Paediatric excipient risk assessment (PERA) tool and application for selecting appropriate excipients for paediatric dosage forms - Part 2.

It is necessary to use a scientifically sound process for excipient risk evaluation, selection, and management in order to develop paediatric medicinal products that are both safe and effective. The "Paediatric Excipient Risk Assessment (PERA)" framework, which proposes a comprehensive approach by considering all relevant factors related to patient, dosage form, and excipient attributes, was developed and published as part 1 of this paper series, to enable the rational selection of excipients for paediatric medicinal products. This article is Part 2 of the series and presents the PERA tool that allows easy adoption of the PERA framework. Using a straightforward heat map scoring approach (Red, Yellow, and Green category) for risk evaluation, the PERA tool can be used to compare and choose excipients. The PERA tool will help users identify potential gaps in excipients information that will help with risk-based mitigation planning. Several case studies covering frequently used and novel excipients for oral, as well as the choice of excipient for parenteral products for neonatal administration, serve to illustrate the PERA tool's usefulness.

Selecting appropriate excipients for paediatric dosage form - Paediatric excipients risk assessment (PERA) framework - Part 1.

Excipients are often the major component of the formulation that critically affect the dosage form, manufacturing process, product performance, stability and safety. They exert different roles and functions in a dosage form. Selecting excipients with appropriate safety and tolerability is a major hurdle in paediatric formulation development. The suitability of a particular excipient will be dependent on the context of its use with regard to the paediatric age range, acute versus chronic use, and clinical risk-benefit of the disease, active and excipient. Scientists are encouraged to apply the principle of risk-benefit to assess the suitability of excipients to the specific paediatric population. Indicative list of parameters that should be taken into consideration and hierarchy of information sources when assessing the excipients risks is provided by regulatory agencies. However, the approach to be taken and details of how the risk evaluation should be undertaken are lacking. There is a need for a systematic approach to selection of excipients and assessment of the risk of excipient exposure. The Paediatric Excipients Risk Assessment (PERA) framework developed and proposed in this paper provides a structured, systematic decision-making framework via customizable tools and processes that can help to improve the transparency and communications on the selection and justification of use of excipients in a paediatric formulation.

A regional examination of the footprint of agriculture and urban cover on stream water quality.

Freshwater systems in cold regions, including the Laurentian Great Lakes, are threatened by both eutrophication and salinization, due to excess nitrogen (N), phosphorus (P) and chloride (Cl-) delivered in agricultural and urban runoff. However, identifying the relative contribution of urban vs. agricultural development to water quality impairment is challenging in watersheds with mixed land cover, which typify most developed regions. In this study, a self-organizing map (SOM) analysis was used to evaluate the contributions of various forms of land cover to water quality impairment in southern Ontario, a population-dense, yet highly agricultural region in the Laurentian Great Lakes basin where urban expansion and agricultural intensification have been associated with continued water quality impairment. Watersheds were classified into eight spatial clusters, representing four categories of agriculture, one urban, one natural, and two mixed land use clusters. All four agricultural clusters had high nitrate-N concentrations, but levels were especially high in watersheds with extensive corn and soybean cultivation, where exceedances of the 3 mg L-1 water quality objective dramatically increased above a threshold of |∼30 % watershed row crop cover. Maximum P concentrations also occurred in the most heavily tile-drained cash crop watersheds, but associations between P and land use were not as clear as for N. The most urbanized watersheds had the highest Cl- concentrations and expansions in urban area were mostly at the expense of surrounding agricultural land cover, which may drive intensification of remaining agricultural lands. Expansions in tile-drained corn and soybean area, often at the expense of mixed, lower intensity agriculture are not unique to this area and suggest that river nitrate-N levels will continue to increase in the future. The SOM approach provides a powerful means of simplifying heterogeneous land cover characteristics that can be associated with water quality patterns and identify problem areas to target management.

Accessory tympanic plate ossicle: a new osteological entity.

