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Tezepelumab is a human monoclonal antibody that blocks thymic stromal lymphopoietin. The drug has been tested previously in the phase 3 NAVIGATOR (NCT03347279) and SOURCE (NCT03406078) studies, and was subsequently approved as a treatment for severe asthma. This extension study recruited from NAVIGATOR and SOURCE and aimed to evaluate the long-term safety and efficacy of tezepelumab in individuals with severe, uncontrolled asthma.

Abstract:This study uses a critical consciousness framework to understand the experiences of higher education and student affairs (HESA) graduate students in an elective Diversity in HIED course. We drew from narrative inquiry to analyze data from selected student coursework in online discussion board conversations and journal entries. Students demonstrated building a foundation for engagement with critical consciousness, particularly through themes of interest in the emotions that surfaced during the course, reconceptualizing “diversity,” and how to apply their learning to HESA practice. Participant learning reflected that HESA graduate programs can foster an important foundation for personal and professional development in this area. This knowledge can help faculty and supervisors support HESA graduate students’ learning and preparation for active engagement regarding critical consciousness in HESA practice.

Tezepelumab is a human monoclonal antibody that blocks the activity of thymic stromal lymphopoietin. SOURCE evaluated the oral corticosteroid-sparing effect of tezepelumab in adults with oral corticosteroid-dependent asthma.

Abstract:This qualitative study explored how U.S. higher education/student affairs (HESA) master’s graduate preparation programs and curriculum socialized graduates for full time HESA work abroad post-graduation. Participants revealed that the formal curriculum was U.S.-centric in classroom conversations, course projects, and electives. The informal curriculum offered the most direct international-related learning opportunities such as study abroad, practicum, and assistantships. The most pervasive aspect was the hidden curriculum including limited application of U.S.-based theories and the support for job searching. Implications for practice include deliberate exposure to internationally-focused opportunities in and out of the classroom. In addition, professional associations may provide valuable connections to assist in graduate students’ socialization for full time HESA work abroad.

ANDHI was done to assess the efficacy of benralizumab, including onset of effect and impact on health-related quality of life (HRQOL), exacerbation rate, lung function, and nasal polyposis symptoms.

Organophosphorus esters (OPs) were originally developed as pesticides but were repurposed as easily manufactured, inexpensive, and highly toxic chemical warfare agents. Acute OP toxicity is primarily due to inhibition of acetylcholinesterase (AChE), an enzyme in the central and peripheral nervous system. OP inhibition of AChE can be reversed using oxime reactivators but many show poor CNS penetration, indicating a need for new clinically viable reactivators. However, challenges exist on how to best measure restored AChE activity in vivo and assess the reactivating agent efficacy. This work reports the development of molecular imaging tools using radiolabeled OP analog tracers that are less toxic to handle in the laboratory, yet inhibit AChE in a similar fashion to the actual OPs. Carbon-11 and fluorine-18 radiolabeled analog tracers of VX and sarin OP agents were prepared. Following intravenous injection in normal Sprague–Dawley rats (n= 3–4/tracer), the tracers were evaluated and compared using noninvasive microPET/CT imaging, biodistribution assay, and arterial blood analyses. All showed rapid uptake and stable retention in brain, heart, liver, and kidney tissues determined by imaging and biodistribution. Lung uptake of the sarin analog tracers was elevated, 2-fold and 4-fold higher uptake at 5 and 30 min, respectively, compared to that for the VX analog tracers. All tracers rapidly bound to red blood cells (RBC) and blood proteins as measured in the biodistribution and arterial blood samples. Analysis of the plasma soluble activity (nonprotein/cell bound activity) showed only 1–6% parent tracer and 88–95% of the activity in the combined solid fractions (RBC and protein bound) as early as 0.5 min post injection. Multivariate analysis of tracer production yield, molar activity, brain uptake, brain area under the curve over 0–15 min, and the amount of parent tracer in the plasma at 5 min revealed the [18F]VX analog tracer had the most favorable values for each metric. This tracer was considered the more optimal tracer relative to the other tracers studied and suitable for future in vivo OP exposure and reactivation studies.

