United States

ABSTRACT:
INTRODUCTION
The increasing prevalence of metabolic diseases, such as non-alcoholic fatty liver disease
(NAFLD) and morbid obesity, has led to extensive research into the role of gut microbiota
and dietary factors in their development. This systematic review aims to synthesize current
evidence on how gut microbiome dysbiosis, and dietary patterns influence these conditions
and to evaluate potential therapeutic strategies. The gut microbiota, a diverse community of
microorganisms, plays a crucial role in regulating host metabolism and immune responses.
Disruptions in microbiota composition, referred to as dysbiosis, have been linked to the
development and progression of various metabolic disorders. This review examines the
intricate relationships between gut microbiota, metabolic health, and dietary influences to
identify potential intervention strategies.
METHODOLOGY
A comprehensive search was conducted across multiple databases to identify studies
investigating the impact of gut microbiota and diet on metabolic diseases. The review
includes longitudinal cohort studies, meta-analyses, and mechanistic research. Studies were
selected based on their focus on gut microbiota composition, dietary effects, and microbial
therapies in relation to NAFLD and obesity.
RESULTS AND DISCUSSION
Dysbiosis and impaired gut barrier function are closely associated with the progression of
metabolic-associated liver diseases and obesity. Microbial metabolites, such as short-chain
fatty acids (SCFAs), play significant roles in modulating liver metabolism and systemic
inflammation. Changes in gut microbiota composition over time correlate with variations in
metabolic parameters. Probiotic and prebiotic interventions demonstrate potential in
improving lipid profiles and insulin resistance.
CONCLUSION
Dietary interventions, probiotics, prebiotics, and emerging microbiota-targeted therapies have
shown promise in restoring gut microbiota balance and improving metabolic health.
However, the path forward requires addressing significant research gaps. These include the
need for large-scale, longitudinal studies to establish causal relationships between dietary-
induced microbiota changes and metabolic diseases, as well as exploring the roles of non-
bacterial components of the microbiota, such as fungi, viruses, and archaea.
Furthermore, personalized nutrition strategies that account for individual variability in
genetics, baseline microbiota composition, and lifestyle factors hold the potential to
revolutionize the prevention and treatment of metabolic diseases.

2025 AMA Research Challenge – Member Premier Access

Role of gut microbes in non-alcoholic fatty liver disease in patients with type 2 diabetes mellitus

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Background: Nutcracker Syndrome is a rare anatomic reduction of the aorto-mesenteric angle (<22°) and distance (<8mm), causing flow congestion and significant pain. It is more commonly symptomatic in 20-40-year-old females, concerning for obstetric consequences due to prolonged pelvic congestion syndrome, anemia, and chronic pain. 
Methods: This single-center retrospective cohort study included 73 female patients who underwent surgical repair for NCS between 2019 and 2025. Statistical comparisons were made using chi-squared and t-tests (significance threshold p < 0.05). Binomial and multivariate logistic regression were performed using Jamovi version 2.6.26 to calculate odds ratios (OR). 
Results: Non-parous patients more often had gastroparesis (p=0.003), POTS (p=0.00004), EDS (p=0.003), mast cell activation syndrome (p=0.0009), and abdominal pain (p=0.005). Parous women more commonly experienced pelvic congestion and heaviness (p=0.003, 0.0007), leg swelling (p=0.005), and varicose veins (p=0.020). Parous patients used more opioids pre-operatively (33.3% vs 13.5%, p=0.031) and no difference was seen post-operatively (50.0% vs 48.6%). Pelvic congestion syndrome prior to surgery predicts symptom resolution (p=0.019, OR=3.9). History of childbirth (OR=4.7) and concurrent antidepressant use (OR=8.4) were independently associated with pre-operative opioid use. 
Conclusions: Parous and non-parous women with NCS present with distinct pain profiles, likely influenced by lasting hemodynamic changes of pregnancy and differences in comorbid conditions. Increased use of opioids by parous patients pre-operatively could be contributed to higher rates of pelvic congestion syndrome and misattributed pain blamed on postpartum and gynecologic causes, portending a longer time to diagnosis. Understanding differences in presentation and likelihood of opioid use is critical, as NCS is rare and prompt recognition is imperative to addressing chronic pain to improve quality of life.


