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2022 AMA Research Challenge

Decoding Pregnancy Loss: Validating a Novel Genetic Biomarker of Poor Egg Quality

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Ricardo Correa, MD, EdD
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Stuart M. Greenstein, MD
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Stephanie Strohbeen, MD
 
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Jessica Li, MD/PhD Candidate
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Charles Lopresto, DO

### Sponsor
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Welcome to the largest national, multi-specialty research event featuring research from 750 medical students, residents and fellows, and international medical graduates.


technical paper

Prior studies using intracranial electroencephalography (iEEG) have shown that thermo-nociceptive stimuli enhances high-frequency (gamma) activity within the insular cortex. Such high frequency activity is thought to be a marker for neural brain activity However, it remains unclear whether this activity is specific to the thermal or nociceptive quality of the stimulus. It is also thought that pain processing differs depending on the region of the insula. We utilized a custom thermoelectric device and psychometric software to investigate thermo-nociception in patients with intracranial electrodes within their insular cortex. Improved understanding of cerebral pain processing will facilitate identification of neuromodulatory targets. 

We recruited 16 (7 females; age: 21-66) patients undergoing iEEG for seizure focus localization to perform our thermo-nociceptive task following all institutional guidelines. Using a maximum-likelihood adaptive procedure, we generated psychometric pain perception curves for each patient. Psychometric curves facilitated the probabilistic classification of insular signals corresponding to thermo-nociceptive stimuli (>hot pain threshold, HPT) and innocuous thermal stimuli (<HPT). Hypothesis tests were performed for statistical distribution comparisons of local field potential spectra for the thermo-nociceptive and innocuous-thermal stimuli. 

Across all 17 patients, we recorded from 24 insula contacts (14 posterior, 10 anterior). Twelve contacts (8 posterior, 4 anterior) across 6 unique patients showed thermo-nociceptive stimuli followed a different distribution than innocuous thermal stimuli for 70-150 Hz (p<0.05). A decrease in power was observed within the contacts showing differential thermo-nociceptive processing for all significant posterior contacts (8/10, p<0.05). Power increased in all three significant anterior contacts (3/3, p<0.05). 

Thermo-nociception appears to cause distinct changes within the posterior insula compared to innocuous thermal stimuli. The 70-150 Hz power changes within the posterior insula during thermo-nociceptive processing are likely specific to the nociceptive quality of the stimulus and not the thermal quality. Additional recording from anterior insula contacts is necessary to investigate differential power changes along the anterior-posterior insula axis. Such work will be an important next step for improved understanding of neuromodulatory targets within the brain.

Differential changes in power within the insular cortex during thermal pain

Background: SARS-CoV-2 has been rapidly evolving with over 1,300 identified lineages. While variants are often first detected in urban centers, the origins of these variants and their patterns of spread remain unclear. Further, little is known about how the virus emerges and spreads among rural communities. Beginning in late 2020, rural areas experienced higher incidences of COVID-19 disease and mortality compared to urban regions, suggesting an increased pandemic burden in rural populations. Despite this, disease mitigation efforts are largely informed by urban-centric data. Here, we study the urban-rural transmission patterns of SARS-CoV-2 variants in Southwest Missouri. 

Methods: COVID-19-positive nasopharyngeal swab samples were collected from CoxHealth, a large medical center in Southwest Missouri. To understand the early evolution and transmission dynamics of SARS-CoV-2 in a vaccine-naïve population, our study period was set to July through December 2020 to exclude biases from the limited testing during the early pandemic, the variations of vaccine distribution and intake, and the sweeping predominance of the variants of concern. We analyzed 1,161 geocoded SARS-CoV-2-positive samples, 966 of which contained sufficient viral load for genomic sequencing (446 rural, 520 urban). Evolutionary dynamics and transmission patterns were studied using Bayesian inference phylogenetic and phylogeographic analyses.

Results: Our results revealed high genomic diversity within our study population, encompassing 51 recognized lineages. Further, we identified five mutations that were first detected in rural and urban communities and three of these have spread globally. Within the eight predominant lineages containing at least 10 urban and 10 rural samples (B.1, B.1.1, B.1.1.337, B.1.2, B.1.234, B.1.240, B.1.311, and B.1.509), 60.5% (n=52) of statistically significant transmission events (Bayes factor ≥ 3, posterior probability ≥ 0.7) originated from rural areas. 