ABSTRACTBackground: Little is known about the impact of a participatory approach in adolescent health research and the specific benefits youth derive from such experiences. This study evaluates the benefits and limitations of involving young patients as co-researchers in the creation and execution of an international participatory health research project. Methods: Standardized feedback surveys and qualitative interviews were employed to evaluate the impact of co-researchers’ personal and academic growth. Participation was determined by the percentage of youth members actively engaged (75% or more), and outcome of a completed project. Results: 16 adolescents aged 13–23 years representing 9 global academic institutions participated. Eighty-one per cent of participants reported interest in health research and 100% felt that their participation made an impact on paediatric healthcare. Discussion: The shift in roles from patient to research partner is echoed in the strong conviction of the newfound possibilities of accomplishment as a group.

Background: To investigate dynamic live tissue organophosphorus nerve agent uptake and distribution fates resulting in acetylcholinesterase inhibition, we recently reported the first-in-class fluorine-18 [18F] radiolabeled Positron Emission Tomography (PET) imaging tracer known as [18F]O-(2-fluoroethyl)-O-(p-nitrophenyl)methylphosphonate. This tracer has been initially studied in live rats with PET imaging. Objective: We sought to evaluate the PET tracer in vivousing a new dose formulation of saline, ethanol and L-ascorbic acid, and compare the influence of this formulation on in vivotracer performance to previous data collected using a CH3CN:PBS formulation. Methods: A high molar activity [18F]tracer radiosynthesis was used. Doses were formulated as saline, ethanol (≤ 1%) and L-ascorbic acid (0.1%), pH 4.0-4.5. Stability was evaluated to 6 h. Dose injection (i.v.) into male rats was followed by either ex vivo biodistribution profiling at 5, 30, 90 min, or dynamic 90 min PET imaging. Rat biodistribution and PET imaging data were compared. Results and Discussion: An optimized radiosynthesis (8 ± 2 % RCY) resulted in stable doses for 6 h (>99%). Arterial blood included a tracer and a single metabolite. The ex vivobiodistribution and live tissue PET imaging data revealed rapid radioactivity uptake and distributed tissue levels: heart and lung, highest; liver, moderate; and brain, lowest. Conclusion: Imaging and biodistribution data were highly correlated with expected radioactivity tissue uptake and distribution in target organs. Lower brain radioactivity levels by PET imaging were found for the new formulation (saline, 1% L-ascorbic acid, < 1% ethanol) as compared to the established CH3CN:PBS formulation. Overall, we found that the i.v. dose formulation changed the in vivoprofile of an organophosphorus PET tracer that is considered an important finding for future organophosphorus PET tracer studies.

Studies with acetylcholinesterase (AChE) inhibited by organophosphorus (OP) compounds with two chiral centers can serve as models or surrogates for understanding the rate, orientation, and postinhibitory mechanisms by the nerve agent soman that possesses dual phosphorus and carbon chiral centers. In the current approach, stereoisomers of O-methyl, [S-(succinic acid, diethyl ester), O-(4-nitrophenyl) phosphorothiolate (MSNPs) were synthesized, and the inhibition, reactivation, and aging mechanisms were studied with electric eel AChE (eeAChE) and recombinant mouse brain AChE (rmAChE). The MSNP RPRCisomer was the strongest inhibitor of both eeAChE and rmAChE at 8- and 24-fold greater potency, respectively, than the weakest SPSCisomer. eeAChE inhibited by the RPRC- or RPSC-MSNP isomer underwent spontaneous reactivation ∼10- to 20-fold faster than the enzyme inhibited by SPRC- and SPSC-MSNP, and only 4% spontaneous reactivation was observed from the SPRC-eeAChE adduct. Using 2-pyridine aldoxime methiodide (2-PAM) or trimedoxime (TMB-4), eeAChE inhibited by RPRC- or SPRC-MSNP reactivated up to 90% and 3- to 4-fold faster than eeAChE inhibited by the RPSC- or SPSC-MSNP isomer. Spontaneous reactivation rates for rmAChE were 1.5- to 10-fold higher following inhibition by RPSC- and SPSC-MSNPs than inhibition by either RCisomer, a trend opposite to that found for eeAChE. Oxime reactivation of rmAChE following inhibition by RPRC- and SPRC-MSNPs was 2.5- to 5-fold faster than inhibition by RPSC- or SPSC-MSNPs. Due to structural similarities, MSNPs that phosphylate AChE with the loss of the p-nitrophenoxy (PNP) group form identical, nonreactivatable adducts to those formed from SP-isomalathion; however, all the MSNP isomers inhibited AChE to form adducts that reactivated. Thus, MSNPs inactivate AChE via the ejection of either PNP or thiosuccinyl groups to form a combination of reactivatable and nonreactivatable adducts, and this differs from the mechanism of AChE inhibition by isomalathion.