Pain and Parity in Nutcracker Syndrome: A Comparative Surgical Cohort Study 

Background
Surgical site infections (SSIs) are one of the most frequent and costly postoperative complications, specifically in open abdominal procedures. Even transient hyperglycemia following surgery, commonly caused by the body's stress response, can compromise immune function and impair wound healing. While the association between diabetes and SSIs is established, the impact of postoperative hyperglycemia, particularly in non-diabetic patients, remains less clearly defined. This study evaluates whether postoperative hyperglycemia increases the risk of SSIs after open abdominal surgery.
Methods
A retrospective cohort analysis was conducted utilizing the TriNetX research platform, which compiles de-identified electronic health records from more than 180 healthcare organizations. Adult patients (≥18 years) who underwent open abdominal surgeries such as exploratory laparotomy, appendectomy, and colectomy were identified. Patients were categorized into two cohorts based on serum glucose levels measured within seven days postoperatively. The two groups were hyperglycemia (glucose ≥180 mg/dL) and normoglycemia (glucose <180 mg/dL). Propensity score matching balanced the cohorts on key demographics (age, sex, race, ethnicity), comorbidities including diabetes mellitus (ICD-10: E08–E13), hypertension (ICD-10: I10–I1A), ischemic heart disease (ICD-10: I20–I25), chronic kidney disease (ICD-10: N18), heart failure (ICD-10: I50), chronic obstructive pulmonary disease (ICD-10: J44), cerebrovascular disease (ICD-10: I60–I69), and baseline laboratory values (BMI, hemoglobin, creatinine, prothrombin time, albumin). The outcome was the incidence of SSIs within 30 days of surgery, identified using ICD-10 code T81.4.
Results
After matching, 78,147 patients were included in each cohort. The average age was 59 years, and the prevalence of diabetes (41.3%) and hypertension (59.8%) was similar. SSIs occurred in 6.0% of patients with postoperative hyperglycemia compared to 5.3% of those with normoglycemia, yielding a risk difference of 0.7% (95% CI: 0.5–1.0%, p < 0.001). Postoperative hyperglycemia was associated with a 13.7% increased risk of SSIs (risk ratio 1.137, 95% CI: 1.092, 1.184, p < 0.001). Additionally, the odds ratio for developing SSIs in the hyperglycemia group was 1.146 (95% CI: 1.098, 1.196, p < 0.001).

Conclusion
Postoperative hyperglycemia significantly increases the risk of surgical site infections following open abdominal surgery. These findings suggest that postoperative glucose monitoring and glycemic management may reduce infection risk and improve surgical outcomes. Further prospective studies are needed to determine optimal glucose thresholds and intervention approaches that minimize complications without introducing additional risks.


Postoperative Hyperglycemia and the Risk of Surgical Site Infections in Open Abdominal Surgery

Background 
As the aging population increases in the United States, social isolation and loneliness have become increasingly prevalent among older adults, contributing to increased risks of cardiovascular disease, cognitive decline, and mortality (Courtin & Knapp, 2015). National estimates indicate that 29% of adults aged 50 to 80 report social isolation, while 33% report feelings of loneliness (Malani et al., 2025). Although technology-based interventions show promise in promoting social connectedness (Sen & Prybutok, 2021), few studies provide detailed frameworks for designing intergenerational phone-based programs connecting older adults with younger adults (Noble et al., 2022; Office et al., 2020). 

This study aims to describe the design, recruitment process, and feasibility of an intergenerational phone-based intervention (Phone Pals) to reduce self-identified loneliness and social isolation among older adults, and to create a replicable model for use in other medical schools and institutions. 

Methods 
Older adults are recruited through surveys distributed across Presbyterian Villages of Michigan senior living communities. Inclusion criteria includes self-identification of loneliness or social isolation. Undergraduate and medical student volunteers are recruited via email outreach to campus honors programs and student organizations. Older adults and students are randomly matched to promote transparency and reproducibility. Each pair engages in weekly 30-minute phone conversations over a 12-week period. As an orientation, older adults receive an overview of the program and guidelines on expectations, while student volunteers complete training that includes readings on geriatric issues and discussion guides covering social support, daily activities, and health maintenance. Primary outcomes include loneliness (UCLA Loneliness Scale) and perceptions of younger generations (Allophilia Scale). Semi-structured interviews will be conducted pre- and post-intervention to evaluate participant experiences and assess program satisfaction. 

