Genetic and pharmacological reduction of CDK14 mitigates synucleinopathy.

Parkinson's disease (PD) is a debilitating neurodegenerative disease characterized by the loss of midbrain dopaminergic neurons (DaNs) and the abnormal accumulation of α-Synuclein (α-Syn) protein. Currently, no treatment can slow nor halt the progression of PD. Multiplications and mutations of the α-Syn gene (SNCA) cause PD-associated syndromes and animal models that overexpress α-Syn replicate several features of PD. Decreasing total α-Syn levels, therefore, is an attractive approach to slow down neurodegeneration in patients with synucleinopathy. We previously performed a genetic screen for modifiers of α-Syn levels and identified CDK14, a kinase of largely unknown function as a regulator of α-Syn. To test the potential therapeutic effects of CDK14 reduction in PD, we ablated Cdk14 in the α-Syn preformed fibrils (PFF)-induced PD mouse model. We found that loss of Cdk14 mitigates the grip strength deficit of PFF-treated mice and ameliorates PFF-induced cortical α-Syn pathology, indicated by reduced numbers of pS129 α-Syn-containing cells. In primary neurons, we found that Cdk14 depletion protects against the propagation of toxic α-Syn species. We further validated these findings on pS129 α-Syn levels in PD patient neurons. Finally, we leveraged the recent discovery of a covalent inhibitor of CDK14 to determine whether this target is pharmacologically tractable in vitro and in vivo. We found that CDK14 inhibition decreases total and pathologically aggregated α-Syn in human neurons, in PFF-challenged rat neurons and in the brains of α-Syn-humanized mice. In summary, we suggest that CDK14 represents a novel therapeutic target for PD-associated synucleinopathy.

Transkingdom Network Analysis (TkNA): a systems framework for inferring causal factors underlying host-microbiota and other multi-omic interactions.

We present Transkingdom Network Analysis (TkNA), a unique causal-inference analytical framework that offers a holistic view of biological systems by integrating data from multiple cohorts and diverse omics types. TkNA helps to decipher key players and mechanisms governing host-microbiota (or any multi-omic data) interactions in specific conditions or diseases. TkNA reconstructs a network that represents a statistical model capturing the complex relationships between different omics in the biological system. It identifies robust and reproducible patterns of fold change direction and correlation sign across several cohorts to select differential features and their per-group correlations. The framework then uses causality-sensitive metrics, statistical thresholds and topological criteria to determine the final edges forming the transkingdom network. With the subsequent network's topological features, TkNA identifies nodes controlling a given subnetwork or governing communication between kingdoms and/or subnetworks. The computational time for the millions of correlations necessary for network reconstruction in TkNA typically takes only a few minutes, varying with the study design. Unlike most other multi-omics approaches that find only associations, TkNA focuses on establishing causality while accounting for the complex structure of multi-omic data. It achieves this without requiring huge sample sizes. Moreover, the TkNA protocol is user friendly, requiring minimal installation and basic familiarity with Unix. Researchers can access the TkNA software at https://github.com/CAnBioNet/TkNA/ .

Association between frailty and sleep quality in people living with multiple sclerosis and obesity: An observational cross-sectional study.

BACKGROUND: A majority of the people with multiple sclerosis (pwMS) experience sleep disturbances. Frailty is also common in pwMS. The geriatric literature strongly suggests that frailty is associated with worse sleep outcomes in community-dwelling older adults, but this association has yet to be explored among pwMS. This study focused on examining the association between frailty and sleep quality in pwMS. METHODS: Seventy-six people with both MS and obesity (mean age: 47.6 ± 10.9 years, 81.6 % female, mean body mass index (BMI): 37.10 ± 5.5 kg/m2, mean Patient Determined Disease Steps (PDDS): 0.82 ± 1.20) were included in this cross-sectional secondary analysis. A comprehensive frailty index (FI) based on 41 health deficits from various health domains was calculated based on standardized procedures. Sleep quality was determined by the Pittsburgh Sleep Quality Index questionnaire (PSQI). RESULTS: Overall, 67.1 % of the participants were identified as non-frail (FI ≤ 0.25), and 32.9 % were identified as frail (FI > 0.25). A significant correlation was observed between FI scores and global PSQI scores (ρ = 0.43, p < 0.05). Cross-tabulation analyses revealed that frail participants had worse subjective sleep quality, sleep latency, habitual sleep efficiency, sleep disturbances, daytime dysfunction, and higher use of sleep medications compared to non-frail participants (p < 0.05). CONCLUSIONS: The current study identified a significant association between frailty and sleep quality in people with both MS and obesity with minimal disability. These findings underscore the importance of untangling the relationship between frailty and sleep quality in pwMS. These results could lead to a more targeted approach for rehabilitation interventions aiming to improve frailty in MS.

