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MicroRNAs (miRNAs) are critical regulators of gene expression. The co-expressed miRNAs, miR-24 and miR-27, are known to restrain T helper 2 (Th2) cell differentiation and the production of cytokines like Interleukin-4 (IL-4), which are central to allergic diseases. However, a comprehensive map of their target network is incomplete. High-throughput sequencing of RNA isolated by crosslinking immunoprecipitation (HITS-CLIP) can identify miRNA targets transcriptome-wide, but analyzing these large datasets to find differential targets between conditions remains a major computational challenge. To address this, we developed DeepRNA-Reg, a novel deep learning algorithm designed for high-fidelity comparative analysis of HITS-CLIP experiments.

2025 AMA Research Challenge – Member Premier Access

A Deep-Learning Based Approach Uncovers Novel Mediators of Micro-RNA Restraint of Type-2 Immunity

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Background 
Medication adherence is a complex and interconnected issue. A patient is considered adherent to medication if taking 80% of their prescribed medication(s). Medication adherence places a huge economic burden on healthcare systems. An estimated annual adjusted disease-specific economic cost of non-adherence per person ranged from $949 to $44,190 in 2015.

Aim 
Our systematic review was to investigate factors affecting medication non-adherence in the adult US population (>18 years) from published literature in the last 10 years (2012-2023). 

Methods 
We performed a systematic review using the PRISMA protocol and MOOSE guidelines to identify articles describing factors affecting medication non-adherence. Using the PubMed search engine, we identified English, full-text, observational studies from 2012 to the present using the following keywords: medication non-adherence, economic impact, factors associated with drug non-adherence, and cost-related medication nonadherence. The primary endpoint was to screen, collect and analyze the data on the factors, burden, and short and long-term impact of medication non-adherence on healthcare. We have also evaluated the methods of assessment and measures of adherence. 

Results 
Of the initial pool of 982 studies describing information medication non-compliance, we found 10 full-length studies describing factors, burden, long-term impact, and method and measure of drug compliance. We found that cost-related non-adherence in adults >65 years of age, diabetics, cardiovascular disease, and hypertension had higher mortality compared to drug-adherent patients. The factors that contribute to medication compliance are broadly classified into 
patient-specific, illness-specific, medication-related, healthcare-related, sociocultural, as well as logistical and financial factors. A Systematic Review investigating cost and regimen complexity affecting medication Adherence in the elderly that included 9 studies identified patient-related factors such as disease-related knowledge, health literacy, and cognitive function, drug-related factors such as adverse effects and polypharmacy, and other factors.

Conclusion 
Medication adherence places a huge economic burden on the healthcare system's specialty amongst the population over >65 years of age. Indicators are always available to identify in each patient like polypharmacy, chronic disease, mental health, etc but those are needed to be recognized at an early level to mitigate the burden of non-adherence and reduce mortality in specific groups of the population.

Factors associated with medical non-adherence - a systematic review

Background
Atrial fibrillation (AF) affects over 10 million people in the United States and is commonly managed via antiarrhythmic drug (AAD) therapy for symptom and rhythm control. While AADs are known to improve cardiac outcomes in AF patients, they often require a three-day inpatient hospitalization to initiate treatment due to the rare risk (<0.6%) of QT prolongation. These hospitalizations can contribute significantly to healthcare costs. The goal of this case series is to present a novel software platform that supports remote AAD therapy initiation and ECG monitoring of varying durations, offering a safe and cost-effective alternative to inpatient care.

Methods
A total of 17 AF patients (7 female, 10 male) underwent software-supported AAD titration (1 dofetilide, 2 amiodarone, 14 sotalol). Baseline ECG parameters were recorded and reviewed by providers who either accepted, modified, or rejected the automated measurements through the SafeBeat Rx software portal. The physicians then approved, modified, or rejected the algorithm-recommended AAD dose, generated based on the manufacturer’s drug label. Heart rate and QTc following each dose were monitored for proarrhythmic effects. 

