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AMA Research Challenge 2023

Uncovering Patterns between Obstructive Sleep Apnea and Disease Comorbidities: An Exploration of Patient Demographics

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Introduction: Thyroid cancer is the most common endocrine cancer reported world-wide, with an increasing incidence over the past decades. Although the effect of numerous variables on thyroid cancer has been studied, the role of socioeconomic status (SES) remains a topic of interest. SES encompasses a range of factors such as occupation, household income, education, and health insurance, which have been shown to influence health outcomes in different diseases. Understanding the correlation between SES and thyroid cancer diagnosis and prognosis is critical for determining potential disparities and developing targeted interventions to improve patient outcomes. We conducted a review to provide a comprehensive synthesis of the existing literature through which we aim to illuminate the relationship between socioeconomic status and key outcomes in thyroid cancer, including diagnostic delays, disease stage at diagnosis, and survival rates. By identifying the specific socioeconomic factors that influence thyroid cancer outcomes, we can target interventions and policies to improving access to timely diagnosis and enhancing patient outcomes in diverse socioeconomic populations.
Methods: A pubmed literature search with the following search strategy was conducted: ("effect"[All Fields] OR "effecting"[All Fields] OR "effective"[All Fields] OR "effectively"[All Fields] OR "effectiveness"[All Fields] OR "effectivenesses"[All Fields] OR "effectives"[All Fields] OR "effectivities"[All Fields] OR "effectivity"[All Fields] OR "effects"[All Fields]) AND ("socioeconomic factors"[MeSH Terms] OR ("socioeconomic"[All Fields] AND "factors"[All Fields]) OR "socioeconomic factors"[All Fields]) AND ("thyroid neoplasms"[MeSH Terms] OR ("thyroid"[All Fields] AND "neoplasms"[All Fields]) OR "thyroid neoplasms"[All Fields] OR ("thyroid"[All Fields] AND "cancer"[All Fields]) OR "thyroid cancer"[All Fields]) AND ("prognosis"[MeSH Terms] OR "prognosis"[All Fields] OR "prognoses"[All Fields]). 
Abstract review of the resulting 13 studies was performed, of which 7 studies were included in the final review per inclusion and exclusion criteria. A comparative analysis was performed considering the methods, results, and conclusions of the studies. 
Results: Socioeconomic status (SES) was examined in seven studies in relation to the outcomes of thyroid cancer. Among these studies, four specifically looked at income, one investigated insurance access, and two considered multiple SES factors. The findings consistently showed that individuals with lower SES had worse overall survival rates (based on four studies) and were more likely to be diagnosed at a later stage (based on two studies), suggesting possible delays in accessing healthcare. Additionally, one study indicated a lower incidence of papillary thyroid cancer among individuals with lower SES indicative of lower early screenings.
Conclusion: Based on findings from the included studies, lower socioeconomic status is associated with unfavorable outcomes in thyroid cancer with delayed diagnoses and poorer overall survival. 


The Effect of Socioeconomic Status on Diagnosis and Prognosis of Thyroid Cancers


Background: It is well known that small bowel length is a dominant prognostic indicator in patients with short bowel syndrome (SBS). The relative importance of jejunum, ileum, and colon is less well defined in children with SBS. Here we review the outcome of children with SBS with respect to the type of remnant intestine. Methods: A retrospective review of 51 children with SBS was conducted at a single institution. The duration of parenteral nutrition use was the main outcome variable. The length of the remaining in- testine as well as the type of intestine were recorded for each patient. KaplaneMeier analyses were conducted to compare the subgroups.
Results: Children with greater than 10% expected small bowel length or more than 30 cm of small bowel achieved enteral autonomy faster than those with less. The presence of ileocecal valve enhanced the ability to wean from parenteral nutrition. The presence of ileum significantly enhanced the ability to wean from parenteral nutrition. Patients with the entire colon also achieved enteral autonomy sooner than those with partial colon.
Conclusions: The preservation of ileum and colon is important in patients with SBS. Approaches to preserve or lengthen ileum and colon may be beneficial for these patients.