Food and non-alcoholic beverage marketing in children and adults: A systematic review and activation likelihood estimation meta-analysis of functional magnetic resonance imaging studies.

Food marketing impacts the food behaviors of children and adults, but the underpinning neural mechanisms are poorly understood. This systematic review and meta-analysis pooled evidence from neuroimaging studies of exposure to food marketing stimuli (vs. control) on brain activations in children and adults to clarify regions associated with responding. Databases were searched for articles published to March 2022. Inclusion criteria included human functional magnetic resonance imaging (fMRI) studies employing a contrast between a food marketing stimulus and a non-food/non-exposure control, published in English in a peer-reviewed journal, reporting whole brain (not Region of Interest [ROI] only) co-ordinates. Eleven studies met inclusion criteria, of which eight were included in the quantitative synthesis (Activation Likelihood Estimation [ALE] meta-analysis). Food marketing exposures (vs. controls) produced greater activation in two clusters lying across the middle occipital gyrus, lingual gyrus, and cuneus (cluster 1), and the postcentral gyrus, precentral gyrus, and the inferior parietal lobule/supramarginal gyrus (cluster 2). Brain responses to food marketing are most consistently observed in areas relating to visual processing, attention, sensorimotor activity, and emotional processing. Subgroup analyses (e.g., adults vs. children) were not possible because of the paucity of data, and sensitivity analyses highlighted some instability in the clusters; therefore, conclusions remain tentative pending further research.

Modifying diet and exercise in multiple sclerosis (MoDEMS): A randomized controlled trial for behavioral weight loss in adults with multiple sclerosis and obesity.

BACKGROUND: Obesity is a risk factor for developing multiple sclerosis (MS) and MS-related disability. The efficacy of behavioral weight loss interventions among people with MS (pwMS) remains largely unknown. OBJECTIVE: Examine whether a group-based telehealth weight loss intervention produces clinically significant weight loss in pwMS and obesity. METHODS: Seventy-one pwMS were randomized to the weight loss intervention or treatment-as-usual (TAU). The 6-month program promoted established guidelines for calorie reduction and increased physical activity. Anthropometric measurements, mobility tasks, self-report questionnaires, and accelerometry were used to assess changes at follow-up. RESULTS: Mean percent weight loss in the treatment group was 8.6% compared to 0.7% in the TAU group (p < .001). Sixty-five percent of participants in the intervention achieved clinically meaningful weight loss (⩾ 5%). Participants in the treatment group engaged in 46.2 minutes/week more moderate-to-vigorous physical activity than TAU participants (p = .017) and showed improvements in quality of life (p = .012). Weight loss was associated with improved mobility (p = .003) and reduced fatiguability (p = .008). CONCLUSION: Findings demonstrate the efficacy of a behavioral intervention for pwMS and obesity, with clinically significant weight loss for two-thirds of participants in the treatment condition. Weight loss may also lead to improved mobility and quality of life.

Pediatric Neural Changes to Physical and Emotional Pain After Intensive Interdisciplinary Pain Treatment: A Pilot Study.

Brain areas activated during pain can contribute to enhancing or reducing the pain experience, showing a potential connection between chronic pain and the neural response to pain in adolescents and youth. This study examined changes in brain activation associated with experiencing physical pain, and the observation of physical and emotional pain in others, by using functional magnetic resonance imaging (fMRI) before and after intensive interdisciplinary pain treatment (IIPT). Eighteen youth (age 14 to 18) with widespread chronic pain completed fMRI testing before and after IIPT to assess changes in brain activation in response to physical and emotional pain. Broadly, brain activation changes were observed in frontal, somatosensory, and limbic regions. These changes suggest improvements in descending pain modulation via thalamus and caudate, and the different pattern of brain activation after treatment suggests better discrimination between physical and emotional pain. Brain activation changes were also correlated with improvements in clinical outcomes of catastrophizing (reduced activation in right caudate, right mid-cingulate, and postcentral gyrus) and pain-related disability (increased activation in precentral gyrus, left hippocampus, right middle occipital cortex, and left superior frontal gyrus). These changes support interpretation that reduced brain protective responses to pain were associated with treatment-related improvements. This pilot study highlights the need for larger trials designed to better understand the brain mechanisms involved in pediatric widespread pain treatment.

