Delivery Protocol Research Articles

Cochlear pharmacokinetics - Micro-computed tomography and learning-prediction modeling for transport parameter determination

Inner ear disorders such as sensorineural deafness and genetic diseases may one day be treated with local drug delivery to the inner ear. Current pharmacokinetic models have been based on invasive methods to measure drug concentrations, limiting them in spatial resolution, and restricting the research to larger rodents. We developed an intracochlear pharmacokinetic model based on an imaging, learning-prediction (LP) paradigm for learning transport parameters in the murine cochlea. This was achieved using noninvasive micro-computed tomography imaging of the cochlea during in vivo infusion of a contrast agent at the basal end of scala tympani through a cochleostomy. Each scan was registered in 3-D to a cochlear atlas to segment the cochlear regions with high accuracy, enabling concentrations to be extracted along the length of each scala. These spatio-temporal concentration profiles were used to learn a concentration dependent diffusion coefficient, and transport parameters between the major scalae and to clearance. The LP model results are comparable to the current state of the art model, and can simulate concentrations for cases involving different infusion molecules and different drug delivery protocols. Forward simulation results with pulsatile delivery suggest the pharmacokinetic model can be used to optimize drug delivery protocols to reduce total drug delivered and the potential for toxic side effects. While developed in the challenging murine cochlea, the processes are scalable to larger animals and different drug infusion paradigms.

Fog-aided wireless networks for content delivery: A file-level carrier sensing based approach

We investigate a novel file-level carrier sensing based content delivery (FL-CSBCD) protocol to accommodate the transmission of multimedia files in fog-aided wireless networks. Particularly, the proposed FL-CSBCD protocol contains two phases, i.e., the file contention phase and the communication contention phase. The file contention phase aims to resolve the contentions among the requested multimedia files at each fog user equipments (F-UEs), such that the cache-hit performance is maximized. The communication contention phase is designed to resolve the collisions among concurrent content deliveries of the same file, such that the mutual interference can be suppressed. By modeling the fog-aided wireless networks with Poisson point process, we capture the density of active F-UEs, and evaluate the successful content delivery probability (SCDP) with the FL-CSBCD protocol. We show by simulations that the FL-CSBCD protocol can enhance the cache-hit performance while guarantee the coverage probability of content delivery.

Efficient and Innocuous Live-Cell Delivery: Making Membrane Barriers Disappear to Enable Cellular Biochemistry: How Better Cellular Delivery Tools Can Contribute to Precise and Quantitative Cell Biology Assays.

The confluence of protein engineering techniques and delivery protocols are providing new opportunities in cell biology. In particular, techniques that render the membrane of cells transiently permeable make the introduction of nongenetically encodable macromolecular probes into cells possible. This, in turn, can enable the monitoring of intracellular processes in ways that can be both precise and quantitative, ushering an area that one may envision as cellular biochemistry. Herein, the author reviews pioneering examples of such new cell-based assays, provides evidence that challenges the paradigm that cell penetration is a necessarily damaging and stressful event for cells, and highlights some of the challenges that should be addressed to fully unlock the potential of this nascent field.

Applications of Manganese-Enhanced Magnetic Resonance Imaging in Ophthalmology and Visual Neuroscience.

Understanding the mechanisms of vision in health and disease requires knowledge of the anatomy and physiology of the eye and the neural pathways relevant to visual perception. As such, development of imaging techniques for the visual system is crucial for unveiling the neural basis of visual function or impairment. Magnetic resonance imaging (MRI) offers non-invasive probing of the structure and function of the neural circuits without depth limitation, and can help identify abnormalities in brain tissues in vivo. Among the advanced MRI techniques, manganese-enhanced MRI (MEMRI) involves the use of active manganese contrast agents that positively enhance brain tissue signals in T1-weighted imaging with respect to the levels of connectivity and activity. Depending on the routes of administration, accumulation of manganese ions in the eye and the visual pathways can be attributed to systemic distribution or their local transport across axons in an anterograde fashion, entering the neurons through voltage-gated calcium channels. The use of the paramagnetic manganese contrast in MRI has a wide range of applications in the visual system from imaging neurodevelopment to assessing and monitoring neurodegeneration, neuroplasticity, neuroprotection, and neuroregeneration. In this review, we present four major domains of scientific inquiry where MEMRI can be put to imperative use — deciphering neuroarchitecture, tracing neuronal tracts, detecting neuronal activity, and identifying or differentiating glial activity. We deliberate upon each category studies that have successfully employed MEMRI to examine the visual system, including the delivery protocols, spatiotemporal characteristics, and biophysical interpretation. Based on this literature, we have identified some critical challenges in the field in terms of toxicity, and sensitivity and specificity of manganese enhancement. We also discuss the pitfalls and alternatives of MEMRI which will provide new avenues to explore in the future.