Importance of Ileum and Colon in Children with Short Bowel Syndrome

Background
Extracorporeal membrane oxygenation (ECMO) is a complex medical intervention that is increasingly being used by the pediatric population. It is associated with significant morbidities and high mortality. ECMO therapy involves multiple ethical dilemmas and is associated with greater moral distress than routine intensive care, including significant parental psychological distress. Communication during ECMO courses is often unclear, with one study reporting that nearly a quarter of parents felt they were not told about the possibility of death until their child failed to improve on ECMO and discontinuation was discussed. High-quality communication is crucial to the support that clinical teams can provide families. To date, no consensus guideline on best practices for communicating during pediatric ECMO therapy exists, nor have areas of disagreement amongst experts been assessed. This study sought to develop the first consensus guideline for communicating during pediatric ECMO therapy and identify areas of disagreement.
Methods
We used the Delphi methodology, which consists of 3 iterative rounds. During Round 1, we conducted semi-structured interviews with each panelist, who were pediatricians from the US and Canada from the following pediatric specialties: intensive care, cardiac intensive care, and neonatology. We then used content analysis to code the interviews and develop potential recommendations. During Round 2, panelists evaluated each item via a Likert scale as a potential recommendation. Before Round 3, panelists were provided personalized feedback reports of the results of Round 2. During Round 3, panelists re-evaluated items that did not reach consensus during Round 2. Items that reached consensus in Rounds 2 and 3 were translated into the final framework.
Results
Consensus was defined as (1) a median rating >7 and (2) >70% of the panelists rating the recommendation >7. The final framework included 105 recommendations. The recommendations emphasized the importance of clarifying the goal of ECMO, its time-limited nature, and the possibility of its discontinuation resulting in patient death. The recommendations also provide guidance on how to share updates with the family and perform compassionate discontinuation.
Conclusion
A panel of experts developed recommendations for communicating with families during pediatric ECMO therapy. The recommendations offer guidance for communicating during the introduction of ECMO, providing updates throughout the ECMO course, and during the discontinuation of ECMO. Areas of disagreement on best communication practices were also identified and should be further explored.

Communicating with families during Pediatric ECMO: recommendations from a Delphi panel

Background
In our original study, we utilized clinical next-generation sequencing to identify pathogenic (P) or likely pathogenic (LP) sequence variations that are not associated with a patient's primary indication for testing within a large pediatric cohort. These variations are called secondary findings (SFs). Our cohort was enriched for Black or African-American (AA) children, which comprised 51.8% (8667 subjects) of the total cohort (16713 subjects) at the Center for Applied Genomics at The Children’s Hospital of Philadelphia. The inclusion rate of individuals (adults and pediatrics) with African ancestry in published genome-wide studies is <3% which highlights the unmet need for further genetics research on this population. The strong representation of Black or AA children in our cohort allowed us to present information on the types and frequencies of P/LP SFs primarily affecting Black or AA children and families.

Methods
The original study searched for P/LP variants in disease-causing genes, specifically in 78 American College of Medical Genetics and Genomics (ACMG)-recommended and 93 non-ACMG genes that were defined as SFs in patients of four large pediatric cohorts. The 93 non-ACMG genes were selected after an extensive literature search for relevant genes proposed for addition to the ACMG list. Variants were filtered by P/LP classification as per ACMG/Association for Molecular Pathology (AMP) recommendations, Combined Annotation Dependent Deletion (CADD) vs Mutation Significance Cutoff (MSC) scores, variant type, presence in disease-causing variant databases, and Integrative Genomics Viewer (IGV) visualization for manual variant quality inspection. We divided the patient's P/LP variants into four disease categories: cancer, cardiovascular, metabolic, and miscellaneous. We further divided our patients by self-reported ethnicity.

Results
Black or AA subjects comprised 307/320 (82%) of TTR variants (ACMG), 29/48 (60%) of RYR1 variants (ACMG), and 22/39 (56%) of LDLR variants (ACMG).
Out of 307 Black or AA subjects with P/LP variants in TTR, the most common variant (304) was p.V142I. The other three variants were p.V50M, p.V113M, and p.D119V.
Additionally, Black or AA subjects comprised 335/350 (95%) of G6PD variants (non-ACMG). The most common variant (327) was p.V98M which was excluded from final reports since it has mild clinical manifestations.

Conclusion
These SF data provide valuable insight into common P/LP genetic variations and associated diseases which mainly affect Black or AA children. The implications of identifying most TTR, RYR1, and LDLR gene variants in this underrepresented patient population include: better informed medical management, reproductive planning, and family member genetic testing for Black or AA children and families specifically.

