Delivery Paradigm Research Articles

Noninvasive, neuron-specific gene therapy can be facilitated by focused ultrasound and recombinant adeno-associated virus.

Recombinant adeno-associated virus (rAAV) has shown great promise as a potential cure for neurodegenerative diseases. The existence of the blood-brain barrier (BBB), however, hinders efficient delivery of the viral vectors. Direct infusion through craniotomy is the most commonly used approach to achieve rAAV delivery, which carries increased risks of infection and other complications. Here, we report a focused ultrasound (FUS)-facilitated noninvasive rAAV delivery paradigm that is capable of producing targeted and neuron-specific transductions. Oscillating ultrasound contrast agents (microbubbles), driven by FUS waves, temporarily 'unlock' the BBB, allowing the systemically administrated rAAVs to enter the brain parenchyma, while maintaining their bioactivity and selectivity. Taking the advantage of the neuron-specific promoter synapsin, rAAV gene expression was triggered almost exclusively (95%) in neurons of the targeted caudate-putamen region. Both behavioral assessment and histological examination revealed no significant long-term adverse effects (in the brain and several other critical organs) for this combined treatment paradigm. Results from this study demonstrated the feasibility and safety for the noninvasive, targeted rAAV delivery, which might have open a new avenue in gene therapy in both preclinical and clinical settings.

Critical care telemedicine: evolution and state of the art.

To review the growth and current penetration of ICU telemedicine programs, association with outcomes, studies of their impact on medical education, associations with medicolegal risks, identify program revenue sources and costs, regulatory aspects, and the ICU telemedicine research agenda. Review of the published medical literature, governmental documents, and opinions of experts from the Society of Critical Care Medicine ICU Telemedicine Committee. Formal ICU telemedicine programs now support 11% of nonfederal hospital critically ill adult patients. There is increasingly robust evidence of association with lower ICU (0.79; 95% CI, 0.65-0.96) and hospital mortality (0.83; 95% CI, 0.73-0.94) and shorter ICU (-0.62 d; 95% CI, -1.21 to -0.04 d) and hospital (-1.26 d; 95% CI, -2.49 to -0.03 d) length of stay. Physicians in training report experiences with telemedicine intensivists that are positive and increased patient safety. Early studies suggest that implementation of ICU telemedicine programs has been associated with lower numbers of malpractice claims and costs. The requirements for Medicare reimbursement and states with legislation addressing providing professional services by telemedicine are detailed. The inclusion of an ICU telemedicine program as a major part of their critical care delivery paradigm has been implemented for 11% of critically ill U.S. adults as a solution for the problem of access to adult critical care services. Implementation of an ICU telemedicine program is one practical way to increase access and reduce mortality as well as length of stay. ICU telemedicine research including comparative effectiveness studies is urgently needed.

Affinity-based drug delivery systems for tissue repair and regeneration.

Affinity-based release systems use transient interactions to sustain and control the release of a therapeutic from a polymeric matrix. The most common affinity-based systems use heparin-based scaffolds to sustain the release of heparin-binding proteins, such as fibroblast growth factor-2 (FGF2) and vascular endothelial growth factor (VEGF). However, novel affinity-based systems based on, for example, protein-protein or DNA-protein interactions, are emerging to control the release of an expanding repertoire of therapeutics. Mathematical models of affinity-based systems have provided a thorough understanding of which parameters affect release rate from these systems, and how these release rates can be tuned. In this review, recent affinity-based release systems will be described, including an overview of the various types of affinity interactions used to modulate release, the mechanisms by which release from these systems is tuned, and the time scales of sustained release. This advanced drug delivery paradigm provides tunable and predictable release rates and has expanded the scope of deliverable therapeutics for tissue repair and regeneration.

