A novel naïve Bayes approach to identifying grooming behaviors in the force-plate actometric platform.

BACKGROUND: Self-grooming behavior in rodents serves as a valuable behavioral index for investigating stereotyped and perseverative responses. Most current grooming analyses rely on video observation, which lacks standardization, efficiency, and quantitative information about force. To address these limitations, we developed an automated paradigm to analyze grooming using a force-plate actometer. NEW METHOD: Grooming behavior is quantified by calculating ratios of relevant movement power spectral bands. These ratios are input into a naïve Bayes classifier, trained with manual video observations. The effectiveness of this method was tested using CIN-d mice, an animal model developed through early-life depletion of striatal cholinergic interneurons (CIN-d) and featuring prolonged grooming responses to acute stressors. Behavioral monitoring was simultaneously conducted on the force-place actometer and by video recording. RESULTS: The naïve Bayes approach achieved 93.7% accurate classification and an area under the receiver operating characteristic curve of 0.894. We confirmed that male CIN-d mice displayed significantly longer grooming durations than controls. However, this elevation was not correlated with increases in grooming force. Notably, the dopaminergic antagonist haloperidol reduced grooming force and duration. COMPARISON WITH EXISTING METHODS: In contrast to observation-based approaches, our method affords rapid, unbiased, and automated assessment of grooming duration, frequency, and force. CONCLUSIONS: Our novel approach enables fast and accurate automated detection of grooming behaviors. This method holds promise for high-throughput assessments of grooming stereotypies in animal models of neuropsychiatric disorders.

A novel naïve Bayes approach to identifying grooming behaviors in the force-plate actometric platform.

Background: Self-grooming behavior in rodents serves as a valuable model for investigating stereotyped and perseverative responses. Most current grooming analyses primarily rely on video observation, which lacks standardization, efficiency, and quantitative information about force. To address these limitations, we developed an automated paradigm to analyze grooming using a force-plate actometer. New Method: Grooming behavior is quantified by calculating ratios of relevant movement power spectral bands. These ratios are then input into a naïve Bayes classifier, trained with manual video observations. To validate the effectiveness of this method, we applied it to the behavioral analysis of the early-life striatal cholinergic interneuron depletion (CIN-d) mouse, a model of tic pathophysiology recently developed in our laboratory, which exhibits prolonged grooming responses to acute stressors. Behavioral monitoring was simultaneously conducted on the force-place actometer and by video recording. Results: The naïve Bayes approach achieved 93.7% accurate classification and an area under the receiver operating characteristic curve of 0.894. We confirmed that male CIN-d mice displayed significantly longer grooming durations compared to controls. However, this elevation was not correlated with increases in grooming force. Notably, haloperidol, a benchmark therapy for tic disorders, reduced both grooming force and duration. Comparison with Existing Methods: In contrast to observation-based approaches, our method affords rapid, unbiased, and automated assessment of grooming duration, frequency, and force. Conclusions: Our novel approach enables fast and accurate automated detection of grooming behaviors. This method holds promise for high-throughput assessments of grooming stereotypies in animal models of tic disorders and other psychiatric conditions.

Prefrontal allopregnanolone mediates the adverse effects of acute stress in a mouse model of tic pathophysiology.

Ample evidence suggests that acute stress can worsen symptom severity in Tourette syndrome (TS); however, the neurobiological underpinnings of this phenomenon remain poorly understood. We previously showed that acute stress exacerbates tic-like and other TS-associated responses via the neurosteroid allopregnanolone (AP) in an animal model of repetitive behavioral pathology. To verify the relevance of this mechanism to tic pathophysiology, here we tested the effects of AP in a mouse model recapitulating the partial depletion of dorsolateral cholinergic interneurons (CINs) seen in post-mortem studies of TS. Mice underwent targeted depletion of striatal CINs during adolescence and were tested in young adulthood. Compared with controls, partially CIN-depleted male mice exhibited several TS-relevant abnormalities, including deficient prepulse inhibition (PPI) and increased grooming stereotypies after a 30-min session of spatial confinement - a mild acute stressor that increases AP levels in the prefrontal cortex (PFC). These effects were not seen in females. Systemic and intra-PFC AP administration dose-dependently worsened grooming stereotypies and PPI deficits in partially CIN-depleted males. Conversely, both AP synthesis inhibition and pharmacological antagonism reduced the effects of stress. These results further suggest that AP in the PFC mediates the adverse effects of stress on the severity of tics and other TS-related manifestations. Future studies will be necessary to confirm these mechanisms in patients and define the circuitry responsible for the effects of AP on tics.