Enrichment of secondary genetic findings of TTR, RYR1, and LDLR in a cohort of 8667 African-American pediatric subjects

Small-for-gestational-age (SGA) children may be at risk for earlier puberty and adverse long-term health sequalae. This study investigates associations between SGA and age at menarche using secondary data analysis of 992 female children in a U.S. birth cohort of primarily non-marital births. SGA was defined as <10th percentile of weight for gestational age within the sample. We estimated unadjusted and adjusted Ordinary Least Squares (OLS) models of associations between SGA and age at menarche in years, as well as unadjusted and adjusted logistic regression models of associations between SGA and menarche before age 11. SGA was associated with slightly earlier menarche, but the difference was not statistically significant even when adjusting for maternal sociodemographic characteristics and when further adjusting for prenatal smoking and maternal pre-pregnancy overweight and obesity. Similarly, SGA was not significantly associated with the odds of menarche before age 11 in unadjusted or adjusted models. Maternal non-Hispanic Black race-ethnicity, Hispanic ethnicity, and pre-pregnancy obesity all had independent associations with earlier age at menarche and menarche before age 11. Therefore, it appears that inherited maternal risk factors play more direct roles.

SGA and age at menarche in a diverse population-based U.S. sample

Background: Hydrogenogenic small intestine bacterial overgrowth (SIBO) has been associated with growth stunting and neurodevelopmental deficits in children from low and middle-income countries. However, methanogenic overgrowth has yet to be studied in this population. We sought to determine if increased methane levels on glucose breath tests (GBT) could predict growth and neurodevelopment.
Methods: GBT was performed at 6, 12, and 18 months on Tanzanian infants as part of the Early Life Interventions for Childhood Growth and Development in Tanzania (ELICIT) study conducted in rural Tanzania. Area under the methane curve was calculated and averaged over the three tests (CH4 AUC). Neurodevelopment was assessed using the Malawi Developmental Assessment Tool (MDAT).
Results: Univariate and multivariate linear regressions were performed to determine if CH4 AUC predicted growth or neurodevelopment and to determine predictors driving CH4 AUC levels. There was significant seasonal variation in CH4 AUC levels per child birth-month, with the highest levels associated with the spring months (March-May). Multivariable analysis showed no significant association between CH4 AUC and length-for-age Z score at 18 months, MDAT total score, or MDAT component scores. Birth month was a significant predictor of CH4 AUC (F= 66.614, p<.001). However, when analyzing patients with significant methanogenic SIBO (as determined by the top 50% of valid CH4 AUC values), antimicrobial administration had a positive but non-significant association with growth LAZ18 ( p=0.05), and nicotinamide administration revealed a significant association for LAZ18 when controlling for significant descriptive variables ( p=0.005) as compared to antimicrobial and nicotinamide administration in patients with negligible methanogenic SIBO (p=0.08, p=0.53, respectively).
Conclusion: This initial study does support a relationship between methanogenic overgrowth and growth stunting through the positive growth effect in positive SIBO children who received nicotinamide treatment, an effect that was not seen in the children without SIBO. Further study is needed to understand the relationship between methanogenic overgrowth and environmental enteric dysfunction and/or gastrointestinal symptomatology.

Analyses of Methanogenic Small Intestine Overgrowth Effects on Growth in Tanzanian Children

Background: 
There are many short and long-term benefits of breastfeeding or providing expressed breast milk (EBM). Colostrum, the first milk produced after birth, has the highest concentration of immune-protective biofactors. When born < 34 weeks gestational age (GA), infant’s oral motor skills limit their ability to orally feed. To overcome this barrier and promote exposure to EBM, oral colostrum care (OCC) allows for the administration of EBM in preterm infants. Promoting OCC may lead to an increase in EBM feedings with earlier establishment of lactogenesis. In April 2019, our neonatal intensive care unit (NICU) initiated a policy for OCC use for all inborn infants < 32 weeks GA for the first 7 days of life (DOL).

Objective: 
Describe OCC practice after implementation of policy in the Children’s Memorial Hermann Hospital (CMHH) level 4 NICU and quantify the impact of OCC on use of EBM at discharge.

