT4 and β-CATENIN but did not alter the expression of β-CATENIN and OCT4 in the mesodermal progenitor cells. BAF250a ablation led to decreased recruitment of OCT4 and β-CATENIN at promoters of key mesodermal lineage genes, such as MESP1 and EOMES. Subsequently, the expression of lineage-specific genes was downregulated, whereas the expression of pluripotent genes was upregulated. In parallel, BAF250a ablation also altered recruitments of OCT4 and β-CATENIN to the promoter of CCND2 and CCND3, two key genes for S phase entry during cell cycle. Consequently, BAF250a deletion led to prolonged S phase in Mesp1+ cardiac progenitor cells, which in turn inhibited efficient differentiation of Mesp1+ to Isl1+ cells. Furthermore, BAF250a deletion abolished the interaction of OCT4 and BRG1 in mesoderm, suggesting that BAF250a is the key component in SWI/SNF complex that determines the interaction of Oct4/β-catenin in mesoderm. In contrast, we found that BAF250a did not regulate the OCT4/β-CATENIN interaction during neuroectoderm differentiation. Altogether, our results suggest that BAF250a specifically controls proper cardiac mesoderm differentiation by reorganizing the binding of OCT4/β-CATENIN and regulates both key lineage differentiation genes and cell cycle genes that coincided in response to WNT/β-CATENIN signal.

Distributed, high-density spatiotemporal observations are proposed for answering many river-related questions, including those pertaining to hydraulics and multi-dimensional river modeling, geomorphology, sediment transport and riparian habitat restoration. We present here a case study of an autonomous, high-resolution robotic spatial mapping of cross-sectional velocity and salt concentration in a river basin. Several experiments for analyzing the spatial and temporal trends at multiple cross-sections of the San Joaquin River were performed during the campaign from August 21-25, 2006. Preliminary analysis from these experiments illustrating the range of investigations is presented. Lessons learned during the campaign are discussed to provide useful insights for similar robotic investigations in aquatic environments.

This paper reports the first application of actuated sensing systems for high spatiotemporal resolution characterization of the threedimensional environment of river and lake aquatic systems. The development of a new method and its verification in these two application areas is described. Both applications involve dynamic phenomena - one resulting from flow of the water and the other from rapidly evolving biological processes. These applications are typical environmental monitoring problems. They exemplify the key challenge in such problems - characterizing phenomena displaying spatiotemporal heterogeneity. In many such examples, the application requires a diverse array of measurements based on sensors for physical, chemical and biological systems. Together, these requirements pose a significant challenge for conventional sensor network methods. We describe the development and applications of a new general purpose method for actuated sensing - Iterative experiment Design for Environmental Applications (IDEA). IDEA introduces a new in-field adaptation of the sensing systems including static and actuated sensors. IDEA addresses the limitations of previous sampling approaches, for example conventional adaptive sampling, by guiding adaptive sampling with an iteratively developed phenomenon model. This paper presents applications of IDEA to: (1) Three-dimensional characterization of contaminant concentration and flow at the confluence of two major rivers; and (2) Characterization of phytoplankton dynamics in a lake system. These applications provide ideal tests by presenting complex structures associated with each phenomenon and enabling a comprehensive evaluation of the general applicability of IDEA methodology. Improved performance using guided adaptive sampling is demonstrated for two existing methodologies, stratified adaptive sampling and hierarchical non-stationary Gaussian Processes. The IDEA experimental results both validate the general applicability of this method and also have advanced the understanding of interrelated physical, chemical and biological processes in these sampled environments.

Environmental monitoring has proven to be a rich source of biological and ecological data but typically does not conform to traditional monitoring techniques. Events of interest are often dynamic and may not tolerate the introduction of a conventional infrastructure without disrupting the environment being monitored. The new NIMS architectures require minimal infrastructure, are rapidly deployable, and have self anchoring coordinate systems. Simple cableways provide system mobility with minimal occlusion of the monitored transect allowing for accurate positioning and high positional resolution within the space of interest. These new systems have been developed to operate in either a two dimensional plane (NIMS-RD: e.g. monitor river or stream properties) or in a three dimensional volume (NIMS-3D: e.g. monitor incident solar radiation under a forest canopy).

In order to understand and control the impact of non-point source pollution in Central California and many semi-arid regions of the world, a multiscale observational network focused on several water quality issues is proposed. Specifically, we are targeting the main stem of the San Joaquin River as a prototypical river system. By developing multiscale modeling approaches, we will endeavor first to understand the hydrodynamics of salt mixing on the San Joaquin at each of the three river confluences (with the Merced, Tuolumne, and Stanislaus Rivers) and create salt-flow rating curves characterizing 5 different flow conditions, and second, to quantify and sample groundwater-surface water interactions along critical reaches of the river where the US Geological Survey is investigating with respect to groundwater accretion.

Following in the footsteps of the field Networked Infomechanical Systems (NIMS) currently deployed at the James San Jacinto Mountain Reserve in Idyllwild California, two smaller scale NIMS architectures have emerged. The Laboratory Systems (NIMS-LS) provides an experimental testbed for verification of actuated sensing of environmental phenomena. The NIMS-LS System also includes emulation of environmental phenomena (i.e. light distribution in ecosystems). The Rapidly Deployable (NIMS-RD) platform provides a flexible means of sampling environmental phenomena directly with minimal infrastructure, rapid deployability and minimal impact on the environment. NIMS-RD has been deployed at the James San Jacinto Mountain Reserve, Medea Creek in the Santa Monica Mountains, Merced River in Merced CA and White Mountains Research Station near Bishop CA.