Slc9a6 mutation causes Purkinje cell loss and ataxia in the shaker rat.

The shaker rat carries a naturally occurring mutation leading to progressive ataxia characterized by Purkinje cell (PC) loss. We previously reported on fine-mapping the shaker locus to the long arm of the rat X chromosome. In this work, we sought to identify the mutated gene underlying the shaker phenotype and confirm its identity by functional complementation. We fine-mapped the candidate region and analyzed cerebellar transcriptomes, identifying a XM_217630.9 (Slc9a6):c.[191_195delinsA] variant in the Slc9a6 gene that segregated with disease. We generated an adeno-associated virus (AAV) targeting Slc9a6 expression to PCs using the mouse L7-6 (L7) promoter. We administered the AAV prior to the onset of PC degeneration through intracerebroventricular injection and found that it reduced the shaker motor, molecular and cellular phenotypes. Therefore, Slc9a6 is mutated in shaker and AAV-based gene therapy may be a viable therapeutic strategy for Christianson syndrome, also caused by Slc9a6 mutation.

Calcium and Phosphate Solubility Curve Equation for Determining Precipitation Limits in Compounding Parenteral Nutrition.

Clinicians have published research and reports on calcium and phosphate solubility within parenteral nutrition (PN) for over 40 years. Foundational empirical laboratory investigation in the 1980s motivated by the prevalence of neonatal rickets and osteomalacia in the Neonatal Intensive Care Unit (NICU) population led to precipitation curves that have guided PN prescribing and compounding. Over subsequent decades, numerous publications have expanded the knowledge of factors influencing calcium and phosphate solubility in formulating optimal and safe PN admixtures. Failure to adhere to known principles has led to serious injury and death. Known solubility curves are derived from empiric analysis of a finite number of conditions and concentrations, whereas custom PN orders vary widely and rarely match the admixture composition in the data set used to derive the published precipitation curves. Various commercial platforms have been developed to aid the pharmacist in assessing the potential for precipitation when evaluating a PN order. Some applications plot the calcium and phosphate concentrations of the prescribed PN against known published graphs most similar to the order, allowing the pharmacist to judge the risk of precipitation. Other approaches use intellectually protected trade secret algorithms to determine calcium and phosphate solubility across a continuum of conditions. This publication reports equations that have been used successfully for over 2 decades in our regional network of NICUs and shared with others to determine safe prescribing limits for calcium and phosphate concentrations using an electronic PN prescribing program.

Suitability of Data-Collection Methods, Tools, and Metrics for Evaluating Market Food Environments in Low- and Middle-Income Countries.

Globalization is transforming food environments in low- and middle-income countries (LMICs) with implications for diets and nutrition. However, most food-environment assessments were developed for use in high-income countries. We evaluated the suitability of 113 data-collection assessments (i.e., methods, tools, and metrics) for eight dimensions of informal and formal market food environments for diverse contexts of LMICs. We used a scoring exercise and a survey of experts (n = 27). According to the scoring exercise, 10 assessments (8 methods, 1 tool, and 1 metric) were suitable without modification for informal markets. Suitability for formal markets was markedly higher, with 41 assessments (21 methods, 14 tools, and 6 metrics) found suitable without modification. Experts considered availability, accessibility, price, and affordability the most important dimensions of market food environments to evaluate in LMICs. Market-basket analysis and vendor audits (which include inventories) were ranked as the most suitable methods to assess multiple dimensions of market food environments, including availability, price, affordability, vendor and product characteristics, marketing, and regulation. Gaps in relevant assessments were found for convenience and desirability. Results demonstrate the need for the development, adaptation, and validation of assessments relevant for informal markets in a diverse range of LMIC contexts to support diets, nutrition, and health globally.

ASPEN lipid injectable emulsion safety recommendations part 2: Neonate and pediatric considerations.