Toward green media delivery: location-aware opportunities and approaches

Mobile media has undoubtedly become the predominant source of traffic in wireless networks. The result is not only congestion and poor quality of experience, but also an unprecedented energy drain at both the network and user devices. In order to sustain this continued growth, novel disruptive paradigms of media delivery are urgently needed. We envision that two key contemporary advancements can be leveraged to develop greener media delivery platforms: The proliferation of navigation hardware and software in mobile devices has created an era of location awareness, where both the current and future user locations can be predicted; and the rise of context-aware network architectures and self-organizing functionalities is enabling context signaling and in-network adaptation. With these developments in mind, this article investigates the opportunities of exploiting location awareness to enable green end-to-end media delivery. In particular, we discuss and propose approaches for location-based adaptive video quality planning, in-network caching, content prefetching, and long-term radio resource management. To provide insights on the energy savings, we then present a cross-layer framework that jointly optimizes resource allocation and multi-user video quality using location predictions. Finally, we highlight some of the future research directions for location-aware media delivery in the conclusion.

A micropatterning approach for imaging dynamic Cx43 trafficking to cell–cell borders

The precise expression and timely delivery of connexin 43 (Cx43) proteins to form gap junctions are essential for electrical coupling of cardiomyocytes. Growing evidence supports a cytoskeletal-based trafficking paradigm for Cx43 delivery directly to adherens junctions at the intercalated disc. A limitation of Cx43 localization assays in cultured cells, in which cell-cell contacts are essential, is the inability to control for cell geometry or reproducibly generate contact points. Here we present a micropatterned cell pairing system well suited for live microscopy to examine how the microtubule and actin cytoskeleton confer specificity to Cx43 trafficking to precisely defined cell-cell junctions. This system can be adapted for other cell types and used to study dynamic intracellular movements of other proteins important for cell-cell communication.

Cloud computing Standardization Initiatives: State of Play

Cloud computing is an evolutionary paradigm for service delivery in IT industry. Technological evolution and adoption of cloud by reputed companies diverge into development of too many standards. With the wide spread of the technology, these standards cause problems like vendor lock-in, portability, interoperability, preventing the future adoption of cloud computing. Many standardized bodies have developed their own standards but still their adoption is difficult and complex. In this paper, a systematic and comprehensive survey is conducted for finding current standard initiatives by different Standard Development Organizations (SDO), Technical Forums and Government Organizations. Aim of the survey is to understand different standards, their standardization area, and gaps in standardization for cloud computing. Survey will provides information for work done till date and helps researchers to not repeat the work which is already done. Based on the result of the survey, some recommendations are suggested which encourages standardization communities to adopt and build common standard by taking consideration from industries and standard development agencies.

Future Trends in Health and Health Care: Implications for Social Work Practice in an Aging Society

Major economic, political, demographic, social, and operational system factors are prompting evolutionary changes in health care delivery. Of particular significance, the “graying of America” promises new challenges and opportunities for health care social work. At the same time, the Patient Protection and Affordable Care Act of 2010, evolution of Accountable Care Organizations, and an emphasis on integrated, transdisciplinary, person-centered care represent fundamental shifts in service delivery with implications for social work practice and education. This article identifies the aging shift in American demography, its impact on health policy legislation, factors influencing fundamentally new service delivery paradigms, and opportunities of the profession to address the health disparities and care needs of an aging population. It underscores the importance of social work inclusion in integrated health care delivery and offers recommendations for practice education.

Cellular Therapeutics Delivery to the Spinal Cord: Technical Considerations for Clinical Application

Current literature demonstrates the efficacy of cell-based therapeutics in small animal models of varied spinal cord diseases. However, logistic challenges remain towards development of an optimized delivery approach to the human spinal cord. Clinical trials utilize a variety of methods to achieve this aim. In this article, the authors review currently employed delivery methods, compare the merits of alternate delivery paradigms, introduce their implementation in completed and ongoing clinical trials, and discuss promising near-term advances in image-guided delivery and in vivo graft tracking.

