Current status and prospect for future advancements of long-acting antibody formulations.

INTRODUCTION: Biologics, especially monoclonal antibodies (mAbs), have become a major class of therapeutics in recent years addressing the needs of millions of patients and becoming one of the best-selling treatments in the pharmaceutical market. A wide range of multifaceted chronic diseases have benefitted from antibody therapeutics. Long-term treatment for chronic diseases with mAb therapies can mean a lifetime of frequent injections. Technologies that can minimize the total number of injections present meaningful value to patients and the companies that develop them. AREAS COVERED: This review summarizes the challenges encountered during the development of long-acting versions of mAbs. The focus will be on questions addressed during drug product development, delivery device selection, business implications, and understanding the market potential of long-acting presentations. EXPERT OPINION: Long-acting drug delivery systems have reached the market for small molecules and peptides. However, these drug delivery systems, and their development lessons, cannot be extrapolated directly to antibodies. We must develop new delivery technologies suitable for biologics, identify critical attributes to capture dynamic changes in proteins during the encapsulation process, and develop analytical processes to evaluate long-term stability.

Developing Recommendations for Cumulative Endpoints and Lifetime Use for Research Animals.

Research animals are important for scientific advancement, and therefore, their long-term welfare needs to be monitored to not only minimize suffering, but to provide positive affective states and experiences. Currently, there is limited guidance in countries around the world on cumulative and experimental endpoints. This paper aims to explore current opinions and institutional strategies regarding cumulative use and endpoints through a scoping survey and review of current regulations and welfare assessment tools, and ultimately to provide recommendations for assessment of cumulative and lifetime use of research animals. The survey found that only 36% of respondents indicated that their institution had cumulative use endpoint policies in place, but these policies may be informal and/or vary by species. Most respondents supported more specific guidelines but expressed concerns about formal policies that may limit their ability to make case-by-case decisions. The wide diversity in how research animals are used makes it difficult for specific policies to be implemented. Endpoint decisions should be made in an objective manner using standardized welfare assessment tools. Future research should focus on robust, efficient welfare assessment tools that can be used to support planning and recommendations for cumulative endpoints and lifetime use of research and teaching animals.

Can interprofessional case conferences effectively teach interprofessional core competencies? A case study.

BACKGROUND: The establishment of interprofessional education (IPE) as an effective method for training future health care providers, the subsequent establishment of IPE requirements in accreditation standards, and the challenges to integrating IPE into professional-centric curricula have created an environment that encourages opportunity for innovation and collaboration in curriculum design. INTERPROFESSIONAL EDUCATION ACTIVITY: Interprofessional Education Collaborative (IPEC) Core Competencies were integrated into an Interprofessional Case Conference (ICC) model that included six annual case conferences involving students from eight health professions across multiple campuses. Students worked in groups of eight with no more than two students from each profession per group. Interprofessional teams facilitated live progressive cases consisting of iterative guided student discussion alternating with group problem solving, followed by "talk-show style" reports. A retrospective pre-post study design using the validated IPEC Competency Self-Assessment V3 and Student Perspective of Interprofessional Clinical Education tools assessed student perspectives of the ICC model. The online survey was sent to participants who attended at least one ICC in 2015-2016 and 2016-2017. DISCUSSION: Pre-/post-data was available from 94 students. Results revealed modest, but significant, score changes across both instruments, confirming the value of IPE and the ICC training model. IMPLICATIONS: The ICC formula allowed flexibility in applying IPE, resolved scheduling and resources challenges, complemented other IPE programming, and assisted in meeting pharmacy accreditation requirements and the diverse IPE needs of health professions education. The model is flexible, inexpensive, and could be readily replicated at other institutions.

Subcutaneous Delivery of High-Dose/Volume Biologics: Current Status and Prospect for Future Advancements.

Subcutaneous (SC) delivery of biologics has traditionally been limited to fluid volumes of 1-2 mL, with recent increases to volumes of about 3 mL. This injection volume limitation poses challenges for high-dose biologics, as these formulations may also require increased solution concentration in many cases, resulting in high viscosities which can affect the stability, manufacturability, and delivery/administration of therapeutic drugs. Currently, there are technologies that can help to overcome these challenges and facilitate the delivery of larger amounts of drug through the SC route. This can be achieved either by enabling biologic molecules to be formulated or delivered as high-concentration injectables (>100 mg/mL for antibodies) or through facilitating the delivery of larger volumes of fluid (>3 mL). The SC Drug Delivery and Development Consortium, which was established in 2018, aims to identify and address critical gaps and issues in the SC delivery of high-dose/volume products to help expand this delivery landscape. Identified as a high priority out of the Consortium's eight problem statements, it highlights the need to shift perceptions of the capabilities of technologies that enable the SC delivery of large-volume (>3 mL) and/or high-dose biologics. The Consortium emphasizes a patient-focused approach towards the adoption of SC delivery of large-volume/high-concentration dosing products to facilitate the continued expansion of the capabilities of novel SC technologies. To raise awareness of the critical issues and gaps in high-dose/volume SC drug development, this review article provides a generalized overview of currently available and emerging technologies and devices that could facilitate SC delivery of high-dose/volume drug formulations. In addition, it discusses the challenges, gaps, and future outlook in high-dose/volume SC delivery as well as potential solutions to exploit the full value of the SC route of administration.

