United States

Background: In the treatment of keratinocyte carcinoma, curettage alone has been described as a simpler, less expensive, and quicker method than electrodessication and curettage; however, there are limited studies examining recurrence rates for such lesions.
Objective: To investigate the 5-year recurrence rates of keratinocyte carcinoma treated with curettage alone and compare these results to previously reported recurrence rates for electrodessication and curettage.
Methods: A retrospective cohort and interview study determined 5-year recurrence rates for 1853 total lesions treated with curettage alone using chart review data and patient phone calls. 
Results: Our study yielded a per-protocol 5-year recurrence rate of 2.41% for BCCs, 4.52% for SCCs, and an average of 3.71% across both types of keratinocyte carcinoma. Lesions on the head and neck displayed a significantly greater recurrence rate of 7.18% when treated with curettage alone.
Limitations: We were limited to the use of previously published data to determine recurrence rates for lesions treated with full electrodessication and curettage.
Conclusion: Curettage alone provides comparable efficacy in curing keratinocyte carcinoma when compared to electrodessication and curettage.


AMA Research Challenge 2024 

Recurrence Rates of Keratinocyte Carcinoma Treated with Curettage Alone, a Retrospective Cohort and Interview Study

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Dear IPSO Virtual Conference Attendees:

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IPSO 2021

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Background
Dissecting cellulitis (DC), also known as perifolliculitis capitis abscedens et suffodiens or Hoffman disease, is characterized by a perifollicular inflammatory infiltrate, comprising lymphocytes, predominantly CD8+ T cells, and neutrophils. Its etiology is attributed to aberrant follicular keratinization, resulting in follicular blockage and subsequent bacterial infection. DC may manifest concomitantly with conditions such as acne conglobata and inverse acne, forming part of the follicular occlusion triad. Symptoms of DC encompass tender nodules, alopecia, and lesions that, despite incision and drainage, demonstrate recurrence. Interconnected sinus tracts form in DC which can either be deep sinus tracts or tortuous ridges linking the nodules and abscesses. Treatment modalities for DC encompass isotretinoin, dapsone, intralesional steroid injections, and doxycycline. Tobacco smoking is recognized as a significant risk factor for the development and subsequent exacerbation of DC. In recent times, Electronic Nicotine Dispensing Systems (ENDS) or vaping has gained popularity; however, the potential risk of DC linked with vaping remains unclear. We hypothesized that the risk of developing DC might be elevated in individuals with a vaping history due to increased exposure to toxic metabolites. Subsequently, we compared the risk of DC development between individuals using vaping devices and tobacco products.

Methods
We conducted a retrospective cohort study utilizing de-identified patient data from the TriNetX platform, a comprehensive electronic health records (EHR) system. Cohorts included patients with vaping history (Cohort A) compared to tobacco smokers (Cohort B). Propensity score matching was utilized to balance baseline characteristics between the cohorts, including age, sex, ethnicity, and comorbidities.

Results
Risk of DC development for Cohort A was 2.53 %, compared to Cohort B 3.94% (p<0.0001 (95% CI (1.269, 1.912); Risk ratio: 1.557).

Conclusion
Benzo(a)pyrene, found in cigarette smoke, has been linked to vitamin A deficiency which can increase the risk of intraductal keratinization of the epithelial cells, potentially obstructing ductal structures. Chemical profiles of ENDSs vary due to manufacturing differences and addition of various flavors and stabilizing agents. While toxic chemicals related to tobacco smoking have been extensively studied, the ENDSs chemicals and their effect on the human body remains a poorly understood area. DC may be misdiagnosed as cystic acne therefore, a punch biopsy is required for accurate diagnosis. Treatment of DC should target both infection and inflation; thus, azithromycin and doxycycline are commonly used for their anti-inflammatory effect. Adalimumab and TNF-α have been reported to be efficacious in treatment of DC.

Risk Associated with Electronic Nicotine Dispensing Systems versus Tobacco Use and Development of Dissecting Cellulitis

Background: Palmoplantar pustulosis (PPP) is a chronic, debilitating inflammatory skin disorder characterized by erythematous pustules and desquamation on the palms and soles with severe impact on quality of life. While IL-17 pathways have been implicated in PPP pathogenesis, clinical trials with IL-17 inhibitors have yielded conflicting results, underscoring the need for a deeper understanding of its underlying mechanisms.
Methods: We employed single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics to analyze skin biopsies from PPP patients (n=3) and healthy controls (n=5). We identified distinct cellular populations, their gene expression profiles, and interactions contributing to PPP pathology.
Results: We analyzed 32,364 cells using scRNAseq, identifying nine major cell types and revealing significant differences in cellular compositions between lesional PPP, nonlesional skin, and healthy controls. Within the lymphocyte population, regulatory T cells (Treg) and T helper 17 cells (Th17) were exclusively presented in PPP samples. Further characterization uncovered two distinct Th17 subpopulations with differential cytokine expression and regulation. A subpopulation termed “regulatory Th17” expressed immune regulatory molecules FOXP3 and CTLA4 and demonstrated elevated levels of IL17F and IL26 in lesional cells. These cells directly interact with IL36G+ supraspinous keratinocytes, amplifying the inflammatory response. Immunohistochemistry analysis further confirmed elevated levels of IL-26 and IL-17 in lesional skin, implicating these cytokines in the inflammatory cascade associated with PPP.
Conclusions: Our findings underscore the complexity of PPP pathogenesis, involving unique immunological environments and T cell plasticity. The identification of regulatory Th17 cells as major IL-26 producers and their interaction with inflammatory keratinocytes suggests potential therapeutic targets. 