Better late than never: why obstetricians must implement enhanced recovery after cesarean

Despite persistent concerns about high cesarean delivery rates internationally, there has been less attention on improving perioperative outcomes for the millions of women who will experience a cesarean delivery each year. Enhanced recovery after surgery, a standardized, evidence-based, interdisciplinary protocol, has been successfully used in other surgical specialties including gynecology to improve quality of care and patient satisfaction while reducing overall health care costs through reduced length of stay. Enhanced recovery after surgery society guidelines for cesarean delivery were just released in August 2018. Obstetric patients, who face the dual challenge of being postpartum and postoperative, could benefit greatly from protocols that optimize their return to physiological function and reduce surgical morbidity. Although enhanced recovery after surgery has been widespread in other surgical specialties, uptake of this protocol in obstetrics has lagged behind. We believe enhanced recovery after surgery for cesarean delivery can effectively address 3 challenges faced by obstetrician/gynecologists. These are: (1) improving care for the high number of women undergoing cesarean deliveries; (2) using evidence-based care bundles to prevent maternal morbidity and mortality, address disparities, and reduce costs; and (3) limiting postoperative opioid prescribing in response to the opioid crisis. Enhanced recovery after surgery for cesarean delivery and other standardized care protocols have the potential to reduce the disproportionately high rates of maternal morbidity and mortality in the United States, and ensure all patients, regardless of demographics or location, receive the same level of high-quality peripartum care.

Dose verification for liver target volumes undergoing respiratory motion.

Respiratory motion has a significant impact on dose delivered to abdominal targets during radiotherapy treatment. Accurate treatment of liver tumours adjacent to the diaphragm is complicated by large respiratory movement, as well as differing tissue densities at the lung-liver interface. This study aims to evaluate the accuracy of dose delivered to superior liver tumours using passive respiratory monitoring, in the absence of gating technology, for a range of treatment techniques. An in-house respiratory phantom was designed and constructed to simulate the lung and liver anatomy. The phantom consisted of adjacent slabs of lung and liver equivalent materials and a cam drive system to emulate respiratory motion. A CC04 ionisation chamber and Gafchromic EBT3 film were used to perform point dose and dose plane measurements respectively. Plans were calculated using an Elekta Monaco treatment planning system (TPS) on exhale phase study sets for conformal, volume modulated arc therapy (VMAT) and intensity modulated radiation therapy (IMRT) techniques, with breathing rates of 8, 14 and 23bpm. Analysis confirmed the conformal delivery protocol currently used for this site within the department is suitable. The experiments also determined that VMAT is a viable alternative technique for treatment of superior liver lesions undergoing respiratory motion and was superior to IMRT. Furthermore, the measurements highlighted the need for respiratory management in these cases. Displacements due to respiration exceeding planned margins could result in reduced coverage of the clinical target volume and much higher doses to the lung than anticipated.

Structure and function of a trauma intensive care unit: A report from the Trauma Intensive Care Unit Prevalence Project.