Affective Images of Climate Change.

Climate change is not only a scientific phenomenon, but also a cultural one. Individuals' opinions on climate change are often based on emotion rather than on scientific evidence. Therefore, research into the emotional characteristics of the imagery that the non-expert public find relevant to climate change is important in order to build a database of effective climate change imagery, which can then be used by scientists, policymakers, and practitioners in mobilizing climate adaptation and resilience efforts. To this end, we collected ratings of relevance to climate change as well as emotional arousal and valence on 320 images to assess the relationship between relevance to climate change and the emotional qualities of the image. In addition, participants' environmental beliefs were measured, to investigate the relationship between beliefs and image ratings. The results suggest that images rated highly relevant to climate change are higher in negative emotional valence and emotional arousal. Overall, images were rated as being more relevant to climate change by participants with higher pro-environmental disposition. Critically, we have compiled the mean relevance, valence, and arousal ratings of each of these 320 images into a database that is posted online and freely available (https://affectiveclimateimages.weebly.com; https://www.nmu.edu/affectiveclimateimages) for use in future research on climate change visuals.

Microneedle-based device for the one-step painless collection of capillary blood samples.

The advancement of point-of-care diagnostics and the decentralization of healthcare have created a need for the simple, safe, standardized and painless collection of blood specimens. Here, we describe the design and implementation of a capillary blood-collection device that is more convenient and less painful than a fingerstick and venepuncture, and collects 100 µl of blood. The technology integrates into a compact, self-contained device an array of solid microneedles, a high-velocity insertion mechanism, stored vacuum, and a microfluidic system containing lithium heparin anticoagulant. The use of the device requires minimal training, as blood collection is initiated by the single push of a button. In a clinical study involving 144 participants, haemoglobin A1c measurements from device-collected samples and from venous blood samples were equivalent, and the pain associated with the device was significantly less than that associated with venepuncture. The device, which has received premarket clearance by the US Food and Drug Administration, should help improve access to healthcare, and support healthcare decentralization.

1-year follow-up of 920 hip and knee arthroplasty patients after implementing fast-track.

BACKGROUND: Fast-track has become a well-known concept resulting in improved patient satisfaction and postoperative results. Concerns have been raised about whether increased efficiency could compromise safety, and whether early hospital discharge might result in an increased number of complications. We present 1-year follow-up results after implementing fast-track in a Norwegian university hospital. METHODS: This was a register-based study of 1,069 consecutive fast-track hip and knee arthroplasty patients who were operated on between September 2010 and December 2012. Patients were followed up until 1 year after surgery. RESULTS: 987 primary and 82 revision hip or knee arthroplasty patients were included. 869 primary and 51 revision hip or knee patients attended 1-year follow-up. Mean patient satisfaction was 9.3 out of a maximum of 10. Mean length of stay was 3.1 days for primary patients. It was 4.2 days in the revision hip patients and 3.9 in the revision knee patients. Revision rates until 1-year follow-up were 2.9% and 3.3% for primary hip and knee patients, and 3.7% and 7.1% for revision hip and knee patients. Function scores and patient-reported outcome scores were improved in all groups. INTERPRETATION: We found reduced length of stay, a high level of patient satisfaction, and low revision rates, together with improved health-related quality of life and functionality, when we introduced fast-track into an orthopedic department in a Norwegian university hospital.

In vivo iontophoretic delivery of salmon calcitonin across microporated skin.

The purpose of this study was to determine the effect of microneedle (MN) technology and its combination with iontophoresis (ITP) on the in vivo transdermal delivery of salmon calcitonin (sCT). Maltose MNs (500 µm) were used to porate skin prior to application of the drug, with or without ITP. Micropores created by maltose MNs were characterized by histological sectioning and calcein imaging studies, which indicated uniformity of the created micropores. In vivo studies were performed in hairless rats to assess the degree of enhancement achieved by ITP (0.2 mA/cm² for 1 h), MNs (81 MNs), and their combination. In vivo studies indicate a serum maximal concentration of 0.61 ± 0.42 ng/mL, 1.79 ± 0.72 ng/mL, and 5.51 ± 0.32 ng/mL for ITP, MNs, and combination treatment, respectively. MN treatment alone increased serum concentration 2.5-fold and the combination treatment increased the concentration ninefold as compared with iontophoretic treatment alone. Combination treatment of ITP and MNs resulted in the highest delivery of sCT and therapeutic levels were achieved within 5 min of administration.

