Studying Grey's Anatomy: A Look into the Demographics of Cases Presented on Prime Time Medical Dramas
Emily Ambler, Cassie Papproth, and Terence Zach
Background: Medical dramas are defined as a television show or movie that is centered on a hospital or other medical facility. Popular medical dramas like Grey's Anatomy and Chicago Med have a significant following, with 4.21 million and 6.52 million viewers, respectively, in their most recent seasons.
Significance of the Problem: Previous studies have shown that medical dramas can influence individuals' views and expectations of the healthcare system. One aspect of medical dramas that could potentially affect viewers are the demographics of patients represented and their respective health outcomes.
Objective: Analysis of patient demographics depicted in medical dramas has not been heavily reported. The goal of this study was to compare the demographics of two current, primetime medical dramas: Grey's Anatomy and Chicago Med.
Methods: Two of the top ranked, ongoing medical dramas were chosen, with one assigned to each of the two researchers. A random sequence generator from Random.org was used to randomize the order of the episodes, and each researcher watched 50 hours of their assigned medical drama. Patient demographics, diagnoses, and deaths were recorded and totaled at the end of the 50 hours. Percentages were then calculated in order to compare differences and similarities between the two medical dramas.
Results: A total of 599 cases were analyzed. Between the two shows, 26.5% cases were pediatric. 28% of all Chicago Med patients were children, while 25% were for Grey's Anatomy. The percent of cases highlighted in the shows following nonwhite patients was 35% for Chicago Med and 30% for Grey's Anatomy, with a total of 32.8% nonwhite patient cases represented between the shows. On Chicago Med, 14.3% nonwhite patients died, while 13.9% of white patients died. On Grey's Anatomy, 8.5% patients of color died, while 9.46% white patients died. In total, between the shows, 12.1% of nonwhite patients died, while 12.0% of white patients died.
Conclusions: Overall, the two medical dramas, Grey's Anatomy and Chicago Med, were comparable in their patient demographic distribution. Both shows predominantly featured adult populations, with an average of a quarter of the cases being pediatric. There was also a consistent predominance of white patients in both shows, with an average one third of patients being nonwhite. Notably, both shows had a similar mortality rate between white and nonwhite patients.
Trevor Lockard and Geetanjali Rathore
A 20-month-old female with past medical history of tuberous sclerosis, epilepsy and infantile spams treated with vigabatrin presented for surveillance Magnetic Resonance Imaging (MRI) for multiple brain hamartomatous lesions and subependymal nodules. MRI showed new restricted diffusion to bilateral thalami and globi pallidi. This finding was concerning for bilateral thalamic strokes, however, due to the patient being asymptomatic with a normal exam, the differential was expanded to infection, metabolic etiologies, or toxic injuries. Without focal or diffuse neurologic symptoms or additional MRI lesions to suggest an acute or chronic pathology, it was determined the MRI signal changes were likely vigabatrin induced. Vigabatrin therapy was continued, and repeat MRI 17 months later showed resolution of the diffusion restriction with no residual sequelae. The patient never developed extrapyramidal symptoms to correlate with her MRI findings during this time, and she remained on vigabatrin therapy without further complications. Vigabatrin-induced MRI abnormalities are an uncommon adverse effect of therapy for infantile spasms, with adverse events being most common in young infants. It is crucial to consider this adverse drug effect in an asymptomatic patient presenting with these MRI lesions as the findings are otherwise suggestive of a serious disease process requiring expensive and invasive workup.
MicroRNAs miR-29a, miR-29b, and miR-29c as Novel Regulators of NK-cell Immune Response in Neuroblastoma
Background: Neuroblastoma is a challenging cancer to treat in pediatric patients. Despite intense treatment regimens, the prognosis for high-risk pediatric neuroblastoma patients remains poor, with less than 40% survival.
Significance of the Problem: One of the major obstacles to effective immunotherapy in neuroblastoma is the defective immune cells. Neuroblastoma tumors generally have impaired T-cell anti-tumor activity due to restricted MHC class I expression on tumor cells. This makes natural killer (NK) cells an attractive alternative for neuroblastoma immunotherapy, as they are not restricted by MHC class I expression on tumor cells. However, the overexpression of immune checkpoint molecules like B7-H3 (gene: CD276) helps tumor cells to escape NK immune surveillance, hindering the effectiveness of NK cell-mediated immunotherapy in neuroblastoma.
Objective: Micro RNAs (miRNAs or miR) play critical roles in nervous system development and post-transcriptional regulation of genes involved in neuroblastoma development. Therefore, exploring the role of upstream miRNAs that can target B7-H3 and regulate NK-mediated anti-tumor immune response in neuroblastoma could lead to the identification of novel therapeutic targets for neuroblastoma treatment.
Methods: Using the TARGET, neuroblastoma patient dataset, we applied the robust bioinformatic workflows incorporating differential expression, co-expression, survival, heatmaps, and box plots.
Results: We present here the role of miRNAs belonging to the miR-29 family, including miR-29a, miR-29b, and miR-29c, in regulating B7-H3 and antitumor immunity in neuroblastoma. Using different neuroblastoma patients' microarray data sets, we show that miR-29a, miR-29b, and miR-29c levels in the tumors were associated with good clinical outcomes and inversely correlated with B7-H3. Higher B7-H3 mRNA was associated with disease progression and poor survival in patients with neuroblastoma. MiR-29a, miR-29b, and miR-29c inhibited B7-H3 expression in neuroblastoma cells. B7-H3 downregulation induced NK cell activation and enhanced its cytotoxic functions against neuroblastoma cells, boosting NK-mediated antitumor immunity. Furthermore, miR-29a, miR-29b, and miR-29c treated neuroblastoma tumors had a large influx of infiltering activated NK and T cells, which is associated with tumor shrinkage, reduced tumor microvessel density, low macrophage infiltration, and enhanced tumor cell apoptosis. In cell culture, overexpression of miR-29a, miR-29b, and miR-29c inhibited proliferation, colony formation, migration, and neurospheres forming ability of neuroblastoma cell lines.
Conclusions: Overall, our findings highlight the therapeutic potential of miR-29a, miR-29b, and miR-29c to boost NK and T cell-mediated immune surveillance of neuroblastoma tumors, strengthening natural anti-tumor immunity and response to anticancer therapies.
Do Additional Pulses per Second in Pediatric Deglutition Studies Increase the Rate of Aspiration Detection?
Background: Deglutition studies are fluoroscopic procedures that utilize swallowed barium with concurrent x-ray imaging to diagnose swallowing disorders. The x-ray images during these studies can occur at variable pulses per second (p/s) depending on the institution and its available fluoroscopy equipment. At many institutions, radiologist preference is the main factor in determining which of the p/s settings is used.