Specialized trauma intensive care unit (TICU) care impacts patient outcomes. Few studies describe where and how TICU care is delivered. We performed an assessment of TICU structure and function at a sample of US trauma center TICUs. This was a multicenter study in which participants supplied information about their trauma centers, staff, clinical protocols, processes of care, and study TICU (the ICU admitting the majority of trauma patients). Forty-five Level I trauma centers trauma centers enrolled through the American Association for the Surgery of Trauma multi-institutional trials platform; 71.1% had less than 750 beds and 55.5% treated 1,000 to 2,999 trauma activations/year. The median number of hospital ICU beds was 109 [66-185]. 46.7% were "closed" ICUs, 20% were "open," and 82.2% had mandatory intensivist consultation. 42.2% ICUs were classified as trauma (≥80% of patients were trauma), 46.7% surgical/trauma, and 11.1% medical-surgical. Trauma ICUs had a median 10 [7-12] intensivists. Intensivists were present 24 hours/day in 80% of TICUs. Centers reported a median of 8 (interquartile range [IQR], 6-10) full-time trauma surgeons, whose ICU duties comprised 25% (IQR, 20%-40%) of their clinical time and 20% (IQR, 20-33) of total work time. A median 16 (IQR, 12-23) ICU beds in use were staffed by 10 (IQR, 7-14) nurses. There was considerable variation in the number and type of protocols used and in diagnostic methods for ventilator-associated pneumonia. Daily patient care checklists were used by 80% of ICUs. While inclusion of families on rounds was performed in 91.1% of ICUs, patient- and family-centered support programs were less common. A study of structure and function of TICUs at a sample of Level I trauma centers revealed that presence of nontrauma patients was common, critical care is a significant component of trauma surgeons' professional practice, and significant variation exists in care delivery models and protocol use. Opportunities may exist to improve care through sharing of best practices. Therapeutic/Care management, level IV.

Incorporating the Raft consensus protocol in containers managed by Kubernetes: an evaluation

ABSTRACT Replication is a technique widely used to improve the reliability of applications. State machine replication is a special approach, where a set of computers are kept synchronised in the same state despite of failures that could occur in the system. The Raft algorithm can be used to implement a total order delivery protocol, delivering requests at the same order at all replicas, which is fundamental since in this approach all replicas must execute the same sequence of requests to present the same evolution in their states. Raft is easy to understand and implement, when compared to the Paxos algorithm. On the other hand, virtualisation can be seen as a technique that helps the development of reliable applications since it maintains each virtual machine (VM) isolated from the others. Virtualisation in data centres is changing from the traditional VMs to containers. In this context, this paper proposes KRaft, an incorporation of Raft in Kubernetes, a system that manages containers. After an evaluation of performance and resource consumption of KRaft, we found that it presents performance close to Raft executing on physical machines. Moreover, KRaft demands more network transmission while Raft executed in physical machines needs more processing power and memory.

Active diffusion limited reactions.

We investigate the one- and two-dimensional diffusion limited reactions A + A → 0 and A + B → 0 with A active Janus particles and B passive particles in thermal equilibrium. We show that by increasing the self-propulsion time of the A particles, the reactant densities decay faster, at least for time transients of potential interest for chemical applications, e.g., to develop smart drug delivery protocols. Asymptotic and transient density decays obey power laws with exponents that depend on the actual annihilation reaction and its dimensionality.

Analysis of Licklider Transmission Protocol for Reliable File Delivery in Space Vehicle Communications With Random Link Interruptions

Delay/disruption tolerant networking (DTN) was proposed as a networking architecture for reliable data delivery in space vehicle communications despite long propagation delays and/or lengthy link disruptions. As one of the main data transport protocols of DTN, Licklider transmission protocol (LTP) was proposed by the NASA for reliable data delivery in challenging space environments in which the existing transport protocols of DTN, TCP, and UDP do not perform effectively. Pair-wise comparisons among LTP, TCP, and UDP running in the DTN stack have previously been done using statistical methods; evaluation results and performance analysis are available in the existing LTP research literature. However, there is as yet no solid analytical model of LTP performance in the presence of link disruptions. In this paper, we present an analytical method to predict transmission performance of LTP for reliable file delivery in space vehicle communications with focus on the expected file delivery delay (or latency) over space channels characterized by random link disruptions. Realistic file-transmission experiments using a PC-based infrastructure are presented to validate the analytical models. The analysis and study results presented in this paper are expected to be useful in understanding the impact of transmission conditions and configurations, on the efficiency of LTP when deployed for reliable data delivery in space missions using communication links that are subject to frequent and random interruptions.

Active Immunoprophylaxis and Vaccine Augmentations Mediated by a Novel Plasmid DNA Formulation.