Results
Average baseline QTc, heart rate, and creatinine averaged 409.76 ± 20.56 ms, 83.47 ± 19.77 beats/min, and 0.95 ± 0.22 mg/dL, respectively (Table I). Remote cardiac interval monitoring ranged from 3 to 22 days. In total, 11 patients were extended to long-term remote monitoring following the drug titration process. No adverse events were reported, and all patients achieved sinus rhythm.

Conclusion
This case series establishes remote and extended QT-interval monitoring during AAD therapy initiation. All patients experienced safe and effective dose administration, suggesting the software platform has the potential to facilitate long-term cardiac therapeutic monitoring of commonly prescribed AADs.

Software-Supported Remote Monitoring of Anti-Arrhythmic Drug Therapy in Atrial Fibrillation Patients: A Case Series

Background
Prurigo nodularis (PN) is a chronic inflammatory, pruritic skin disorder characterized by raised papules and hyperkeratotic nodules. PN has been linked to malignancy, though cancer types and mechanisms remain unclear. To analyze the relationship between PN and skin cancer, we used the All of Us Research Program, a U.S.-based electronic health record and genomic database with data from over one million participants, to assess PN and cutaneous neoplasms.
Methods
We identified 869 individuals with PN using concept ID 4272156 and propensity matched them to two controls (n = 1738) based on age, sex, race, and ethnicity. Diagnoses of basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (cSCC), and melanoma were identified through curated concept sets and relevant concept IDs to maximize capture. We extracted demographic and clinical variables, smoking status, insurance, income, family skin cancer history, and healthcare use.
Univariate associations were tested using χ2 or Fisher’s exact t-test. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Multivariable logistic regression models were adjusted for age, race, ethnicity, sex, income, insurance, smoking status, family history of skin cancer, and healthcare utilization.
Results
PN cases had a higher prevalence of any NMSC (16.3% vs 5.2%; P < 0.001), with significant increases in BCC (11.4% vs 3.9%; P < 0.001), SCC (9.7% vs 1.8%; P < 0.001) and melanoma (4.3% vs 1.5%; P < 0.001). Univariable logistic regression showed PN was associated with increased odds of BCC (OR 3.16; 95% CI 2.29–4.35; P < 0.001), SCC (OR 5.89; 95% CI 3.87– 8.97; P < 0.001) and melanoma (OR 2.93; 95% CI 1.76–4.87; P < 0.001). These associations persisted after multivariable adjustment for demographics, risk factors, and healthcare utilization, with adjusted OR (aOR) 3.31 (95% CI 2.33–4.69; P < 0.001) for BCC, aOR 6.09 (95% CI 3.89– 9.53; P < 0.001) for SCC and aOR 3.01 (95% CI 1.77–5.13; P < 0.001) for melanoma.
Conclusion
Chronic scratching and repeated trauma to the skin, hallmarks of PN, may lead to inflammation and compromised skin barrier integrity, potentially promoting keratinocyte carcinogenesis. PN is associated with a chronic Th2-skewed inflammatory milieu—characterized by elevated IL-4 and IL-13, and prolonged use of immunosuppressants may similarly impair antitumor immunity. Future PN studies should examine IL-4/IL-13 pathway inhibitors on long-term cancer risk. Given the potential association with cutaneous neoplasms, routine skin exams may be appropriate in individuals with long-standing or extensive PN.

Risk of Skin Cancer in Prurigo Nodularis: A Case-Control Study Using the All of Us Research Program



Background:
In people with chronic use of cannabis, Cannabinoid Hyperemesis Syndrome (CHS) is an illness associated with symptoms of cyclic vomiting, nausea, and abdominal pain. Conventional antiemetic medications frequently offer very modest relief. Topical capsaicin works by activating the transient receptor potential vanilloid 1 (TRPV1) in response to high temperatures and substance P regulation. This leads to pain relief by depleting substance P over time. Capsaicin has recently drawn interest since it mimics heat exposure from hot showers, which has been shown to reduce symptoms. This study was performed to investigate the effect of topical Capsaicin in treating CHS. 

