Economic Evidence and Point-of-Care Testing

Health economics has been an established feature of the research, policymaking, practice and management in the delivery of healthcare. However its role is increasing as the cost of healthcare begins to drive changes in most healthcare systems. Thus the output from cost effectiveness studies is now being taken into account when making reimbursement decisions, e.g. in Australia and the United Kingdom. Against this background it is also recognised that the health economic tools employed in healthcare, and particularly the output from the use of these tools however, are not always employed in the routine delivery of services. One of the notable consequences of this situation is the poor record of innovation in healthcare with respect to the adoption of new technologies, and the realisation of their benefits.The evidence base for the effectiveness of diagnostic services is well known to be limited, and one consequence of this has been a very limited literature on cost effectiveness. One reason for this situation is undoubtedly the reimbursement strategies employed in laboratory medicine for many years, simplistically based on the complexity of the test procedure, and the delivery as a cost-per-test service. This has proved a disincentive to generate the required evidence, and little effort to generate an integrated investment and disinvestment business case, associated with care pathway changes.Point-of-care testing creates a particularly challenging scenario because, on the one hand, the unit cost-per-test is larger through the loss of the economy of scale offered by automation, whilst it offers the potential of substantial savings through enabling rapid delivery of results, and reduction of facility costs. This is important when many health systems are planning for complete system redesign. We review the literature on economic assessment of point-of-care testing in the context of these developments.     

Recent developments in the use of transgenic plants for the production of human therapeutics and biopharmaceuticals

In recent years there has been a dramatic increase in the application of plant biotechnology for the production of a variety of commercially valuable simple and complex biological molecules (biologics) for use in human and animal healthcare. Transgenic whole plants and plant cell culture systems have been developed that have the capacity to economically produce large-scale quantities of antibodies and antibody fragments, antigens and/or vaccine epitopes, metabolic enzymes, hormones, (neuro)peptides and a variety of biologically active complexes and secondary metabolites for direct use as therapeutic agents or diagnostic tools in the medical healthcare industry. As the products of genetically modified plants make their way from concept to commercialization the associated risks and acceptance by the public has been become a focal point. In this paper, we summarize the recent advances made in the use of transgenic plants and plant cell cultures as biological factories for the production of human therapeutics and biopharmaceuticals and discuss the long-term potential of `molecular farming' as a low-cost, efficient method for the production of biological materials with demonstrated utility to the pharmaceutical industry or medical community.     

Recent Trends in Drug Delivery System Using Protein Nanoparticles

Engineered nanoparticles that can facilitate drug formulation and passively target tumours have been under extensive research in recent years. These successes have driven a new wave of significant innovation in the generation of advanced particles. The fate and transport of diagnostic nanoparticles would significantly depend on nonselective drug delivery, and hence the use of high drug dosage is implemented. In this perspective, nanocarrier-based drug targeting strategies can be used which improve the selective delivery of drugs to the site of action, i.e. drug targeting. Pharmaceutical industries majorly focus on reducing the toxicity and side effects of drugs but only recently it has been realised that carrier systems themselves may pose risks to the patient. Proteins are compatible with biological systems and they are biodegradable. They offer a multitude of moieties for modifications to tailor drug binding, imaging or targeting entities. Thus, protein nanoparticles provide outstanding contributions as a carrier for drug delivery systems. This review summarises recent progress in particle-based therapeutic delivery and discusses important concepts in particle design and biological barriers for developing the next generation of particles drug delivery systems.     

Synthesis and characterization of a photocleavable cross-linker and its application on tunable surface modification and protein photodelivery

A heterobifunctional photocleavable cross-linker based on an o-nitrobenzyl ester moiety was synthesized. The cross-linker has N-hydroxysuccinimidyl and disulfide groups attached at each end and thus can anchor a protein to a gold-coated substrate surface. Steady-state spectroscopic studies suggest that the cross-linker undergoes a clean C-O fragmentation upon irradiation with a quantum yield of 0.1. Consequently, immobilized proteins (such as avidin or antibodies) on a substrate surface can be released efficiently (>95%) under UV irradiation (lambda > 300 nm) without degrading the protein functionality. We also demonstrated protein delivery via bioconjugation of protein molecules to a gold-coated atomic-force microscope (AFM) tip. When the proteins are photoreleased from the AFM tip, they are delivered to the substrate surface as protein clusters of uniform size. This has been confirmed using both AFM and fluorescence microscopy. The application of bioconjugation in this study opens a new avenue for tunable surface modification and controllable protein delivery in studies of biological systems on the nanometer scale.     

