Engineering Electrode Rinse Solution Fluidics for Carbon-Based Reverse Electrodialysis Devices.

Natural salinity gradients are a promising source of so-called "blue energy", a renewable energy source that utilizes the free energy of mixing for power generation. One promising blue energy technology that converts these salinity gradients directly into electricity is reverse electrodialysis (RED). Used at its full potential, it could provide a substantial portion of the world's electricity consumption. Previous theoretical and experimental works have been done on optimizing RED devices, with the latter often focusing on precious and expensive metal electrodes. However, in order to rationally design and apply RED devices, we need to investigate all related transport phenomena─especially the fluidics of salinity gradient mixing and the redox electrolyte at various concentrations, which can have complex intertwined effects─in a fully functioning and scalable system. Here, guided by fundamental electrochemical and fluid dynamics theories, we work with an iron-based redox electrolyte with carbon electrodes in a RED device with tunable microfluidic environments and study the fundamental effects of electrolyte concentration and flow rate on the potential-driven redox activity and power output. We focus on optimizing the net power output, which is the difference between the gross power output generated by the RED device and the pumping power input, needed for salinity gradient mixing and redox electrolyte reactions. We find through this holistic approach that the electrolyte concentration in the electrode rinse solution is crucial for increasing the electrical current, while the pumping power input depends nonlinearly on the membrane separation distance. Finally, from this understanding, we designed a five cell-pair (CP) RED device that achieved a net power density of 224 mW m-2 CP-1, a 60% improvement compared to the nonoptimized case. This study highlights the importance of the electrode rinse solution fluidics and composition when rationally designing RED devices based on scalable carbon-based electrodes.

HerediGene Population Study IT infrastructure: A model to support genomic research recruitment and precision public health.

The HerediGene Population Study is a large research study focused on identifying new genetic biomarkers for disease prevention, diagnosis, prognosis, and development of new therapeutics. A substantial IT infrastructure evolved to reach enrollment targets and return results to participants. More than 170,000 participants have been enrolled in the study to date, with 5.87% of those whole genome sequenced and 0.46% of those genotyped harboring pathogenic variants. Among other purposes, this infrastructure supports: (1) identifying candidates from clinical criteria, (2) monitoring for qualifying clinical events (e.g., blood draw), (3) contacting candidates, (4) obtaining consent electronically, (5) initiating lab orders, (6) integrating consent and lab orders into clinical workflow, (7) de-identifying samples and clinical data, (8) shipping/transmitting samples and clinical data, (9) genotyping/sequencing samples, (10) and re-identifying and returning results for participants where applicable. This study may serve as a model for similar genomic research and precision public health initiatives.

The Development of an Infrastructure to Facilitate the Use of Whole Genome Sequencing for Population Health.

The clinical use of genomic analysis has expanded rapidly resulting in an increased availability and utility of genomic information in clinical care. We have developed an infrastructure utilizing informatics tools and clinical processes to facilitate the use of whole genome sequencing data for population health management across the healthcare system. Our resulting framework scaled well to multiple clinical domains in both pediatric and adult care, although there were domain specific challenges that arose. Our infrastructure was complementary to existing clinical processes and well-received by care providers and patients. Informatics solutions were critical to the successful deployment and scaling of this program. Implementation of genomics at the scale of population health utilizes complicated technologies and processes that for many health systems are not supported by current information systems or in existing clinical workflows. To scale such a system requires a substantial clinical framework backed by informatics tools to facilitate the flow and management of data. Our work represents an early model that has been successful in scaling to 29 different genes with associated genetic conditions in four clinical domains. Work is ongoing to optimize informatics tools; and to identify best practices for translation to smaller healthcare systems.

Microscale hydrodynamic confinements: shaping liquids across length scales as a toolbox in life sciences.