Methods:
We searched PubMed, Embase, and Scopus and selected nine articles that were performed between 2013 and 2024, including clinical trials, case reports, and case series that evaluated capsaicin use in patients with CHS. Information about Caspacicin dosage, formulation, and adverse effects was studied. 

Results:
A total of 196 patients from nine selected studies were included. We found that applying 0.025%–0.1% capsaicin cream to the abdomen or thorax consistently resulted in rapid symptom alleviation (within 30–90 minutes). Capsaicin found to be better than conventional antiemetics in terms of symptom recurrence and time to resolution. Localized burning was the most frequent side effect, and no major adverse effects were observed in any of the studies. The effectiveness of Capsaicin was seen whether or not cannabis was stopped.

Conclusion:
We found that topical Capsaicin is a safe, quick-acting, and affordable supplement for traditional antiemetics in CHS. Its symptom-relief characteristics and convenience of usage make it particularly helpful in emergency situations. To develop conclusive treatment procedures and maximize the use of Capsaicin as a first-line treatment for CHS, more randomized trials are required.



The Effectiveness of Topical Capsaicin for Management of Cannabinoid Hyperemesis Syndrome: A Literature Review 


Background
Normal pressure hydrocephalus (NPH) is commonly treated with ventriculoperitoneal shunting, though shunt revisions remain a frequent complication and wound dehiscence, albeit rare, may lead to full revision surgery. The Valve-Agnostic Cranial Implant (VACI, “InvisiShunt®” Longeviti, Inc.), is designed to countersink ventriculoperitoneal shunt valves, to reduce dehiscence and the need for revision. These were first implanted in 2019 and offer a low-profile alternative to traditional subgaleal shunt placement. However, only one prior clinical trial report of its use exists to date (n=25). This case series of twenty-five patients seeks to add to the existing literature on VACI efficacy in NPH patients.
Methods
Twenty-five patients diagnosed with NPH underwent implantation of the VACI (InvisiShunt®), at a mean age of 76.4 ± 10.1 years. This case series was conducted at Hoag Medical Center, Newport Beach, CA, USA, from November 2022 to March 2023. Follow-up ranged from 4 to 24 months. Patient demographics, comorbidities, preoperative symptoms, surgical details, postoperative outcomes, and complications were collected and analyzed.
Results
No intraoperative complications occurred. Six patients demonstrated either altered mental status, abdominal pain, or generalized weakness, unrelated to the implant. There were no infections reported within the 30-day post-operative period and up to 24 months of follow-up. There was one incidence of wound dehiscence that necessitated full revision surgery. Patients underwent an average of 2.3 ± 1.4 reprogramming events. Post-operative outcomes included improvements in gait disturbance (n=18; 72.0%) and urinary incontinence (n=9; 36.0%), and cognitive disturbances (n=8; 32%).
Conclusion
Our findings support the potential of VACI as a viable and safe low-profile alternative to traditional subgaleal shunt valve placement for NPH treatment, with no increase in morbidity. Further research with extended follow-up is needed to confirm these preliminary results and evaluate long-term efficacy.

Valve-Agnostic Cranial Implant (InvisiShunt®) in Normal Pressure Hydrocephalus Ventriculoperitoneal Shunting: A Case Series

Objectives:
• Recognize histiocytoid Sweet syndrome (HSS) as a potential dermatologic manifestation of MDS and AML.
• Assess the role of hypomethylating agents (decitabine and azacitidine) in triggering HSS.