A pilot study evaluating the prefeasibility of a behavioral weight loss program in people with multiple sclerosis.

Weight loss interventions seldom include individuals with neurologic disease. The aims of the present study were to: 1) develop and assess the prefeasibility of a 6-month telehealth behavioral weight loss program for people with multiple sclerosis (MS) and obesity and 2) examine changes in weight loss (primary outcome), physical activity, and fruit/vegetable consumption at follow-up. Participants with obesity and MS engaged in a 24-week weight loss program. Participants followed established diet, exercise, and self-monitoring guidelines and attended weekly online group meetings. Median percentage weight loss was 10.54 % (SD = 7.19). Participants who adhered more closely to the self-monitoring guidelines (r = 0.81, p =.02), and who averaged higher weekly active minutes (r = 0.91, p =.002) achieved greater percentage weight loss. Six of the eight pilot participants achieved clinically meaningful weight loss (>5%) after 6-months.

Potential biomarker of brain response to opioid antagonism in adolescents with eating disorders: a pilot study.

Background: Eating Disorders (ED) affect up to 5% of youth and are associated with reward system alterations and compulsive behaviors. Naltrexone, an opioid antagonist, is used to treat ED behaviors such as binge eating and/or purging. The presumed mechanism of action is blockade of reward activation; however, not all patients respond, and the optimal dose is unknown. Developing a tool to detect objective drug response in the brain will facilitate drug development and therapeutic optimization. This pilot study evaluated neuroimaging as a pharmacodynamic biomarker of opioid antagonism in adolescents with ED. Methods: Youth aged 13-21 with binge/purge ED completed functional magnetic resonance imaging (fMRI) pre- and post-oral naltrexone. fMRI detected blood oxygenation-level dependent (BOLD) signal at rest and during two reward probes (monetary incentive delay, MID, and passive food view, PFV) in predefined regions of interest associated with reward and inhibitory control. Effect sizes for Δ%BOLD (post-naltrexone vs. baseline) were estimated using linear mixed effects modeling. Results: In 12 youth (16-21 years, 92% female), BOLD signal changes were detected following naltrexone in the nucleus accumbens during PFV (Δ%BOLD -0.08 ± 0.03; Cohen's d -1.06, p = 0.048) and anterior cingulate cortex during MID (Δ%BOLD 0.06 ± 0.03; Cohen's d 1.25, p = 0.086). Conclusion: fMRI detected acute reward pathway modulation in this small sample of adolescents with binge/purge ED. If validated in future, larger trials, task-based Δ%BOLD detected by fMRI may serve as a pharmacodynamic biomarker of opioid antagonism to facilitate the development of novel therapeutics targeting the reward pathway, enable quantitative pharmacology trials, and inform drug dosing. Clinical trial registration: https://clinicaltrials.gov/ct2/show/NCT04935931, NCT#04935931.

Nutritional considerations for a new era: A CF foundation position paper.

OBJECTIVE: To provide interim advice and considerations to the CF Community around CF nutrition in the current era. METHODS: The Cystic Fibrosis (CF) Foundation organized a multidisciplinary committee to develop a Nutrition Position Paper based on the rapidly changing nutrition landscape in CF, due in part to widespread use of cystic fibrosis transmembrane regulator highly effective modulator therapy (HEMT). Four workgroups were formed: Weight Management, Eating Behavior/Food Insecurity, Salt Homeostasis and Pancreatic Enzyme use. Each workgroup conducted their own focused review of the literature. RESULTS: The committee summarized current understanding of issues pertaining to the four workgroup topics and provided 6 key take-aways around CF Nutrition in the new era. CONCLUSION: People with CF (pwCF) are living longer, particularly with the advent of HEMT. The traditional high fat, high calorie CF diet may have negative nutritional and cardiovascular consequences as pwCF age. Individuals with CF may have poor diet quality, food insecurity, distorted body image, and an higher incidence of eating disorders. An increase in overweight and obesity may lead to new considerations for nutritional management, given potential effects of overnutrition on pulmonary and cardiometabolic parameters.