Rapidly growing stress on the natural environment has created an urgent demand for new environmental exploration systems that operate remotely and autonomously. As sensor networks are applied to these critical environmental monitoring problems, a series of new requirements have emerged for extensive characterization of dynamic phenomena in three-dimensional environments. The unpredictable presence of obstacles to sensing and the inherent temporal evolution of events create limitations for optimal deployment of sensors in the environment. Networked Infomechanical Systems (NIMS) technology has been developed to introduce precise and sustainable actuation for distributed sensing. NIMS devices are suspended on cable infrastructure to provide a combination of broad range motion combined with accurate localization.

The impacts of anthropogenic inputs on streams in urban watersheds include seasonal algal blooms, high bacteria levels, elevated nutrient concentrations, and altered channel morphology, all of which are commonplace in southern California urban streams. Although it is clear that urbanization effects stream health, the complex mechanisms leading to symptoms such as elevated algal biomass are not well understood. In order to better understand the relationship between urbanization and stream health, the temporal and spatial variation of stream water parameters in urban streams need to be known. Understanding these patterns will help elucidate the driving mechanisms leading to stream degradation and allow for improved management practices. Using various water quality sensors and NIMS technology, the temporal (daily, weekly, and monthly) and spatial (cross sectional and reach scale) variation in Medea Creek in Agoura Hills, CA is being monitored. By analyzing the correlations between these parameters we will be able to determine the driving biotic and abiotic mechanisms leading to the excess algal biomass and nutrient concentrations in Medea Creek.

Rapidly growing stress on the natural environment has created an urgent demand for new environmental exploration systems that operate remotely and autonomously. As sensor networks are applied to these critical environmental monitoring problems, a series of new requirements have emerged for extensive characterization of dynamic phenomena in three-dimensional environments. The unpredictable presence of obstacles to sensing and the inherent temporal evolution of events create limitations for optimal deployment of sensors in the environment.

2005 CENS Summer Intern:NIMS (Networked Info-Mechanical Systems) is a sensor system utilizing fixed and actuated sensors to monitor environmental changes. A new, rapidly deployable NIMS (NIMS RD) allows for more mobility and versatility in the field. With short-term deployments, data is able to be read quickly and in-field calibrations are possible. A variety of sensor nodes can be attached to the system allowing it to work in diverse environments. As a result of this, many deployments have been possible and much environmental data has been collected at Medea Creek, the James Reserve, and the White Mountains.

Cool ambient air temperatures and warm soil and rock surfaces in alpine fellfield ecosystems produce sharp and dynamic spatial gradients in surface temperatures, with profound impacts on plant ecophysiology. Spot measurements of plant and soil surface temperatures are not sufficient to understand the complexity of this environment. Thermal scanner instrumentation mounted on a NIMS-RD system can provide dense measurements of spatial and temporal patterns of surface temperatures across a fellfield habitat, as well as a photographic log of transect position.

The ability to remotely monitor the dynamics of a natural environment is an increasingly important avenue for investigating and ultimately protecting natural ecosystems and safeguarding public health. NIMS provides a new capability for mobile monitoring of complex environments. NIMS enables the first spatiotemporally resolved sensing capability for applications including microclimate characterization in the forest canopy by using this new multisensor module.

The Chinese Language Classroom Environment Inventory (CLCEI) is a bilingual instrument developed for use in measuring students' and teachers' perceptions toward their Chinese Language classroom learning environments in Singapore secondary schools. The English version of the CLCEI was customised from the English version of the "What is happening in this class? (WIHIC)" questionnaire (Fraser, Fisher, & McRobbie, 1996) and its Chinese version was modified from the Taiwanese Chinese version of the WIHIC questionnaire (Huang & Fraser, 1997). The CLCEI consists of six 8-item scales examining 6 different dimensions of the Chinese language classroom learning environments, namely, "Student Cohesiveness, Teacher Support, Involvement, Cooperation, Task Orientation and Equity". It was validated with a sample of 1460 secondary three (grade 9) students from 50 express stream (above average academic ability) classes in 25 secondary schools in Singapore. Various statistical procedures were undertaken to examine the factor structure, validity and reliability of the scales of the CLCEI. The validation results indicated that each of the scales exhibited high internal consistency reliability and satisfactory discriminant and factorial validity. The validation results also indicated that each scale of the CLCEI had the ability to differentiate between perceptions of students from different Chinese language classes. (Contains 4 tables.)

One common objective of instructional multimedia products is enhancement of learning. It follows that one of the primary tasks of the interface designer is the creation of a user-interface that is motivating, interactive, intuitive and at the same time imposing as minimal as possible a cognitive load on the learner. To achieve this goal, qualities such as learnability, efficiency, memorability, low error rates and high user satisfaction are essential. A well-designed interface should inform the user what do the objects on the screen stand for and what they might do and allows the user to break down a task into subtasks and map them on to the system's functions easily and naturally. By doing so, it enables the user to build a functional mental model of the system that does not require user's rote memorization. These qualities of a well-designed interface are commonly known as the "usability" of software. To date, many methods that allow systematic ways of evaluating usability in instructional multimedia have been developed. By integrating these methods into the various stages within the life cycle of instructional multimedia design and development, the usability of instructional multimedia, and hence its educational value, could be assured. However, there has been little attempt to consolidate these methods into a more integrative and self-explanatory model. This paper attempts to review these various methods under a proposed framework in the hope that it may help readers to select the most appropriate usability evaluation method according to their needs.