Results 
Currently, 13 older adults and 12 student volunteers have enrolled. All training materials and implementation protocols have been finalized, with program initiation scheduled in the coming weeks. This initial stage demonstrates that recruiting participants, organizing logistics, and building enthusiasm among older adults and student volunteers can be effectively achieved. 

Conclusions 
Preliminary findings indicate that developing an intergenerational phone-based intervention is both feasible and adaptable. The Phone Pals program offers a detailed, scalable design that institutions can use to address social isolation among older adults. By combining accessible training materials and consistent telephone engagement, this approach can strengthen social connectedness and improve intergenerational attitudes. This study addresses a pressing public health challenge and provides a replicable strategy relevant to health systems. By documenting the design process, Phone Pals lays a foundation for other institutions to implement similar programs and contribute to empowering older adults.

Phone Pals: Development and Implementation of an Intergenerational Phone-Based Program to Address Social Isolation and Loneliness in Older Adults

Introduction: Tuberous Sclerosis Complex (TSC) is an autosomal dominant disease that affects nearly 2 million people worldwide. In most cases, mutations in either TSC2 (70%), or TSC1 (20%) induce the growth of benign tumors in multiple organ systems. Angiomyolipomas (AMLs) are benign tumors associated with TSC and are specific to the kidney. Importantly, approximately 40% of pediatric TSC patients will have cysts and/or AMLs by age 10. It is currently unclear why AMLs develop at different stages in life as the mechanisms of incomplete penetrance has yet to be elucidated. Importantly, metabolic changes occur in TSC cells, as evident by enhanced macropinocytosis, and changes to nucleic acid and lipid metabolism, which have been identified as potential therapeutic targets. Our goal is to understand the metabolic reprogramming in TSC, which may yield insights into the drivers of disease progression for clinical application. We hypothesize that AMLs in TSC patients show a distinct metabolic signature compared to those without AMLs. 
Methods: Utilizing the Tuberous Sclerosis Alliance Biosample Repository, we analyzed serum from 35 patients with TSC, confirmed by genetic testing. Concentrations of 276 metabolites were quantified in patients with AMLs (n = 18) and without AMLs (n = 17) using a LC/MS- based platform. We detected concentrations for 221 metabolites which were assessed using t-tests, and fold change (log2) analysis, to determine differentially abundant metabolites between TSC patients with or without AMLs. Statistical and pathway enrichment analyses were performed using MetaboAnalyst 6.0. Confirmatory t-tests were performed using PRISM.
Results: 21 metabolites had greater than 2-fold (log2) change in serum concentration in AML vs. non-AML patients (17 increased, 4 decreased). We discovered that the endogenous metabolites picolinic acid (1.239, p=0.009), and ribulose 5-phosphate (1.432, p=0.003) levels were strongly increased in AML vs. non-AML patients. Pathway enrichment analysis showed that methylhistidine metabolism, and homocysteine metabolism showed increased metabolite saturation in patients with AMLs, compared to those without AMLs.
Conclusions: Our data highlight the metabolic reprogramming that is characteristic of TSC and show that there are potential metabolic signatures intrinsic to TSC-associated AML tumorigenesis. Additional studies with larger patient cohorts may allow the development of prognostic indicators for formation of AMLs. 


Angiomyolipoma-associated Metabolic Reprogramming in TSC: Insights from Serum Metabolomics 

Background
TCF7L2 is a transcription factor and critical effector of the Wnt/β-catenin pathway, with pleiotropic roles across human biology and disease. Intronic SNPs in TCF7L2 have been linked to increased risk for type 2 diabetes, colon cancer, schizophrenia, and autism spectrum disorder (ASD). In 2021, a case series of pediatric patients with mono-allelic predicted loss-of-function (pLOF) variants in TCF7L2 were described as having similar features, including developmental delays and variable myopia, autism, and ADHD, among other features. Defining the genetic and phenotypic spectrum and natural history of this patient population – herein referred to as TCF7L2-related neurodevelopmental disorder (TRND) – is urgently required.