Drug delivery and nanoparticles:applications and hazards

The use of nanotechnology in medicine and more specifically drug delivery is set to spread rapidly. Currently many substances are under investigation for drug delivery and more specifically for cancer therapy. Interestingly pharmaceutical sciences are using nanoparticles to reduce toxicity and side effects of drugs and up to recently did not realize that carrier systems themselves may impose risks to the patient. The kind of hazards that are introduced by using nanoparticles for drug delivery are beyond that posed by conventional hazards imposed by chemicals in classical delivery matrices. For nanoparticles the knowledge on particle toxicity as obtained in inhalation toxicity shows the way how to investigate the potential hazards of nanoparticles. The toxicology of particulate matter differs from toxicology of substances as the composing chemical(s) may or may not be soluble in biological matrices, thus influencing greatly the potential exposure of various internal organs. This may vary from a rather high local exposure in the lungs and a low or neglectable exposure for other organ systems after inhalation. However, absorbed species may also influence the potential toxicity of the inhaled particles. For nanoparticles the situation is different as their size opens the potential for crossing the various biological barriers within the body. From a positive viewpoint, especially the potential to cross the blood brain barrier may open new ways for drug delivery into the brain. In addition, the nanosize also allows for access into the cell and various cellular compartments including the nucleus. A multitude of substances are currently under investigation for the preparation of nanoparticles for drug delivery, varying from biological substances like albumin, gelatine and phospholipids for liposomes, and more substances of a chemical nature like various polymers and solid metal containing nanoparticles. It is obvious that the potential interaction with tissues and cells, and the potential toxicity, greatly depends on the actual composition of the nanoparticle formulation. This paper provides an overview on some of the currently used systems for drug delivery. Besides the potential beneficial use also attention is drawn to the questions how we should proceed with the safety evaluation of the nanoparticle formulations for drug delivery. For such testing the lessons learned from particle toxicity as applied in inhalation toxicology may be of use. Although for pharmaceutical use the current requirements seem to be adequate to detect most of the adverse effects of nanoparticle formulations, it can not be expected that all aspects of nanoparticle toxicology will be detected. So, probably additional more specific testing would be needed.     

Health System Challenges in Organizing Quality Diabetes Care for Urban Poor in South India

Background

Weak health systems in low- and middle-income countries are recognized as the major constraint in responding to the rising burden of chronic conditions. Despite recognition by global actors for the need for research on health systems, little attention has been given to the role played by local health systems. We aim to analyze a mixed local health system to identify the main challenges in delivering quality care for diabetes mellitus type 2.

Methods

We used the health system dynamics framework to analyze a health system in KG Halli, a poor urban neighborhood in South India. We conducted semi-structured interviews with healthcare providers located in and around the neighborhood who provide care to diabetes patients: three specialist and 13 non-specialist doctors, two pharmacists, and one laboratory technician. Observations at the health facilities were recorded in a field diary. Data were analyzed through thematic analysis.

Result

There is a lack of functional referral systems and a considerable overlap in provision of outpatient care for diabetes across the different levels of healthcare services in KG Halli. Inadequate use of patients’ medical records and lack of standard treatment protocols affect clinical decision-making. The poor regulation of the private sector, poor systemic coordination across healthcare providers and healthcare delivery platforms, widespread practice of bribery and absence of formal grievance redress platforms affect effective leadership and governance. There appears to be a trust deficit among patients and healthcare providers. The private sector, with a majority of healthcare providers lacking adequate training, operates to maximize profit, and healthcare for the poor is at best seen as charity.

Conclusions

Systemic impediments in local health systems hinder the delivery of quality diabetes care to the urban poor. There is an urgent need to address these weaknesses in order to improve care for diabetes and other chronic conditions.     

Kinetically controlled cellular interactions of polymer-polymer and polymer-liposome nanohybrid systems

Although bioactive polymers such as cationic polymers have demonstrated potential as drug carriers and nonviral gene delivery vectors, high toxicity and uncontrolled, instantaneous cellular interactions of those vectors have hindered the successful implementation In Vivo. Fine control over the cellular interactions of a potential drug/gene delivery vector would be thus desirable. Herein, we have designed nanohybrid systems (100-150 nm in diameter) that combine the polycations with protective outer layers consisting of biodegradable polymeric nanoparticles (NPs) or liposomes. A commonly used polycation polyethylenimine (PEI) was employed after conjugation with rhodamine (RITC). The PEI-RITC conjugates were then encapsulated into (i) polymeric NPs made of either poly(lactide-co-glycolide) (PLGA) or poly(ethylene glycol)-b-poly(lactide-co-glycolide) (PEG-PLGA); or (ii) PEGylated liposomes, resulting in three nanohybrid systems. Through the nanohybridization, both cellular uptake and cytotoxicity of the nanohybrids were kinetically controlled. The cytotoxicity assay using MCF-7 cells revealed that liposome-based nanohybrids exhibited the least toxicity, followed by PEG-PLGA- and PLGA-based NPs after 24 h incubation. The different kinetics of cellular uptake was also observed, the liposome-based systems being the fastest and PLGA-based systems being the slowest. The results present a potential delivery platform with enhanced control over its biological interaction kinetics and passive targeting capability through size control.     