Significance of the Problem: Increasing the p/s setting increases the patient's exposure to ionizing radiation, and the risks of radiation exposure have been well-established in literature for both children and adults. Exposure to radiation has been linked to increased rates of leukemia and a wide array of solid organ cancers. Compared to adults, children are more sensitive to radiation and ten times more likely to develop these radiation-induced cancers. Exposure to ionizing radiation during diagnostic imaging has demonstrated a small but significant increase in cancer development in children. While undergoing a deglutition study at a higher p/s setting increases the patient's exposure to radiation, it is possible that a higher p/s setting may be more sensitive at detecting swallowing disorders since additional imaging frames are collected and analyzed. Increasing p/s setting may also lead to a more accurate diagnosis with a more fitting treatment plan.
Hypothesis: If the higher p/s setting has a significantly higher rate of aspiration compared to the lower p/s setting, then we can conclude the higher p/s setting is more sensitive for detecting aspiration. On the contrary, if no difference is found in the aspiration rate between different p/s groups, then this study will help limit unnecessary radiation exposure by recommending lower p/s settings for future deglutition studies.
Methods: We conducted a large-scale, retrospective study where we collected data from each deglutition study performed at Children's Hospital & Medical Center over a two-year period that met specific criteria. A separate data point was included for each consistency tested within each deglutition study. For each consistency tested, we tracked whether aspiration was present and the p/s setting used for that consistency. Chi-square tests of independence were performed to examine the relationship between the rate of aspiration and the two p/s settings for each of the five consistencies: thins, thin nectar, thick nectar, honey, and puree. We utilized an alpha level of .05 for significance.
Results: Aspiration rate was not significantly impacted by whether the 3 or 7.5 p/s settings was used when the type of swallowed consistency (thins, thin nectar, thick nectar, honey, and puree) was controlled for chi-square. In other words, p/s setting and rate of aspiration were found to be independent of one another.
Conclusions: Our results suggest that aspiration rate was not significantly different between the 3 and 7.5 p/s settings when the type of swallowed consistency was controlled for. Therefore, we can conclude that the rate of aspiration detection does not increase with use of the higher 7.5 p/s setting.
Because our data concludes that the higher 7.5 p/s setting does not increase aspiration detection, we recommend utilizing the lower 3 p/s setting for future deglutition studies to minimize unnecessary radiation exposure.
Nadia Abraham M.D. and Aleisha Nabower M.D.
The majority of pediatric patients in Nebraska are cared for by Family Medicine physicians but there has been minimal analysis done to show whether current resident training is adequate to prepare these physicians. The previous unpublished study was presented at the Pediatric Academic Society meeting in 2006 which was conducted prior to residency work restrictions being enacted. These restrictions significantly changed many clinical experiences. The aim of this study is to assess the knowledge and confidence of Family Medicine residents in the diagnosis and management of common pediatric clinical scenarios to determine if adjustments in curriculum are necessary.
A survey was created with the assistance of a survey methodologist within REDCap to collect demographic data, program information, and to evaluate each resident’s knowledge and confidence in dealing with pediatric conditions that are within the top ten most common pediatric diagnoses. These diagnoses were determined utilizing billing data in a community outpatient Family Medicine practice and a community inpatient Pediatric Hospital Medicine practice. The survey was piloted with pediatric faculty to assure content validity. Additionally, free text questions were included to determine areas that residents desired more education and how they preferred to be taught this information. The survey was distributed via email with a link to the REDCap survey to all Family Medicine Residents in Nebraska during March of 2022.
Data is still in the final stages of being collected. Preliminary results show that 50% of Family Medicine residents lack confidence in diagnosing and managing respiratory illnesses in pediatric patients despite 83% being able to correctly identify incorrect management plans for two different respiratory disease processes. This correlated with respiratory illnesses being the most common condition residents requested more education on. While, the majority of residents described themselves as being confident in determining abnormal vital signs in a pediatric patient, less than 10% of them were able to correctly determine that a set of vital signs did not require intervention, indicating another potential area of curriculum development.
Data is in the final stages of being collected and has not been fully analyzed at this time. Conclusions are pending.
Novel M4 Pediatrics Chief Program Utilizing Near-peer Teaching and Mentoring to Enhance Clerkship Curricula
Lindsey E. Beard MD, Nicholas R. Braukmann MD, Joslynn M. Hoburg MD, Emily A. Leyden MD, and John W. Schmidt MD
Introduction: Near-peer teachers add many benefits to the academic, clinical performance, and enjoyment of near-peer learners in medical education. This enterprise describes and examines how the Creighton University School of Medicine M4 Pediatrics Chief Program fills a gap in medical education by offering an organized and formal methodology for near-peer teaching. The Creighton University M4 Pediatrics Chief Program utilizes select fourth year medical students to orient, teach basic clinical skills, mentor, and participate in curriculum development for the third year Pediatric clerkship students.
Methods: Third year students (n=43) in their Pediatrics clerkship from September 2020 to February 2021 completed surveys at the end of the clerkship to assess the quality and effectiveness of the M4 Pediatrics Chief Program.
Results: Students rated effectiveness of the Chiefs most highly as clerkship guides (4.29, SD=0.79), teachers (4.21, SD=0.92), and mentors (4.19, SD=0.75). Near-peer perspectives, education, provision of pertinent content, serving as a clerkship resource, and being a source of encouragement were the most beneficial aspects of the program. Students reported strong agreement all clerkships should have an M4 Chief Program (4.53, SD=0.88).
Discussion: Because of the positive reviews by the third years students, the M4 Pediatrics Chief Program is now a permanent part of the Pediatric Clerkship. Additionally, other third year clerkships at Creighton University School of Medicine are adopting this model. Finally, the M4 students acting as the chiefs gain valuable leadership and educational skills.
Conclusion: Based on positive perceptions of the “M4 Chief Program”, the authors recommend other medical schools consider initiating similar programs within their third year clerkships.
Lucas Betts and Terence Zach
Heterotaxy is a rare congenital condition that involves abnormal arrangement of the thoracic and abdominal organs across the left-right axis and often includes complex cardiac malformations. A case of heterotaxy with concurrent transposition of the great arteries, situs inversus totalis, and coarctation of the aorta is presented in a newborn male who had an uncomplicated vaginal delivery at 39 weeks gestation. The infant was started on continuous positive airway pressure due to low oxygen saturations, and intravenous prostaglandin E1 was administered to maintain ductus patency. After 5 days, the infant underwent a successful arterial switch, ductus arteriosus ligation, atrial septal defect closure and aortic coarctation repair. Further evaluation revealed presumptive functional asplenia as ultrasound showed potential splenic tissue located in the right upper quadrant. The patient was started on and discharged with amoxicillin prophylaxis due to increased risk of life-threatening encapsulated bacterial infections. He was discharged to home at 22 days of age.