Plasmid DNA (pDNA) gene delivery is a highly versatile technology that has the potential to address a multitude of unmet medical needs. Advances in pDNA delivery to host tissue with the employment of in vivo electroporation (EP) have led to significantly enhanced gene expression and the recent demonstration of clinical efficacy with the platform. Building upon this platform, this study reports that enzyme-mediated modification of the muscle tissue extracellular matrix structure at the site of pDNA delivery operates in a synergistic manner with EP to enhance both local and systemic gene expression further. Specifically, administration of chondroitinase ABC (Cho ABC) to the site of intramuscular delivery of pDNA led to transient disruption of chondroitin sulfate scaffolding barrier, permitting enhanced gene distribution and expression across the tissue. The employment of Cho ABC in combination with CELLECTRA® intramuscular EP resulted in increased gene expression by 5.5-fold in mice and 17.98-fold in rabbits. The study demonstrates how this protocol can be universally applied to an active prophylaxis platform to increase the in vivo production of functional immunoglobulin G, and to DNA vaccine protocols to permit drug dose sparing. The data indicate the Cho ABC formulation to be of significant value upon combination with EP to drive enhanced gene expression levels in pDNA delivery protocols.

Mixed therapy in cancer treatment for personalized drug administration using model reference adaptive control

The paper presents Model Reference Adaptive Control (MRAC) design strategy to determine personalized drug delivery protocol for mixed therapy with chemotherapy and immunotherapy in cancer treatment. We consider a nonlinear mathematical ODE set for cancer dynamics that includes tumor, natural killers, circulating lymphocytes and cytotoxic T-cells population together with the interaction of chemotherapy and immunotherapy. For researchers and physicians, the main challenge in mathematical models is the determination of the exact model parameters. In order to have a drug administration policy for a patient with unknown parameter set, we develop State Dependent Riccati Equations (SDRE) based MRAC design approach to determine the personalized drug delivery protocol for patients with unknown model parameters. First of all, we determine the optimal drug delivery scenario for a reference patient with known dynamics parameters using SDRE approach. Then for any patient with unknown parameters, the personalized mixed therapy protocol is determined based on the treatment regimen of the reference patient. In the proposed methodology, unknown patients are considered as a black-box simulator in the design and the mathematical model parameters of the patient are not essential for the design of drug administration protocol. In addition, the Bang-Bang and continuous drug delivery regimens could be obtained using proper adaptation gains in the presented MRAC methodology. The simulation results demonstrate the effectiveness of the proposed MRAC approach for prescribing a treatment regimen of chemo-immunotherapy.

Accumulating Transcriptome Drift Precedes Cell Aging in Human Umbilical Cord-Derived Mesenchymal Stromal Cells Serially Cultured to Replicative Senescence.

In preclinical studies, mesenchymal stromal cells (MSCs) exhibit robust potential for numerous applications. To capitalize on these benefits, cell manufacturing and delivery protocols have been scaled up to facilitate clinical trials without adequately addressing the impact of these processes on cell utility nor inevitable regulatory requirements for consistency. Growing evidence indicates that culture-aged MSCs, expanded to the limits of replicative exhaustion to generate human doses, are not equivalent to early passage cells, and their use may underpin reportedly underwhelming or inconsistent clinical outcomes. Here, we sought to define the maximum expansion boundaries for human umbilical cord-derived MSCs, cultured in chemically defined xeno- and serum-free media, that yield consistent cell batches comparable to early passage cells. Two male and two female donor populations, recovered from cryostorage at mean population doubling level (mPDL) 10, were serially cultivated until replicative exhaustion (senescence). At each passage, growth kinetics, cell morphology, and transcriptome profiles were analyzed. All MSC populations displayed comparable growth trajectories through passage 9 (P9; mPDL 45) and variably approached senescence after P10 (mPDL 49). Transcription profiles of 14,500 human genes, generated by microarray, revealed a nonlinear evolution of culture-adapted MSCs. Significant expression changes occurred only after P5 (mPDL 27) and accumulated rapidly after P9 (mPDL 45), preceding other cell aging metrics. We report that cryobanked umbilical cord-derived MSCs can be reliably expanded to clinical human doses by P4 (mPDL 23), before significant transcriptome drift, and thus represent a mesenchymal cell source suited for clinical translation of cellular therapies. Stem Cells Translational Medicine 2019;8:945&958.