Conclusion: In this study, we demonstrated that rural communities have become an important source of new SARS-CoV-2 variants and of transmission to both rural and urban areas. These results suggest that rural communities have a critical role in SARS-CoV-2 evolution and transmission. Genomic studies should strengthen sampling from rural communities, and granular geographic metadata should be integrated into the analyses to better our understanding of the evolution and disease burdens of SARS-CoV-2.

Early Urban-Rural Evolution and Transmission of SARS-CoV-2

Background
Obesity prevalence is increasing in the US and is particularly prevalent among Black Americans. Increasing clinical and policy attention focuses on the role of education and income in disparities. Prior evidence linked education to lower obesity prevalence among Black and Hispanic men. Understanding heterogeneity in the relationships between these factors and obesity may guide interventions and shed further light on the role of these factors in health broadly.

Methods
We use the 2019 National Health Interview Survey (NHIS) to examine the relationships between obesity (body mass index ≥ 30), education, and per-capita household income among US adults. Stratifying by race, ethnicity, and sex, we use logistic regression to identify varying effects of education and income on the likelihood of having obesity conditional on age.

Results
Among Black men, increasing education is not associated with higher levels of obesity. This contrasts sharply with Hispanic men, non-Black non-Hispanic men, and Black women, among whom the odds ratios for having obesity are 0.48, 0.56, and 0.53 with a college degree (p<0.01), and contrasts with older evidence. Regarding income, among non-Black non-Hispanic men, doubling income lowers odds of obesity (OR=0.87, p<0.01). Over 50% of this relationship is education related – conditional on education; the odds ratio rises to 0.94 (p<0.05). The income-obesity relationship runs in the opposite direction among black men. Doubling income is related to a 1.15x increase in the odds of obesity (p<0.1). Among Hispanic men, income and obesity are unrelated. Among non-Black non-Hispanic women, the income-obesity relationship is stronger– decreasing odds by 0.74x when income doubles. Among Black and Hispanic women, the odds of having obesity decline by 0.85x and 0.79x, respectively, when income doubles (p<0.01).

Conclusion
Education and income are considered fundamental social determinants of health. Concerning obesity, their role is not straightforward, varying substantially by race and sex. Black men stand out in this regard, as education is unrelated to obesity, and higher-income raises the risk of obesity, contrasting with every other demographic group. Clinical and policy efforts which address economic and education-linked determinants of health are not likely to alone be sufficient in closing obesity disparities by race.

Examining race, ethnicity, and gender disparities in obesity by socioeconomic status in the United States

Introduction: 
Among all professionals, physicians suffer from some of the highest burnout rates. While physician burnout has recently come to the forefront of many media cycles because of the COVID-19 pandemic, these high rates of burnout have long persisted in the field of medicine. In this study, we evaluate general trends of physician burnout and analyze gender differences over the last half-decade. 

Methods: Data provided by Medscapes Annual Burnout and Depression Surveys was analyzed for differences in reported burnout rates among all physicians in the United States (2017-2021). Univariate logistic regression was performed in order to compare differences in burnout rates between the various years and between different genders.

Results: Of the 71,000 physicians surveyed during the study period, the odds of reported burnout were significantly higher in 2018 (OR: 1.18, 95%CI 1.13-1.23), 2019 (OR: 1.09, 95%CI 1.04-1.14), 2020 (OR: 1.09, 95%CI 1.04-1.14), and 2021 (OR: 1.33, 95%CI 1.27-1.39) when compared to the year 2017. Over the five-year period, burnout was more commonly reported among female physicians (OR versus males: 1.65, 95%CI 1.60-1.70), with the effect estimate for burnout being greater among women versus men across all years as compared to 2017. In 2018 (versus 2017), odds of burnout among male physicians were 1.04, 95%CI 0.98-1.21, while ORfemales 1.08, 95%CI 1.00-1.16; 2019 ORmales 0.96, 95%CI 0.90-1.02, while ORfemales 1.00, 95%CI 0.93-1.07; 2020 ORmales 0.92, 95%CI 0.86-0.97 while ORfemales 1.13, 95%CI 1.04-1.22; and 2021 ORmales 1.13, 95%CI 1.07-1.21 while ORfemales 1.38, 95%CI 1.28-1.49.

Conclusion:
The general trend of increasing burnout rates, particularly among female physicians, highlights the need to implement modern solutions. Further investigation is warranted to discern specific variables & their impact on these findings, so these solutions can be optimized.