Sulfur mustard burns are characterized by delayed symptoms, slow healing, and recurrence after closure. Incomplete debridement at the level of the basement membrane is the postulated cause. Graham pioneered laser debridement of mustard burns. For field or mass-casualty use, saline wet-to-wet or antibiotic-soak debridement is more practical. In this study, we compared laser, saline, and antibiotic debridement in a porcine model of deep partial-thickness injury. Deep-dermal sulfur mustard burns were produced in 18 anesthetized Gottingen minipigs using 10-μl saturated vapor cap exposure time of 90 minutes. Debridement was started 48 hours postinjury and consisted of a single laser treatment; 5 days of 5% aqueous mafenide acetate wet-to-wet dressings; or 7 to 12 days of saline wet-to-wet dressings. Wounds were treated with daily silver sulfadiazine for 30 days and, then, assessed by histopathology, silver-ion analysis, colorimetry, and evaporimetry. All wounds healed well with no sign of infection. Antibiotic debridement showed no advantage over saline debridement. There were no significant differences between groups for colorimetry or evaporimetry. Histopathology was graded on a mustard-specific scale of 1 to 15 where higher values indicate better healing. Mean histology scores were 13.6 for laser, 13.9 for mafenide, and 14.3 for saline. Saline debridement statistically outperformed laser (P < .05) but required the longest debridement time. Laser debridement had the benefit of requiring a single treatment rather than daily dressing changes, significantly decreasing need for wound care and personnel resources. Development of a ruggedized laser for field use is a countermeasures priority.

BackgroundEngaging patients and the public as collaborators in research is increasingly recognised as important as such partnerships can help improve research relevance and acceptability. Young Persons’ Advisory Groups (YPAGs) provide a forum for clinical researchers and triallists to engage with children and young people on issues relevant to the design, conduct and translation of paediatric clinical trials. Until fairly recently, there was very little information available to guide the successful development and operation of YPAGs.ObjectiveTo develop an evidence-based tool to guide clinical researchers and triallists in the establishment and operation of a YPAG.MethodsAn online needs assessment survey was conducted using SurveyMonkey with 60 known paediatric drug researchers to identify knowledge gaps around YPAG engagement, development and operation. Semistructured interviews with founders and coordinators of five well-established existing YPAGs and a review of the literature were performed to identify best-practice processes for starting up and operating YPAG.ResultsThe majority of 12 survey respondents (20%) from 12 different centres indicated that while they felt YPAGs could benefit their research, guidance on how to develop and operate a YPAG was needed. Most preferred a web-based guidance tool. Ten core steps in starting up and operating a YPAG were identified and developed into an online YPAG guidance tool, now freely accessible for use by paediatric clinical researchers worldwide. Plans to evaluate the impact are in place.ConclusionsThis novel tool, developed with an internationally based group of public involvement leads working across paediatric clinical research areas, provides harmonised guidance for researchers seeking to develop and operate YPAGs to help improve the quality and impact of paediatric clinical research studies.