Neurocomputational mechanisms of food and physical activity decision-making in male adolescents.

We examined the neurocomputational mechanisms in which male adolescents make food and physical activity decisions and how those processes are influenced by body weight and physical activity levels. After physical activity and dietary assessments, thirty-eight males ages 14-18 completed the behavioral rating and fMRI decision tasks for food and physical activity items. The food and physical activity self-control decisions were significantly correlated with each other. In both, taste- or enjoyment-oriented processes were negatively associated with successful self-control decisions, while health-oriented processes were positively associated. The correlation between taste/enjoyment and healthy attribute ratings predicted actual laboratory food intake and physical activities (2-week activity monitoring). fMRI data showed the decision values of both food and activity are encoded in the ventromedial prefrontal cortex, suggesting both decisions share common reward value-related circuits at the time of choice. Compared to the group with overweight/obese, the group with normal weight showed stronger brain activations in the cognitive control, multisensory integration, and motor control regions during physical activity decisions. For both food and physical activity, self-controlled decisions utilize similar computational and neurobiological mechanisms, which may provide insights into how to promote healthy food and physical activity decisions.

Transkingdom Network Analysis (TkNA): a systems framework for inferring causal factors underlying host-microbiota and other multi-omic interactions.

Technological advances have generated tremendous amounts of high-throughput omics data. Integrating data from multiple cohorts and diverse omics types from new and previously published studies can offer a holistic view of a biological system and aid in deciphering its critical players and key mechanisms. In this protocol, we describe how to use Transkingdom Network Analysis (TkNA), a unique causal-inference analytical framework that can perform meta-analysis of cohorts and detect master regulators among measured parameters that govern pathological or physiological responses of host-microbiota (or any multi-omic data) interactions in a particular condition or disease. TkNA first reconstructs the network that represents a statistical model capturing the complex relationships between the different omics of the biological system. Here, it selects differential features and their per-group correlations by identifying robust and reproducible patterns of fold change direction and sign of correlation across several cohorts. Next, a causality-sensitive metric, statistical thresholds, and a set of topological criteria are used to select the final edges that form the transkingdom network. The second part of the analysis involves interrogating the network. Using the network's local and global topology metrics, it detects nodes that are responsible for control of given subnetwork or control of communication between kingdoms and/or subnetworks. The underlying basis of the TkNA approach involves fundamental principles including laws of causality, graph theory and information theory. Hence, TkNA can be used for causal inference via network analysis of any host and/or microbiota multi-omics data. This quick and easy-to-run protocol requires very basic familiarity with the Unix command-line environment.

Pediatric Tube Weaning: A Meta-Analysis of Factors Contributing to Success.

Approximately 3-10% of children have severe feeding issues, and some require enteral/tube nutrition to grow and thrive. For many children, tube feeding is temporary, making efficacious interventions for tube weaning essential. We conducted a systematic review and meta-analysis of tube weaning treatments. Outcomes included percentage of participants completely weaned from the tube, and mean percentage of kilocalories consumed orally following treatment. Data were extracted from 42 studies, including cohort studies and single-subject research design studies. We evaluated moderators of treatment success, including treatment setting, use of behavioral approaches, use of hunger provocation, and use of a multidisciplinary approach. Results indicated that, after treatment, children received significantly more calories orally, and 67-69% of children were fully weaned. These analyses suggest that current interventions are generally effective; however, variability within treatments exist. Prospective randomized clinical trials are needed to understand effective components of weaning interventions.

Reinforcer pathology, probabilistic choice, and medication adherence in patients with multiple sclerosis.

The reinforcer pathology model posits that core behavioral economic mechanisms, including delay discounting and behavioral economic demand, underlie adverse health decisions and related clinical disorders. Extensions beyond substance use disorder and obesity, however, are limited. Using a reinforcer pathology framework, this study evaluates medical adherence decisions in patients with multiple sclerosis. Participants completed behavioral economic measures, including delay discounting, probability discounting, and a medication purchase task. A medical decision-making task was also used to evaluate how sensitivity to mild side effect risk and efficacy contributed to the likelihood of taking a hypothetical disease-modifying therapy. Less steep delay discounting and more intense (greater) medication demand were independently associated with greater adherence to the medication decision-making procedure. More generally, the pattern of interrelations between the medication-specific and general behavioral economic metrics was consistent with and contributes to the reinforcer pathology model. Additional research is warranted to expand these models to different populations and health behaviors, including those of a positive health orientation (i.e., medication adherence).