Methods:
A three-year retrospective cohort study from January 2019 through May 2022 included inborn infants < 32 weeks GA. During this period, n=1184 qualified for OCC, 25 infants were randomly sampled per year. The infants were divided into two groups: those who received OCC and those who received no OCC. Categorical and continuous variables were compared using Fisher's exact test and the Mann-Whitney U test, respectively. 

Results:
Included in the analysis were OCC infants (n= 92) and non-OCC infants (n=8). Both groups were comparable in baseline characteristics except OCC infants were an average of 16 days younger than non-OCC infants (p=0.031). Length of stay was more than double in OCC infants compared to non-OCC infants (52.5 vs 25.0 days, p=0.072). No difference appreciated between groups in feeding outcomes within 72 hours of discharge (p=0.157). 1.1% OCC infants received exclusive human milk (either donor human milk ((DHM) or EBM), compared to 12.5% non-OCC infants received exclusive human milk. 58.7% OCC infants received formula, compared to 37.5% non-OCC infants received formula. 38% OCC infants received fortified human milk (either DHM or EBM) and formula, compared to 50% of non-OCC infants (p=0.157). No difference in hours after birth the infant received first EBM (66 vs 52 hours, p=0.434) or for documented EBM volume throughout hospitalization (2332.5 mL vs 2573 mL, p=0.722) between OCC infants and non-OCC infants. 

Conclusions: 
OCC use occurred in 92% of our sample. Non-OCC infants had greater exclusive human milk volume within 72 hours of discharge, greater parental visits, received first EBM sooner, and had greater EBM volume received throughout hospitalization.

Oral Colostrum Care to Predict Expressed Breast Milk at Discharge

Cerebral palsy (CP) is the leading cause of childhood physical disability. Children with CP receive several therapies designed to improve gross motor skills, but further research is needed to understand the impact of these therapies on motor learning and optimal therapeutic dose.
The aim of this study is to compare motor learning and variability between children with CP and typically developing (TD) children. We hypothesize that (1) children with CP and TD children will have differing patterns of motor learning, and (2) children with CP will show greater variability in motor learning compared to TD peers, but this variability will reduce for both groups with training.
The motor task involved a stability platform. Participants were instructed to keep the platform within 5 degrees of its horizontal position. Training consisted of 15, 30 s trials/day for 5 days, pre- and post-testing were 5, 30 s trials/day. Performance was determined by quantifying time the participant maintained the platform within 5 degrees of horizontal and variability by time spent on either side of the 5 degrees.
Mixed-model ANOVA was performed with time (pre-test vs. post-test) as the within-subject variable and group (CP vs. TD) as the between-subject variable. Dependent variables were mean center time and variability. 
TD children improved an average of 6.7 seconds (20.8 s to 27.5 s) from pre-test to post-test. Children with CP improved an average of 11.9 seconds (9.85 to 21.7 s). TD children decreased variability an average of 3.35 seconds (4.58 to 1.23 s). Children with CP decreased variability an average of 6 seconds (10.1 to 4.1 s). 
ANOVA showed significant main effects for time on mean center time (F (1,40) = 26.0, p < 0.001) and group on mean center time (F (1,40) = 20.9, p < 0.001), as well as time on variability (F (1,40) = 1, p < 0.001) and group on variability (F (1,40) = 1, p < 0.001). 
Both groups showed motor learning with five days of balance training. Children with CP showed greater variability in their balance performance than TD children. 
While TD children achieved almost maximum performance with training, children with CP may need more training to achieve this same performance. Alternatively, children with CP may reach maximum motor learning potential after a certain dose, therefore requiring other therapeutic interventions. Participant recruitment and data collection is ongoing.

Differences in Motor Learning Between Children with Cerebral Palsy and Typically Developing Peers Using a Dynamic Balance Task

Background:
Alzheimer's Disease (AD) is a progressive neurodegenerative disease that causes cognitive and functional impairments. Abnormal amyloid plaque accumulation is known to be specific for AD, demonstrated by previous amyloid Positron Emission Tomography (PET) studies showing abnormal amyloid plagues levels in subjects in the early stages of the disease, not exhibiting clinical manifestations. This study explores the possible relationship between the amyloid plaque level visible on amyloid PET scans and non-specific Physical Performance Tests such as Timed Up and Go (TUG) among subjects.