Vincristine Side Effects with Concomitant Fluconazole Use during Induction Chemotherapy in Pediatric Acute Lymphoblastic Leukemia
Caleb A. Cave, Reyna C. Ramirez, Robin High, James B. Ford, Chittalsinh M. Raulji, and Jill C. Beck
As a mainstay of treatment for acute lymphoblastic leukemia (ALL), vincristine’s side effect profile is well known. Parallel administration of the antifungal fluconazole has been shown to interfere with the metabolism of vincristine, potentially resulting in increased side effects. We conducted a retrospective chart review to determine whether concomitant administration of vincristine and fluconazole during pediatric ALL therapy impacted side effects of vincristine, namely, hyponatremia and peripheral neuropathy. We also evaluated whether the incidence of opportunistic fungal infections was impacted by fluconazole prophylaxis. Medical charts of all pediatric ALL patients treated with induction chemotherapy at Children’s Hospital and Medical Center in Omaha, NE from 2013-2021 were retrospectively reviewed. We found no correlation between fluconazole use and increased incidence of peripheral neuropathy or hyponatremia. Additionally, the rate of fungal infections was not impacted by fluconazole prophylaxis. Empiric fungal prophylaxis with fluconazole during pediatric ALL induction, although safe, may not be necessary.
Sukanya Chakraborty, Bhopal C. Mohapatra, Sameer Mirza, Aaqib Bhat, Matthew D. Storck, Isidro Machado, Jose Antonio Lopez, Antonio Llombart Bosch, Donald W. Coulter, Gargi Ghosal, Vimla Band, and Hamid Band
Background and Significance: Ewing Sarcoma (EWS) is the second most common malignant bone tumor of children and adolescents. Patients with metastatic or recurrent disease have very poor outcomes. The receptor tyrosine kinase(RTK) insulin-like-growth-factor-1-receptor (IGF-1R) is upregulated in 93% of EWS patients with anti-IGF-1R antibodies and kinase inhibitors in clinical studies. However, with only ~10% of patients achieving objective responses, delineation of novel pathways that facilitate IGF-1R-driven oncogenesis in EWS could provide avenues for more effective therapy. The RTK levels and compartmentalization at the cell surface determine their access to growth factors, thus dictating the downstream oncogenic signaling. Our lab has demonstrated that EPS15-homology-domain-containing-protein-1 (EHD1) regulates traffic of cell surface receptors, including RTKs. We observed high frequency (67%) of EHD1 overexpression in 266 primary EWS patient tumor tissues, and Kaplan-Meier survival analysis of publicly available mRNA expression data showed that high EHD1 expression was associated with shorter patient survival.
Objective/Question: This study aims to comprehend the underlying role of EHD1 in EWS oncogenesis.
Experimental design and Results: In both dox-inducible EHD1-shRNA knockdown and EHD1-CRISPR-Cas9-knockout (KO) EWS cell line models(TC71, A673, and SKES1), we observed a significant impairment of in vitro oncogenic properties namely, cell proliferation, migration, invasion, soft-agar colony formation, and tumor-sphere formation, and the phenotypes were restored upon mouse-EHD1 rescue. Furthermore, by orthotopically implanting TC71 cells in the tibia of nude mice(xenograft model), we demonstrated a significant reduction in tumor size upon EHD1-depletion. Using a phospho-RTK profiling antibody array, we found reduced phospho-IGF-1R levels upon EHD1-KD, identifying IGF-1R as a potential target of regulation by EHD1. EHD1-KO reduced surface IGF-1R levels under steady-state and ligand-free conditions in EWS cells. IGF-1R and EHD1 were also found to colocalize intracellularly and co-immunoprecipitate after IGF-1 stimulation. Notably, EHD1-KO impaired the IGF-1R-mediated activation of downstream AKT and MAPK pathways. Mechanistically, EHD1 was shown to regulate traffic of newly synthesized IGF-1R and recycled pools from the Golgi to the cell surface, and in absence of EHD1, intracellular IGF-1R was shunted to the lysosome resulting in degradation. Finally, by dual targeting of EHD1 (genetic depletion) and IGF-1R (small-molecule-inhibitor Linsitinib), we observed an additive effect on inhibition of EWS cell proliferation and migration and upregulation of apoptosis.
Conclusions: Our studies indicate a novel regulatory pathway of EHD1 requirement in IGF-1R cell surface display and sustaining IGF-1R-mediated oncogenesis in EWS. This highlights the prospects of therapeutic co-targeting of EHD1 and IGF-1R, thus enhancing IGF-1R targeted therapies in EWS.
Impact of the Filmarray® Meningitis/Encephalitis Panel On Clinical Practice In Pediatrics; A Multicentered Study
John Chatterton, Aleisha Nabower, Nathan Gollehon, Nathaniel Goodrich, Prabi Rajbhandari, Jaclyn Eisenberg, Kimberly Martin, Megan Woslager, Maheswari Ekambaran, Krow Ampofo, Elizabeth Lyden, and Jessica Snowden
The FilmArray® Meningitis/Encephalitis Panel (MEP) is a rapid multiplex assay that tests cerebrospinal fluid (CSF) for 14 common central nervous system (CNS) pathogens, with results available in hours as opposed to days with the gold standard CSF culture. Current literature on the impact of MEP testing on length of stay (LOS) and antimicrobial use in pediatric patients is from only single site studies with variable results.
MEP testing in pediatric patients would be associated with a decreased LOS, time on IV antibiotics, and time to narrowing antibiotics.
We conducted a retrospective study of 5 sites. Inclusion criteria were children 0-18 years with lumbar puncture (LP) performed within 48 hours of presentation for suspected CNS infection between January 2015 and February 2019. Children with a neurosurgical history or immunosuppression were excluded. Collected data included demographics, presenting clinical features, laboratory and radiographic findings, antimicrobial use, and clinical outcomes. Mann-Whitney and Fisher’s exact test were used to compare continuous variables and categorical variables, respectively. A linear mixed model was used to analyze the effect of the MEP on LOS adjusting for clinical site, age, antibiotic pretreated LP, highest level of care, positive body fluid culture, CSF white blood cell count, and brain imaging consistent with meningitis/encephalitis.
This study included 2,436 children, 833 received MEP testing. Patients in the MEP group were more likely to be younger, receive ICU level care, be unimmunized, have neurological symptoms at presentation, have a higher median CSF WBC count, or have received antibiotic treatment prior to LP (p=0.002, p<0.0001, p<0.0001, p<0.0001, p<0.0001, p=0.03, p<0.0001). Patients in the MEP group were more likely to have abnormal head imaging, an infectious diseases consult, or a PICC line placed (p<0.0001). In the univariate analysis the MEP group had a longer median LOS and this difference persisted after adjusting for the seven covariates (p<0.0001, p=0.0017). There was no statistically significant difference in median total IV antibiotic time or median time to narrowing antibiotics (p=0.12, p=0.33).
Contrary to our hypothesis we found that patients who had MEP testing performed had a longer LOS, despite no difference being noted in the duration of IV antibiotics and time to narrowing antibiotics. Further analysis is needed to identify clinical scenarios in which MEP testing is most effective.
