United States

Abstract Title
Large Saccular Intracranial Aneurysm in a Child with RASA1-Associated Capillary Malformation AVM Syndrome

Background
Large cerebral aneurysms are much less common in children than in adults. Thus, when they present, these lesions require careful surgical evaluation and comprehensive genetic testing. RASA1-associated capillary malformation-arteriovenous malformation (RASA1-CM-AVM) syndrome is a rare disorder of angiogenic remodeling known to cause port-wine stains and arteriovenous fistulas but not previously associated with pediatric aneurysms.

Case Presentation
The authors report a case of a previously healthy 6-year-old boy who presented with seizure-like activity. Imaging demonstrated a lesion in the right ambient cistern with compression of the temporal lobe. Imaging characteristics were suggestive of a thrombosed aneurysm versus an epidermoid cyst. The patient underwent craniotomy, revealing a large saccular aneurysm, and clip ligation and excision were performed. The patient recovered well from surgery with no postoperative complications or neurological deficits. Postoperative histology was consistent with a saccular cerebral aneurysm. Postoperative genetic analysis revealed a RASA1-CM-AVM syndrome. 

Discussion
This represents the first documented case of a RASA1-associated pediatric cerebral aneurysm in the neurosurgical literature. This unique case highlights the need for maintaining a broad differential diagnosis as well as the utility of genetic testing for detecting underlying genetic syndromes in young children presenting with cerebral aneurysms.

AMA Research Challenge 2024 

Large Saccular Intracranial Aneurysm in a Child with RASA1-Associated Capillary Malformation AVM Syndrome

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Objective: The purpose of this study is to investigate the connection between the prevalence of metabolic syndrome and circadian misalignment in night shift workers. Understanding the impact of circadian rhythm disturbance on metabolic health is essential, especially in light of the growing incidence of night shift employment and its possible health consequences.
Methods: We searched Pubmed, Google Scholar, Cochrane Library and PLOS Medicine using relevant keywords such as “circadian misalignment, circadian rhythm disorders, circadian rhythm, metabolic syndrome, night-shift workers, insulin resistance”. We used “AND” and “OR” boolean operators for these keywords. We included peer-reviewed studies in humans that were published in the last 10 years (i.e., 2014–2024). The reference list of selected articles was also screened for relevant studies. Outcomes of interest were cardiometabolic outcomes, including obesity/body mass index (BMI), cardiovascular disease, diabetes, high blood pressure, fatty liver disease, and insulin resistance. This review focused on clinical trials, randomized clinical trials and meta-analysis. However, relevant observational studies were also included. There were no limitations on sample size or study location; however, only studies published in English and with adult participants over the age of 19 were considered in this review.
Results: A total of 37 articles met inclusion criteria and were added to the review. The key findings from these results show that compared to day workers, night shift workers have a higher chance of acquiring metabolic syndrome. Among night shift workers who experienced circadian misalignment, key metabolic syndrome components such as obesity, insulin resistance, dyslipidemia, and hypertension were common. The suggested pathophysiological processes include interrupted sleep patterns, modified eating behaviors, hormone abnormalities, and impaired glucose metabolism.
Conclusion: This review provides significant evidence that circadian misalignment in night shift workers contributes to the development of metabolic syndrome. The disruption of natural sleep-wake cycles contributes to metabolic syndrome, emphasizing the importance of tailored therapies to reduce its effects. Interventions targeting the reduction of circadian disturbance, such as the implementation of regulated lighting conditions, optimizing work schedules, and lifestyle adjustments, are crucial for minimizing the metabolic health hazards linked to night shift work. Additionally, implementing interventions that promote circadian alignment, such as improving sleep hygiene, and educating people about the benefits of regular sleep patterns, may help minimize the incidence of metabolic syndrome in this sensitive population. Future research should prioritize conducting longitudinal studies and intervention trials in order to demonstrate a causal relationship and develop efficacious preventive interventions.
Keywords: circadian misalignment, circadian rhythm disorders, circadian rhythm, night shift workers, insulin resistance, cardiovascular diseases, metabolic syndrome.