Patient engagement in health care has been an emerging priority in the global effort and move toward the consideration of patients as experts of their own conditions. However, the input of pediatric patients and their families have not been consistently requested nor regarded as valuable when deriving protocols for, as well as assessing the outcomes of, pediatric clinical trials. Extending this mutual collaboration further upstream is important, especially in the area of pediatric drug development where the lack of formalized trials for children and adolescents result in the increased use of off-label prescribing and risk of adverse effects. While recent changes to European and North American legislation contributed to the inclusion of children and youth in pediatric drug development, the lack of systematic guidelines and methodologies in literature serve as barriers for practical application. When combined with the work of external pediatric advocacy and patient advisory groups, the hope is that pediatric patient voices can be brought forward for the future. This article brings together international experts to review current best practices, progress from regulatory agencies, as well as global advocacy efforts to involve patients and families in the pursuit of drug development processes that value the voice of children and youth.

Patient engagement in health care has been an emerging priority in the global effort and move toward the consideration of patients as experts of their own conditions. However, the input of pediatric patients and their families have not been consistently requested nor regarded as valuable when deriving protocols for, as well as assessing the outcomes of, pediatric clinical trials. Extending this mutual collaboration further upstream is important, especially in the area of pediatric drug development where the lack of formalized trials for children and adolescents result in the increased use of off-label prescribing and risk of adverse effects. While recent changes to European and North American legislation contributed to the inclusion of children and youth in pediatric drug development, the lack of systematic guidelines and methodologies in literature serve as barriers for practical application. When combined with the work of external pediatric advocacy and patient advisory groups, the hope is that pediatric patient voices can be brought forward for the future. This article brings together international experts to review current best practices, progress from regulatory agencies, as well as global advocacy efforts to involve patients and families in the pursuit of drug development processes that value the voice of children and youth.

The organophosphate O-(2-fluoroethyl)-O-(p-nitrophenyl) methyphosphonate 1is the first-in-class, fluorine-18 radiolabeled organophosphate inhibitor ([18F]1) of acetylcholinesterase (AChE). In rats, [18F]1localizes in AChE rich regions of the brain and other tissues where it likely exists as the (CH3)(18FCH2CH2O)P(O)-AChE adduct (ChE-1). Characterization of this adduct would define the inhibition mechanism and subsequent postinhibitory pathways and reactivation rates. To validate this adduct, the stability (hydrolysis) of 1and ChE-1reactivation rates were determined. Base hydrolysis of 1yields p-nitrophenol and (CH3) (FCH2CH2O)P(O)OH with pseudo first order rate constants (kobsd) at pH 7.4 (PBS) of 3.25 × 10–4min–1(t1/2= 35.5 h) at 25 °C and 8.70 × 10–4min–1(t1/2= 13.3 h) at 37 °C. Compound 1was a potent inhibitor of human acetylcholinesterase (HuAChE; ki= 7.5 × 105M–1min–1), electric eel acetylcholinesterase (EEAChE) (ki= 3.0 × 106M–1min–1), and human serum butyrylcholinesterase (HuBChE; 1.95 × 105M–1min–1). Spontaneous and oxime-mediated reactivation rates for the (CH3) (FCH2CH2O)P(O)-serine ChE adducts using 2-PAM (10 μM) were (a) HuAChE 8.8 × 10–5min–1(t1/2= 131.2 h) and 2.41 × 10–2min–1(t1/2= 0.48 h), (b) EEAChE 9.32 × 10–3min–1(t1/2= 1.24 h) and 3.33 × 10–2min–1(t1/2= 0.35 h), and (c) HuBChE 1.16 × 10–4min–1(t1/2= 99.6 h) and 4.19 × 10–2min–1(t1/2= 0.27 h). All ChE-1adducts undergo rapid and near complete restoration of enzyme activity following addition of 2-PAM (30 min), and no aging was observed for either reactivation process. The fast reactivation rates and absence of aging of ChE-1adducts are explained on the basis of the electron-withdrawing fluorine group that favors the nucleophilic reactivation processes but disfavors cation-based dealkylation aging mechanisms. Therefore, the likely fate of radiolabeled compound 1in vivois the formation of (CH3)(FCH2CH2O)P(O)-serine adducts and monoacid (CH3)(FCH2CH2O)P(O)OH from hydrolysis and reactivation.