Lipid injectable emulsions (ILEs) are complex pharmaceutical formulations intended as a source of energy and fatty acids for parenteral nutrition (PN) therapy. Part 1 of this series addressed issues associated with and safety recommendations pertaining to adult ILE use. Part 2 addresses ILE safety in neonatal and pediatric patients. Considerations for ILE use in the neonatal and pediatric populations differ from those of adults. For example, these patients often require higher doses compared with adult counterparts to support growth, development, and daily metabolic needs. ILE is also frequently administered as a separate infusion as opposed to in a total nutrient admixture owing to compatibility and stability issues and limitations to intravenous access in the neonatal and pediatric populations. ILE is the most frequent PN ingredient associated with PN errors occurring in the administration, prescribing, and transcribing processes. Concerns exist with use of in-line filters and repackaging of commercial products for infusion. ILE use in neonatal and pediatric patients has been associated with both minor and major adverse effects, which most often occur with doses exceeding manufacturer recommendations. Gaps in ILE best practices for neonatal and pediatric patients predispose to errors in the PN use system. This paper describes safe-use considerations for ILE products available in the United States in neonatal and pediatric patients, including indications, prescribing, order review, preparation, administration, and monitoring. This paper has been approved by the American Society for Parenteral and Enteral Nutrition (ASPEN) Board of Directors.

Computational investigation of the impact of deep brain stimulation contact size and shape on neural selectivity.

Background.Understanding neural selectivity is essential for optimizing medical applications of deep brain stimulation (DBS). We previously showed that modulation of the DBS waveform can induce changes in orientation-based selectivity, and that lengthening of DBS pulses or directional segmentation can reduce preferential selectivity for large axons. In this work, we sought to investigate a simple, but important question from a generalized perspective: how do the size and shape of the contact influence neural selectivity?Methods.We created multicompartment neuron models for several axon diameters and used finite element modeling with standard-sized cylindrical leads to determine the effects on changing contact size and shape on axon activation profiles and volumes of tissue activated. Contacts ranged in size from 0.04 to 16 mm2, compared with a standard size of 6 mm2.Results.We found that changes in contact size are predicted to induce substantial changes in orientation-based selectivity in the context of a cylindrical lead, and changes in contact width or height can alter this selectivity. Smaller contact sizes were more effective in constraining neural activation to small, nearby axons. However, micro-scale contacts enable only limited spread of neural activation before exceeding standard charge density limitations; further, energetic efficiency is optimized by somewhat larger contacts.Interpretations.Small-scale contacts may be optimal for constraining stimulation in nearby grey matter and avoiding orientation-selective activation. However, given charge density limitations and energy inefficiency of micro-scale contacts, we predict that contacts sized similarly to or slightly smaller than segmented clinical leads may optimize energy efficiency while avoiding charge density limitations.

Detecting and Quantifying Ataxia-Related Motor Impairments in Rodents Using Markerless Motion Tracking With Deep Neural Networks.

In this study we evaluate the application of video-based markerless motion tracking based on deep neural networks for the analysis of ataxia-specific movement abnormalities in rodent models of cerebellar ataxia. Based on a small amount (<100) of manually labeled video frames, markerless motion tracking enabled the extraction of movement trajectories and parameters characterizing ataxia-specific movement abnormalities. In the first experiment, we analyzed videos of 6 shaker and 4 wildtype rats and were able to reproduce thê5 Hz tremor frequency in the shaker rat without the usage of a force plate. In the second experiment, we investigated a spinocerebellar ataxia type 3 (SCA3) mouse model (6 mice aged 3 months and 3 mice aged 9 months) in a beam-balancing task. By establishing a parameter for the assessment of rhythmicity of gait (RoG), we not only found a significantly higher RoG in wildtype mice compared to affected SCA3 mice aged 9 months, but were also able to reveal a significantly lower than typical RoG in SCA3 mice aged 3 months which exhibit no abnormalities in visual inspection. These prototypical results suggest the capability of the presented methods for the application in upcoming therapeutic intervention trials to identify subtle changes in movement behavior.

Parenteral Provision of Micronutrients to Pediatric Patients: An International Expert Consensus Paper.