Polymer actuator valves toward controlled drug delivery application

A novel controlled drug delivery system in which drug release is achieved by electrochemically actuating an array of polymeric valves on a set of drug reservoirs has been developed. The valves are bilayer structures, made in shape of a flap hinged on one side to a valve seat, consisting of thin films of evaporated gold and electrochemically deposited polypyrrole (PPy). Drugs (dry or wet) were pre-stored in an array of these reservoirs and their release is accomplished by bending the bilayer flaps away from the substrate with a small applied bias. In vitro color dye release experiment has been conducted. Seventy-five percent less energy consumption was achieved with this bilayer polymer valve design to open a same size reservoir compared to metal-corrosion based valves. Complex release patterns such as multiple drug pulsatile release and continuous linear release have been successfully implemented through flexible control of valve actuation sequence. These valves can be actuated under closed-loop-control of sensors responding to a specific biological or environmental stimulus, leading to potential applications in advanced responsive drug delivery systems.     

A methodology for developing clinical collaborative communication systems

As healthcare organizations are struggling to enhance healthcare qualities and efficiencies, they focus on secure and efficient sharing of clinical information among healthcare providers including doctors, nurses, medical laboratories, and informal caregivers, throughout the entire healthcare life cycle. Any failure or error during this clinical collaborative communication can have negative impact on the efficiencies of the whole healthcare delivery system. This paper suggests a methodological approach to address the needs in this area and proposes a methodology for developing clinical collaborative communication (C\(^{3})\) systems. Since C\(^{3}\) demands a variety of collaborative communications among multiple healthcare stakeholders, the proposed approach focuses on the effective system design and analysis with the objective to enhance collaboration and communication in healthcare organizations.     

Protein-based tissue engineering in bone and cartilage repair

Bioactive proteins signal host or transplanted cells to form the desired tissue type. Matrix systems are utilized to locally deliver the proteins and to maintain effective protein concentrations. For some indications, a matrix is required to define the physical form of the regenerated tissue. Substantial progress has been made in bone tissue engineering in recent years, based on the results of controlled clinical studies using bone morphogenetic proteins. Ongoing research in this area centers on the design of additional delivery matrices to expand the clinical indications, using synthetic delivery systems that mimic biological qualities of the natural materials currently in use. Although a similar rationale exists for the regeneration of articular cartilage with bioactive factors, advancement in this area has not been as substantial.     

Effects of reactant heterogeneity and mixing on catabolite repression in cultures of Saccharomyces cerevisiae

An experimental study was conducted into the effect of reactant heterogeneity on glucose-fed continuous cultures of S. cerevisiae, The heterogeneity was altered by varying mixing intensity in the nutrient entry region within a static mixing device. Experimental results confirm simulation predictions based upon a simple growth model, showing that mixing in the entry region can govern macroscopic culture behavior. Specifically, at high dilution rates, the biomass concentration was reduced by mixing patterns that increased the size of regions where glucose exceeded the threshold for catabolite repression. Because the size of such repressive regions is not uniquely determined by reactant segregation, the authors argue that in biological systems (and others involving a threshold response) an alternative measure of mixing quality should be used. Conclusions are drawn concerning the simulation of biological reactors for design purposes, and the importance of nutrient delivery systems to reactor performance.     

Nanodrug Delivery Systems: A Promising Technology for Detection,Diagnosis, and Treatment of Cancer

Nanotechnology has enabled the development of novel therapeutic and diagnostic strategies, such as advances in targeted drug delivery systems, versatile molecular imaging modalities, stimulus responsive components for fabrication, and potential theranostic agents in cancer therapy. Nanoparticle modifications such as conjugation with polyethylene glycol have been used to increase the duration of nanoparticles in blood circulation and reduce renal clearance rates. Such modifications to nanoparticle fabrication are the initial steps toward clinical translation of nanoparticles. Additionally, the development of targeted drug delivery systems has substantially contributed to the therapeutic efficacy of anti-cancer drugs and cancer gene therapies compared with nontargeted conventional delivery systems. Although multifunctional nanoparticles offer numerous advantages, their complex nature imparts challenges in reproducibility and concerns of toxicity. A thorough understanding of the biological behavior of nanoparticle systems is strongly warranted prior to testing such systems in a clinical setting. Translation of novel nanodrug delivery systems from the bench to the bedside will require a collective approach. The present review focuses on recent research efforts citing relevant examples of advanced nanodrug delivery and imaging systems developed for cancer therapy. Additionally, this review highlights the newest technologies such as microfluidics and biomimetics that can aid in the development and speedy translation of nanodrug delivery systems to the clinic.     