Background: Obtaining assent from children participating in clinical trials acknowledges autonomy and developmental ability to contribute to the consent process. This critical step in pediatric drug development remains poorly understood, with significant room for improving the clarity, efficiency, and implementation of the assent process. Beyond ethical necessity of informing children about their treatment, the assent process provides the advantages of including children in discussions about their diagnosis and treatment—allowing greater understanding of interventions included in the study. A formalized assent process acknowledges the child as a volunteer and provides a forum for questions and feedback. Legal, cultural, and social differences have historically prevented the development of clear, concise, and accessible materials to ensure children understand the clinical trial design. Published guidelines on obtaining pediatric assent are vague, with many decisions left to local institutional review boards and ethics committees, underscoring the need for collaboratively designed standards. To address this need, 2 surveys were conducted to quantify perspectives on assent in pediatric clinical trials. Methods: Two digital surveys were circulated in the United States and internationally (October 2014 to January 2015). The first survey targeted children, parents, and/or caregivers. The second polled clinical trial professionals on their organizations’ experience and policies regarding pediatric assent. Results: Forty-five respondents completed the child and parent/caregiver survey; 57 respondents completed the industry survey. Respondents from both surveys detailed experiences with clinical trials and the impediments to securing assent, offering potential solutions to attaining assent in pediatric patients. Conclusions: An important opportunity exists for standardized practices and tools to ensure pediatric patients make well-informed decisions regarding their participation in clinical trials, using materials appropriate to their level of understanding. These tools would establish a baseline standard for the assent process and be made available to researchers, improving their ability to secure assent from young patients.

Background: Obtaining assent from children participating in clinical trials acknowledges autonomy and developmental ability to contribute to the consent process. This critical step in pediatric drug development remains poorly understood, with significant room for improving the clarity, efficiency, and implementation of the assent process. Beyond ethical necessity of informing children about their treatment, the assent process provides the advantages of including children in discussions about their diagnosis and treatment—allowing greater understanding of interventions included in the study. A formalized assent process acknowledges the child as a volunteer and provides a forum for questions and feedback. Legal, cultural, and social differences have historically prevented the development of clear, concise, and accessible materials to ensure children understand the clinical trial design. Published guidelines on obtaining pediatric assent are vague, with many decisions left to local institutional review boards and ethics committees, underscoring the need for collaboratively designed standards. To address this need, 2 surveys were conducted to quantify perspectives on assent in pediatric clinical trials.Methods: Two digital surveys were circulated in the United States and internationally (October 2014 to January 2015). The first survey targeted children, parents, and/or caregivers. The second polled clinical trial professionals on their organizations’ experience and policies regarding pediatric assent.Results: Forty-five respondents completed the child and parent/caregiver survey; 57 respondents completed the industry survey. Respondents from both surveys detailed experiences with clinical trials and the impediments to securing assent, offering potential solutions to attaining assent in pediatric patients.Conclusions: An important opportunity exists for standardized practices and tools to ensure pediatric patients make well-informed decisions regarding their participation in clinical trials, using materials appropriate to their level of understanding. These tools would establish a baseline standard for the assent process and be made available to researchers, improving their ability to secure assent from young patients.