INTRODUCTION: Micronutrients (vitamins and trace elements) are essential to all nutrition. For children and neonates who are dependent upon nutrition support therapies for growth and development, the prescribed regimen must supply all essential components. This paper aims to facilitate interpretation of existing clinical guidelines into practical approaches for the provision of micronutrients in pediatric parenteral nutrition. METHODS: An international, interdisciplinary expert panel was convened to review recent evidence-based guidelines and published literature to develop consensus-based recommendations on practical micronutrient provision in pediatric parenteral nutrition. RESULTS: The guidelines and evidence have been interpreted as answers to 10 commonly asked questions around the practical principles for provision and monitoring of micronutrients in pediatric patients. CONCLUSION: Micronutrients are an essential part of all parenteral nutrition and should be included in the pediatric nutrition therapy care plan.

ASPEN Lipid Injectable Emulsion Safety Recommendations, Part 1: Background and Adult Considerations.

Lipid injectable emulsions (ILEs) are complex pharmaceutical formulations used as a source of energy and essential fatty acids in parenteral nutrition. Issues associated with ILE use are distinctly different from oral fat and arise from emulsion stability, dose, and infusion tolerance. Since 1975, soybean oil has been the consistent source oil used in ILE formulations in the US. Partly because of safety concerns with the soybean-based ILE and frequent and long-standing problems with product inventory shortages, new ILE products have become available. Gaps in ILE best practices create a risk for ILE safety errors in prescribing, compounding, and administration of these products. This paper provides information on appropriate indications, dosing, and methods to avoid potential errors with ILE products in the US. This paper (Part 1) will focus on ILE background, information, and recommendations for adult patients, whereas Part 2 of this series will focus on neonatal and pediatric patient-specific information.

Neural selectivity, efficiency, and dose equivalence in deep brain stimulation through pulse width tuning and segmented electrodes.

BACKGROUND: Achieving deep brain stimulation (DBS) dose equivalence is challenging, especially with pulse width tuning and directional contacts. Further, the precise effects of pulse width tuning are unknown, and recent reports of the effects of pulse width tuning on neural selectivity are at odds with classic biophysical studies. METHODS: We created multicompartment neuron models for two axon diameters and used finite element modeling to determine extracellular influence from standard and segmented electrodes. We analyzed axon activation profiles and calculated volumes of tissue activated. RESULTS: We find that long pulse widths focus the stimulation effect on small, nearby fibers, suppressing distant white matter tract activation (responsible for some DBS side effects) and improving battery utilization when equivalent activation is maintained for small axons. Directional leads enable similar benefits to a greater degree. Reexamining previous reports of short pulse stimulation reducing side effects, we explore a possible alternate explanation: non-dose equivalent stimulation may have resulted in reduced spread of neural activation. Finally, using internal capsule avoidance as an example in the context of subthalamic stimulation, we present a patient-specific model to show how long pulse widths could help increase the biophysical therapeutic window. DISCUSSION: We find agreement with classic studies and predict that long pulse widths may focus the stimulation effect on small, nearby fibers and improve power consumption. While future pre-clinical and clinical work is necessary regarding pulse width tuning, it is clear that future studies must ensure dose equivalence, noting that energy- and charge-equivalent amplitudes do not result in equivalent spread of neural activation when changing pulse width.

Parkinsonism and subthalamic deep brain stimulation dysregulate behavioral motivation in a rodent model.

BACKGROUND: Apathy and impulsivity constitute opposite poles of a behavioral motivation spectrum often disrupted by both the symptoms and therapies for Parkinson's Disease (PD). Upwards of 70% of PD patients experience symptoms of apathy, frequently unresolved or worsened by deep brain stimulation (DBS) of the subthalamic nucleus (STN). Worse, more than half of patients receiving DBS for PD experience new-onset impulse control disorders of varying severity following therapy initiation. While these symptoms and side-effects have been widely reported in clinical studies, they are largely unexplored in animal models. METHODS: We applied high-frequency DBS in a 6-OHDA hemiparkinsonian rat model. We trained rats on a series of go/stop and go/no-go behavioral paradigms and examined how parkinsonism and DBS modulated task responses. RESULTS: STN DBS in healthy rodents drove impulsive behavior in the form of stop and no-go task failure, impulsive reward seeking, and noninstructed task attempts. While trained rats without DBS only tended to fail stop and no-go cues very shortly after the cue, DBS led to failures at significantly later time points. Hemiparkinsonism slowed response times and reduced response rates, not alleviated by effective DBS. INTERPRETATIONS: PD interrupts neural signaling responsible for healthy action selection, not restored by DBS. PD may be associated with a dearth of action commands, manifesting as apathy. Conversely, effective DBS may bias the system toward the impulsive end of the behavioral motivation spectrum without restoring behaviorally reasonable actions, mis-weighting reward-based action selection and manifesting as impulsivity, aided by DBS interfering with stop signaling.