Methods
We identified an international cohort of 76 patients with neurodevelopmental features and pLOF TCF7L2 variants from 2022-2024 using multiple recruitment strategies (GeneMatcher, DECIPHER, and clinician outreach following literature review and screening of public/private repositories). We phenotypically characterized these patients with a clinician-facing survey, extracting 81 enriched Human Phenotype Ontology (HPO) terms and 11 broader categories of phenotypic features. In parallel, we interrogated ~60,000 adult PennMedicine BioBank (PMBB) patients to identify a distinct group of 11 patients with pLOF TCF7L2 variants. 

Results
We identified 76 patients with truncating (n=10), out-of-frame indel (n=18), missense (n=33), splice site (n=10), in-frame indel (n=1), and CNV (n=4) variants in TCF7L2 meeting clinical and variant-specific criteria. Speech delay (95%), craniofacial dysmorphisms (73%), ophthalmologic conditions (65%), ASD (62%), and orthopedic abnormalities (53%) were most commonly observed, comprising the defining syndromic features of TRND. Ear morphology abnormalities (22%), hypertelorism (21%), down-slanted palpebral fissures (19%), and frontal bossing (16%) were the most frequent craniofacial features, co-occurring in a subset of patients. Phenotypic differences did not grossly cluster by variant type or genomic locus. Among PMBB patients, compared to an age/sex-matched PMBB control group, there was a nominal increased risk for type 2 diabetes with renal manifestations (nominal P=0.03), inviting neurodevelopmental follow-up to correlate with our cohort of pediatric patients and further functional investigation. 

Conclusion
We have assembled the most comprehensive characterization of the largest panel of patients to date with TRND, a new neurodevelopmental syndrome with hallmark speech, ophthalmologic, and orthopedic abnormalities. We launched a Simons Searchlight registry that is now accepting patients and the TRND Network, a coalition of TRND patients, researchers, physicians, and families. Alongside international patient recruitment, we plan to leverage this study tool to build a foundation for longitudinal investigation and generate clinical guidelines to improve patient care.

Characterization of the genetic and phenotypic spectrum of a new neurodevelopmental syndrome, TCF7L2-related neurodevelopmental disorder (TRND)

Abstract
Background: Postoperative cognitive dysfunction (POCD) is a frequent complication 
following brain tumor excision. Citicoline has neuroprotective properties, and selenium and 
zinc may enhance recovery after neurosurgical procedures.
Objective: This research aimed to assess the impacts of selenium and citicoline versus zinc and 
citicoline versus citicoline alone on cognitive recovery in postoperative brain tumor excision 
patients in the ICU, and to compare the safety and adverse impacts of these supplementation 
strategies.
Methods: This was a blind, prospective, randomized controlled study. Cases (n=144) 
undergoing brain tumor excision have been assigned to 1 of 3 groups: Selenium + Citicoline, 
Zinc + Citicoline, or Citicoline only. Cognitive function (MoCA scale), inflammatory markers 
(CRP, ESR), incidence of delirium, and ICU stay duration were assessed.
Results: Selenium supplementation with citicoline led to the most favorable cognitive 
outcomes and greater reductions in inflammatory markers. The selenium group also had the 
lowest incidence of delirium and the shortest ICU stays.
Conclusion: Selenium, followed by zinc, optimized postoperative cognitive recovery, reduced 
inflammation, and minimized delirium and ICU stay, suggesting that combining citicoline with 
antioxidants could enhance outcomes in patients undergoing brain tumor excision.
Keywords: Postoperative cognitive dysfunction, Brain tumor excision, Citicoline, Selenium, 
Zinc, Neuroprotection, Inflammation.


Effect of Selenium and Citicoline vs. Zinc and Citicoline vs. Citicoline Only on 
Postoperative Brain Tumor Excision Patients in the ICU