Relationship between Circadian Misalignment in Nightshift Workers and Metabolic Syndrome

Although the clinical results of infection with infectious prion proteins (PrPSc) have been well-studied, the physiological function of the cellular conformation (PrPc) has not been identified. One of the most common hypotheses is based around the assumption that the function of PrPc is one of protection primarily through anti-apoptosis. Using structural biology techniques to analyze sequence and structure, we compared the cellular prion protein to other known anti-apoptotic proteins in order to narrow down their true function. Our results showed that there was no significant similarity between the anti-apoptotic proteins and PrPc at either the active site or the N-terminus. These results emphasized that further research should be done to elucidate the physiological function of prion proteins in order to hopefully discover more effective treatments for prion diseases.

Narrowing Down the Physiologcal Function of the Cellular Prion Protein

Background: Type 1 Diabetes affects over 2.1 million patients in the United States and cost the healthcare system $14.4B in 2016. The current clinical standard for Type 1 Diabetes is daily glucose monitoring and exogenous insulin administration, which is medically and financially intensive. Islet cell transplantation could provide a curative solution but requires intense immunosuppression to avoid graft rejection.
Rapamycin, one part of this immunosuppressive protocol, delivered directly to antigen-presenting cells (APCs) maintains them in an immature state that leads to “co-stimulation blockade”, leading to anergy of T-cells. Polyethylene glycol- b-polypropylene sulfide polymers self-assemble into nanovesicles (PS) that can be loaded with hydrophobic drugs such as rapamycin (rPS). When injected subcutaneously, rPS is preferentially uptaken by macrophages, leading to targeted costimulation blockade4.
Burke et al. (2022) demonstrate that rPS induces extended survival of MHC- mismatched islet allografts and normoglycemia in a drug-induced diabetic mouse model4. We seek to validate these results in a non-obese diabetic (NOD) mouse model that replicates the inflammatory and autoimmune environment of Type 1 Diabetes pathology. Studies (Table 1) show that certain gut microbiome bacteria have increased populations in the states of immune tolerance.

Methods: NOD mice (age = 12 weeks) were injected with varying concentrations of rPS (0 mg/kg [PBS], 0.5 mg/kg, 1 mg/kg, 2 mg/kg, n =5 for each group) every 3 days for 18 days (total 6 doses). After the final dosing, mice were euthanized and their brachial/pancreatic lymph nodes, spleen, and cecal content were harvested. Cecal content was sent to Zymo Research for microbiological sequencing while lymph node and spleen samples were processed for flow cytometry.

Results: rPS exhibits a significant and positive dose dependent effect on the prevalence of the Blautia genus associated with induction of regulatory T cells and allograft survival. In the Lactobacillus genus, a statistically non-significant increase in prevalence is seen in the rPS 2 mg/kg group. Genus Alistipes was significantly decreased in prevalence in the 0.5 mg/kg rPS group.
Many rejection associated bacteria were not prevalent at all in the microbiota of both the controls and treatments.

Conclusions: The significant and dose associated effect of rPS on the Blautia genus shows that one mechanism of rPS’s tolerogenic effects may be through change of the gut microbiome. These results agree with previous pharmacologic characterization of rPS in significantly changing the immune population of CD80/86+ APCs and regulatory T cells.
The mechanism by which rPS affects the gut microbiome still needs to be elucidated. It is unclear whether rPS modulates the microbiome directly or if rPS’s previously established effects on the immune system allow for bacterial species associated with tolerance to flourish. In addition, each experimental group was not adequately powered to find significant associations in species outside of the Blautia genus. A larger study is required to confirm these results and establish the mechanism of causality.