A 1-day course to improve the teaching effectiveness of health professions faculty members.

OBJECTIVE: To determine the effect of a 1-day teaching-methods course for pharmacy and nursing faculty members on teaching proficiency and perceptions of effective teaching. DESIGN: A 1-day teaching-methods course was created and presented to 12 pharmacy and nursing faculty members. Participants' teaching sessions were video-recorded pre- and post-course. ASSESSMENT: A panel of educators evaluated pre- and post-course video-recorded teaching presentations to assess teaching effectiveness. Participants completed pre- and post-course self-evaluations and surveys. Panelists' assessments confirmed significant improvement in 7 of 10 domains. Perceptions of teaching efficacy and proficiency to teach effectively improved after completion of the course. CONCLUSION: A 1-day teaching-methods course, requiring minimal resources, is a valuable development resource that can improve teaching effectiveness through enhanced communication and teaching techniques. Because effective teaching is positively correlated with students' learning, training seminars can be integral to comprehensive quality improvement.

Designing research with hospice and palliative care populations.

Research in palliative care and hospice populations is important for improving quality of care, quality of life, and provider understanding of individuals at the end of life. However, this research involves many potential challenges. This review seeks to inform and assist researchers targeting to design studies targeting hospice and palliative care patients by presenting a thorough review of the published literature. This review covers English-language articles published from 1990 through 2009 listed in the PsycInfo, Medline, or CINAHL research databases under relevant keywords. Articles on pediatric hospice were not included. Issues discussed include study design, informed consent, and recruitment for participants. Synthesized recommendations for researchers in these populations are presented.

Studies in drug transport vs. current in iontophoretic onychomycosis treatment.

An iontophoretic treatment system for onychomycosis, using drug applicators targeting either toe nail only or nail and surrounding tissue, is analyzed. Phase 1 clinical data shows levels of drug delivery that differ unexpectedly from relative dosing level to multiple tissue types. Current monitoring and analysis techniques, coupled with assays of drug delivery into excised nail and cadaver toe, were used to evaluate drug delivery vs. current flow. The results indicate good correlation with piecewise linear models of current flow and extracted drug in the nail-only application. For the nail and surrounding tissue application, assayed drug levels indicate that on average, drug load per unit dose (mA-min) is more efficient into nail than into surrounding tissue (2.38:1 ug/mA-min nail vs. surrounding tissue, n=6, p=0.009).

An ex vivo toe model used to assess applicators for the iontophoretic ungual delivery of terbinafine.

PURPOSE: An ex vivo intact toe model was developed to assess two different applicator designs for iontophoretic delivery of terbinafine into the nail only or the nail and surrounding skin. METHODS: Iontophoretic permeation studies were carried out on intact cadaver toes using nail-only and nail/skin applicators with a current dose of 10 mA*min (0.5 mA for 20 min). RESULTS: Iontophoresis enhanced drug permeation and tissue loading with both applicators tested. Greater drug delivery was observed with the nail/skin applicator due to the additional terbinafine being delivered directly through the lower impedance skin area surrounding the nail. The concentration of drug loaded into the contact area of the nail with the nail-only and nail/skin applicator was ~13 and ~7 fold higher than their respective passive delivery levels but equivalent from each other in total drug mass delivered over the whole nail plate. In vitro release of drug from the iontophoretically loaded nails into agar suggests that a single treatment could have a prolonged effect (>50 days). CONCLUSIONS: This study demonstrates that the ex vivo toe model was useful in assessing the functionality of the different applicator designs. These results suggest that iontophoresis can significantly enhance the delivery of drugs to both the hard and soft tissues of the toe for the treatment of onychomycosis and other nail disorders.

Hollow metal microneedles for insulin delivery to diabetic rats.

The goal of this study was to design, fabricate, and test arrays of hollow microneedles for minimally invasive and continuous delivery of insulin in vivo. As a simple, robust fabrication method suitable for inexpensive mass production, we developed a modified-LIGA process to micromachine molds out of polyethylene terephthalate using an ultraviolet laser, coated those molds with nickel by electrodepostion onto a sputter-deposited seed layer, and released the resulting metal microneedle arrays by selectively etching the polymer mold. Mechanical testing showed that these microneedles were sufficiently strong to pierce living skin without breaking. Arrays containing 16 microneedles measuring 500 microm in length with a 75 microm tip diameter were then inserted into the skin of anesthetized, diabetic, hairless rats. Insulin delivery through microneedles caused blood glucose levels to drop steadily to 47% of pretreatment values over a 4-h insulin delivery period and were then approximately constant over a 4-h postdelivery monitoring period. Direct measurement of plasma insulin levels showed a peak value of 0.43 ng/ml. Together, these data suggest that microneedles can be fabricated and used for in vivo insulin delivery.