The auricular cartilage, which is typically soft and flexible, can calcify or ossify because of diseases such as diabetes mellitus, trauma, radiation therapy for cancer, and more commonly from frostbite. Calcified, ossified, or hardened auricular cartilage is a rare finding in the clinical literature and appears to be absent in the physical and forensic anthropological literature. This study examines the ossified auricular cartilage and tests whether the hypothesis can be identified in postmortem skeletonized tissue and be part of the external auditory meatus. A total of 290 crania were examined for accessory ossicles. A descriptive and interpretative analysis was performed grossly, histologically, and morphometrically to document the morphology and location of the ossicles, investigate their structure, and perform hypothesis testing. Results revealed that seven females and one male crania from a total of 290 crania (2.76%) exhibit semi-ossified auricular cartilage attached to the tympanic plate of the temporal bone. The morphology and location of the ossicles at the junction of the auricle and external auditory meatus indicate they are hardened auricular cartilage that was verified with histological observations. Regression analysis indicates that addition of the ossicle to the depth of the auditory tube significantly changes coefficient of determination (R2) with respect to cranial breadth. In conclusion, results indicate that small cartilaginous structures of the external ear may ossify forming accessory tympanic plate ossicles that potentially could be identified in skeletal remains as a new osteological entity. This report highlights the types of information that can be gained using an approach that integrates forensic anthropology, gross anatomy, and histology.

Oral Drug Product Administration via Enteral Feeding Tubes: In Vitro Testing.

Medication administration via enteral feeding tubes (EFT) is a necessary practice for patients unable to swallow oral dosage forms due to a medical condition or treatment that affects the ability to swallow or the function of the gastrointestinal tract. Off-label administration of oral drug products via EFT raises concerns for pharmaceutical sponsors, regulators, and healthcare practitioners (HCPs) because of the potential risks this practice introduces to both the patient and the caregiver. These risks can be mitigated by generating data-supported instructions that patients and HCPs can use to ensure safe and accurate administration of oral drug products via EFT. This commentary presents an industry perspective on the testing that should be conducted to enable development of product-specific instructions in the labeling to support or advise against administration of oral drug products via enteral feeding tube. The proposal outlined in this commentary takes a risk-based approach, addressing recommendations from both regulatory agencies as well as considerations for expanding this testing to address needs specific to neonatal and pediatric populations.

The atypical 'hippocampal' glutamate receptor coupled to phospholipase D that controls stretch-sensitivity in primary mechanosensory nerve endings is homomeric purely metabotropic GluK2.

A metabotropic glutamate receptor coupled to phospholipase D (PLD-mGluR) was discovered in the hippocampus over three decades ago. Its pharmacology and direct linkage to PLD activation are well established and indicate it is a highly atypical glutamate receptor. A receptor with the same pharmacology is present in spindle primary sensory terminals where its blockade can totally abolish, and its activation can double, the normal stretch-evoked firing. We report here the first identification of this PLD-mGluR protein, by capitalizing on its expression in primary mechanosensory terminals, developing an enriched source, pharmacological profiling to identify an optimal ligand, and then functionalizing it as a molecular tool. Evidence from immunofluorescence, western and far-western blotting indicates PLD-mGluR is homomeric GluK2, since GluK2 is the only glutamate receptor protein/receptor subunit present in spindle mechanosensory terminals. Its expression was also found in the lanceolate palisade ending of hair follicle, also known to contain the PLD-mGluR. Finally, in a mouse model with ionotropic function ablated in the GluK2 subunit, spindle glutamatergic responses were still present, confirming it acts purely metabotropically. We conclude the PLD-mGluR is a homomeric GluK2 kainate receptor signalling purely metabotropically and it is common to other, perhaps all, primary mechanosensory endings.

Cattle grazing management affects soil microbial diversity and community network complexity in the Northern Great Plains.