Purpose: 
Eyelid keloids may be associated with increased ocular morbidity, but this has not been previously investigated extensively. This study aimed to characterize outcomes of eyelid lacerations in patients with keloids.
Methods:
This retrospective cohort study used de-identified electronic records from the TriNetX database. Patients who sustained an eyelid laceration with a keloid diagnosis versus those without (matched controls) were identified. Charts were abstracted for eyelid surgical interventions, as well as follow-up duration. In addition, ocular complications within a three-year follow-up, if any, were recorded. Propensity matching was performed to control for age, sex, race, ethnicity, and laceration severity. Significance was defined as p<0.05 for the Odds Ratio (OR) with an adjusted hazard ratio (aHR) threshold of > 1.1or < 0.9.
Results:
After matching (n=6,099), patients with keloids had a lower likelihood of undergoing surgical repair of their eyelid laceration (35.8% vs. 50.5%; OR=0.546; p< 0.001) and a longer follow-up duration (729.8 ± 409.7 vs 553.1 ± 466.7 days). Additionally, patients with keloids who underwent an eyelid surgical intervention related to the laceration (n=2,817) had higher incidence of conjunctivitis (aHR=1.644 (1.314–2.055), keratitis (aHR=2.307 (1.792–2.971), eyelid infections (aHR=1.789 (1.292–2.478), diplopia (aHR=1.426 (1.044-1.946), eyelid retraction/blepharoptosis (aHR=2.100 (1.445–3.052), MGD (aHR=2.750 (1.922–3.936), and dry eye syndrome (aHR=2.363 (1.881–2.968).
Conclusion:
Patients with a history of keloids were less likely to undergo surgical repair following eyelid laceration compared to matched controls without keloids. Among patients who underwent repair, a keloid diagnosis was associated with increased postoperative ocular morbidity, including conjunctivitis, keratitis, infections, diplopia, eyelid malposition, Meibomian gland dysfunction, and dry eye syndrome, relative to non-keloid controls.


Outcomes of Eyelid Laceration in Patients with Keloids in a Large Database

Background: Methicillin-resistant Staphylococcus aureus (MRSA) is a significant public health problem, particularly in rural regions with health disparities, where it complicates infection management and consequentially increases morbidity and mortality. Adverse effects of pharmacotherapy and growing antibiotic resistance create a need for alternative treatment options. We investigated the potential of phytochemicals, antioxidants, antimicrobial peptides (AMPs), and Osteopathic Manipulative Therapy (OMT) as additional therapy for MRSA infections. These treatments have been shown to enhance the body's defense mechanisms against infection.

Objectives: We sought to investigate the potential of alternative treatments for MRSA infections, including phytochemicals, antioxidants, AMPs, and OMT.

Methods: A comprehensive literature review was conducted using Google Scholar and PubMed to identify studies on MRSA in Appalachia, antibiotic use, and alternative treatment approaches. Relevant data was extracted and synthesized to identify key trends and disparities.

Results: Phytochemicals possess antimicrobial properties that inhibit MRSA growth and biofilm formation, while antioxidants reduce oxidative stress and inflammation, enhancing immune response and tissue healing. AMPs target bacterial membranes by disrupting MRSA's defenses and minimize resistance development. The Multicenter Osteopathic Pneumonia Study (MOPSE) trial found that patients aged 50 and older who received standardized OMT protocol had reduced mortality, respiratory failure rates, length of hospital stay, and antibiotic use.

Conclusions: Alternative therapies such as phytochemicals, antioxidants, AMPs, and OMT show promise in treating MRSA by targeting MRSA's defense mechanisms while actively enhancing the body's immune response. Future research should include qualitative studies to investigate the specific factors contributing to MRSA's prevalence in Appalachia, focusing on the region’s social determinants of health (SDOH). Additionally, clinical trials should assess the efficacy of alternative therapies as adjunctive treatments for MRSA.

Potential of Adjunctive Treatment Approaches in Improving Methicillin-Resistant Staphylococcus Aureus (MRSA) Outcomes in the Appalachian Region

Background
Wearable devices such as biosensors and smartwatches have demonstrated clinical utility in arrhythmia detection in adult populations, but their integration into pediatric congenital heart disease (CHD) care remains limited. Despite advances in CHD management, challenges persist in the timely identification of arrhythmias in children. The use of wearables in pediatrics is constrained by research gaps, adherence issues, and complex data interpretation. Traditional tools like Holter monitors and event recorders face limitations in detecting intermittent arrhythmias and ensuring compliance. These devices cannot leverage artificial intelligence (AI) and machine learning (ML) to enhance ECG interpretation. This study analysis evaluates the potential of AI-augmented wearable biosensors to detect arrhythmias and early signs of decompensation more accurately and promptly than conventional methods, aiming to optimize outcomes in this vulnerable population.