Single-Cell Analysis Reveals Distinct Subpopulations of T Cells and Elevated
IL-26 and IL-17 Levels in Palmoplantar Pustulosis Lesions

Background: Basal cell carcinoma (BCC) is the most prevalent skin malignancy, with a growing global incidence attributed to increased UV exposure and an aging population. While early-stage BCC can be treated with Mohs surgery and photodynamic therapy, options for advanced cases are limited. Existing systemic therapies, including SMOOTHENED inhibitors that target the Hedgehog (HH)-signaling pathway in BCC, are associated with significant adverse effects, such as muscle spasms, hair loss, and teratogenicity. Additionally, the emergence of resistance to these inhibitors underscores the need for diversifying systemic treatment options. This study aims to deepen our understanding of HH-signaling pathway, with the goal of identifying FDA-approved drugs with favorable genetics profile to disrupt this pathway.

Methods: Expression levels of mRNA transcripts for six key genes involved in BCC pathogenesis—Gli1, Gli2, Gli3, Shh, Ptch1, Ptch2, and Smo—were acquired from 269 human neck skin tissues in the Gene Network 2.0 database. Pearson Correlation Matrix analysis revealed statistically significant correlations among these genes (p < 0.05). Signaling network analysis with NetworkAnalyst 3.0 identified key molecular pathways shared among these genes. Subsequently, a protein-protein interaction (PPI) network was constructed based on the six key genes using the IMEx Interactome database, and functional annotation analysis was conducted using KEGG, REACTOME, and Gene Ontology databases to identify associated biological processes, molecular functions, and cellular components. Lastly, a Protein-Drug Network analysis was performed using DrugBank 5.0 database to identify FDA-approved drugs capable of inhibiting protein components of the PPI network.

Results: Pearson correlation matrix analyses revealed significant positive correlations among Gli1, Gli2, Ptch1, and Ptch2 expressions. Notably, positive correlations were observed for Gli1-Gli2 (r = 0.651, p < 0.05), Ptch1-Ptch2 (r = 0.734, p < 0.01), and Gli1-Ptch1 (r = 0.528, p < 0.05). Signaling network analysis identified notable pathways, such as 'Chemokine signaling,' ‘RAS signaling,’ ‘Proteoglycans in cancer,’ and ‘Apelin signaling,’ latter of which has not been previously explored in the context of BCC pathogenesis. Subsequent PPI networks identified 198 proteins regulating various cancer-related pathways, specifically Histone Deacetylase 1 (HDAC1), AKT Serine/Threonine Kinase 2 (AKT2), Phosphatase and Tensin Homolog (PTEN) that are frequently dysregulated in cancerous cells. Subsequent functional annotation analysis identified ‘Positive regulation of transcription,’ ‘Chromatin binding,’ and ‘Nucleus’ as the primary associated biological process, molecular function, and cellular compartment. Finally, Protein-Drug analysis of the PPI network identified six FDA-approved drugs—Amitriptyline, Nintedanib, Pazopanib, Ponatinib, Regorafenib, and Sorafenib—that may disrupt the PPI network by targeting proteins involved in 'PI3K-AKT signaling pathway,’ 'RAS signaling pathway,' and 'Chemokine signaling pathway.'

Conclusion: This study provides deeper insights into the molecular components and signaling pathways in BCC pathogenesis. The significant correlations and identified pathways highlight interdependent regulation of Gli1, Gli2, Ptch1, and Ptch2 expressions. Identifying FDA-approved drugs that may disrupt HH-signaling pathways suggests potential therapeutic strategies to diversify treatment for advanced BCC. These findings support repurposing existing drugs to improve treatment options, warranting further research and clinical trials.

Systems Genetics of Hedgehog-signaling Pathway May Incentivize Repurposing of FDA-approved Drugs Against Advanced Basal Cell Carcinoma

Background: Atopic Dermatitis (AD) is a chronic, pruritic inflammatory cutaneous disease that affects people of all ages and demographics. In the United States, AD affects over 30 million people and 10.2% of adults. AD is known to be cumbersome and financially taxing, significantly affecting patients’ quality of life (QoL). As disease prevalence increases and new therapies arise, a better understanding of the socioeconomic burden becomes critical. The objective of this study is to assess the financial implications across various socioeconomic backgrounds and community types from the patient perspective within a single institution that serves rural, suburban, and urban areas.