Novel nanomedicine increases tolerance-associated species in the gut microbiota of non-obese diabetic mice

Biosafety of Intramuscular Autoinjection of Sulfanegen, a New Cyanide Antidote, in a Porcine Model
Deepali Shrivastava, Arreh Jain, Steven E. Patterson, Walt Tollison, John Carney, David Beebe, Kumar G. Belani
Background: Sulfanegen is a potent antidote to severe cyanide toxicity and can be administered intramuscularly. A proprietary intramuscular autoinjector has been developed for rapid administration during emergencies. This study investigated the safety of sulfanegen administered via the autoinjector in a porcine model, focusing on its systemic biochemical and metabolic toxicity and local tissue reaction.
Methods: After IACUC approval, eight healthy juvenile Yorkshire pigs (16-20 kg) were sedated with Tiletemine/Zolazepam (2-7 mg/kg) and Xylazine (0.2-1 mg/kg). Monitoring in these spontaneously breathing pigs included continuous EKG, pulse oximetry, respiratory rate, blood pressure, and temperature. Surface warming ensured normothermia. Blood samples were collected via peripheral venous blood before sulfanegen injection with a novel automatic injection system. The calculated body weight dose of Sulfanegen (75 mg/kg) was divided between two injectors and injected simultaneously into each of the hind thigh muscles. Hemodynamic parameters such as heart rate, respiratory rate, oxygen saturation, and core temperature were monitored throughout the procedure. Pre- and post-injection blood samples were collected for biochemical evaluation. After the Sulfanegen injection, the pigs recovered and observed for 7 days. They were then sedated again with the tiletamine/zolazepam and Xylazine mixture to collect metabolic blood samples and humanely euthanized for a necropsy. The muscle injection sites were grossly examined. Hemodynamic and biochemical data were analyzed using SPSS v27.
Results: All the pigs survived the Sulfanegen injection. Hemodynamics and biochemical parameters remained stable during and immediately following the injection without significant changes. Following emergence from anesthesia, all pigs were active and feeding appropriately. At necropsy, the local muscle tissue at the injection sites showed only minimal inflammation and no necrosis. Liver function, hematological, and metabolic tests at necropsy were within normal range.
Conclusion: In this porcine model, the intramuscular injection of Sulfanegen using the proprietary autoinjector device did not exert any adverse biochemical, hematological, or hemodynamic effects. There was only minimal local irritation at the injection sites. The next steps would be to examine the effects of increased doses of sulfanegen on muscle tissue in this model.


Biosafety of Intramuscular Autoinjection of Sulfanegen, a New Cyanide Antidote, in a Porcine Model

Introduction: Glenohumeral instability has been shown to be common in sporting activities, with the highest rates particularly within contact sports such as wrestling. While operative management of shoulder instability has been published in the literature, few studies highlight outcomes and return to wrestling (RTW) in this subset of athletes. As such, the purpose of this study was to systematically review the current literature to identify reports of wrestlers with glenohumeral shoulder instability injuries to better understand the current state of treatment, outcomes, and RTW rate. 

Methods: We performed a systematic review examining treatments and RTW rates in competitive wrestlers. Studies published in PubMed, EMBASE, and the Cochrane Library reporting on competitive wrestlers who experienced shoulder instability from inception to July 2024 were identified. Human subjects, articles published in English, and studies reporting treatment (operative versus nonoperative), outcomes, RTW rates, and any complications were included. 

Results: 8 studies, consisting of 134 wrestlers presenting with shoulder instability with a weighted mean follow-up of 58.3 months, were identified. Weighted mean patient age was 18.8 years (range, 17-22 years), with 99% of patients included in this study being male. The most frequently reported instability was anterior shoulder instability, with 73.9% (n = 99/134) of athletes experiencing this shoulder instability. Instability events were reported in 132 athletes, with first time instability events occurring in 50.7% (n = 68/134) of athletes. Anterior labral tears were the most reported pathologic finding on imaging (n = 69/373), with anteroinferior labral tears representing 89.9% (n = 62/69) of these tears. Operative management was performed in 96.3% (n = 129/134) of athletes, and arthroscopic Bankart procedures were the most frequent surgical procedure at 76% (n = 98/129). Complications following treatment were reported in 17.9% (n = 24/134) of patients, with recurrent instability comprising 87.5% (n = 21/24) of noted complications. Eligibility for RTW was reported in 65% (n = 87/134) of wrestlers, with 62% (n = 54/87) RTW, while 60% (n = 52/87) returned to their previous level of activity. 