Soil microbial communities play a vital role in the biogeochemical cycling and ecological functioning of grassland, but may be affected by common land uses such as cattle grazing. Changes in microbial diversity and network complexity can affect key ecosystem functions such as nutrient cycling. However, it is not well known how microbial diversity and network complexity respond to grazing in the Northern Great Plains. Consequently, it is important to understand whether variation in grazing management alters the diversity and complexity of grassland microbial communities. We compared the effect of intensive adaptive multi-paddock (AMP) grazing and conventional grazing practices on soil microbial communities using 16S/ITS amplicon sequencing. Samples were collected from grasslands in 13 AMP ranches and 13 neighboring, conventional ranches located across the Canadian prairies. We found that AMP grazing increased fungal diversity and evenness, and led to more complex microbial associations. Acidobacteria, Actinobacteria, Gemmatimonadetes, and Bacteroidetes were keystone taxa associated with AMP grazing, while Actinobacteria, Acidobacteria, Proteobacteria, and Armatimonadetes were keystone taxa under conventional grazing. Besides overall grazing treatment effects, specific grazing metrics like cattle stocking rate and rest-to-grazing ratio affected microbial richness and diversity. Bacterial and fungal richness increased with elevated stocking rate, and fungal richness and diversity increased directly with the rest-to-grazing ratio. These results suggest that AMP grazing may improve ecosystem by enhancing fungal diversity and increasing microbial network complexity and connectivity.

Using "Real-World Data" to Study Cleft Lip/Palate Care: An Exploration of Speech Outcomes from a Multi-Center US Learning Health Network.

OBJECTIVE: To assess the ability of a cleft-specific multi-site learning health network registry to describe variations in cleft outcomes by cleft phenotypes, ages, and treatment centers. Observed variations were assessed for coherence with prior study findings. DESIGN: Cross-sectional analysis of prospectively collected data from 2019-2022. SETTING: Six cleft treatment centers collected data systematically during routine clinic appointments according to a standardized protocol. PARTICIPANTS: 714 English-speaking children and adolescents with non-syndromic cleft lip/palate. INTERVENTION: Routine multidisciplinary care and systematic outcomes measurement by cleft teams. OUTCOME MEASURES: Speech outcomes included articulatory accuracy measured by Percent Consonants Correct (PCC), velopharyngeal function measured by Velopharyngeal Competence (VPC) Rating Scale (VPC-R), intelligibility measured by caregiver-reported Intelligibility in Context Scale (ICS), and two CLEFT-Q™ surveys, in which patients rate their own speech function and level of speech distress. RESULTS: 12year-olds exhibited high median PCC scores (91-100%), high frequency of velopharyngeal competency (62.50-100%), and high median Speech Function (80-91) relative to younger peers parsed by phenotype. Patients with bilateral cleft lip, alveolus, and palate reported low PCC scores (51-91%) relative to peers at some ages and low frequency of velopharyngeal competency (26.67%) at 5 years. ICS scores ranged from 3.93-5.0 for all ages and phenotypes. Speech Function and Speech Distress were similar across phenotypes. CONCLUSIONS: This exploration of speech outcomes demonstrates the current ability of the cleft-specific registry to support cleft research efforts as a source of "real-world" data. Further work is focused on developing robust methodology for hypothesis-driven research and causal inference.

Identification of herbarium specimen sheet components from high-resolution images using deep learning.

Advanced computer vision techniques hold the potential to mobilise vast quantities of biodiversity data by facilitating the rapid extraction of text- and trait-based data from herbarium specimen digital images, and to increase the efficiency and accuracy of downstream data capture during digitisation. This investigation developed an object detection model using YOLOv5 and digitised collection images from the University of Melbourne Herbarium (MELU). The MELU-trained 'sheet-component' model-trained on 3371 annotated images, validated on 1000 annotated images, run using 'large' model type, at 640 pixels, for 200 epochs-successfully identified most of the 11 component types of the digital specimen images, with an overall model precision measure of 0.983, recall of 0.969 and moving average precision (mAP0.5-0.95) of 0.847. Specifically, 'institutional' and 'annotation' labels were predicted with mAP0.5-0.95 of 0.970 and 0.878 respectively. It was found that annotating at least 2000 images was required to train an adequate model, likely due to the heterogeneity of specimen sheets. The full model was then applied to selected specimens from nine global herbaria (Biodiversity Data Journal, 7, 2019), quantifying its generalisability: for example, the 'institutional label' was identified with mAP0.5-0.95 of between 0.68 and 0.89 across the various herbaria. Further detailed study demonstrated that starting with the MELU-model weights and retraining for as few as 50 epochs on 30 additional annotated images was sufficient to enable the prediction of a previously unseen component. As many herbaria are resource-constrained, the MELU-trained 'sheet-component' model weights are made available and application encouraged.