Alex Ciurej and Melissa Acquazzino
Febrile neutropenia is defined as a temperature of ≥38.0°C with an absolute neutrophil count (ANC) <1500. This is a common reason for hospital admission in pediatric cancer patients given the myelosuppressive effects of many chemotherapeutic agents. In one study, nearly 20% of emergency department visits in pediatric cancer patients were due to fever, and periods of severe neutropenia (ANC < 500) present the highest risk of morbidity and mortality due to infection. For this reason, pediatric oncology patients with fever and severe neutropenia are admitted to the hospital for management. These hospital stays lead to risks of nosocomial infection, mounting healthcare costs, and lessened quality of life. We aim to observe the safety and impact on length of stay for early discharge (prior to count recovery) on oral antibiotics in the treatment of febrile neutropenia in pediatric oncology patients.
This retrospective case-control study compares 1) unplanned readmission rates within 96 hours and 2) length of stay in pediatric oncology patients with febrile neutropenia who were discharged home on oral levofloxacin before count recovery (cases) or stayed until evidence of count recovery (controls). Study patients had an oncologic diagnosis admitted with or developed febrile neutropenia at Children’s Hospital Omaha, without history of Trisomy 21, acute myeloid leukemia, bone marrow transplant, and without discharge home on IV antibiotics.
Cases (n=32) were an average of 8.7 years of age (1.2-19.3) at hospital admission and controls (n=64) were 7.4 years of age (0.9-17.9). Oncologic diagnoses for each group included: leukemia (66% cases and 64% controls), solid tumor (22% cases and 28% controls), and lymphoma (12% cases and 8% controls). Discharge ANC was 97 (0-500) in the cases and 1,067 (20-15,000) in the controls. Length of admission ranged from 2-13 days (mean of 5) in the cases and 1-18 days (mean of 4.8) in the controls. Unplanned readmissions within 96 hours of discharge were 0 and 1 in the case and control groups, respectively.
We find no significant difference in unplanned readmission rates after 96 hours between cases and controls. Discharging patients home on oral antibiotics before count recovery avoided longer hospital admissions for the individual patient, with no unplanned readmissions, safely allowing more time at home, lessened risk of nosocomial infection, and less healthcare spending. It is our hope this study will guide future trials and guidelines regarding febrile neutropenia in pediatric oncology.
Sarah Craven and Terence Zach
Non-invasive prenatal testing (NIPT) uses cell-free DNA (cfDNA) in maternal blood to screen for fetal aneuploidy. Maternal and fetal cfDNA are both present in maternal blood; however, fragmentation patterns are different. This allows the fetal fraction to be identified and screened for autosomal chromosome aneuploidy, specifically Trisomy 13, 18, and 21. Although not currently recommended for routine use, NIPT can also be used to screen for sex chromosome abnormalities. This practice is increasingly common, as allows parents to determine the baby’s sex earlier than ultrasound. Klinefelter syndrome (XXY karyotype) is one sex chromosome aneuploidy that NIPT may recognize. Currently, mean age of diagnosis of Klinefelter syndrome is 30 years, with up to 75% of cases never diagnosed. Thus, increased NIPT use could result in a major shift in its recognition. We present two cases of Klinefelter syndrome diagnosed by NIPT.
PATIENT PRESENTATION, DIAGNOSTICS, PLAN OF CARE
Case 1: A 29-year-old, gravida 4 para 3 pregnant woman was curious about her fetus’ sex and requested NIPT, which returned with a karyotype of XXY. A 2670-gram male infant was born without dysmorphic features and normal genitalia with descended testes. Fluorescent in situ hybridization and blood chromosomes confirmed XXY karyotype. He was discharged with follow up by genetic counselors and close monitoring for developmental delays.
Case 2: A 19-year-old, primigravid woman had NIPT at 12 weeks gestation that revealed a fetal karyotype of XXY, confirmed by amniocentesis at 14 weeks gestation. A 2000-gram male infant was born without dysmorphic features and normal genitalia with descended testes. Fluorescent in situ hybridization and blood chromosomes confirmed XXY karyotype. He was discharged with follow up by genetic counselors and close monitoring for developmental delays.
DISCUSSION AND IMPLICATIONS FOR PRACTICE
NIPT allows for earlier detection of Klinefelter syndrome, as occurred in the cases described; however, whether this should be routine remains contested. For parents, early recognition could cause undue stress. Given the importance of early intervention for learning disabilities, developmental delays, and neuropsychiatric disorders—all of which Klinefelter syndrome patients are at higher risk for—one could argue for increased NIPT screening. Despite controversy over the necessity of its universality, with the increase in usage of NIPT, fortuitous diagnoses will continue to occur. This indicates a need for the medical community to define guidelines for early management and observation of patients with Klinefelter syndrome.
Assessing Body Fat in Pediatric Osteogenesis Imperfecta: A Preliminary Comparison of Anthropometric Techniques
Arianna Dalamaggas, Megan Gillespie, Adriano DellaPolla, Kaeli Samson, Elizabeth Strudthoff, Vincent Eaton, and Maegen Wallace
Background: Osteogenesis Imperfecta (OI) is a genetic disorder causing brittle bones, extremity deformities, short stature, and scoliosis, resulting in decreased physical function. Body Mass Index (BMI) is used as a proxy for body fat in the general population, however, it is particularly inaccurate measure to gauge body fat in OI patients due to skeletal deformities and short stature. There is a critical need to identify the anthropometric and body composition characteristics that contribute to important health outcomes and improve disease management in patients with OI. Current literature is lacking data on percent body fat (% BF) composition in patients with OI due to several of the current methods to estimate % BF cannot be safely performed. The purpose of this study is to compare two safe measures using air displacement plethysmography (ADP) via the BOD POD® (COSMED USA Inc. Concord, CA) and 3D Body Scanner Styku™ (Styku, LLC, Los Angeles, CA) precision to one another to evaluate body fat percentage in OI patients. Our hypothesis is %BF and BMI percentiles measured between these two devices will not be statistically dissimilar.
Methods: Patients were recruited from Children’s Omaha multidisciplinary OI clinic and underwent anthropometric measures using BOD POD® and Styku™. Air displacement plethysmography (ADP) via the BOD POD® and 3D Body Scanner with Styku™ associations between continuous variables were assessed using Spearman correlations. Difference scores between Styku and BodPod measurements were calculated, and were assessed to see if they significantly differed from zero (i.e. no difference) using a Signed Rank test All analyses were performed using SAS software version 9.4 (SAS Institute Inc., Cary, NC).
Results: Higher body fat percentages as measured by the Styku™ and BOD POD® tended to be associated with higher BMI percentiles (rho = 0.56; 0.45), however this was not significant (p = 0.07; 0.09). The median difference between Styku and BodPod % BF measurements was 3.4 (-2.2, 8.7), however, this was not significantly different from zero (p = 0.21).