Hosts of obligate avian brood parasites often evolve defense mechanisms to avoid rearing unrelated young. One common defense is egg rejection, for which hosts often rely on eggshell color. Most research has assumed that hosts respond to perceived color differences between their own eggs and parasite eggs regardless of the particular color; however, recent experiments have found that many hosts respond more strongly to brown foreign eggs than to equally dissimilar blue eggs. Yet, none of these prior studies tested a brown-egg-laying species and, with only one exception, all were conducted in open nests where light levels are considered sufficient for effective color-based egg discrimination. Here, we explored how two cavity-nesting hosts of the parasitic brown-headed cowbird (Molothrus ater) – the blue-egg-laying eastern bluebird (Sialia sialis) and the brown-egg-laying house wren (Troglodytes aedon) – respond to experimental eggs painted six distinct colors ranging from blue to brown. Rejection responses of both hosts were best predicted by perceived differences in color between the model egg and their own eggs. Specifically, we found that house wrens preferentially rejected eggs bluer than their own eggs. However, although we found that bluebirds relied on perceived differences in color for their egg rejection decisions, further tests are needed to determine whether they preferentially rejected brown eggs or simply responded to absolute perceived differences in color. These findings demonstrate that these cavity-nesting birds treat perceived color differences in distinct ways, which has important implications on the coevolutionary arms races and the interpretation of avian-perceived color differences.

Between 2006 and 2010, the North Carolina Department of Public Instruction intervened in 128 low-performing schools, combining approaches consistent with school restructuring and transformation. In improved schools, local educators reconstructed key school functions, a distinctly nonlinear process more like the work of skilled craftsmen than that of design engineers that we refer to as “scaffolded craftsmanship.” We interviewed key stakeholders in 12 high schools to learn about the dynamics accounting for the improvement or stalemate at each school. In sum, in the improved schools we studied, the turnaround process was not a matter of initial external design and subsequent implementation, but a non-linear process of planning, inventing, adjusting, and re-planning as well as a process of learning, doing, and learning from doing. The improvement generally began with the installation of new leadership and involved four main components: new commitment, climate, and culture; improved knowledge and skills; strategically organized and managed structures and supports for instruction; and strengthened external support. Our findings suggest that judicious personnel replacement followed by professional development and coaching targeted to key functions may be a more effective method for implementing school turnaround than the structural approaches promoted via NCLB sanctions and Race to the Top.

In November 2014, the American Academy of Pediatrics convened key stakeholders to discuss the feasibility of accelerating children’s medical advances by creating an independent global Pediatric Clinical Trials Network. The Forum identified challenges posed by the US and global clinical trial systems regarding testing and disseminating drugs and devices for pediatric patients. Stakeholders mapped a vision to improve the safety and efficacy of pediatric drugs, biological products, and medical devices by creating a global Pediatric Clinical Trials Network. Such a Network would act as a central infrastructure for pediatric subspecialties and enable dedicated staff to provide clinical research sites with scientific, medical, and operational support. A Network would facilitate development and availability of innovative, high-quality therapies to extend and enhance the lives of neonates, infants, children, adolescents, and young adults. Participants expressed strong interest in forming such a Network, since drugs and devices still come to market without adequate pediatric indications—particularly in neonatology and rare diseases. Participants developed a Consensus Statement expressing their shared vision for a Network: Attendees of the Pediatric Clinical Trials Stakeholder Forum resolved to establish a Global Pediatric Clinical Trials Network and are committed to engage in the work to create and sustain it.

In this work, we present our advances to develop and apply digital twins for drilling fluids and associated wellbore phenomena during drilling operations. A drilling fluid digital twin is a series of interconnected models that incorporate the learning from the past historical data in a wide range of operational settings to determine the fluids properties in real-time operations. Our specific focus is on prediction of cuttings bed thickness along the wellbore in hole cleaning and prediction of high-pressure high-temperature (HPHT) rheological properties (in downhole conditions). In both applications, we present procedures to develop accurate digital twins for prediction of drilling fluid properties in real-time drilling operations. In the hole cleaning application, we develop accurate computational fluid dynamics (CFD) models to capture the effects of rotation, eccentricity, and bed height on local fluid velocities above cuttings bed. We then run 55,000 CFD simulations for a wide range of operational settings to generate training data for machine learning. For rheology monitoring, thousands of lab experiment records are collected as training data for machine learning. In this case, the HPHT rheological properties are determined based on rheological measurement in the American Petroleum Institute (API) condition (14.7 psi and 150 °F) together with the fluid type and composition data. We compare the results of the application of several machine learning algorithms to represent CFD simulations (for hole cleaning) and lab experiments (for monitoring HPHT rheological properties). Rotating cross-validation method is applied to ensure accurate and robust results. In both cases, models from the gradient boosting and the artificial neural network algorithms provided the highest accuracy (about 0.95 in terms of R2) for test datasets. With developments presented in this paper, the hole cleaning calculations can be performed in real time, and the HPHT rheological properties of drilling fluids can be estimated at the rig site avoiding the need to wait for the laboratory experimental results.