Intravenous Vancomycin Therapeutic Drug Monitoring in Children: Evaluation of a Pharmacy-Driven Protocol and Collaborative Practice Agreement.

BACKGROUND: Vancomycin optimization is challenging, requiring careful therapeutic drug monitoring (TDM) to avoid toxicity and ensure an efficacious concentration. Most prescriptions are empiric and often discontinued within 72 hours, which makes early TDM unnecessary. Although TDM using trough levels is common, the area under the concentration-time curve (AUC) is the preferred pharmacodynamic target. We studied the effect of a pharmacy-driven vancomycin collaborative practice agreement (CPA) at a children's hospital that delayed TDM up to 72 hours and targeted a 2-point 24-hour AUC of ≥400 mg × h/L. METHODS: We retrospectively reviewed vancomycin courses in patients aged ≥30 days who received vancomycin between April 1, 2011, and August 30, 2017. We implemented the CPA on June 1, 2014. Outcomes included CPA use, use of TDM, dosage adjustments, and development of acute kidney injury; we compared courses given while monitoring only trough levels (TO-TDM) with those given while using the CPA (AUC-TDM). We performed interrupted time series analyses to account for preintervention trends. RESULTS: We included 2379 courses in the TO-TDM period and 2155 in the AUC-TDM period. During AUC-TDM, 87% of the courses were managed by the CPA. In adjusted interrupted time series analyses, CPA implementation was associated with an initial change in level of -0.265 (95% confidence interval [CI], -0.336 to -0.189) TDM and an initial change in level of -0.332 (95% CI, -0.506 to -0.163) dosage adjustments. The 1-year risk of acute kidney injury decreased after CPA implementation (odds ratio, 0.695 [95% CI, 0.539-0.91]). CONCLUSION: The pharmacy-driven vancomycin CPA resulted in less monitoring and fewer dose adjustments without increasing AKI.

Influencing the timing of parenteral nutrition initiation in the pediatric intensive care unit.

BACKGROUND: Lack of benefit and potential harm of early parenteral nutrition (PN) initiation in critically ill children was highlighted in the 2016 published results of a large multicenter, randomized controlled trial. OBJECTIVES: The purpose of this project was to implement a process to delay PN initiation for up to five days after admission to our pediatric intensive care unit (PICU). METHODS: Patients greater than thirty days of age, admitted to the PICU beginning July 1, 2016 were included in the analysis of the healthcare improvement initiative to decrease early PN initiation. A meeting was held with PICU fellows, attending physicians, dietitians, and pharmacists to reach a consensus to delay initiation of parenteral nutrition until PICU day five. The dietitian, with pharmacist support, reiterated recommendations on rounds and in formal notes. RESULTS: A total of 2333 patients were identified in the pre-intervention group and a total of 2491 patients in the post-intervention group. The percentage of patients receiving PN prior to day five within the PICU was 5.5% in the pre-intervention group versus 3.1% in the delayed PN group (p<0.001). PICU patients receiving PN less than or equal to three days decreased from 2.6% pre-intervention to 1.5% post-intervention (p=0.01). For the subset of patients who were initiated on PN after admission to the PICU, median PICU length of stay was 7 days versus 6 days in the pre-intervention versus post-intervention group (p=0.26). CONCLUSIONS: Decrease in PN utilization was seen in the pre and post-intervention groups as assessed by percentage of patients initiated on PN prior to day five of PICU admission. Consensus among practitioners with consistent recommendations from the frontline dietitian and pharmacist, with nutrition support team collaboration, contributed to the evidence based quality initiative results. Delaying PN did not adversely affect length of stay pre versus post-intervention.

Retrospective comparison of two enoxaparin dosing and monitoring protocols at a pediatric hospital.