Conclusion: More patients are needed to increase the power of the study in order to determine if there truly is a difference between Styku™ and BOD POD® measurements in %BF and BMI percentiles. If there is not a difference between these measures it is foreseeable to use either Styku™ and BOD POD® to assess %BF in OI patients as an overall measure of health.
Vincent Eaton, Kaeli Samson, Elizabeth Strudthoff, Adriano DellaPolla, and Maegen Wallace
Background: Osteogenesis Imperfecta (OI) is a collagen disorder with numerous multisystemic manifestations, including potential for increased vascular fragility and, consequently, increased bleeding. Since these patients are prone to fractures and multiple surgeries, the associated risk of increased intraoperative blood loss is potentially elevated compared to the general population.
Significance: Knowing if OI type, bone, or the number of bones operated on simultaneously is associated with more intraoperative blood loss can aid in preoperative planning in this population.
Hypothesis: We aim to investigate intraoperative blood loss in OI patients undergoing intramedullary rodding of lower extremity long bones to assess quantitative differences in intraoperative estimated blood loss (EBL). We hypothesize that more severe OI types, surgeries involving femurs, and/or surgeries with more bones operated on simultaneously will have a higher EBL.
Experimental Design: A retrospective review of OI patients' first surgeries between 2003-2018 at a single hospital was completed. We identified 127 patients with OI who had undergone intramedullary rodding of a lower extremity long bone. Variables included OI type, EBL per surgery (in mL), length of surgery, which bone was operated on, number of bones operated on per procedure, and whether they required a blood transfusion. Statistical analyses were performed using Chi-Square, Kruskal Wallis, and Wilcoxon Rank Sum tests.
Results/Data: Among patients with the three most common OI types, there was no significant difference in median EBL/hour (type I = 41.9, type III = 11.2, and type IV = 10.3; p = 0.10), nor in percentage who required transfusions, p = 0.94. Patients who had one bone operated on had significantly higher median EBL/hour (40.7) relative to patients who had 2 or 3 bones operated on (11.0 and 9.3, respectively; p = 0.01 for both). Which bones were operated on was statistically significant, with unilateral femurs alone having significantly higher median EBL/hour (50.9) versus bilateral femurs with (10.9) or without (10.3) other bones operated on simultaneously (p = 0.01 and 0.002, respectively).
Conclusions: EBL, both total blood loss and blood loss per hour, and the need for a blood transfusion are not significantly associated with OI type. EBL/hour is, however, associated with how many and which bones are being operated on simultaneously, with unilateral femurs having the highest median EBL/hour.
Vincent Eaton, Makayla Schissel, Elizabeth Strudthoff, and Maegen Wallace
Background: This study aims to evaluate the safety and efficacy of tranexamic acid (TXA) usage to reduce blood loss in surgeries in children with Osteogenesis Imperfecta (OI). We want to assess the potential benefits, risks, and complications involved in the usage of TXA in this pediatric orthopedic population.
Significance of Problem: Due to increased fracture burden and bone deformity caused by OI, patients tend to have numerous operations throughout their life. In addition to these skeletal manifestations, there is a potential increase in susceptibility to bleeding due to the increased frequency of orthopedic procedures. Increased blood loss during orthopedic procedures warrants investigation into potential ways to mitigate any risk of excessive intraoperative blood loss.
Hypothesis, Problem, or Question: Our hypothesis is that there will be a reduction in intraoperative blood loss and perioperative transfusion rate between OI patients that received TXA intraoperatively during femoral rodding procedures versus those who did not receive the intervention.
Experimental Design: TXA-receiving patients (cases) were matched 1:1 with non-TXA receiving controls on the following criteria: age within 2 years, bone category, and OI Type. Descriptive statistics were used to summarize the data. Fisher’s Exact Test was performed to compare transfusion status between groups. A Wilcoxon Rank Sum test was performed to assess differences between the groups in days of stay, length of surgery, and EBL. All analyses were conducted using SAS version 9.4. P <0.05 was considered statistically significant.
Results/Data: Our TXA-receiving population of 30 patients consisted of 11 females and 19 males. 1 patient was OI type I, 13 were OI type III, 14 were OI type IV, and 2 were categorized as other (not one of the four most common types). We found a significant difference in transfusion status (p = 0.02), with no TXA patients requiring a transfusion compared to 20% of the control cases. There is also a significant difference in median EBL (p = 0.0004) between groups, with TXA patients having a lower intraoperative EBL (20 mL versus 62.5 mL). There was also a difference in median days of post-operative stay between TXA receiving and non-TXA receiving patients (p = 0.001; 2.6 days versus 4 days).
Conclusions: Our study concluded that the use of TXA in this patient population is associated with a lower rate of perioperative transfusions and intraoperative blood loss. These results support the standard usage of TXA in these patients to reduce intraoperative blood loss.
Retrospective Study on Maternal BMI and Length of Stay for Neonates With Hypoxic Ischemic Encephalopathy Treated With Hypothermia
Sonya Flaten, Emily Poellinger, and Terence Zach
Neonatal hypoxic ischemic encephalopathy (HIE) causes significant morbidity and mortality. Therapeutic hypothermia (TH) is an important treatment in HIE. There is a need to better understand the antepartum factors associated with HIE. Maternal obesity has been previously identified as a risk factor for HIE. There is likely a positive correlation between the severity of HIE, abnormal MRI results, and the length of a neonate’s NICU stay before discharge.
This retrospective study compares the maternal BMI at delivery to the MRI results of the newborn at 4-7 days after birth and to the NICU length of stay with HIE and TH. We aim to discern whether a relationship exists between these metrics.
47 infants born between 4/2014 and 7/2021 were managed with TH at Creighton University Medical Center – Bergan Mercy Hospital for HIE. 43 had data on maternal BMI at time of delivery, MRI results, and length of stay in NICU.
We found a positive correlation between maternal BMI and NICU length of stay. Additionally, we observed a higher incidence of abnormal MRIs in neonates born to mothers with higher BMIs.
Implications for clinical practice
Increased NICU length of stay and abnormal MRI results may be due to more severe HIE in infants born to mothers with larger BMIs. Further studies will evaluate other factors associated with severe HIE and maternal BMI.
Evaluation of Tocopherol Isoforms in Maternal Breast Milk and Their Relationship with Maternal Dietary Intake
Alyssa Freeman, Alex Hergenrader, Olivia Paetz, Sarah Sweeney, Lauren Wegner, Nicole Bender, Ridhi Chaudhary, Khadijjta Ali, Matthew Van Ormer, Maranda Thompson, Rebecca Slotkowski, Corrine K. Hanson, Melissa K. Thoene, and Ann Anderson-Berry
Background: Vitamin E is an essential, fat-soluble nutrient with four isoforms: α-, β-, δ-, and γ-tocopherol. These isoforms differentially modulate inflammation and show variable associations with perinatal outcomes, such as preterm delivery and Apgar scores. However, little is known about the role of these isoforms on post-natal outcomes and their presence in maternal breast milk, a neonate’s ideal nutrition source.