Conclusion: In competitive wrestlers, anterior instability represents the most common direction of shoulder instability. Operative management was the most preferred treatment option, being reported in 96.3% of cases. Given the low RTW rate and relatively high rate of recurrent instability, alternative procedures such as laterjet or open bankart repair may serve as more beneficial treatments in shoulder instability. Future studies should build on the present literature for wrestlers, to include increased detail regarding reoperation rates and time to RTW for various surgical revision procedures, as well as identifying when to perform adjunct procedures when treating these competitive athletes to gauge optimal management strategies. 


Shoulder Instability Treatment and Outcomes in Competitive Wrestlers: A Systematic Review​

Background
Congenital heart disease presents unique challenges in pregnant patients due to the physiological changes of pregnancy. This case discusses a pregnant patient with incomplete D- loop miso/dextrocardia with situs solitus and Shone's complex who presented after a cardiac arrest.

Case Presentation
A 33-year-old pregnant female with a past medical history of congenital heart disease incomplete D-loop, meso/dextrocardia with situs solitus, and Shone's complex), paroxysmal atrial fibrillation, and schizophrenia was brought in following PEA cardiac arrest with ROSC achieved in the field by EMS personnel. Cardiac workup was largely benign, with no signs of ischemia on EKG and initially elevated but quickly downtrending troponin levels. Transthoracic echocardiogram was stable from baseline and showed a reduced left ventricular ejection fraction of 25-30% with global hypokinesis of the left ventricle, bioprosthetic aortic valve, congenital transposition of the great vessels, and perimembranous VSD. ICU course was complicated by refractory status epilepticus secondary to anoxic brain injury, necessitating a Cesarean section at 34 weeks, to allow for the introduction of additional anti-epileptic drugs (AEDs). After a lengthy hospital stay of 2 months, she was discharged to an LTAC.

Discussion
The management of adult individuals with congenital cardiac abnormalities is quite difficult as they are quite rare, and the variant anatomy may respond atypically to classical treatments. This case was complicated by pregnancy and the number of congenital cardiac conditions which are discussed next. An incomplete d-loop which refers to how the normal inflow portion of the right ventricle lies to the right of the left ventricle but in this patient, only partially does. Dextrocardia is the normal position of the heart but this patient instead partially suffered from a midline heart, or mesocardia. To qualify for Shone’s syndrome, at least 3 of 8 criteria must be satisfied: this patient had a bicuspid aortic valve, hypoplastic left ventricle, small aortic arch, and supramitral ring. While no clear etiology for the cardiac arrest was determined, it was presumed that heavy alcohol use with pregnancy placed too much of a strain on heart with these many abnormalities. Pregnancy also played a role in management of seizures as certain AEDs are extremely teratogenic and initially limited the 4 AED regiment. The case underscores the importance of a multidisciplinary approach involving numerous specialties and tailored management plans for patients with extremely complicated medical histories.

Cardiac Arrest in a Pregnant Patient with Congenital Heart Disease and Shone’s Complex

Background: With improving technology, children are surviving with increasingly complex medical conditions, and most are living at home. Given the shortage of home-based clinicians for children with medical complexity (CMC), parents often provide nearly 24/7 support with few if any breaks, resulting in poor long-term mental and physical health outcomes. Studies have found that respite – supports and resources that provide direct care so parents can rest – can foster greater resilience and longevity for those parents. This qualitative study aimed to identify how parents of CMC find respite and recharge. We anticipated that key themes would include a lack of opportunities for rest and recharge, including inadequate home care.