Introduction:
Sweet syndrome (SS) is an acute febrile neutrophilic dermatosis, and its histiocytoid variant (HSS) is a rare, yet increasingly recognized form characterized as an infiltrate of immature myeloid cells that resemble histiocytes. Common triggers of HSS discussed in literature include underlying hematologic malignancies, especially MDS, as well as certain drugs, including hypomethylating agents [1, 2, 3, 4]. These cases mainly focus on the initial presentation of HSS but to our information, no published case reports have described occurrence and recurrence of HSS by two distinct hypomethylating agents.
We present a case of elderly female patient with MDS with progression to AML who initially presented with biopsy-diagnosed HSS and had recurrence of HSS after initiation of Azacitadine. Recognizing this rare syndrome and its common triggers can have significant diagnostic and therapeutic implications.

Case Presentation:
An 83-year-old woman with a history of DCIS and newly diagnosed MDS-EB-2, who had completed her first cycle of decitabine one week earlier, presented with a painful ulcerative lesion on the left lower extremity along with widespread purple papules and plaques. A skin punch biopsy demonstrated histiocytic and neutrophilic inflammation consistent with the diagnosis of Histiocytoid Sweet syndrome. Patient was initially treated with topical steroids with improvement of her dermatologic symptoms. Of note, during this time, patient did not receive any additional Decitabine therapy and had lab findings significant for 28% blasts, consistent with progression of disease to AML. Given new diagnosis AML, patient was started on Azacitidine (and Venotoclax) with recurrence and worsening of her rash requiring topical and oral steroids.

Discussion:
This case highlights several important and underrecognized aspects of histiocytoid Sweet syndrome (HSS) in myeloid malignancies. HSS is most often triggered by underlying hematologic disease, such as MDS or AML, and by certain chemotherapy agents. While decitabine and azacitidine have both been linked to Sweet syndrome, we found no prior reports of sequential HSS flares from two different hypomethylating agents in the same patient.
Our patient first developed biopsy-proven HSS shortly after receiving decitabine and during progression of MDS to AML. The timing suggests that both the progression of her leukemia and exposure to decitabine may have played a role. It remains unclear whether worsening hematologic disease itself increases the risk of HSS, or whether drug exposure simply unmasks the underlying inflammatory response.
The second episode, following initiation of azacitidine, is also notable. While azacitidine-induced Sweet syndrome has been documented, recurrence with another hypomethylating agent has not been reported. Our case suggests that in some patients, the broader class of hypomethylating agents may predispose to recurrence of HSS, especially when underlying disease is active.
Overall, this case adds to the limited literature on drug-induced HSS and raises important clinical questions: Does disease progression increase susceptibility to Sweet syndrome? Should clinicians be cautious about recurrence of Sweet syndrome when re-exposing patients to similar hypomethylating agents? Answering these questions will require further study, but awareness of this potential complication is key to early recognition and treatment.

Sweet Troubles in AML: Sequential Histiocytoid Sweet Syndrome Triggered by Hypomethylating Therapy

Background
Acute appendicitis is a common condition that classically occurs with periumbilical pain that radiates to the right lower quadrant, accompanied by nausea, vomiting, fever, and decreased oral intake. But in patients with complex abdominal surgical history, anatomical defects can lead to atypical presentations. Here, we have acute appendicitis in an 82-year-old male with a prior Whipple procedure and cholecystectomy, who presented without "typical" appendicitis symptoms.

Case Presentation
An 82-year-old man with a history of pancreatic cancer (status post-Whipple procedure), prostate cancer, and cholecystectomy was seen from a referral hospital with five days of fevers and progressively worsening intake. He complained of no abdominal pain aside from a chronic, years-long, postoperative gassy distress. Leukocytosis (WBC 20,000) and positive blood cultures for Klebsiella were found upon initial presentation to our hospital. His abdominal ultrasound was normal as well. However, CT imaging, which was only ordered once he got to VAMC, found a dilated appendix that was suspicious for an acute appendicitis. Due to his surgical history, the appendix was possibly seen to be in an ectopic location, posterior to his liver. It was deemed he was not an optimal candidate for surgery due to his age and history of prior abdominal operations. Nonoperative treatment with IV antibiotics was initiated subsequently. Over the course of a week, he came with clinical improvement with resolution of leukocytosis and was discharged in stable condition.