Sol–gel silica controlled release thin films for the inhibition of methicillin-resistant Staphylococcus aureus

The incidence of methicillin-resistant Staphylococcus aureus (MRSA) infection has significantly increased. Generally, the success of this bacterium as a pathogen is attributed to its ability to adhere to surfaces and remain there, under the protection of an extracellular matrix known as biofilm. To combat MRSA with regular doses of vancomycin, efforts are continuously underway to increase its effectiveness. A promising technique is to use combinational therapeutics. In vitro experiments showed that farnesol can be used as an adjuvant with conventional antibiotics. Farnesol is a natural sesquiterpenoid and quorum-sensing molecule. The biggest obstacle to using this concept is that farnesol is highly water insoluble. This compromises its bioavailability if it were to be used along with vancomycin at the site of infection when the treatment needs to be administered in vivo. Herein we designed an efficient therapeutic strategy for the simultaneous delivery of both antibiotic and adjuvant in order to treat MRSA infections. We demonstrate that sufficient quantities of both vancomycin and farnesol can be incorporated into sol–gel silica applied as thin films on an implant surface. The incorporation of the hydrophobic farnesol does not affect the stability of the thin films and neither does it affect the controlled release of vancomycin. The data demonstrate the potent adjuvant effect of farnesol on vancomycin in inhibiting MRSA infection. In vitro experiments show the complete inhibition (106 fold reduction in growth compared to control) of methicillin-sensitive S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) when the ratio of vancomycin to farnesol in the sol–gel silica films is optimized. The local delivery of antibiotics minimizes the need for systemic antibiotics. The incorporation of vancomycin and farnesol into thin sol–gel films represents a new treatment paradigm for the topical delivery of antibiotics with adjuvant. The potential clinical benefits are significant and include avoiding the need for revision surgery, preventing surgical site infection and controlling healthcare costs.

A new era for resident duty hours in surgery calls for greater emphasis on resident wellness

A new era for resident duty hours in surgery calls for greater emphasis on resident wellness

A Theocratical Exploration of Governance, as a Paradigm for Social Welfare Delivery

A Theocratical Exploration of Governance, as a Paradigm for Social Welfare Delivery

Bombarding cancer: biolistic delivery of therapeutics using porous Si carriers.

A new paradigm for an effective delivery of therapeutics into cancer cells is presented. Degradable porous silicon carriers, which are tailored to carry and release a model anti-cancer drug, are biolistically bombarded into in-vitro cancerous targets. We demonstrate the ability to launch these highly porous microparticles by a pneumatic capillary gene gun, which is conventionally used to deliver cargos by heavy metal carriers. By optimizing the gun parameters e.g., the accelerating gas pressure, we have successfully delivered the porous carriers, to reach deep targets and to cross a skin barrier in a highly spatial resolution. Our study reveals significant cytotoxicity towards the target human breast carcinoma cells following the delivery of drug-loaded carriers, while administrating empty particles results in no effect on cell viability. The unique combination of biolistics with the temporal control of payload release from porous carriers presents a powerful and non-conventional platform for designing new therapeutic strategies.

α-Lipoic acid antioxidant treatment limits glaucoma-related retinal ganglion cell death and dysfunction.

Oxidative stress has been implicated in neurodegenerative diseases, including glaucoma. However, due to the lack of clinically relevant models and expense of long-term testing, few studies have modeled antioxidant therapy for prevention of neurodegeneration. We investigated the contribution of oxidative stress to the pathogenesis of glaucoma in the DBA/2J mouse model of glaucoma. Similar to other neurodegenerative diseases, we observed lipid peroxidation and upregulation of oxidative stress-related mRNA and protein in DBA/2J retina. To test the role of oxidative stress in disease progression, we chose to deliver the naturally occurring, antioxidant α-lipoic acid (ALA) to DBA/2J mice in their diet. We used two paradigms for ALA delivery: an intervention paradigm in which DBA/2J mice at 6 months of age received ALA in order to intervene in glaucoma development, and a prevention paradigm in which DBA/2J mice were raised on a diet supplemented with ALA, with the goal of preventing glaucoma development. At 10 and 12 months of age (after 4 and 11 months of dietary ALA respectively), we measured changes in genes and proteins related to oxidative stress, retinal ganglion cell (RGC) number, axon transport, and axon number and integrity. Both ALA treatment paradigms showed increased antioxidant gene and protein expression, increased protection of RGCs and improved retrograde transport compared to control. Measures of lipid peroxidation, protein nitrosylation, and DNA oxidation in retina verified decreased oxidative stress in the prevention and intervention paradigms. These data demonstrate the utility of dietary therapy for reducing oxidative stress and improving RGC survival in glaucoma.