Methods: This multi-site, cross-sectional qualitative study included semi-structured interviews with parents of CMC receiving care from the pediatric palliative care team or the pediatric complex care team at two academic children’s hospitals in Boston, Massachusetts and with home-based clinicians (HBC) working in those children’s households. Interviews explored 4 domains: work of care, rest and sleep, recharge, and engagement with the existing respite care system, including home care. Qualitative data was analyzed using rapid qualitative analysis and mixed inductive-deductive thematic analysis. Data were analyzed by an interprofessional research team with expertise in pediatric palliative care, pediatric complex care, and qualitative methods.

Results: Twenty parents of 19 children and 8 HBC participated. Parents confirmed the incessant work of care and the lack of respite, with three themes related to barriers to home care: (1) overall inaccessibility of HBC, (2) mismatch between families’ needs (e.g., number of hours’ coverage, time of day, intensity of care tasks) and clinician availability, and (3) burden on parents to train home-based clinicians on the unique needs of their child. HBC reported overwhelming case-loads and inadequate incentivization for HBC. Both parents and HBC advocated for improved resource navigation to match children and their parents with appropriate home care providers.

Conclusion: Parents of CMC lack opportunities for rest and recharge. In concept, home health care can be a key tool for providing effective respite services, yet parents and home-based clinicians report barriers to clinicians providing effective respite in the home. The findings from this qualitative study should inform improved resource development as well as reform of pediatric home care policy, including Medicaid and CHIP.

Respite Support for Family Caregivers of Children with Medical Complexity: Preliminary Findings

The Dermatology Medical Literacy and Advocacy (DMLA) program aims to advance diversity within dermatology by engaging underrepresented undergraduate students and equipping them with essential knowledge and skills. Through a blend of lectures, hands-on workshops, and discussions on health disparities, DMLA fosters a more inclusive pipeline into the field while preparing participants to address the needs of underserved communities. The program emphasizes not only clinical competence but also the importance of community engagement, empowering students to share their knowledge and advocate for dermatological health within their communities. 
This study analyzes pre- and post-course survey data to evaluate improvements in participants’ knowledge of dermatological conditions, confidence in clinical skills, and understanding of health disparities. Results show significant gains in these areas, reflecting the effectiveness of the program’s structure. While progress in community engagement was modest, the program’s evolving focus on outreach aims to better prepare participants for future roles as advocates. These findings highlight the DMLA program’s role in promoting both diversity and health equity, with future iterations focused on expanding outreach opportunities and enhancing participant readiness for community-based advocacy.


Dermatology Medical Literacy and Advocacy Program: Fostering Diversity in Dermatology while Empowering Communities


Background
Infection with human immunodeficiency virus (HIV) increases risk for developing cancer.1 However, clinical presentations of malignancies may be subtle. Clinical suspicion for cancer in patients living with HIV (PLWH) should remain high. 

Case Presentation
A 50-year-old male with history of HIV with undetectable viral load on ART and unilateral orchiectomy for testicular cancer presented to the emergency department for evaluation of left eye blurriness, ptosis, and ophthalmoplegia. History was notable for emergency department and outpatient ophthalmology visits one month prior resulting in a diagnosis of cranial nerve six palsy. Magnetic resonance angiography (MRA) did not reveal any acute findings. He developed difficulty opening his left eye and reported having weight loss over the past month. 

On exam, vital signs were within normal limits. Labs notable for uric acid 8.0 mg/dL and WBC 9.34 K/uL. Repeat orbital imaging showed infiltrative soft tissue throughout the cavernous sinuses. Magnetic resonance imaging of the brain and positron emission tomography revealed widely distributed lesions and lymphadenopathy throughout the brain, chest, abdomen, pelvis, and skeleton suspicious for malignancy. Bone marrow and lymph node biopsy revealed B cell lymphoma, CD10+/CD5- lambda monotypic. Cytogenetic analysis revealed IGH::MYC rearrangement. Pathology confirmed diagnosis of Epstein-Barr virus (EBV) negative Burkitt lymphoma (BL). Patient began chemotherapy, EPOCH-R, and follow up 6 months later shows continued response to therapies. 