Discussion
This case illustrates the diagnostic challenge of appendicitis in patients with altered surgical anatomy. Classic migratory pain to the right lower quadrant is a reliable predictor of appendicitis, but this patient lacked this presentation due to post-surgical anatomical change, as well as his abdominal pain presenting as a years-long, chronic, non-specific bloating pain. As a learning point, one must have a high index of suspicion for appendicitis in elderly patients with extensive surgical history with ambiguous systemic symptoms, and manage appropriately. Initial imaging is crucial to avoid delayed diagnosis and appropriate guiding treatment.


Atypical Presentation of Acute Appendicitis in an 82-Year-Old Man with Complex Surgical History

Background
Angelman Syndrome (AS) is a rare neurogenetic disorder caused by maternal UBE3A dysfunction, resulting in intellectual disability, hypotonia, ataxia, epilepsy, and language impairment. Antisense oligonucleotide (ASO) therapy is an investigational approach that aims to restore UBE3A expression by reactivating the normally silenced paternal allele. Early trials suggest intrathecal ASO infusions are generally well tolerated, but pediatric neurological complications remain underreported. We present a case of transient cauda equina radiculopathy after intrathecal ASO infusion in a child with AS and Autism Spectrum Disorder (ASD), emphasizing diagnostic and management challenges in nonverbal children with developmental delays.

Case Presentation
The patient was a 9-year-old male with a history of AS, ASD, and a tonic-clonic seizure. At baseline, he was nonverbal, used fewer than five words or signs, and had inconsistent verbal comprehension. He ambulated independently with a wide-based gait and climbed stairs with one hand. He exhibited hypotonia, required assistance with dressing, and lacked bladder control. Four weeks after intrathecal ASO infusion in a clinical trial, he developed progressive unsteadiness, difficulty climbing stairs, and behavioral changes including irritability, clinginess, and movement anxiety. No trauma, seizure activity, or regression were reported. The exam showed symmetrical facial movements, intact cranial nerves, wide-based gait, normal reflexes, and no focal deficits. Imaging revealed mild diffuse enhancement of multiple cauda equina rootlets on lumbar spine MRI, consistent with radiculopathy. Brain MRI and X-rays were unremarkable. Lumbar puncture showed no pleocytosis, and autoimmune and cytokine panels were negative. Differential diagnoses considered included post-infectious cerebellar inflammation, unwitnessed injury, and UBE3A progression. All were ruled out clinically and radiographically. Initial management with steroids and benzodiazepines was ineffective and gabapentin provided temporary relief. A course of intravenous immunoglobulin (IVIG) with continued gabapentin led to gradual resolution of symptoms and return to baseline.

Discussion
This case illustrates cauda equina radiculopathy as a rare potential complication of intrathecal ASO therapy. Preclinical data suggest repeated ASO infusions may provoke spinal immune activation, leading to inflammation and nerve root compression. Other mechanisms include procedural trauma, direct neurotoxicity, or hypersensitivity. In nonverbal children, behavioral changes such as irritability or clinginess may indicate neurologic complications. Due to communication barriers, clinicians should maintain a high index of suspicion following intrathecal procedures. Early recognition and evaluation, including imaging and labs, support timely intervention to prevent irreversible outcomes such as bladder dysfunction or paralysis. This case underscores the importance of behavioral monitoring in nonverbal patients as early indicators of neurologic injury.