How Obamacare Will Impact Reproductive Health

For many years, health care delivery in the United States was accomplished through a complicated and evolving series of publicly and privately available insurance programs. In recent years, the increasing cost of health care as well as the relatively large number of individuals without any health care insurance coverage has prompted repeated attempts to modify or overhaul the current health care delivery paradigm. The largest legislative change to this system occurred on March 23, 2010, when President Barack Obama signed into law the Patient Protection and Affordable Care Act (PPACA).The PPACA is a multifaceted and sweeping piece of legislation. The law introduces a myriad number of changes into both public and private health insurance. Understanding the law, its implications, and how to navigate through these changes is essential to provide high-quality health care to patients. Although the law or parts of it are still at risk of being modified either through judicial or political action, it is important to recognize the current aspects of the law to understand any future modifications. Providing health care coverage in the United States is sure to be as it has always been: a constantly changing and evolving set of private and public policies that carry with them significant complexities and challenges. Health care providers must constantly strive to maximize access to and quality of medical care in whatever paradigm evolves in the future.

An initial and rapid step of lytic granule secretion precedes microtubule organizing center polarization at the cytotoxic T lymphocyte/target cell synapse

It is presently assumed that lethal hit delivery by cytotoxic T lymphocytes (CTLs) is mechanistically linked to centrosome polarization toward target cells, leading to dedicated release of lytic granules within a confined secretory domain. Here we provide three lines of evidence showing that this mechanism might not apply as a general paradigm for lethal hit delivery. First, in CTLs stimulated with immobilized peptide-MHC complexes, lytic granules and microtubule organizing center localization into synaptic areas are spatio-temporally dissociated, as detected by total internal reflection fluorescence microscopy. Second, in many CTL/target cell conjugates, lytic granule secretion precedes microtubule polarization and can be detected during the first minute after cell-cell contact. Third, inhibition of microtubule organizing center and centrosome polarization impairs neither lytic granule release at the CTL synapse nor killing efficiency. Our results broaden current views of CTL biology by revealing an extremely rapid step of lytic granule secretion and by showing that microtubule organizing center polarization is dispensable for efficient lethal hit delivery.

Sonoporation as a Cellular Stress: Induction of Morphological Repression and Developmental Delays

For sonoporation to be established as a drug/gene delivery paradigm, it is essential to account for the biological impact of this membrane permeation strategy on living cells. Here we provide new insight into the cellular impact of sonoporation by demonstrating in vitro that this way of permeating the plasma membrane may inadvertently induce repressive cellular features even while enhancing exogenous molecule uptake. Both suspension-type (HL-60) and monolayer (ZR-75-30) cells were considered in this investigation, and they were routinely exposed to 1-MHz pulsed ultrasound (pulse length, 100 cycles; pulse repetition frequency, 1 kHz; exposure period, 60 s) with calibrated field profile (spatial-averaged peak negative pressure, 0.45 MPa) and in the presence of microbubbles (cell:bubble ratio, 10:1). The post-exposure morphology of sonoporated cells (identified as those with calcein internalization) was examined using confocal microscopy, and their cell cycle progression kinetics were analyzed using flow cytometry. Results show that for both cell types investigated, sonoporated cells exhibited membrane shrinkage and intra-cellular lipid accumulation over a 2-h period. Also, as compared with normal cells, the deoxyribonucleic acid synthesis duration of sonoporated cells was significantly lengthened, indicative of a delay in cell cycle progression. These features are known to be characteristics of a cellular stress response, suggesting that sonoporation indeed constitutes as a stress to living cells. This issue may need to be addressed in optimizing sonoporation for drug/gene delivery purposes. On the other hand, it raises opportunities for developing other therapeutic applications via sonoporation.