Feasibility and acceptability of a CF-specific cognitive-behavioral preventive intervention for adults integrated into team-based care.

BACKGROUND: A cystic fibrosis (CF)-specific cognitive-behavioral therapy intervention (CF-CBT) was developed in partnership with the CF community to advance preventive mental health care. Multidisciplinary providers across three centers were trained to deliver CF-CBT for this pilot assessing feasibility/acceptability and preliminary effectiveness of an integrated model of care. METHODS: The 8-session CF-CBT was delivered to 14 adults with mild depression and/or anxiety symptoms in-person and via audio telehealth. Assessment of attrition, engagement, homework completion, treatment satisfaction, and treatment fidelity informed feasibility/acceptability assessment. Mental health outcomes included depression, anxiety, quality of life (Cystic Fibrosis Questionnaire-Revised [CFQ-R), perceived stress and coping. Preliminary effectiveness was evaluated with Cohen's d metric of effect sizes (ES) of pre-post mean change scores. RESULTS: A total of 108 sessions were conducted; 13 adults completed the intervention; 1 discontinued early. Engagement, homework completion, and treatment acceptability were highly rated (mean = 30; SD = 2, range: 27-32 on a 32-point scale). Fidelity scores ranged from 85.7% to 93.6%. Large ES changes reflected improvements in depressive symptoms (-0.83), CFQ-R (Vitality scale: 1.11), and Relaxation Skills (0.93); moderate ES for CFQ-R Role Functioning (0.63), Awareness of Tension (0.62), Coping Confidence (0.70) and CF-specific Coping (0.55); and small ES for anxiety symptoms (-0.22), perceived stress (-0.25), Behavioral Activation (0.29), and several CFQ-R domains, including Emotional Functioning (0.29). Two CFQ-R subscales decreased (Body Image, Eating Concerns). CONCLUSIONS: Results indicated feasibility and acceptability of CF-CBT and its integration into team-based CF care with promising effectiveness, especially for depression. A multicenter randomized controlled trial of CF-CBT will further examine effectiveness of a CF-specific integrated care model.

Oral Sensory Sensitivity Influences Attentional Bias to Food Logo Images in Children: A Preliminary Investigation.

Background: Children's sensory processing patterns are linked with their eating habits; children with increased sensory sensitivity are often picky eaters. Research suggests that children's eating habits are also partially influenced by attention to food and beverage advertising. However, the extent to which sensory processing influences children's attention to food cues remains unknown. Therefore, we examined the attentional bias patterns to food vs. non-food logos among children 4-12 years with and without increased oral sensory sensitivity. Design: Children were categorized into high (n = 8) vs. typical (n = 36) oral sensory sensitivity by the Sensory Profile-2. We used eye-tracking to examine orientation and attentional bias to food vs. non-food logos among children with high vs. typical oral sensory sensitivity. We used a mixed model regression to test the influence of oral sensory sensitivity to attentional biases to food vs. non-food logos among children. Results: Results showed that children with high oral sensory sensitivity showed attentional biases toward non-food logos; specifically, children with high oral sensory sensitivity oriented more quickly to non-food logos as compared to food logos (p < 0.05), as well as spent more time looking at non-food logos as compared to food logos (p < 0.05). Findings were in the opposite direction for children with typical oral sensory sensitivity. Conclusion: Sensory sensitivity may be an individual characteristic that serves as a protective mechanism against susceptibility to food and beverage advertising in young children.

Reverse-translational identification of a cerebellar satiation network.