Significance of Problem: To analyze the role of tocopherols on post-natal growth and inflammation, it is critical to first assess their presence in maternal breast milk. Relating these measures to maternal dietary intake can advance our understanding of breast milk micronutrient composition and provide an avenue for counseling lactating mothers on the importance of maternal nutrition to ensure their neonate’s health.
Experimental Design: Breast milk samples were collected from postpartum mothers (N=24) whose infants were admitted to the neonatal intensive care unit (NICU) and analyzed for α-, δ-, and γ-tocopherol concentrations using high-performance liquid chromatography (HPLC). Maternal dietary intake was assessed using the Harvard Food Frequency Questionnaire. Median tocopherol concentrations and isoform proportions were generated for breast milk concentrations and intake values. Tocopherol intake adequacy was defined using the Institute of Medicine’s recommendation of 19mg of α-tocopherol daily. Mann-Whitney U-tests compared median breast milk tocopherol concentrations between intake adequate vs. deficient mothers and assessed for differences in isoform proportions between dietary intake and breast milk samples. A p-value <0.05 was statistically significant.
Results: 63.6% of mothers had deficient tocopherol intake (median daily intake=15.3mg α-tocopherol). Median concentrations of α-, δ-, and γ-tocopherol (ug/L) in breast milk samples were 3866.5, 768.1, and 118.6, respectively. There were no significant differences in breast milk tocopherol concentrations between intake adequate vs. deficient mothers. For both dietary intake and breast milk, α-tocopherol had the highest relative proportion (MBM=83%, intake=52%), followed by γ-tocopherol (MBM=14%, intake=39%) and δ-tocopherol (MBM=3% intake=8%). Proportions of δ- and γ-tocopherol were significantly higher in dietary intake compared to maternal breast milk (both p<0.001).
Conclusions: This study highlights the prevalence of overall tocopherol intake deficiency and increased proportional consumption of δ- and γ-tocopherol among lactating mothers. It also suggests a mechanism for maintaining breast milk α-tocopherol concentrations despite intake deficiency. Differences in the proportions of tocopherol isoforms between breast milk and intake measures further indicates that proportions of individual tocopherol isoforms in breast milk are influenced by factors other than dietary intake.
Alyssa Freeman, Alex Hergenrader, Olivia Paetz, Sarah Sweeney, Lauren Wegner, Nicole Bender, Ridhi Chaudhary, Khadijjta Ali, Matthew Van Ormer, Maranda Thompson, Rebecca Slotkowski, Corrine K. Hanson, Melissa K. Thoene, and Ann Anderson-Berry
Background: Vitamin E is a fat-soluble nutrient consisting of α-, β-, δ-, and γ-tocopherol isoforms that has established effects on neonatal growth in utero. Higher maternal plasma tocopherol concentrations in pregnancy are associated with increased neonatal weight, length, and head circumference percentiles at birth. However, less is known about the impacts of tocopherols on post-natal growth. Since many neonates consume maternal breast milk as their post-natal nutrient source, it is important to understand the tocopherol content of breast milk and associations with neonatal growth.
Significance of Problem: Although the tocopherols demonstrate positive associations with neonatal growth in utero, the role of these breast-milk-derived nutrients on post-natal growth is unclear. Enhanced understanding of these relationships can help clinicians and mothers ensure ideal nutrition and growth in their neonates.
Hypothesis: We hypothesize there will be positive correlations between maternal breast milk tocopherol concentrations and post-natal growth parameters in neonates.
Experimental Design: Breast milk samples were collected from postpartum mothers (N=24) whose neonates were admitted to the neonatal intensive care unit (NICU) and analyzed for α-, δ-, and γ-tocopherol concentrations using high performance liquid chromatography (HPLC). Neonatal anthropometric percentiles at 36 weeks corrected gestational age (CGA) and discharge were collected from the medical record. The Fenton growth chart was used for neonates born <37 weeks CGA and the WHO growth chart for neonates born>37 weeks CGA. Spearman correlations assessed the relationships between breast milk tocopherol concentrations and neonatal growth percentiles. A p-value <0.05 was statistically significant.
Results: 70% of neonates were born preterm (median CGA=35.9 weeks). At 36 weeks CGA, median growth percentiles were 59.9 for weight, 68.4 for length, and 60.9 for head circumference. At discharge, median growth percentiles dropped to 33.6, 41.6, and 48.3, respectively. Breast milk concentrations of α- and γ-tocopherol were significantly correlated to increased neonatal length percentile at 36 weeks CGA (both R=0.70, both p=0.016), with γ-tocopherol concentration also correlating with increased weight percentiles at 36 weeks CGA (R=0.62, p=0.033). There were no significant associations between breast milk tocopherol content and discharge growth percentiles.
Conclusions: This study demonstrates the potential role of increased maternal breast milk tocopherol content on post-natal growth at 36 weeks CGA for preterm neonates. Limitations of this study include a small sample size and variability among neonates in total breast milk consumption prior to reported growth measures. Future research should assess total breast milk intake in neonates and evaluate neonatal plasma tocopherol concentrations.
Assessing The Impact Of Socioeconomic Status On Maternal And Cord Serum Omega-3 Polyunsaturated Fatty Acid Levels
Alexandra Hergenrader, Matthew Van Ormer, Maranda Thompson, Rebecca Slotkowski, Alyssa Freeman, Olivia Paetz, Sarah Sweeney, Lauren Wegner, Khadijjta Ali, Nicole Bender, Ridhi Chaudhary, Melissa K. Thoene, Corrine K. Hanson, and Ann Anderson-Berry
Background: Omega-3 (n-3) polyunsaturated fatty acids (PUFAs) modulate inflammation throughout the lifespan and are essential in fetal growth and development. Previous studies have demonstrated that individuals with lower socioeconomic status (SES) may be at risk for low intake of n-3 PUFAs; however, no research has compared the concentrations of these nutrients present in maternal and cord serum between markers of SES.
Significance of Problem: Individuals with low serum levels of n-3 PUFAs may suffer from unfavorable birth and pregnancy outcomes. Therefore, it is important to identify populations who may have decreased serum levels of these nutrients in order to provide nutritional recommendations to optimize prenatal care.
Objective: The purpose of this study is to assess the relationship between markers of SES and levels of n-3 PUFAs in maternal and cord serum in a group of patients delivering at a Midwest Academic Medical Center.
Methods: An IRB-approved study enrolled mother-infant pairs (n=55) at the time of delivery for collection of maternal and cord serum samples. n-3 PUFA levels quantified included Eicosapentaenoic acid (EPA), Docosahexaenoic acid (DHA), and total n-3 PUFAs. Markers of SES include private vs public insurance, income ≤150% of the poverty line vs >150%, and college degree earners vs no college degree. Descriptive statistics were run for all variables. The Mann-Whitney U test was used to assess differences in n-3 PUFA levels between SES groups. A p<0.05 was considered statistically significant.