Gender Differences in Physician Burnout

Background: Sociodemographic factors affect surgical outcomes and can present major obstacles to long-term survival and treatment of patients with head and neck cancers. This study aims to compare gender disparities in patients undergoing microsurgical glossectomy reconstruction. 

Methods: A retrospective cohort study was conducted of patients undergoing free flap reconstruction for glossectomy defects between June 2000 and April 2021. Demographics, oncological and surgical outcomes were examined, and differences in outcomes were compared between females and males. 

Results: 612 patients underwent glossectomy microsurgical reconstruction, of which 59.3% were female and 40.7% were male. Females had more comorbidities including obesity (female= 32.9%, male=23.8%, p=0.002), smoking (female=24.8%, male=14.5%, p<0.0001), alcohol consumption (female=22.9%, male=12.9%, p=0.002), and coronary artery disease (female=11.3%, male=2.4%, p<0.0001). More females also received pre-operative chemotherapy (female=4.7%, male=1.6%, p=0.04). Males had a longer average length of hospital stay (female=7.5 days, male=8.4 days, p<0.0001) and significantly more flap-related reoperations (female=0.18, male=0.22, p=0.04). In terms of the flap reconstruction, significantly more female patients underwent reconstruction using an ALT (female=31.1%, male=21.3%, p=0.007) and AMT flap (female=1.9%, male=0%, p=0.028), and using the facial artery, lingual, superior thyroid, and transverse cervical arteries as recipient vessels (60.22% facial, 13.72% lingual, 23.52% superior thyroid, 1.4% transverse cervical arteries, p=0.04). Female patients required larger couplers (2.5-4mm) than their male counterparts (female= 94.4%, male=85.9%, p<0.0001). In terms of surgical outcomes, more females experienced osteoradionecrosis (female=4.7%, male=1.6%, p=0.04) and donor wound healing complications (female=2.8%, male=0%, p=0.008) than males. More female patients were also in need of a tracheostomy (female=98.9%, male=95.9%, p=0.018). More male patients underwent reconstruction using a lateral arm free flap (female=3.6%, male=7.63%, p=0.027), and the ascending pharyngeal, descending pharyngeal, and external carotid arteries as recipient vessels (female=1.1%, male=5.8%, p=0.036). Significantly more male patients experienced partial flap loss complications (female=0.5%, male=2.81%, p=0.022), however, the total flap loss was comparable between both genders. 

Conclusion: This paper delineates gender discrepancies in surgical outcomes following microsurgical glossectomy reconstruction. This study showed that males and females experienced significant differences in comorbidities, length of hospital stay, number of flap-related reoperations, type of flap and recipient vessels used for reconstruction, coupler sizes, and post-operative complications. While male patients had a longer length of hospital stay and more

Gender Disparities in Glossectomy Reconstruction Outcomes

Background
Hepatitis B (HBV) is one of the most prevalent infectious diseases worldwide. It is preventable with vaccination and experts recommend screening for HBV immunity in all patients with chronic liver disease. The 2019 novel coronavirus (COVID-19) pandemic disrupted ambulatory care clinics throughout the United States, interfering with normal vaccination screening and administration. In the subsequent years after the pandemic began, clinicians and patients alike have had to play catch up on healthcare maintenance. This study was done to determine if the rate of screening and vaccination of patients with chronic liver disease for Hepatitis B changed in the subsequent years after the onset of the COVID-19 pandemic at our single institution.

Methods
A retrospective study was performed from January 2000 to January 2019 and from February 2022 to April 2022 on patients seen in the ambulatory clinic of our community-based hospital. The criteria to be vaccinated for Hepatitis B was patients with chronic liver disease (defined as cirrhosis, nonalcoholic fatty liver disease, alcoholic liver disease, autoimmune hepatitis, and transaminitis (ALT or AST >2x ULN) not immune to HBV. 790 patients were selected from the first period and 86 patients were selected from the second period.

Results
We found that there were increases in the rate of screening for HBV immunity (+6.4%) as well as the rate of vaccination against HBV (+4.7% complete immunization) in the post-COVID onset years compared to the pre-COVID onset years.