PURPOSE: The study analyzes the effectiveness and safety of a higher than standard enoxaparin dosing protocol implemented for pediatric patients requiring initiation of therapeutic anticoagulation. METHODS: A retrospective review of 2 enoxaparin dosing and monitoring protocols was performed. The standard protocol used 1.5 mg/kg/dose (in patients <3 months of age) and 1 mg/kg/dose (in patients ≥3 months of age) with anti-Xa monitoring following the first dose. The high-dose protocol was implemented at 1.7 mg/kg/dose (in patients <3 months of age), 1.5 mg/kg/dose (in patients 3 through 11 months of age), 1.2 mg/kg/dose (in patients 1 through 4 years of age), and 1.1 mg/kg/dose (in patients 5 through 17 years of age), with anti-Xa monitoring after the second dose. Primary outcomes were number of dosing changes prior to and time to first target anti-Xa level. Secondary outcomes included percentage of patients with anti-Xa levels above target level. RESULTS: The median number of dose changes required to achieve a target anti-Xa level was 1 (interquartile range [IQR], 0-1.5) and 0 (IQR, 0-1) for the standard-dose (n = 87) and high-dose groups (n = 132) (p = 0.17), respectively. The median number of dose adjustments to achieve target anti-Xa levels in the 3 through 11 months of age subgroup declined from 2 (IQR, 1-3.25) to 0 (IQR, 0-1) in the standard- versus high-dose groups, respectively (p < 0.01). No difference was seen in other age subgroups. Patients with above-target levels did not differ statistically between groups. CONCLUSION: Initiating enoxaparin at higher doses in pediatric patients may result in fewer dosing changes than standard dosing. Benefit was demonstrated for the 3-11 months of age high-dose subgroup. Across all groups, the high-dose strategy was safe and did not result in a statistically significant increase in above-target levels.

Influencing the timing of parenteral nutrition initiation in the pediatric intensive care unit

Background: Lack of benefit and potential harm of early parenteral nutrition (PN) initiation in critically ill children was highlighted in the 2016 published results of a large multicenter, randomized controlled trial. Objectives: The purpose of this project was to implement a process to delay PN initiation for up to five days after admission to our pediatric intensive care unit (PICU). Methods: Patients greater than thirty days of age, admitted to the PICU beginning July 1, 2016 were included in the analysis of the healthcare improvement initiative to decrease early PN initiation. A meeting was held with PICU fellows, attending physicians, dietitians, and pharmacists to reach a consensus to delay initiation of parenteral nutrition until PICU day five. The dietitian, with pharmacist support, reiterated recommendations on rounds and in formal notes. Results: A total of 2333 patients were identified in the pre-intervention group and a total of 2491 patients in the post-intervention group. The percentage of patients receiving PN prior to day five within the PICU was 5.5% in the pre-intervention group versus 3.1% in the delayed PN group (p<0.001). PICU patients receiving PN less than or equal to three days decreased from 2.6% pre-intervention to 1.5% post-intervention (p=0.01). For the subset of patients who were initiated on PN after admission to the PICU, median PICU length of stay was 7 days versus 6 days in the pre-intervention versus post-intervention group (p=0.26). Conclusions: Decrease in PN utilization was seen in the pre and post-intervention groups as assessed by percentage of patients initiated on PN prior to day five of PICU admission. Consensus among practitioners with consistent recommendations from the frontline dietitian and pharmacist, with nutrition support team collaboration, contributed to the evidence based quality initiative results. Delaying PN did not adversely affect length of stay pre versus post-intervention

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Current Opinions and Consensus for Studying Tremor in Animal Models.

Tremor is the most common movement disorder; however, we are just beginning to understand the brain circuitry that generates tremor. Various neuroimaging, neuropathological, and physiological studies in human tremor disorders have been performed to further our knowledge of tremor. But, the causal relationship between these observations and tremor is usually difficult to establish and detailed mechanisms are not sufficiently studied. To overcome these obstacles, animal models can provide an important means to look into human tremor disorders. In this manuscript, we will discuss the use of different species of animals (mice, rats, fruit flies, pigs, and monkeys) to model human tremor disorders. Several ways to manipulate the brain circuitry and physiology in these animal models (pharmacology, genetics, and lesioning) will also be discussed. Finally, we will discuss how these animal models can help us to gain knowledge of the pathophysiology of human tremor disorders, which could serve as a platform towards developing novel therapies for tremor.