金纳米粒在药物传递系统中的应用

金纳米粒是一种新型纳米载体,具有独特的理化、光学和生物学性质,且具有低毒性、低免疫原性、生物相容性好、体表面积大、易制备、粒径和形态可控、表面易修饰等优点,在生物医学领域和药物传递系统中具有广阔的应用前景。综述金纳米粒在小分子药物和基因药物传递系统中的应用研究新进展。     

The role of particle size distribution on bioavailability of cyclosporine: novel drug delivery system

During the long period of cyclosporine-containing dosage forms development a lot of significant findings have been done especially in the field of drug delivery systems. Currently available drugs are based, from technological point of view, on self-dispersible drug delivery systems, which contain cyclosporine solved in pharmaceutically acceptable vehicle. One can find difference among particular systems a) at particle size distribution after dispergation, b) at composition and c) at bioavailability of cyclosporine. As far as improvement of bioavailability between original brand leader formulation Sandimmune and recent brand leader formulation Neoral was followed by significant improvement in particle size distribution it was generally assumed that the reason for this improvement have been found. Several other formulations e.g. Consupren or SangCyA--self-dispersible systems, more or less correspond with above mentioned theory that smaller is better and by this principle bridged liquid based dosage forms with solid dosage forms. Bioavailability of novel drug delivery system which gives coarse dispersion with average particle size between 1-150 microns when dispersed have been tested on healthy volunteers. No difference among pharmacokinetic parameters of novel drug delivery system and microemulsion system have been observed in spite of fact that average particle size of novel system is almost 1000x bigger.     

Optical-Resolution Photoacoustic Microscopy: Auscultation of Biological Systems at the Cellular Level

Photoacoustic microscopy (PAM) offers unprecedented sensitivity to optical absorption and opens a new window to study biological systems at multiple length- and timescales. In particular, optical-resolution PAM (OR-PAM) has pushed the technical envelope to submicron length scales and millisecond timescales. Here, we review the state of the art of OR-PAM in biophysical research. With properly chosen optical wavelengths, OR-PAM can spectrally differentiate a variety of endogenous and exogenous chromophores, unveiling the anatomical, functional, metabolic, and molecular information of biological systems. Newly uncovered contrast mechanisms of linear dichroism and Förster resonance energy transfer further distinguish OR-PAM. Integrating multiple contrasts and advanced scanning mechanisms has capacitated OR-PAM to comprehensively interrogate biological systems at the cellular level in real time. Two future directions are discussed, where OR-PAM holds the potential to translate basic biophysical research into clinical healthcare.     

Light-activated proteins

A wide assortment of caged compounds, which are species whose biological activity can be unleashed with light, have been synthesized and used to investigate a variety of biological phenomena. In contrast, the construction of caged proteins and their application to biological systems has lagged far behind. Recent advances in the synthesis of caged proteins, as well as the development of intracellular protein delivery systems, furnish a framework upon which light-activated proteins can be designed, synthesized and employed to address questions of biological significance.     

Potential for industrial ecology to support healthcare sustainability: Scoping review of a fragmented literature and conceptual framework for future research

Healthcare is a critical service sector with a sizable environmental footprint from both direct activities and the indirect emissions of related products and infrastructure. As in all other sectors, the “inside‐out” environmental impacts of healthcare (e.g., from greenhouse gas emissions, smog‐forming emissions, and acidifying emissions) are harmful to public health. The environmental footprint of healthcare is subject to upward pressure from several factors, including the expansion of healthcare services in developing economies, global population growth, and aging demographics. These factors are compounded by the deployment of increasingly sophisticated medical procedures, equipment, and technologies that are energy‐ and resource‐intensive. From an “outside‐in” perspective, on the other hand, healthcare systems are increasingly susceptible to the effects of climate change, limited resource access, and other external influences. We conducted a comprehensive scoping review of the existing literature on environmental issues and other sustainability aspects in healthcare, based on a representative sample from over 1,700 articles published between 1987 and 2017. To guide our review of this fragmented literature, and to build a conceptual foundation for future research, we developed an industrial ecology framework for healthcare sustainability. Our framework conceptualizes the healthcare sector as comprising “foreground systems” of healthcare service delivery that are dependent on “background product systems.” By mapping the existing literature onto our framework, we highlight largely untapped opportunities for the industrial ecology community to use “top‐down” and “bottom‐up” approaches to build an evidence base for healthcare sustainability.     