Hydrodynamic phenomena can be leveraged to confine a range of biological and chemical species without needing physical walls. In this review, we list methods for the generation and manipulation of microfluidic hydrodynamic confinements in free-flowing liquids and near surfaces, and elucidate the associated underlying theory and discuss their utility in the emerging area of open space microfluidics applied to life-sciences. Microscale hydrodynamic confinements are already starting to transform approaches in fundamental and applied life-sciences research from precise separation and sorting of individual cells, allowing localized bio-printing to multiplexing for clinical diagnosis. Through the choice of specific flow regimes and geometrical boundary conditions, hydrodynamic confinements can confine species across different length scales from small molecules to large cells, and thus be applied to a wide range of functionalities. We here provide practical examples and implementations for the formation of these confinements in different boundary conditions - within closed channels, in between parallel plates and in an open liquid volume. Further, to enable non-microfluidics researchers to apply hydrodynamic flow confinements in their work, we provide simplified instructions pertaining to their design and modelling, as well as to the formation of hydrodynamic flow confinements in the form of step-by-step tutorials and analytical toolbox software. This review is written with the idea to lower the barrier towards the use of hydrodynamic flow confinements in life sciences research.

Reconfigurable microfluidics: real-time shaping of virtual channels through hydrodynamic forces.

To break the current paradigm in microfluidics that directly links device design to functionality, we introduce microfluidic "virtual channels" that can be dynamically shaped in real-time. A virtual channel refers to a flow path within a microfluidic flow cell, guiding an injected reagent along a user-defined trajectory solely by hydrodynamic forces. Virtual channels dynamically reproduce key microfluidic functionality: directed transport of minute volumes of liquid, splitting, merging and mixing of flows. Virtual channels can be formed directly on standard biological substrates, which we demonstrate by sequential immunodetection at arrays of individual reaction sites on a glass slide and by alternating between local and global processing of surface-adherent cell-block sections. This approach is simple, versatile and generic enough to form the basis of a new class of microfluidic techniques.

Fluidic Bypass Structures for Improving the Robustness of Liquid Scanning Probes.

OBJECTIVE: We aim to improve operational robustness of liquid scanning probes. Two main failure modes to be addressed are an obstruction of the flow path of the processing liquid and a deviation from the desired gap distance between probe and sample. METHODS: We introduce a multi-functional design element, a microfluidic bypass channel, which can be operated in dc and in ac mode, each preventing one of the two main failure modes. RESULTS: In dc mode, the bypass channel is filled with liquid and exhibits resistive behavior, enabling the probe to passively react to an obstruction. In the case of an obstruction of the flow path, the processing liquid is passively diverted through the bypass to prevent its leakage and to limit the buildup of high pressure levels. In ac mode, the bypass is filled with gas and has capacitive characteristics, allowing the gap distance between the probe and the sample to be monitored by observing a phase shift in the motion of two gas-liquid interfaces. For a modulation of the input pressure at 4 Hz, significant changes of the phase shift were observed up to a gap distance of 25 µm. CONCLUSION: The presented passive design element counters both failure modes in a simple and highly compatible manner. SIGNIFICANCE: Liquid scanning probes enabling targeted interfacing with biological surfaces are compatible with a wide range of workflows and bioanalytical applications. An improved operational robustness would facilitate rapid and widespread adoption of liquid scanning probes in research as well as in diagnostics.

Clinical, computed tomographic, magnetic resonance imaging, and histologic findings associated with myxomatous neoplasia of the temporomandibular joint in two dogs.

CASE DESCRIPTION A 15-year-old neutered female mixed-breed dog (dog 1) and an 11-year-old neutered female Labrador Retriever (dog 2) were examined because of unilateral exophthalmus, third eyelid protrusion, and periorbital swelling that failed to respond to antimicrobial treatment. CLINICAL FINDINGS Both dogs underwent ultrasonographic, CT, and MRI examination of the head. In both dogs, advanced imaging revealed a poorly defined, peripherally contrast-enhancing, mucous-filled cystic mass that radiated from the temporomandibular joint and infiltrated the periorbital tissues and retrobulbar space. Both dogs underwent surgical biopsy of the periorbital mass. A viscous, straw-colored fluid was aspirated from the retrobulbar region in both dogs. The initial histologic diagnosis for dog 1 was zygomatic sialadenitis and sialocele. However, the clinical signs recurred, and histologic examination of specimens obtained during a second surgical biopsy resulted in a diagnosis of myxoma. The histologic diagnosis was myxosarcoma for dog 2. TREATMENT AND OUTCOME In both dogs, clinical signs recurred within 2 weeks after surgery and persisted for the duration of their lives. Dog 1 received no further treatment after the second surgery and was euthanized 34 months after initial examination because of multicentric lymphoma. Dog 2 was treated with various chemotherapy agents and was euthanized 11 months after initial examination because of a dramatic increase in periocular swelling and respiratory stertor. CLINICAL RELEVANCE Temporomandibular myxomatous neoplasia can be confused with zygomatic sialocele on the basis of clinical signs but has characteristic MRI features. Representative biopsy specimens should be obtained from areas close to the temporomandibular joint to avoid misdiagnosis.