Methods
A comprehensive literature review was conducted using data from observational studies, randomized controlled trials, and pediatric cohorts. The primary outcome was the performance of wearable devices capable of ECG capture, photoplethysmography, or physiological pattern recognition integrated with AI or ML algorithms. Pediatric-focused studies were prioritized, though adult findings were considered when applicable to children. A secondary outcome assessed the incidence of postoperative arrhythmias in common CHDs and strategies for long-term rhythm surveillance.

Results
Commercial wearables, especially smartwatches, have shown promise in detecting atrial fibrillation (AF). In one study, smartwatch-detected AF achieved 96.2% sensitivity and 93.1% accuracy, with strong concordance with cardiologist interpretation. The Apple Heart Study (420,000 adults) reported that 0.5% received an irregular pulse notification; 34% of these were confirmed to have AF on follow-up ECG. Although Apple Watch ECG features are approved for users ≥22 years old, one pediatric-focused study found that 71% of new arrhythmias were detected using these devices, 29% of which were missed by traditional monitors. ML-enhanced AF detection further improved sensitivity to 100% and specificity to 96%. Tandon et al. demonstrated that AI can efficiently process complex datasets and detect early deviations from individual health baselines.

Conclusion
While limited, emerging data suggest AI-integrated wearables could transform arrhythmia detection in pediatric CHD. These technologies promise earlier identification, timely intervention, and better long-term outcomes. There is an urgent need for further research and funding to develop pediatric-specific, AI-driven wearable monitoring solutions.

Wearable Devices for Early Arrhythmia Detection: A Systematic Review ofLong-Term Clinical Outcomes

Abstract Title
Assessing the Burden of Agitation in Hospitalized Traumatic Brain Injury Patients with Comorbid Substance Use Disorders

Background
Traumatic brain injury (TBI) is a major cause of morbidity and prolonged hospitalization in the United States. While substance use disorders (SUD) frequently co-occur in this population, their role in shaping the incidence and severity of post-TBI agitation remains poorly understood. Prior research has seldom examined how premorbid SUD influences agitation-related outcomes or care needs. This study aims to fill this gap by characterizing the relationship between SUD, agitation, and clinical outcomes in hospitalized patients with acute TBI.

Methods
This single-center retrospective cohort study reviewed 650 consecutive TBI admissions at an academic Level I trauma center from March 2024 to March 2025. Patients hospitalized for at least three days were included (n=467). Agitation was defined by documented clinical observations, use of physical restraints, or administration of agitation-targeted medications. SUD was determined based on documented diagnoses within the preceding year, patient or collateral reports, toxicology results (excluding substances administered emergently), and referrals to addiction services. TBI severity was classified by the best Glasgow Coma Scale (GCS) score within 24 hours of admission. Patients were categorized into three groups: no agitation, agitation without SUD, and agitation with SUD. Primary endpoints included ICU and hospital length of stay, agitation duration, restraint utilization, and addiction-related consults.

Results
Among 467 patients meeting inclusion criteria, 52.2% demonstrated clinically significant agitation, exceeding previously reported estimates of 31.7%. SUD was identified in 40.7% of patients, most frequently involving alcohol (31.4%) and tobacco (12.2%), with 37.8% exhibiting polysubstance use. The mean ICU length of stay was significantly longer in patients with agitation compared to those without agitation (19.26 vs. 9.32 days; p<0.001). Although patients with both agitation and SUD experienced a longer mean duration of agitation (13.46 vs. 11.18 days; p=0.23) relative to those without SUD, this difference did not reach statistical significance. This interim analysis, representing 30% of planned enrollment, identified significant associations between agitation and increased ICU utilization, while differences in agitation duration by SUD status did not achieve significance.

Conclusion
These findings demonstrate a high prevalence of agitation and SUD among hospitalized TBI patients, emphasizing the need for systematic screening and targeted management strategies. Although premorbid SUD was linked to numerically longer agitation duration, this association was not statistically significant. Significant relationships were observed between agitation and greater ICU resource use and restraint application. Ongoing data collection will help determine whether integrated approaches addressing SUD and withdrawal can improve outcomes after TBI.


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Pain and Parity in Nutcracker Syndrome: A Comparative Surgical Cohort Study

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