A Grey Wolf Optimization Approach for Improving the Performance of Wireless Sensor Networks

Optimizing the energy consumption of sensor nodes have been a big design issue in wireless sensor networks (WSNs). Energy efficient WSN usually compromise with network stability which is a crucial factor in ensuring full, lasting and reliable coverage of the network. Connected dominating set (CDS) based virtual backbone and traditional cluster based approach are two most commonly used data delivery protocols in a WSN. The paper proposes a distance based stable connected dominating set methodology using a meta-heuristic algorithm grey wolf optimization (DBSCDS-GWO) for achieving a stable, balanced and energy efficient CDS based WSN. We also propose a distance based stable clustering algorithm using GWO (DBSC-GWO) for improving the performance of cluster based WSN. DBSCDS-GWO performs better than RMCDS-GA and SAECDS-GA by 70.5% and 67.7% respectively and DBSC-GWO performs better than LEACH and DRESEP by 74.7% and 50.6% respectively in terms of both network stability and energy efficiency. Performance of the proposed algorithm is validated using Matlab simulation and Netsim Emulator.

MemepiC: Towards a Unified In-Memory Big Data Management System

In-memory data management systems have recently gained a lot of attraction due to cheaper and faster DRAM and other hardware advancement. However, these systems are either pure storage systems with online data query service, or just offline batch processing systems with data analytics functionality. Heavy data movement (e.g., data loading) occurs in order to analyze the data. In this paper, we propose an innovative in-memory data management system—MemepiC, which unifies both online data query and data analytics functionality, allowing low-latency storage service and efficient in-situ data analytics. We also explore the emerging RDMA technique in the context of in-memory data management systems, by designing an RDMA-based communication protocol for message delivery inside MemepiC, and proposing to overlap execution and RDMA communication. Extensive experiments are conducted to show the superior performance of MemepiC in terms of both the storage and the data analytics services, compared against other in-memory systems.

Successful Genetic Transfection of the Colonic Protistan Parasite Blastocystis for Reliable Expression of Ectopic Genes

The microbial parasite Blastocystis colonizes the large intestines of numerous animal species and increasing evidence has linked Blastocystis infection to enteric diseases with signs and symptoms including abdominal pain, constipation, diarrhea, nausea, vomiting, and flatulence. It has also recently been reported to be an important member of the host intestinal microbiota. Despite significant advances in our understanding of Blastocystis cell biology and host-parasite interactions, a genetic modification tool is absent. In this study, we successfully established a robust gene delivery protocol for Blastocystis subtype 7 (ST7) and ectopic protein expression was further tested using a high sensitivity nano-luciferase (Nluc) reporter system, with promoter regions from several genes. Among them, a strong promoter encompassing a region upstream of the legumain 5′ UTR was identified. Using this promoter combined with the legumain 3′ UTR, which contains a conserved, precise polyadenylation signal, a robust transient transfection technique was established for the first time in Blastocystis. This system was validated by ectopic expression of proteins harbouring specific localization signals. The establishment of a robust, reproducible gene modification system for Blastocystis is a significant advance for Blastocystis research both in vitro and in vivo. This technique will spearhead further research to understand the parasite’s biology, its role in health and disease, along with novel ways to combat the parasite.

Validation of an integrated satellite-data-driven response to an effusive crisis: the April–May 2018 eruption of Piton de la Fournaise

Satellite-based surveillance of volcanic hot spots and plumes can be coupled with modeling to allow ensemble-based approaches to crisis response. We complete benchmark tests on an effusive crisis response protocol aimed at delivering product for use in tracking lava flows. The response involves integration of four models: MIROVA for discharge rate (TADR), the ASTER urgent response protocol for delivery of high-spatial resolution satellite data, DOWNFLOW for flow path projections, and PyFLOWGO for flow run-out. We test the protocol using the data feed available during Piton de la Fournaise’s April–May 2018 eruption, with product being delivered to the Observatoire du Piton de la Fournaise via Google Drive. The response was initialized by an alert at 19:50Z on 27 April 2018. Initially DOWNFLOW-FLOWGO were run using TADRs typical of Piton de la Fournaise, and revealed that flow at >120 m 3 /s could reach the island belt road. The first TADR (10–20 m 3 /s) was available at 09:55Z on 28 April, and gave flow run-outs of 1180–2510 m. The latency between satellite overpass and TADR provision was 105 minutes, with the model result being posted 15 minutes later. An InSAR image pair was completed two hours after the eruption began, and gave a flow length of 1.8 km; validating the run-out projection. Thereafter, run-outs were updated with each new TADR, and checked against flow lengths reported from InSAR and ASTER mapping. In all, 35 TADRs and four InSAR image pairs were processed during the 35-day-long eruption, and 11 ASTER images were delivered.