The brain is the seat of body weight homeostasis. However, our inability to control the increasing prevalence of obesity highlights a need to look beyond canonical feeding pathways to broaden our understanding of body weight control1-3. Here we used a reverse-translational approach to identify and anatomically, molecularly and functionally characterize a neural ensemble that promotes satiation. Unbiased, task-based functional magnetic resonance imaging revealed marked differences in cerebellar responses to food in people with a genetic disorder characterized by insatiable appetite. Transcriptomic analyses in mice revealed molecularly and topographically -distinct neurons in the anterior deep cerebellar nuclei (aDCN) that are activated by feeding or nutrient infusion in the gut. Selective activation of aDCN neurons substantially decreased food intake by reducing meal size without compensatory changes to metabolic rate. We found that aDCN activity terminates food intake by increasing striatal dopamine levels and attenuating the phasic dopamine response to subsequent food consumption. Our study defines a conserved satiation centre that may represent a novel therapeutic target for the management of excessive eating, and underscores the utility of a 'bedside-to-bench' approach for the identification of neural circuits that influence behaviour.

Shared Dynamics of Food Decision-Making in Mother-Child Dyads.

This study explored risk parameters of obesity in food decision-making in mother-child dyads. We tested 45 children between 8-12 years and their biological mothers to measure the decision weights of food health attributes, the decision weights of food taste attributes, self-regulated food decisions, and self-reported self-control scores. Maternal body mass index (BMI), and children's BMI-percentiles-for-age were also measured. We found a positive correlation between children's and their mothers' decision weights of taste attributes in food decision-making. We also found a positive correlation between children's BMI %iles and their mothers' BMIs. Children with overweight/obesity demonstrated lower correlations between health and taste ratings and a lower percentage of self-regulated food decisions (i.e., resisting to eat tasty but unhealthy foods or choosing to eat not-tasty but healthy foods) than children with healthy weight. Our findings suggested that the decision weights of taste attributes and weight status shared similar patterns in mother-child dyads. Also, the findings suggested that establishing dynamics of unhealthy food-decision making may increase the risk of childhood obesity. Helping children to develop the dynamics of healthy food-decision making by increasing the importance of health while decreasing the importance of taste may promote resilience to susceptibility to unhealthy eating and weight gain.

Modifying Diet and Exercise in MS (MoDEMS): Study design and protocol for a telehealth weight loss intervention for adults with obesity & Multiple Sclerosis.

Weight loss improves overall health, and reduces inflammation, risk of stroke, heart attack, diabetes, certain cancers, and death among individuals with obesity. Weight loss also improves mobility, increases stamina, and elevates mood. Between 25 and 33% of people with Multiple Sclerosis (pwMS) have obesity. Multiple Sclerosis (MS) and obesity are independently associated with reduced mobility, increased fatigue, and depression. Most behavioral weight loss trials exclude individuals with neurologic disease. Consequently, few studies have examined the effects of weight loss on symptom presentation and health outcomes among pwMS and obesity. This is the first study examining the efficacy of a comprehensive behavioral weight loss intervention designed specifically for pwMS. The purpose of this study is to develop and assess the efficacy of a telehealth administered weight loss intervention tailored for pwMS. Additionally, we aim to determine if weight loss reduces physical and emotional symptoms in individuals with obesity and MS. We will enroll 70 pwMS in a wait-list crossover trial to examine the efficacy of our intervention. If successful, findings will help determine whether we can help participants lose clinically significant weight - and whether weight loss among pwMS and overweight/obesity reduces fatigue, and improves mobility, mood, and quality of life.

iKanEat: protocol for a randomized controlled trial of megestrol as a component of a pediatric tube weaning protocol.

BACKGROUND: Although tube feeding routinely saves the lives of children who do not eat by mouth, chronic tube feeding can be a burden to patients, caregivers, and families. Very few randomized trials exist regarding the best methods for weaning children from their feeding tubes. METHODS: The current paper describes a randomized controlled trial of an empirically supported outpatient treatment protocol for moving children from tube to oral eating called iKanEat. Specifically, we describe the methods of randomized double-blind, placebo-controlled trial which includes a 4-week course of megestrol, the only medication used in the iKanEat protocol, to determine whether the addition of megestrol results in improved child outcomes. The primary and secondary aims are to assess the safety and efficacy of megestrol as part of the iKanEat protocol. The third aim is to provide critical information about the impact of the transition from tube to oral feeding on parent stress and parent and child quality of life. DISCUSSION: This trial will provide data regarding whether megestrol is a safe and effective component of the iKanEat tube weaning protocol, as well as important data on how the tube weaning process impacts parent stress and parent and child quality of life. TRIAL REGISTRATION: ClinicalTrials.gov NCT#03815019 . Registered on January 17, 2019.