Research and innovation are critical to improving the health and well-being of the world’s children; clinical trials yield important information on a medical product’s safety, dosing, and effectiveness. While the prescribing information available to pediatric providers has substantially improved, approximately 50% of medicines still do not have data on their labels to guide their appropriate use in children. Regulatory bodies have recently taken measures to ensure, if drugs have a potential pediatric indication, that the safety and efficacy clinical trials include the pediatric population. However, there are significant challenges with pediatric trials, including study design and feasibility, suitable formulations, and patient recruitment and retention. The authors propose that these challenges can be addressed by actively involving young people and families in study design so their insights can inform successful trial implementation. As the volume of pediatric research increases, there needs to be a concomitant effort for researchers and providers to seek input from patients and families in the development of their work, which can lead to a transformation of the cultural and regulatory environment of pediatric medicine. The benefits of patient and public involvement in research have been well documented. In 2006, the National Institute for Health Research Clinical Research Network: Children started its first Young Persons’ Advisory Group in an effort to include young people in the design and delivery of pediatric research. Since their initial efforts, the youth advisory concept has grown into a global effort known as the International Children’s Advisory Network (iCAN). This article describes the foundational building blocks of iCAN and provides tools to investigators and practitioners in an effort to increase the instances of children and families being invited to share their unique point of view in medicine.

The palatability of oral drugs influences patient adherence to prescribed regimens, especially for children. Various factors influence palatability, including smell, taste, texture, and dose volume. Evaluation of these factors plays an important role in pediatric drug development and is a target for regulatory scrutiny. The Global Alliance for Pediatric Therapeutics, a public-private consortium under the guidance of the Institute for Pediatric Innovation, convened the Alliance Palatability Working Group to discuss the issues related to the assessment of palatability in the development of pediatric oral dosage forms. An extensive scientific literature search was conducted, in addition to a multicompany industry survey and a series of workshops with the Alliance Palatability Working Group. Based on the results, 3 best practice recommendations emerged regarding the assessment of palatability for oral dosage forms in pediatric drug development. These best practice recommendations offer researchers guidance for the preclinical and clinical assessment of palatability of oral dosage forms and serve to operationalize the assessment process within the overall drug development program.

Research and innovation are critical to improving the health and well-being of the world’s children; clinical trials yield important information on a medical product’s safety, dosing, and effectiveness. While the prescribing information available to pediatric providers has substantially improved, approximately 50% of medicines still do not have data on their labels to guide their appropriate use in children. Regulatory bodies have recently taken measures to ensure, if drugs have a potential pediatric indication, that the safety and efficacy clinical trials include the pediatric population. However, there are significant challenges with pediatric trials, including study design and feasibility, suitable formulations, and patient recruitment and retention. The authors propose that these challenges can be addressed by actively involving young people and families in study design so their insights can inform successful trial implementation. As the volume of pediatric research increases, there needs to be a concomitant effort for researchers and providers to seek input from patients and families in the development of their work, which can lead to a transformation of the cultural and regulatory environment of pediatric medicine. The benefits of patient and public involvement in research have been well documented. In 2006, the National Institute for Health Research Clinical Research Network: Children started its first Young Persons’ Advisory Group in an effort to include young people in the design and delivery of pediatric research. Since their initial efforts, the youth advisory concept has grown into a global effort known as the International Children’s Advisory Network (iCAN). This article describes the foundational building blocks of iCAN and provides tools to investigators and practitioners in an effort to increase the instances of children and families being invited to share their unique point of view in medicine.