Conclusion
We believe that the increases in both screening rates and subsequent vaccination are due to both patient and physician driven motives. Our patients are requesting re-evaluation of vaccination history with increased compliance in vaccination course. We have also noticed a more thorough review of patient history by our physicians, focusing on what was missed during the years since the onset of the pandemic and prior. Further studies qualifying these observations are underway, however, we believe it is important to present these results now to demonstrate that we can continue to improve the care we provide in the outpatient setting despite the pandemic. In fact, the COVID-19 pandemic itself may have improved the overall care we provide for patients.

Hepatitis B Vaccination in Patients with Chronic Liver Disease in the Era of COVID-19

Background
High-deductible health plans (HDHPs) have grown rapidly in recent years, and now cover more than half of U.S. workers. Patients in HDHPs are liable for the costs of all cancer-related care until their annual deductible is met, with the exception of screening tests such as colonoscopy and mammography. Due to higher out-of-pocket costs, patients may postpone presenting for concerning symptoms or diagnostic testing, leading to delayed diagnosis. We sought to assess the impacts of HDHPs on the timing of metastatic cancer detection in a nationally representative cohort of cancer patients.

Methods
Using a cohort of privately insured patients age 18-64 in a national commercial and Medicare Advantage database (2003-2017), we studied 2,703 individuals with cancer whose employers mandated a switch from a low-deductible (≤$500) plan to a high-deductible (≥$1,000) plan. Our control group consisted of 43,005 contemporaneous individuals with cancer whose employers offered only low-deductible plans. Both groups had a 1-year baseline period when all members were enrolled in low-deductible plans. Members were followed for a maximum of 4 years. To address potential confounding, HDHP and control participants were matched on demographic variables, morbidity score, baseline health care utilization, cancer type and timing, follow-up duration, and employer characteristics. We assessed time to metastatic cancer diagnosis in the baseline and follow-up periods using a weighted Cox proportional hazards model. 

Results
The mean age of participants was 53; 59% were female. We detected 4,741 cases of metastatic progression. There were no differences in time to metastatic diagnosis in the baseline year, prior to the HDHP switch (HR 0.99, p = 0.93). After employer-mandated HDHP switch, cancer patients enrolled in HDHPs experienced later detection of metastatic cancer (HR 0.70, p = 0.04), equivalent to a delay of 8.5 months relative to the control group. 

Conclusion
Compared with conventional insurance, HDHPs are associated with delayed detection of metastatic cancer. These findings imply that cancer patients postpone seeking care for concerning symptoms or defer diagnostic testing when exposed to high cost-sharing. Future policy efforts should aim to protect cancer patients from burdensome costs-sharing requirements to ensure timely detection and treatment of metastatic cancer.

Impact of high-deductible health plans on delays in metastatic cancer diagnosis

Background: The annual bleeding risk for a brain arteriovenous malformation (AVM) is 2-8%, but obliterating the nidus reduces the risk to near population levels. We evaluate the outcomes of linear accelerator (LINAC)-based stereotactic radiosurgery (SRS) in the treatment of brain AVMs in our institutional cohort.
Methods: The study comprises patients treated with SRS for AVMs with follow-up care greater than one month from 2014-2021. Baseline characteristics were compared between pediatric and adults in the sample. Time-to-event analyses were conducted using the Kaplan-Meier survival method. Statistical significance is defined as P<0.05; all tests were two-tailed; no adjustments were made for multiple comparisons. Influences of baseline characteristics were evaluated using simple or multiple logistic regression.
Results: Among 29 qualifying patients with SRS-treated AVMs, a mean nidus volume of 6.26cm3 (SD=9.12, Range=0.13-40.2) and nidus max diameter of 24.8mm (SD=15.9, Range=2- 60) were observed. The distribution of Spetzler-Martin (SM) grades were SM1 (3.3%), SM2 (23.3%), SM3 (50%), SM4 (16.7%) and SM5 (6.7%). Pretreatment included intervention for hemorrhage (65.5%), embolization (43.3%), and microsurgery (13.3%). SRS for the AVM involved VMAT approach (50%), conformal arc (36.7%) and step-and-shoot IMRT (10%). The mean target dose was 18.72Gy (SD=1.7, Range=13.5-22) and delivered primarily in one fraction (86.7%). Obliteration occurred in 53.3% of patients and median time to obliteration was 27.1 months. Mortality was 10.3% with only one-cause specific death (AVM hemorrhage). Median follow-up was 23.6 months (Range=3-50.7). Comparing adult and pediatric patients, significant factors affecting likelihood of SRS delivery were sex (p=0.05), race (p=0.0089), nidus max diameter (p=0.033), pre-treatment SRS (p=0.027) and neurological deficits at presentation (p=0.0169). Likelihood of obliteration decreased with increasing nidus volume with an estimated 10% for each additional cm3 (OR=0.90, 95% CI=0.82-0.99, p=0.027). Adverse Events (AE) were observed in 55.2% of patients with a median time to AE of 11.4 months. Nidus max diameter significantly affected rate of AE (HR=1.36, 95% CI=1.03-1.8, p=0.031).
Conclusion: SRS resulted in 53.3% of our cohort achieving obliteration (mean follow-up: 23.6mos). Adverse events occurred in 55.2% of patients, but most were mild and resolved. Pediatric patients obliterate at similar rates to their adult counterparts but on an accelerated time course.