The Identification of Quality Attributes for SaaS in Cloud Computing

Cloud computing is a new paradigm for delivery of applications, platforms, or computing resources (processing power/bandwidth/storage) to customers in a “pay-as-you-go-model”. It can be categorized Software as a Service (SaaS), Platform as a Service (PaaS) and Infrastructure as a Service (PaaS). Especially, SaaS is a potential segment and have many advantages such as investment reduction, performance improvement, time saving, easier collaboration, global accessibility, and so on. However, in spite of these importance and advantages, there are few researches about identification for the quality and making quality attributes for SaaS in cloud computing. In this paper, we propose identification of quality attributes for QoS of SaaS in cloud computing. In order to construct their quality’s attributes fitting on SaaS characteristics, we extract their attributes from ISO/IEC 9126 and design the QoS model for SaaS.

Achieving Holistic Health for the Individual through Person-Centered Collaborative Care Supported by Informatics

ObjectivesThis article seeks to describe the current state of informatics supported collaborative care and to point out areas of future research in this highly interdisciplinary field.MethodsIn this article, person-centered collaborative care is seen as a concept addressing both the provision of care over organizational borders between health and social care, and within care teams as well as the changed patient/client-care provider relationship characterized by increased patient/client involvement.ResultsFrom a health systems perspective, there are several attempts to describe the conceptual and theoretical basis for collaborative care indicating that agreement on core concepts and terminology is difficult. From an informatics perspective, focus is on standardization of clinical content models and terminology to achieve interoperability of information technology systems and to support standardized care pathways. Few examples look into how ad-hoc collaborative care processes can be supported using information technology and informatics standards. Nevertheless, promising examples do exist showing that integrational Information Communication Technology services can be supportive for collaborative care developments. However, the current landscape consists of many fragmented, often technology-driven eHealth solutions targeting specific diagnostic groups in geographically and/or organizationally restricted settings.ConclusionsA systematic approach incorporating organizational, clinical, informatics and social science knowledge is needed to perform further research in areas such as virtual team partnerships, new paradigms of care delivery, data and knowledge management as well as its secure sharing. Also organizational and legal aspects need to be further researched in order to facilitate the coordinated provision of health and social care to citizens including self-management, utilizing informatics support in a societal context.

A View Of Cloud Computing

Today’s IT infrastructure is under tremendous pressure and is finding it difficult to keep up. In distributed computing environments, up to 85 percent of computing capacity sits idle. 66 percent of every dollar on IT is spent on maintaining current IT infrastructures versus adding new capabilities. In history, operations have industrialized to become smarter. Cloud Computing is positioned to industrialize the IT delivery of the future. It is a natural evolution of the widespread adoption of multiple technical advances in the distributed computing area including virtualization, grid computing, autonomic computing, utility computing and software-as-a-service. It provides a new paradigm for consumption and delivery of IT based services – It provides an enhanced user experience with a self-service user interface for IT management. It abstracts the technical details from end-users so that they no longer need expertise in, or control over, the technology infrastructure “in the cloud” that supports them. It provides flexible pricing based on pay per usage. It enables flexible delivery and sourcing models including private, public and hybrid clouds. Finally, it provides automated provisioning and elastic scaling of IT infrastructure. This paper presents several views on different perspectives of Cloud Computing, including technical advancement, IT delivery and deployment modes, and economics.

A hybrid approach for the personalisation of cloud-based e-governance services

Cloud computing is a new and promising paradigm for service delivery including computing resources over the internet. Cloud computing standards and architecture play an important role in benefiting governments by reducing operating costs and increasing governance effectiveness. Cloud-based e-governance contributes to managing security, reducing cost based on a pay-as-you-go method, IT labour cost reduction, and increasing scalability. Given the importance of cloud computing in the today's emerging technologies, personalisation in cloud computing is also significant in supporting users to obtain what they need without being required to request it explicitly. This research will focus mainly on a personalisation algorithm to for cloud computing. A case study in which a user can suggest the language they want to use without making an explicit request will be provided to assist further understanding of the new algorithm, which is a combination of the TOPSIS and Pearson correlation coefficient methods.