Centimeter-Scale Surface Interactions Using Hydrodynamic Flow Confinements.

We present a device and method for selective chemical interactions with immersed substrates at the centimeter-scale. Our implementations enable both, sequential and simultaneous delivery of multiple reagents to a substrate, as well as the creation of gradients of reagents on surfaces. The method is based on localizing submicroliter volumes of liquids on an immersed surface with a microfluidic probe (MFP) using a principle termed hydrodynamic flow confinement (HFC). We here show spatially defined, multiplexed surface interactions while benefiting from the probe capabilities such as non-contact scanning operation and convection-enhanced reaction kinetics. Three-layer glass-Si-glass probes were developed to implement slit-aperture and aperture-array designs. Analytical and numerical analysis helped to establish probe designs and operating parameters. Using these probes, we performed immunohistochemical analysis on individual cores of a human breast-cancer tissue microarray. We applied α-p53 antibodies on a 2 mm diameter core within 2.5 min using a slit-aperture probe (HFC dimension: 0.3 mm × 1.2 mm). Further, multiplexed treatment of a tissue core with α-p53 and α-ß-actin antibodies was performed using four adjacent HFCs created with an aperture-array probe (HFC dimension: 4 × 0.3 mm × 0.25 mm). The ability of these devices and methods to perform multiplexed assays, present sequentially different liquids on surfaces, and interact with surfaces at the centimeter-scale will likely spur new and efficient surface assays.

Convection-Enhanced Biopatterning with Recirculation of Hydrodynamically Confined Nanoliter Volumes of Reagents.

We present a new methodology for efficient and high-quality patterning of biological reagents for surface-based biological assays. The method relies on hydrodynamically confined nanoliter volumes of reagents to interact with the substrate at the micrometer-length scale. We study the interplay between diffusion, advection, and surface chemistry and present the design of a noncontact scanning microfluidic device to efficiently present reagents on surfaces. By leveraging convective flows, recirculation, and mixing of a processing liquid, this device overcomes limitations of existing biopatterning approaches, such as passive diffusion of analytes, uncontrolled wetting, and drying artifacts. We demonstrate the deposition of analytes, showing a 2- to 5-fold increase in deposition rate together with a 10-fold reduction in analyte consumption while ensuring less than 6% variation in pattern homogeneity on a standard biological substrate. In addition, we demonstrate the recirculation of a processing liquid using a microfluidic probe (MFP) in the context of a surface assay for (i) probing 12 independent areas with a single microliter of processing liquid and (ii) processing a 2 mm(2) surface to create 170 antibody spots of 50 × 100 µm(2) area using 1.6 µL of liquid. We observe high pattern quality, conservative usage of reagents, micrometer precision of localization and convection-enhanced fast deposition. Such a device and method may facilitate quantitative biological assays and spur the development of the next generation of protein microarrays.

Untangling autophagy measurements: all fluxed up.

Autophagy is an important physiological process in the heart, and alterations in autophagic activity can exacerbate or mitigate injury during various pathological processes. Methods to assess autophagy have changed rapidly because the field of research has expanded. As with any new field, methods and standards for data analysis and interpretation evolve as investigators acquire experience and insight. The purpose of this review is to summarize current methods to measure autophagy, selective mitochondrial autophagy (mitophagy), and autophagic flux. We will examine several published studies where confusion arose in data interpretation, to illustrate the challenges. Finally, we will discuss methods to assess autophagy in vivo and in patients.

Computerization of Mental Health Integration complexity scores at Intermountain Healthcare.

Intermountain Healthcare's Mental Health Integration (MHI) Care Process Model (CPM) contains formal scoring criteria for assessing a patient's mental health complexity as "mild," "medium," or "high" based on patient data. The complexity score attempts to assist Primary Care Physicians in assessing the mental health needs of their patients and what resources will need to be brought to bear. We describe an effort to computerize the scoring. Informatics and MHI personnel collaboratively and iteratively refined the criteria to make them adequately explicit and reflective of MHI objectives. When tested on retrospective data of 540 patients, the clinician agreed with the computer's conclusion in 52.8% of the cases (285/540). We considered the analysis sufficiently successful to begin piloting the computerized score in prospective clinical care. So far in the pilot, clinicians have agreed with the computer in 70.6% of the cases (24/34).