Transdermal delivery of insulin using microneedles in vivo.

PURPOSE: The purpose of this study was to design and fabricate arrays of solid microneedles and insert them into the skin of diabetic hairless rats for transdermal delivery of insulin to lower blood glucose level. METHODS: Arrays containing 105 microneedles were laser-cut from stainless steel metal sheets and inserted into the skin of anesthetized hairless rats with streptozotocin-induced diabetes. During and after microneedle treatment, an insulin solution (100 or 500 U/ml) was placed in contact with the skin for 4 h. Microneedles were removed 10 s, 10 min, or 4 h after initiating transdermal insulin delivery. Blood glucose levels were measured electrochemically every 30 min. Plasma insulin concentration was determined by radioimmunoassay at the end of most experiments. RESULTS: Arrays of microneedles were fabricated and demonstrated to insert fully into hairless rat skin in vivo. Microneedles increased skin permeability to insulin, which rapidly and steadily reduced blood glucose levels to an extent similar to 0.05-0.5 U insulin injected subcutaneously. Plasma insulin concentrations were directly measured to be 0.5-7.4 ng/ml. Higher donor solution insulin concentration, shorter insertion time, and fewer repeated insertions resulted in larger drops in blood glucose level and larger plasma insulin concentrations. CONCLUSIONS: Solid metal microneedles are capable of increasing transdermal insulin delivery and lowering blood glucose levels by as much as 80% in diabetic hairless rats in vivo.

Insertion of microneedles into skin: measurement and prediction of insertion force and needle fracture force.

As a hybrid between a hypodermic needle and transdermal patch, we have used microfabrication technology to make arrays of micron-scale needles that transport drugs and other compounds across the skin without causing pain. However, not all microneedle geometries are able to insert into skin at reasonable forces and without breaking. In this study, we experimentally measured and theoretically modeled two critical mechanical events associated with microneedles: the force required to insert microneedles into living skin and the force needles can withstand before fracturing. Over the range of microneedle geometries investigated, insertion force was found to vary linearly with the interfacial area of the needle tip. Measured insertion forces ranged from approximately 0.1-3N, which is sufficiently low to permit insertion by hand. The force required to fracture microneedles was found to increase with increasing wall thickness, wall angle, and possibly tip radius, in agreement with finite element simulations and a thin shell analytical model. For almost all geometries considered, the margin of safety, or the ratio of fracture force to insertion force, was much greater than one and was found to increase with increasing wall thickness and decreasing tip radius. Together, these results provide the ability to predict insertion and fracture forces, which facilitates rational design of microneedles with robust mechanical properties.

Microfabricated needles for transdermal delivery of macromolecules and nanoparticles: fabrication methods and transport studies.

Arrays of micrometer-scale needles could be used to deliver drugs, proteins, and particles across skin in a minimally invasive manner. We therefore developed microfabrication techniques for silicon, metal, and biodegradable polymer microneedle arrays having solid and hollow bores with tapered and beveled tips and feature sizes from 1 to 1,000 microm. When solid microneedles were used, skin permeability was increased in vitro by orders of magnitude for macromolecules and particles up to 50 nm in radius. Intracellular delivery of molecules into viable cells was also achieved with high efficiency. Hollow microneedles permitted flow of microliter quantities into skin in vivo, including microinjection of insulin to reduce blood glucose levels in diabetic rats.

Bacterial Retention and Cleanability of Plastic and Wood Cutting Boards with Commercial Food Service Maintenance Practices.

The retention of bacteria on wood and plastic cutting board surfaces and their removal by washing, using protocols consistent with commercial food service, was examined. Plastic and wood boards were subjected to repeated hand and machine washing to simulate wear that would occur during commercial usage. Electron microscopy revealed a more pronounced wearing of the wood surface as compared to the plastic, with cracks on the wood that were sufficiently wide to entrap bacteria. New and previously washed wood and plastic surfaces were inoculated with Escherichia coli and then washed using standard food service washing and sanitizing procedures. The cleanliness of the resulting surfaces was estimated by measuring the residual adenosine triphosphate (ATP). The plastic surfaces were consistently cleaner than wood surfaces by this measure, and wood surfaces that had been hand washed five times prior to inoculation were significantly less clean than any other surfaces or treatments. Bacterial retention after washing on the surface was demonstrated by agar overlay. Even after standard food service washing and sanitizing, colonies of the inoculated bacteria were observed sporadically, but only on wood surfaces and not on plastic. These results suggest that wood surfaces can absorb moisture and in effect can absorb contaminating bacteria, and the difficulty in removing these bacteria may make this material less desirable from a food safety perspective.