Methods: 
Data were analyzed on n= 2076 Participants (from the Health and Aging Brain Study- Health Disparities). All participants underwent as part of the HABS-HD protocol cognitive testing, functional/medical examination, blood draw, and neuroimaging. Amyloid PET scans were conducted with defined regions of intertest (ROIs) in the brain. All participants completed the Timed UP and Go (TUG) test along with other gait measures as part of the functional examine. Chi-square (Sex) and t-tests (Age, Education, TUG performance) were used to examine differences in demographic characteristics across ethnic groups. Linear regression models were conducted to examine the relationship between Amyloid PET imaging and a functional measure (TUG) and the significance was set at p<0.05


Results: 
In our study, we found a statistically significant correlation between TUG time and increased amyloid uptake only in the lateral parietal region in Mexican American subjects (p=0.049). The other ROIs in Mexican American subjects showed no statistically significant correlation between TUG time and increased amyloid uptake. 

Conclusion: 
This study aimed to examine the relationship between physical performance measures (such as the TUG) and amyloid uptake. Using PET scans, we theorized that TUG results might correlate with the amyloid plaque level; However, our results were inconsistent with our initial hypothesis. However, this study did reveal a correlation between TUG time and increased amyloid uptake (only in the lateral parietal region) with subjects of Mexican descent, therefore; highlighting the importance of exploring ethnic differences in AD research. Finally, this study is limited by a small sample size, and future work with additional samples should help examine the TUG and amyloid uptake relationship and ethnic differences.

Correlation Between Timed Up and Go Test and Neuroimaging in Mexican American and Non-Hispanic Americans with Alzheimer’s Disease

Background 
Dynamic lumbar instability evaluated on flexion-extension radiographs has been a longstanding convention in clinical decision-making for the management of low back pain by interventionalists and surgeons. However, these radiographs often underestimate the degree of lumbar spondylolisthesis, limiting their diagnostic utility. Significant variability remains in current guidelines regarding the most appropriate imaging modalities to adequately evaluate instability. Thus, identifying more efficacious imaging techniques to improve diagnostic utility, minimize radiation exposure, and reduce unnecessary healthcare costs is warranted. We compared different diagnostic images of single-level anterior spondylolisthesis and hypothesize that positional changes will affect the degree of dynamic instability, with spondylolisthesis observed in prone position providing greater sensitivity for instability compared to standing or supine positions. 

Methods 
Single center retrospective cohort of L4-5 anterolisthesis between 2014 – 2022 with standing radiographs (CR), prone CT scans (CT), or supine MRI images (MRI). Exclusion criteria: presence of lumbar hardware, patients with missing imaging modalities (either CR, CT or MRI), time between any modalities exceeding 13 months, no evidence of anterolisthesis, or poor image quality precluding the ability to fully visualize and assess spondylolisthesis. 

Results 
The average translation (± SD) measured were 4.9 ± 2.2 mm (CR), 2.5 ± 2.6 mm (CT), and 3.7 ± 2.6 mm (MRI) (p < 0.001). The mean difference in anterolisthesis among imaging modalities were 2.7 ± 1.8 mm between CR and CT (p < 0.001) and 1.8 ± 1.4 mm between CR and MRI (p < 0.001). Ninety two of 102 patients (90.2%) showed greater anterolisthesis on CR compared to CT, 72 of 102 (70.6%) comparing CR to MRI, and 27 of 102 (26.5%) comparing CT to MRI.  

Comparing CR with MRI, we found that 17.6% of patients exhibited > 3 mm anterior translation, whereas 38.2% patients were identified comparing CR with CT imaging, indicating a 20.6% difference in missed lumbar instability (χ2 test p = 0.0009, post-hoc Fisher’s exact test p = 0.0006 between CR and CT). Only a small percentage of patients showed increased segmental translation between flexion-standing (5.9%) and extension-standing radiographs (11.8%). We identified comparable results using 2 mm and 4.5 mm thresholds. 

Conclusion 
Comparing standing CR versus prone CT revealed the greatest degree of single level lumbar segmental translation (L4-5. Prone positioning also significantly reduced L4-5 anterolisthesis compared to flexion-extension standing X-rays, suggesting that comparing prone positioning to standing lateral views may increase detection of dynamic instability at L4-5 compared to standard stress views.

Next from AMA Research Challenge 2023

The Effect of Socioeconomic Status on Diagnosis and Prognosis of Thyroid Cancers