Results: Median gestational age at delivery was 39.3 weeks in this cohort. Significantly higher nutrient levels were present in college-educated mothers vs less than college-educated mothers for maternal EPA (9.44 µg/mL vs 5.13 µg/mL, p=0.010), cord EPA (1.88 µg/mL vs 1.40 µg/mL, p=0.011), cord DHA (37.96 µg/mL vs 32.80 µg/mL, p=0.014), and total cord n-3 PUFAs (44.23 µg/mL vs 39.34 µg/mL, p=0.024). Median cord EPA levels were significantly higher in those with private insurance compared to public (1.79 µg/mL, 1.18 µg/mL, p=0.022). Additionally, median cord EPA levels were significantly higher in those >150% the poverty line (1.79 µg/mL, 1.10 µg/mL, p=0.030). No other significant differences were observed between SES groups and n-3 PUFA levels.
Conclusion: Our findings suggest that individuals with lower SES may be at risk for lower serum levels of n-3 PUFAs in pregnancy, which could predispose them to adverse birth and pregnancy outcomes. Future studies should focus on replicating these results in a larger, more heterogeneous sample and should consider analyzing additional markers of SES.
Omega-3 and Omega-6 Polyunsaturated Fatty Acid Levels in Placental Tissue and Association With Maternal Dietary Intake
Alexandra Hergenrader, Matthew Van Ormer, Maranda Thompson, Rebecca Slotkowski, Alyssa Freeman, Olivia Paetz, Sarah Sweeney, Lauren Wegner, Khadijjta Ali, Nicole Bender, Ridhi Chaudhary, Melissa K. Thoene, Corrine K. Hanson, and Ann Anderson-Berry
Background: Omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFAs) are precursors to lipid mediators that modulate inflammation throughout the body. Derivatives of n-3 PUFAs have anti-inflammatory properties and promote growth and neurodevelopment in the fetus. Conversely, n-6 PUFA metabolites exert pro-inflammatory effects and may contribute to adverse pregnancy and birth outcomes. Studies have shown that maternal dietary intakes of n-3 and n-6 PUFAs are associated with their levels in maternal serum, but less is known about the association between PUFA intake and placental levels of these nutrients. A fetus must obtain essential PUFAs from their mother through the placenta, therefore it is important to ascertain how maternal diet may impact placental PUFAs. Understanding this relationship may help inform dietary recommendations in pregnancy.
Objective: The purpose of this study is to assess the relationship between dietary intake of n-3 and n-6 PUFAs and their levels in placental tissue.
Methods: An IRB-approved study enrolled 29 mother-infant pairs who were delivering at a Midwest Academic Medical Center. Placental tissue samples were obtained at delivery and levels of n-3 and n-6 PUFAs (including Eicosapentaenoic acid (EPA), Docosahexaenoic acid (DHA), Docosapentaenoic acid (DPA), a-Linolenic acid (ALA), Linoleic acid (LA), and Arachidonic acid (AA)) were quantified in each sample. The Harvard Food Frequency Questionnaire (FFQ) was used to assess maternal dietary intake of n-3 and n-6 PUFAs. Descriptive statistics were run for all variables. Spearman correlations were used to assess the relationships between dietary intake and placental PUFA levels. A p<0.05 was considered statistically significant.
Results: Median gestational age at delivery was 39.7 weeks in this cohort. Significant positive correlations were observed between maternal EPA intake and levels of placental DHA (R=0.52, p<0.01), total placental n-3 PUFAs (R=0.50, p<0.01), and placental AA (R=0.38, p=0.046). Conversely, maternal EPA intake was negatively correlated with the ratio of placental n-6:n-3 PUFAs (R=-0.45, p=0.02). Maternal DHA intake demonstrated significant positive correlations with placental DHA (R=0.46, p=0.01) and total placental n-3 PUFAs (R=0.43, p=0.02). No significant associations were observed between n-6 PUFA intake and placental levels of n-3 or n-6 PUFAs.
Conclusion: Our findings suggest that maternal dietary intakes of EPA and DHA are correlated with n-3 and n-6 PUFA levels in the placenta. This information may help guide optimal dietary guidelines for n-3 PUFAs during pregnancy. A limitation to our study is the small sample size; thus, future studies should focus on replicating these results in a larger sample.
Sheridan Jost, Jason Burrows, and Michelle Howell-Smith
Background: Though hospital triage is typically considered a role of pediatric hospitalists, these skills are important for residents to learn for any pediatric subspeciality. Additionally, many of these skills are addressed in the Accreditation Council for Graduate Medical Education’s (ACGME) Pediatric Milestones and the American Board of Pediatrics’ (ABP) Entrustable Professional Activities (EPA) as competencies expected of residency graduates. Currently, the pediatric residents at our medium-sized midwestern program do not participate in hospital triage, leaving this as a large gap in their education.
Objective: To evaluate how a Pediatric Hospital Medicine (PHM) Triage Curriculum enhances pediatric residents’ knowledge, skills, and attitudes pertaining to hospital triage.
Methods: After developing learning goals and objectives, we implemented a 2-week rotation for third- or fourth-year pediatric residents to lead supervised hospital triage phone calls. Asynchronous self-study materials included a triage guide and handoff checklist, and learning occurred through the Experiential Learning Cycle with explicit self-reflection and instructional guidance from the supervising attending. The curriculum was evaluated through a case study-mixed methods explanatory sequential design with 1. A quantitative retrospective post-pre survey assessing self-perceived knowledge and skills, and 2. A qualitative post-rotation interview. Results to date have been reviewed with descriptive statistics and a general qualitative approach.
Results: 12 residents have completed the rotation with a 10/12 (83%) response rate. 10/10 (100%) residents agreed or strongly agreed that it is important to learn skills of triage hospital medicine and stated that they are comfortable leading triage calls much more or somewhat more than before. Themes identified in the qualitative interview include increased comfort in leading triage calls; improved assessment of patients over the phone to determine disposition and level of care; improved patient care; and applicability to all their future careers.
Conclusions: All residents had perceived improvements in knowledge and skills pertaining to triage medicine after completing the rotation, and they recognized the utility of these skills for their future careers. We will continue to address the logistical and systemic barriers to resident and faculty engagement in the curriculum.
Health Care Access and Use Among Children & Adolescents with History of Parental Incarceration — United States, 2019
Rohan Khazanchi, Nia Heard-Garris, and Tyler N.A. Winkelman
Background: Children and adolescents exposed to parental incarceration (PI) have suboptimal health care access, utilization, and outcomes in adulthood. However, very little is known about health care access and use during childhood itself for children and adolescents exposed to PI.