Institutional Experience of Linear Accelerator-Based Stereotactic Radiosurgery For Brain Arteriovenous Malformations 


Compassionate behavior, or the ability to help others in need, is a cornerstone of prosocial interactions. To benefit others, it is necessary for individuals not only to perceive the internal states or emotions of others but also to take appropriate actions. Yet, how mammalian neurons precisely link social-specific information with adaptive behavior has been a major challenge to understand. Here, we developed a place-preference assay that allowed mice to directly control in real-time the experience of a nearby conspecific partner while also allowing the animal’s own actions to be dissociated from the other’s identity. Behaviorally, we found that wild-type male mice consistently chose to reduce aversive experiences of familiar but not unfamiliar partners, actions not observed when visual and olfactory cues were blocked. By recording from anterior insular (AI) neurons, we identified cells that encoded task relevant information, including the social identity of the animal’s partners and their specific experiences. Dorsal anterior cingulate (dACC) neurons, by contrast, preferentially encoded information about the act of helping their partners, displaying changes in activity prior to making their decisions. Further, whereas information about the experience of others could be predominantly decoded from AI activity, information about the animal’s prosocial actions could be predominantly decoded from dACC activity; demonstrating a partitioning of information within the insular-prefrontal circuit. Finally, chemogenetic excitation of AI-to-dACC projectors but not dACC-to-AI projections increased compassionate behavior while inhibitions of both dACC to AI as well as AI to dACC projectors, on the other hand, decreased this behavior with familiar partners. Taken together, these findings identify a putative insular-prefrontal circuit for driving compassionate behavior and a mechanism that could allow insular neurons to instruct social-specific actions through prefrontal control.

Insular-prefrontal circuit driving compassionate social behavior

Background: Pneumocystis jirovecii pneumonia (PJP) remains a cause of mortality in HIV-negative patients. The clinical benefit of adjuvant corticosteroids in these patients is uncertain. This study aimed to determine if corticosteroids reduced mortality in a cohort of HIV-negative PJP patients and to propose a novel mechanism explaining corticosteroid benefits in patients regardless of HIV status. 
Methods: We examined a retrospective case series of patients diagnosed with PJP at the University of Colorado Hospital between 1995-2019. Data were collected from 71 PJP-infected patients. Twenty-eight patients were HIV-negative, and 43 were infected with HIV. We performed bivariate and forward, stepwise multivariable logistic regressions to identify predictors of mortality. 
Results: Common underlying conditions in HIV-negative patients were hematologic malignancies (28.6%), autoimmune disorders (25.9%), or solid organ transplantation (10.7%). HIV-negative patients had higher rates and duration of mechanical ventilation and ICU stay. Survival was significantly increased in HIV-negative patients receiving adjunct corticosteroids, with 100% mortality in patients not receiving corticosteroids vs 60% mortality in patients receiving corticosteroids (p=0.034). In an adjusted multivariable model, corticosteroids were associated with lower mortality (OR 13.5, 95% CI: 1.1-158.5, p= 0.039) regardless of HIV status. We propose corticosteroids reduce immune-mediated lysis of Pneumocystis organisms that curtails the surfactant-disabling effect of PJP internal contents. 
Conclusions: We found substantial mortality among HIV-negative patients with PJP, and adjuvant corticosteroid use was associated with decreased mortality. Decreased PJP lysis reduces surfactant disruption resulting from pneumocystis internal substances. Suppressing pneumocystis lysis best explains the adjuvant corticosteroid mortality-lowering effect.


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Decoding Pregnancy Loss: Validating a Novel Genetic Biomarker of Poor Egg Quality

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Differential changes in power within the insular cortex during thermal pain

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