Discussion
HIV is a known carcinogen for eleven different types of cancer, including so-called “AIDS-defining cancers” (ADC), and non-AIDS defining cancers (NADC).1 A 2017 study including 448,258 HIV-infected individuals showed PLWH have a standardized incidence ratio of 1.69 for cancer compared to the general population (ADC 14.0, NADC 1.21).2 Introduction of ART has decreased the burden caused by ADC, but has increased the burden caused by NADC.3,4 Specifically, Burkitt lymphoma and Hodgkin lymphoma have been noted in the literature to occur paradoxically in patients with higher CD4 counts (e.g. >250 cell/mcL).3,5 Our patient presented with an undetectable viral load, CD4 count of 776 four days prior, and an incomplete earlier infectious workup. His ultimate diagnosis of EBV-negative BL highlights the importance of investigating cancer etiologies in the absence of positive serology. Patients with HIV are at increased risk of malignancy due to alterations in their immune system. Evaluation of atypical illness should include early imaging and biopsy. Preventive actions include thorough routine history and physical (including skin and mucosal exams), optimization of HIV treatment, and comprehensive vaccination (HBV, HPV, VZV).
References

1. Engels EA, Shiels MS, Barnabas RV, et al. State of the science and future directions for research on HIV and cancer: Summary of a joint workshop sponsored by IARC and NCI. Int J Cancer. 2024;154(4):596-606. doi:10.1002/ijc.34727
2. Hernández-Ramírez RU, Shiels MS, Dubrow R, Engels EA. Cancer risk in HIV-infected people in the USA from 1996 to 2012: a population-based, registry-linkage study. Lancet HIV. 2017;4(11):e495-e504. doi:10.1016/S2352-3018(17)30125-X
3. Rubinstein PG, Aboulafia DM, Zloza A. Malignancies in HIV/AIDS: from epidemiology to therapeutic challenges. AIDS. 2014;28(4):453-465. doi:10.1097/QAD.0000000000000071
4. Ceccarelli M, Venanzi Rullo E, Marino MA, et al. Non-AIDS defining cancers: a comprehensive update on diagnosis and management. Eur Rev Med Pharmacol Sci. 2020;24(7):3849-3875. doi:10.26355/eurrev_202004_20852
5. Guech-Ongey M, Simard EP, Anderson WF, et al. AIDS-related Burkitt lymphoma in the United States: what do age and CD4 lymphocyte patterns tell us about etiology and/or biology?. Blood. 2010;116(25):5600-5604. doi:10.1182/blood-2010-03-275917

Hiding in Impaired Vision - immune deficiency as a cause of cancer

Cardiovascular disease remains the leading cause of death in the United States, largely due to the unsuccessful recovery of cardiac tissue following hypoxic events. The severity of these events varies based on differences in an individual’s genetic makeup. Despite extensive research, the specific genes involved in mediating the response to a hypoxic event remain unclear. Our study aims to identify these genetic markers that will be crucial for early intervention in isolating populations at high risk for hypoxic events. 

To achieve this, we induced hypoxic stress on hypoxia-sensitive (CD1) and hypoxia-resistant (C57BL/6J) mice strains. We performed a microarray on cardiac tissue samples from these mice to quantify the expression patterns of coding and non-coding (lncRNAs) genes and then compared the differential gene expression patterns between the two mice strains. Our data revealed that the most significant lncRNA differential expression patterns are involved in “protein secretion”. Specifically, the Gm40082 lncRNA exhibited an increase in expression in response to hypoxia. Gm40082 overlaps with the coding gene Fhip1a and may play a role in regulating its gene expression in response to hypoxia. These lncRNAs can serve as potential genetic markers for individuals at higher mortality risk from cardiovascular events, aiding in the development of preventative and targeted therapies.


Next from AMA Research Challenge 2024

Relationship between Circadian Misalignment in Nightshift Workers and Metabolic Syndrome

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