Significance: The United States incarcerates more people and at a higher rate than any other country in the world, with stark spillover impacts on the lives of over 5 million children who have had an incarcerated parent.
Objective: Using the nationally representative 2019 National Health Interview Survey (NHIS) Child Sample, we examined the relationship between PI and key measures of health care utilization and access.
Design: We conducted a survey-weighted cross-sectional analysis of in-home interviews conducted with the guardians of 7,405 children 2-17 years old. Respondents were asked about outcomes across the 12 months preceding the interview, including poor preventive care access (lack of usual source of care, well visit, or routine dental cleaning), unmet health care needs due to cost (delayed or forgone dental, medical, or mental health care), and health care use (urgent care use, emergency department use, or hospitalization). First, we used χ2 tests for bivariate associations between PI exposure and each outcome. Then, we estimated marginal effects from multivariable logistic regressions modeling the associations between PI and each outcome, with adjustment for age, sex, race/ethnicity, parental education, family structure, rurality, income, insurance, and disability. We multiplied these marginal effects by weighted sample sizes to generate population-wide estimates.
Results: Of 7,405 individuals, 467 (weighted 6.2% [95% CI 5.5-6.9]) were exposed to PI. In bivariate analyses, children exposed to PI had significantly worse access to a usual source of care; greater rates of delayed or forgone dental, medical, and mental health care due to cost; and higher likelihood of emergency department use and hospitalization (p<0.05). In adjusted analyses, exposure to PI was associated with a predicted increase of ~2.1 million children lacking a usual source of care, ~2.2 million forgoing needed dental care, ~1.1 million delaying needed mental health care, and ~795,000 forgoing needed mental health care.
Conclusion: Exposure to PI is associated with worse access to a usual source of care and unmet dental and mental health care needs due to cost, impacting millions of US children and adolescents. This nationally representative study extends and updates existing literature about PI and suboptimal access to care in adulthood by demonstrating that these trends start within childhood itself.
Yi Luan, Seok-Yeong Yu, Ibrahim F. Elesh, Rosemary Dong, Amirhossein Abazarikia, and So-Youn Kim
Background: Cancer therapies cause serious side effects, affecting the quality of life for young cancer survivors. The ovary is affected by cancer therapies, causing premature ovarian insufficiency, leading to endocrine dysfunction, infertility, and ovarian aging. Thus, maintaining ovarian function against cancer treatment is an unmet need for female cancer patients. Cyclophosphamide (CPA), a common chemotherapeutic agent, forms DNA crosslinks to induce apoptosis in rapidly proliferating tumor cells. However, the underlying mechanism of the CPA-induced oocyte death in ovarian reserve remains unclear.
Experimental design: This study aims to investigate the mechanism of oocyte death in primordial follicles by generating oocyte-specific Abl1 and p63 knockout and Pik3ca* knockin mouse models using Gdf9-iCre+. Prepubertal day 7 female mice were utilized for further analysis.
Results: The quantification of surviving follicles validated that 90% of the primordial follicles from oocyte-specific Abl1 knockout mice were lost following CPA treatment in vivo and in vitro. Concurrently, high expression of CHK2 was detected in the oocytes of the ovary cultured with CPA metabolite in vitro. Most importantly, p63 knockout oocytes were rescued after CPA treatment and maintained functional fertility in the mating trials. To better understand the CPA-induced primordial follicle loss, Pik3ca* mice were examined with or without CPA administration. As expected, ovarian primordial follicles with constitutive PI3K expression inside of oocytes in the Pik3ca* mice survived against CPA. Accordingly, the apoptosis markers, BAX and cleaved PARP were highly induced with CPA injection in a time-dependent manner in the ovaries of wild-type female mice but not from the p63 knockout. The double-strand break also occurred in the nucleus of oocytes post CPA administration as γH2AX was detected. Interestingly, OPA1, a protein required for mitochondrial fusion, was highly induced inside the oocyte cytoplasm of the p63 knockout, while oocytes in wild-type mice time-dependently lost the OPA1 expression by CPA treatment. This indicates that oocytes without p63 in the nucleus survive and induce mitochondrial fusion to escape apoptosis by mitochondrial damage.
Conclusion: cAbl is dispensable for primordial follicle depletion caused by CPA. However, TAp63 is the key regulator in CPA-induced apoptosis in oocytes. Furthermore, CHK2 is upregulated in the oocytes of primordial follicles post CPA exposure. Activated follicles resist gonadotoxic agents, even though p63 is expressed inside their oocytes. Therefore, CPA induces depletion of oocytes in primordial follicles through the CHK2-TAp63 apoptotic pathway.
Joseph Maes and Terence Zach
Kelli Mans, Whitney Bossert, Nathaniel Goodrich, and Terri L. Love
A 14-month-old male with constipation and a recent viral exanthem presents with 8 weeks of progressive gross motor regression. He no longer walks, crawls, or sits unassisted. No loss of social, speech, or fine motor milestones. No fever, rash, cough, congestion, or diarrhea. No known trauma. Family history negative for muscle, nerve, autoimmune, and developmental conditions. He was born abroad and lived on a dairy farm in New Zealand until 5 months ago. Vaccines up to date. Recently exposed to raw honey and a petting zoo.
Neurologic and musculoskeletal exams pertinent for refusal to bear weight or crawl. Resists sitting as well as flexion or extension of hips. Moves all extremities purposefully and spontaneously. Rolls over in both directions. Head lag present. Achilles reflexes 1+ bilaterally. No eyelid drooping, facial asymmetry, or trouble swallowing. Exam was otherwise unremarkable. CBC and iron studies revealed microcytic iron deficiency anemia, thyroid studies showed subclinical hypothyroidism, and mild elevation of CRP and ESR present. Screening metabolic and leukodystrophy workup unremarkable. MRI brain with bilateral confluent T2 signal hypersensitivity in the periventricular white matter. MRI spine notable for destruction of the L2-L3 disc with 4mm fluid collection within the disc space consistent with spondylodiscitis.
Interventional radiology performed disc space aspiration and bone biopsy for culture. Empiric IV cefazolin initiated. Biopsy culture returned positive for Kingella kingae, sensitive to cefazolin. His imaging and culture findings were consistent with a diagnosis of L2-L3 spondylodiscitis. He completed 6 weeks of IV antibiotics. Repeat MRI showed significant improvement with near complete resolution. With ongoing physical therapy he is now crawling, cruising, and sitting with improving endurance.
Spondylodiscitis encompasses both infectious discitis and vertebral osteomyelitis. Common presenting symptoms include back pain, limp, fever, irritability, and refusal to walk. Diagnosis is often delayed in children because of the rarity (estimated 2-4 cases per 1,000,000 per year), but also complicated because of poorly defined manifestations in children who are often not able to vocalize symptoms, requiring a high index of suspicion. The most common pathogen is Staphylococcus aureus, however there has been an increase in Kingella kingae reported in recent literature that must be considered when choosing empiric therapy.
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