Normalization and standardization of electronic health records for high-throughput phenotyping: the SHARPn consortium.

RESEARCH OBJECTIVE: To develop scalable informatics infrastructure for normalization of both structured and unstructured electronic health record (EHR) data into a unified, concept-based model for high-throughput phenotype extraction. MATERIALS AND METHODS: Software tools and applications were developed to extract information from EHRs. Representative and convenience samples of both structured and unstructured data from two EHR systems-Mayo Clinic and Intermountain Healthcare-were used for development and validation. Extracted information was standardized and normalized to meaningful use (MU) conformant terminology and value set standards using Clinical Element Models (CEMs). These resources were used to demonstrate semi-automatic execution of MU clinical-quality measures modeled using the Quality Data Model (QDM) and an open-source rules engine. RESULTS: Using CEMs and open-source natural language processing and terminology services engines-namely, Apache clinical Text Analysis and Knowledge Extraction System (cTAKES) and Common Terminology Services (CTS2)-we developed a data-normalization platform that ensures data security, end-to-end connectivity, and reliable data flow within and across institutions. We demonstrated the applicability of this platform by executing a QDM-based MU quality measure that determines the percentage of patients between 18 and 75 years with diabetes whose most recent low-density lipoprotein cholesterol test result during the measurement year was <100 mg/dL on a randomly selected cohort of 273 Mayo Clinic patients. The platform identified 21 and 18 patients for the denominator and numerator of the quality measure, respectively. Validation results indicate that all identified patients meet the QDM-based criteria. CONCLUSIONS: End-to-end automated systems for extracting clinical information from diverse EHR systems require extensive use of standardized vocabularies and terminologies, as well as robust information models for storing, discovering, and processing that information. This study demonstrates the application of modular and open-source resources for enabling secondary use of EHR data through normalization into standards-based, comparable, and consistent format for high-throughput phenotyping to identify patient cohorts.

Effect of bevacizumab on angiogenesis and growth of canine osteosarcoma cells xenografted in athymic mice.

Objective-To investigate the effects of bevacizumab, a human monoclonal antibody against vascular endothelial growth factor, on the angiogenesis and growth of canine osteosarcoma cells xenografted in mice. Animals-27 athymic nude mice. Procedures-To each mouse, highly metastasizing parent osteosarcoma cells of canine origin were injected into the left gastrocnemius muscle. Each mouse was then randomly allocated to 1 of 3 treatment groups: high-dose bevacizumab (4 mg/kg, IP), low-dose bevacizumab (2 mg/kg, IP), or control (no treatment). Tumor growth (the number of days required for the tumor to grow from 8 to 13 mm), vasculature, histomorphology, necrosis, and pulmonary metastasis were evaluated. Results-Mice in the high-dose bevacizumab group had significantly delayed tumor growth (mean ± SD, 13.4 ± 3.8 days; range, 9 to 21 days), compared with that for mice in the low-dose bevacizumab group (mean ± SD, 9.4 ± 1.5 days; range, 7 to 11 days) or control group (mean ± SD, 7. 2 ± 1.5 days; range, 4 to 9 days). Mice in the low-dose bevacizumab group also had significantly delayed tumor growth, compared with that for mice in the control group. Conclusions and Clinical Relevance-Results indicated that bevacizumab inhibited growth of canine osteosarcoma cells xenografted in mice, which suggested that vascular endothelial growth factor inhibitors may be clinically useful for the treatment of osteosarcoma in dogs. Impact for Human Medicine-Canine osteosarcoma is used as a research model for human osteosarcoma; therefore, bevacizumab may be clinically beneficial for the treatment of osteosarcoma in humans.

Comparison of compliance for colorectal cancer screening and surveillance by colonoscopy based on risk.