Electroporation of short hairpin RNAs for rapid and efficient gene knockdown in the starlet sea anemone, Nematostella vectensis

A mechanistic understanding of evolutionary developmental biology requires the development of novel techniques for the manipulation of gene function in phylogenetically diverse organismal systems. Recently, gene-specific knockdown by microinjection of short hairpin RNA (shRNA) was applied in the sea anemone Nematostella vectensis, demonstrating that the shRNA approach can be used for efficient and robust sequence-specific knockdown of a gene of interest. However, the time- and labor-intensive process of microinjection limits access to this technique and its application in large scale experiments. To address this issue, here we present an electroporation protocol for shRNA delivery into Nematostella eggs. This method leverages the speed and simplicity of electroporation, enabling users to manipulate gene expression in hundreds of eggs or embryos within minutes. We provide a detailed description of the experimental procedure, including reagents, electroporation conditions, preparation of Nematostella eggs, and follow-up care of experimental animals. Finally, we demonstrate the knockdown of several endogenous and exogenous genes with known phenotypes and discuss the potential applications of this method.

Secure and efficient data delivery for fog-assisted wireless body area networks

The growth of remote patient monitoring technology introduces new opportunities for improving patient outcomes, and Wireless Body Area Networks (WBANs) are a key piece in building a successful system. However, due to the limited power and computational resources of WBAN sensor nodes, combined with user mobility and large network coverage areas, integrating WBANs with cloud and fog computing presents one of the most viable options for successful remote monitoring. In order to help maintain the real-time operations of a fog-assisted WBAN, we propose a secure and efficient data delivery protocol that will reduce delay and protect against malicious attacks on the wireless signal. The protocol is composed of three custom algorithms that address channel assignment, gateway association, and introduce a new delay- and energy-aware routing metric. The channel assignment algorithm is designed to minimize and avoid interference, including jamming nodes. The fog gateway association algorithm helps to improve the efficiency and security of the connection between the WBAN and the remote resources. Similarly, the proposed routing metric is used to construct routes that both minimize delay and conserve power at the nodes along the path for improved efficiency and lifespan of the network. The system was simulated and tested under a variety of conditions to evaluate its performance in regards to mutual interference, human mobility, fog density, and attacks by jamming nodes. The results showed clear improvements in the efficiency and resiliency of the fog-assisted WBAN system when utilizing our protocol.

Influence of implementing a protocol for an intravenously administered ammonia scavenger on the management of acute hyperammonemia in a pediatric intensive care unit.

The purpose of the study was to evaluate the influence of establishing a protocol for the use of combined sodium benzoate and sodium phenylacetate (SBSP) (Ammonul®) to treat acute hyperammonemia. This was a retrospective, single-center study in a 24-bed medical and surgical pediatric intensive care unit (PICU) in a tertiary care teaching maternal-child hospital in Canada. Inclusion criteria were age < 18 years, PICU admission between 1 January 2000 and 30 June 2016, and SBSP treatment. An SBSP delivery protocol was implemented in our hospital on 30 August 2008 in order to improve management of acute hyperammonemia. Patients were assigned to one of the two groups, without or with protocol, depending on date of admission. SBSP was ordered 34 times during the study period, and 23 orders were considered for analysis (14 with and 9 without protocol). Patient characteristics were similar between groups. The median time from diagnosis to prescription was significantly shorter in the protocol group [40 min (21-82) vs 100 min (70-150), p = 0.03)] but the median time from diagnosis to administration of the treatment was equivalent [144 min (90-220) vs 195 (143-274), (p = 0.2)]. Other clinical outcomes did not differ. This study is the first to compare two SBSP delivery strategies in the treatment of acute hyperammonemia in this PICU setting. Implementation of a delivery protocol shortened the time from diagnosis of hyperammonemia to prescription of SBSP and helped us identify other parameters that can be improved to optimize treatment delivery.