Cauda Equina Radiculopathy After Intrathecal ASO Infusion in an Adolescent with
Angelman Syndrome

Background :
Herpes simplex virus (HSV) esophagitis is an uncommon condition, typically occurring in immunocompromised individuals. It presents with inflammation and ulceration of esophageal mucosa. Both HSV-1 and HSV-2 can be implicated. Prompt diagnosis and treatment are essential to prevent complications. 

Case Presentation :
We report a case of a 57-year-old female with a history of mixed connective tissue disorder and Raynaud’s phenomenon, currently on corticosteroid therapy. She presented with a two-month history of progressive dysphagia to both solids and liquids, odynophagia, and significant weight loss. Physical examination revealed pallor. Laboratory investigations showed anemia (Hb: 8.5 g/dL), leukopenia (TLC: 2800/mm³), and thrombocytopenia (Platelets: 110,000/mm³). Upper gastrointestinal endoscopy revealed superficial ulcers with exudates throughout the esophagus. Histopathological examination of biopsy samples showed characteristic features of HSV infection, including multinucleated giant cells, ground-glass nuclei, nuclear molding, and intranuclear inclusions with perinuclear halo. A diagnosis of HSV esophagitis was confirmed. The patient was treated with oral acyclovir 800 mg QID for 21 days, resulting in clinical improvement and endoscopic healing of esophageal ulcers. 

Discussion:
HSV esophagitis should be considered in immunocompromised patients presenting with odynophagia, dysphagia, and weight loss. Diagnosis is established through endoscopy and histopathological confirmation. Early initiation of antiviral therapy is effective and leads to favorable outcomes. This case highlights the importance of maintaining a high index of suspicion for HSV esophagitis in at-risk populations.


A Case of Herpes Simplex Esophagitis

Background 
The CDC reports that 15% of Americans live in rural areas (population <50,000). Rural residents are generally older, have higher rates of chronic illnesses like osteoarthritis, and experience more musculoskeletal injuries than urban populations. Unfortunately, local access to both urgent and elective orthopaedic care in these areas remains limited. 

Despite residency program expansion, the shortage of rural orthopaedic surgeons persists. From 2013 to 2018, the total number of orthopaedic surgeons grew by 1.9%, but the proportion practicing in rural areas declined by 0.9%. Little data exists on why orthopaedic residents aren’t choosing rural practice despite the clear need. 

This study aims to explore orthopaedic surgery residents’ views on rural practice and the key factors influencing their decisions, providing insights for educators and healthcare leaders addressing rural orthopaedic care gaps. 


Methods 
A 22-question survey was created in REDCap. Questions captured basic individual demographic information, information about the participant’s training program, future practice plans, interest in rural practice, and reasons for or against practice in rural areas. Interested orthopaedic surgery residency Program Directors (PD) at various institutions were identified through the Collaborative Orthopaedic Education Research Group’s (COERG) database. A letter of invitation to participate was sent to the program directors at interested institutions. 

Of the 29 program directors expressing interest in the study, 16 (55.17%) confirmed they had forwarded the survey to their trainees. Demographics were compared by responses to interest in future rural practice: yes, no, and maybe (have or haven't considered rural practice). 


Results 
107 orthopaedic surgery residents (25 women, 82 men) of a total of 404 (response rate 26.7%) completed the survey. Results are shown in Table 1. Only 6 respondents (5.6%) plan to practice in rural areas, with 3 planning full-time rural practice. Thirty-two (30%) reported no interest in rural practice. 
There were no significant differences in rural practice interest based on gender or parental status. However, residents from hometowns with populations under 50,000 were more likely to consider rural practice. 
The main reasons for choosing rural practice were growing up in rural areas, proximity to family, and recreational opportunities. Reasons against it included limited recreation, family preferences, and personal wellbeing (Table 2). 


Conclusion 
Given the prevalence of orthopaedic conditions among those living in rural America, there is a need for more orthopaedic surgeons to practice in these areas. Addressing this issue is complex and will require collaboration at all levels- including medical schools, local community leaders, orthopaedic surgeons, and professional associations.

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