PURPOSE: To compare colonoscopy screening/surveillance rates by level of risk for colorectal cancer based on age, personal history of adenomatous polyps or colorectal cancer, or family history of colorectal cancer. METHODS: Participants were aged 30-90 years, were seen within 5 years at Intermountain Healthcare, and had family history in the Utah Population Database. Colonoscopy rates were measured for those with/without risk factors. RESULTS: Among those aged 60-69 years, 48.4% had colonoscopy in the last 10 years, with rates declining after age 70 years. Percentages of those having had a colonoscopy in the last 10 years generally increased by risk level from 38.5% in those with a familial relative risk <1.0 to 47.6% in those with a familial relative risk >3.0. Compared with those with no family history, the odds ratio for being screened according to guidelines was higher for those with one first-degree relative diagnosed with colorectal cancer ≥ 60 years or two affected second-degree relatives (1.54, 95% confidence interval: 1.46-1.61) than those with one affected first-degree relative diagnosed <60 years or ≥2 affected first-degree relatives (1.25, 95% confidence interval: 1.14-1.37). CONCLUSIONS: Compliance with colonoscopy guidelines was higher for those with familial risk but did not correspond with the degree of risk.

A multicenter study of vesicovaginal fistula following incidental cystotomy during benign hysterectomies.

INTRODUCTION AND HYPOTHESIS: To evaluate factors for vesicovaginal fistula (VVF) formation following incidental cystotomies during benign hysterectomies. METHODS: Hysterectomies performed at two university centers between January 1, 2000 and December 31, 2008 were reviewed. Demographic and operative data were abstracted. Patients who developed VVF were compared to those with no VVF. RESULTS: During the study period, 5,698 hysterectomies performed for benign indications were identified. One hundred two (1.8%) cystotomies occurred with 6 (5.9%) developing a VVF. Patients with VVF were more likely to have uteri weighing > 250 g (83% vs. 36%, P = 0.03), had longer surgeries (317 ± 82 vs. 208 ± 10 min, P = 0.02) and more ureteral injuries (33% vs. 1%, P = 0.009). American Association for the Surgery of Trauma (AAST) grade V bladder injuries (OR, 93.00; 95% CI, 10.30-838.92) were associated with VVF formation. CONCLUSIONS: Patients with AAST grade V bladder injuries are at increased risk for developing vesicovaginal fistulas following incidental cystotomies during benign hysterectomies.

How well does family history predict who will get colorectal cancer? Implications for cancer screening and counseling.

PURPOSE: Using a large, retrospective cohort from the Utah Population Database, we assess how well family history predicts who will acquire colorectal cancer during a 20-year period. METHODS: Individuals were selected between ages 35 and 80 with no prior record of colorectal cancer diagnosis, as of the year 1985. Numbers of colorectal cancer-affected relatives and diagnosis ages were collected. Familial relative risk and absolute risk estimates were calculated. Colorectal cancer diagnoses in the cohort were counted between years 1986 and 2005. Cox regression and Harrell's C were used to measure the discriminatory power of resulting models. RESULTS: A total of 431,153 individuals were included with 5,334 colorectal cancer diagnoses. Familial relative risk ranged from 0.83 to 12.39 and 20-year absolute risk from 0.002 to 0.21. With familial relative risk as the only predictor, Harrell's C = 0.53 and with age only, Harrell's C = 0.66. Familial relative risk combined with age produced a Harrell's C = 0.67. CONCLUSION: Family history by itself is not a strong predictor of exactly who will acquire colorectal cancer within 20 years. However, stratification of risk using absolute risk probabilities may be more helpful in focusing screening on individuals who are more likely to develop the disease.

Retroperitoneal hematoma presenting as an adnexal mass after femoral catheterization.

BACKGROUND: One complication of femoral artery catheterization is postprocedure pelvic hematoma. These hematomas can be difficult to differentiate from adnexal masses. CASES: Two women who had undergone femoral artery catheterization presented with pelvic pain within 3 months of the procedure. Imaging studies revealed a nonspecific adnexal mass, and CA 125 levels were normal. Both women underwent exploratory laparotomy for an adnexal mass and were found to have an organized retroperitoneal hematoma. CONCLUSION: An organizing or well-formed retroperitoneal hematoma should be added to the differential diagnosis in a patient with a poorly defined adnexal mass who has had a recent femoral artery catheterization. In patients with a mass less than 10 cm and normal CA 125 (less than 35 units/mL), continued close observation or magnetic resonance imaging scan may be considered.