The palatability of oral drugs influences patient adherence to prescribed regimens, especially for children. Various factors influence palatability, including smell, taste, texture, and dose volume. Evaluation of these factors plays an important role in pediatric drug development and is a target for regulatory scrutiny. The Global Alliance for Pediatric Therapeutics, a public–private consortium under the guidance of the Institute for Pediatric Innovation, convened the Alliance Palatability Working Group to discuss the issues related to the assessment of palatability in the development of pediatric oral dosage forms. An extensive scientific literature search was conducted, in addition to a multicompany industry survey and a series of workshops with the Alliance Palatability Working Group. Based on the results, 3 best practice recommendations emerged regarding the assessment of palatability for oral dosage forms in pediatric drug development. These best practice recommendations offer researchers guidance for the preclinical and clinical assessment of palatability of oral dosage forms and serve to operationalize the assessment process within the overall drug development program.

Effective delivery of small interfering RNA (siRNA) requires efficient cellular uptake and release into cytosol where it forms an active complex with RNAi induced silencing complex (RISC). Despite rapid developments in RNAi therapeutics, improvements in delivery efficiency of siRNA are needed to realize the full potential of this modality in broad therapeutic applications. We evaluated potential physiological and biochemical barrier(s) to the effective liver delivery of siRNA formulated in lipid nanoparticle (LNP) delivery vehicles. The comparative siRNA delivery performance of three LNPs was investigated in rats. They were assembled with either C14- or C18-anchored PEG-lipid(s), cationic lipid(s), and various helper lipid(s) and contained the same siRNA duplex. These LNPs demonstrated differentiated potency with ED50’s ranging from 0.02 to 0.25 mg/kg. The two C14-PEG-LNPs had comparable siRNA exposure in plasma and liver, while the C18-PEG-LNP demonstrated a higher plasma siRNA exposure and a slower but sustained liver uptake. RISC bound siRNA within the liver, a more proximal measure of the pharmacologically active siRNA species, displayed loading kinetics that paralleled the target mRNA knockdown profile, with greater RISC loading associated with more potent LNPs. Liver perfusion and hepatocyte isolation experiments were performed following treatment of rats with LNPs containing VivoTag-fluorescently labeled siRNA. One hour after dosing a majority of the siRNA within the liver was associated with hepatocytes and was internalized (within small subcellular vesicles) with no significant cell surface association, indicating good liver tissue penetration, hepatocellular distribution, and internalization. Comparison of siRNA amounts in hepatocytes and subcellular fractions of the three LNPs suggests that endosomal escape is a significant barrier to siRNA delivery where cationic lipid seems to have a great impact. Quantitation of Ago-2 associated siRNA revealed that after endosomal escape further loss of siRNA occurs prior to RISC loading. This quantitative assessment of LNP-mediated siRNA delivery has highlighted potential barriers with respect to endosomal escape and incomplete RISC loading for delivery optimization efforts.

Background: Palatability and swallowability of oral dosage forms are important considerations in the development of medications for pediatric populations. As a result of recent legislation, the number of pharmaceutical products being developed with formulations for children is increasing. However, there are limited recommendations and published literature regarding appropriate palatability and swallowability assessment scales in pediatric patients. Objective: This systematic literature review aimed to identify and evaluate tools currently utilized to assess palatability and swallowability in clinical trials for pediatric oral dosage forms and identify any potential relationships between palatability and treatment adherence. Literature databases were searched for clinical trials that evaluated palatability of oral dosage forms targeted for pediatric patients. The searches were limited to papers in the English language from January 2008 to March 2013. Results: A total of 137 citations were identified, with 27 articles included in the final full-text analysis. Conclusions: Various limitations to this systematic review exist, primarily focused on the unavailability of published, early phase development data related to palatability. However, based on results of this review, palatability is often assessed in clinical trials of pediatric dosage forms through the utilization of 2 unvalidated, yet widely accepted, visual scales. There is no standard statistical methodology for analyzing the results of these scales or the cross-comparison of results across studies. Limited evidence regarding a correlation between palatability and treatment adherence in pediatric patients was identified.