Systems healthcare: a holistic paradigm for tomorrow

Systems healthcare is a holistic approach to health premised on systems biology and medicine. The approach integrates data from molecules, cells, organs, the individual, families, communities, and the natural and man-made environment. Both extrinsic and intrinsic influences constantly challenge the biological networks associated with wellness. Such influences may dysregulate networks and allow pathobiology to evolve, resulting in early clinical presentation that requires astute assessment and timely intervention for successful mitigation. Herein, we describe the components of relevant biological systems and the nature of progression from at-risk to manifest disease. We illustrate the systems approach by examining two relevant clinical examples: Alzheimer’s and cardiovascular diseases. The implications of systems healthcare management are examined through the lens of economics, ethics, policy and the law. Finally, we propose the need to develop new educational paradigms to enhance the training of the health professional in an era of systems medicine.     

Bombesin/oligoarginine fusion peptides for gastrin releasing peptide receptor (GRPR) targeted gene delivery

The development of non-viral gene delivery systems, with the capacity to overcome most of the biological barriers facing gene delivery, is challenging. We have developed peptide-based, multicomponent, non-viral delivery systems, incorporating: a bombesin peptide ligand (BBN(6–14)), to selectively target the gastrin releasing peptide receptor (GRPR); oligoarginine peptides (hexa- (R₆) and nona-arginine (R₉)), for plasmid DNA (pDNA) condensation; and GALA, to facilitate endosome escape. The uptake and endosome escape efficiency of bombesin/oligoarginine and bombesin/oligoarginine/GALA fusion peptides for oligonucleotide delivery was evaluated in terms of their complex size, cellular uptake, endosome escape, and cellular toxicity. Complex size and cell uptake studies demonstrated that the nona-arginine/bombesin delivery system was more efficient at condensing and delivering pDNA into PC-3 prostate cancer cells compared to the hexa-arginine/bombesin delivery system. Further, competition with free bombesin peptide, and comparative uptake studies in Caco-2 cells, which express GRPR at a lower level, suggested that GRPR contributes to the targeted uptake of this system. The addition of GALA into the nona-arginine/bombesin-based system further increased the pDNA cellular uptake at all tested N/P ratios; facilitated endosomal pDNA release; and had limited effects on cell viability. In conclusion, the delivery system combining BBN(6–14) with nona-arginine and GALA had optimal characteristics for the delivery of pDNA into the GRPR overexpressing cell line PC-3.     

Biological Scaling Problems and Solutions in Amphibians

Size is a primary feature of biological systems that varies at many levels, from the organism to its constituent cells and subcellular structures. Amphibians populate some of the extremes in biological size and have provided insight into scaling mechanisms, upper and lower size limits, and their physiological significance. Body size variation is a widespread evolutionary tactic among amphibians, with miniaturization frequently correlating with direct development that occurs without a tadpole stage. The large genomes of salamanders lead to large cell sizes that necessitate developmental modification and morphological simplification. Amphibian extremes at the cellular level have provided insight into mechanisms that accommodate cell-size differences. Finally, how organelles scale to cell size between species and during development has been investigated at the molecular level, because subcellular scaling can be recapitulated using Xenopus in vitro systems.Size is a fundamental biological feature that impacts physiology at all levels, from organism to organ to cell to subcellular structures/organelles. One basic aspect of size is its absolute value, which has upper and lower limits because of functional requirements. For example, a vertebrate organ, such as an eye or an inner ear, may require a minimum number of cells, or a minimum physical size, to operate. Importantly, surface area and volume scale differently with size, and this also has physiological consequences at both the organism and cellular levels, affecting basic processes, such as desiccation and diffusion. A second important feature of size is scaling relationships, as the overall size of an organism or tissue is determined both by cell size and cell number. At the subcellular level, size scaling may or may not occur depending on the organelle, as absolute values are constrained by the nature and flexibility of constituent molecular building blocks. For example, whereas the size of the nucleus varies significantly and scales with cell size, organelle transport vesicles are of more uniform size owing to the conserved structure of their coat proteins. Extremes in amphibian size and scaling relationships derive primarily from dramatic variations in genome size, and provide instructive examples of size relationships, underlying molecular mechanisms, and above all the remarkable flexibility and power of evolution to adapt biological function across a wide range of size scales.