Methods: A 22-question cross-sectional survey was conducted through telephone calls. Inclusion criteria included patients ≥18 years old with an ICD code for AD seen at our institution over the past 10 years. Patients were adults of varying ages, genders, races, and ethnicities. Patients self-reported information on their AD diagnosis, socioeconomic status, education level, affordability, expenses related to their AD, and factors affecting their QoL. Statistical analysis was performed using SPSS.

Results: Sixty-four patients participated in the survey, with a response rate of 78%. Responders were predominantly female (55%), with a mean age of 41. Participants were 48% White or Caucasian, 36% Black or African American, and 16% Asian or Asian American. Self-reported disease severity was labeled as mild (17%), moderate (33%), or severe (50%). Yearly income levels were reported as less than $50k (23%), $50-100k (14%), $100-150k (16%), more than $150k (20%), and 27% declined to answer. Thirteen respondents (21%) reported that they had been unable to afford their medications at some point, only three had household incomes of less than $50,000/year. Most respondents (36%) stated that over-the-counter treatments and supplies were the most expensive aspects of their AD care. The financial burden of AD for each income level did not differ significantly across income levels. Regarding education, 36% had less than a college degree, 42% earned a college degree, and 22% earned a postgraduate degree. Most individuals answered that they almost or completely understood their disease and treatment options when asked (81%). When asked to select up to three factors from a list that affect their QoL due to AD, 14 respondents identified financial burdens, five chose transportation, five selected access to medical care, and two indicated access to supplies. These factors did not vary significantly across different income groups.

Conclusions: Our study found that one in five patients have been unable to afford treatment at some point. The understanding of disease and treatment options may not be based on education level but rather on health literacy. Understanding the socioeconomic impact of disease facilitates better resource allocation and knowledge of how we can better serve the evolving patient population.

The Influence of Finances and Education on Quality of Life in Atopic Dermatitis

Title
Unraveling Allergy-Related Factors Contributing to Hair Loss

Background 
Frontal Fibrosing Alopecia, Lichen Planopilaris, and Central Centrifugal Cicatricial Alopecia are inflammatory alopecias that can be challenging to treat. Previous studies showed LPP and FFA patients are significantly more likely to have positive patch tests and evidence of allergic contact dermatitis. Allergen avoidance improved scalp inflammation. Those studies did not include CCCA common in people of African descent. The purpose of this study was to determine if our data at one institute was similar to previous studies, while including CCCA patients. 

Methods
A retrospective chart review was conducted on all hair loss patients who received patch testing from January 2021 to June 2023 at KMC Dermatology in Mission, Kansas. Patients were stratified based on diagnosis of FFA, LPP, or CCCA, patch testing, allergens, and anti-inflammatory therapy. 

Results
46 of the 80 total patients (57.55%) had a positive patch reaction. Of the 48 LPP patients, 30 (62.5%) had a positive reaction. The majority of the patients that tested positive had LPP (30 of 46). Of the 10 FFA patients, 7 (70%) had a positive reaction. Of the 9 CCCA patients, 5 (55.56%) had a positive reaction. The most common allergen was toluenediamine sulfate (6 patients, 7.5%). 

63 of the 80 (78.75%) total patients received anti-inflammatory therapy. Of the 48 patients with LPP, 39 (81.25%) received anti-inflammatory therapy. Of the 10 patients with FFA, 7 (70%) received anti-inflammatory therapy. Of the 9 patients with CCCA, 8 (88.89%) received anti-inflammatory therapy. The most common anti-inflammatory was Doxycycline (34 patients, 42.5%). 

Conclusion
57.5% of patients had a positive reaction. Similar to previous studies, a significant number of patients had a positive patch test. It demonstrated the most common allergens were toluenediamine sulfate, benzoyl peroxide, and propylene glycol. Previous studies lacked CCCA and including these patients offers insight on this understudied disease. 55.56% CCCA patients were patch test positive, with the most common allergen being propylene glycol. 78.75% of patients received anti-inflammatory therapy. The most common were Doxycycline, Naltrexone, and Tofacitinib. Lower magnitude of reaction to the patch testing can result if the patient is on anti-inflammatory medication. It’s possible that a reduction in positive results occurred as a large majority of the patients received these medications. Overall, the study confirmed that patients with LPP, FFA, and CCCA can benefit from patch testing evaluation. Encouraging patch testing in these patients, may help to identify allergic triggers, potentially limiting further hair loss.

Unraveling Allergy-Related Factors Contributing to Hair Loss

Study Objectives: Patients who prefer to communicate in a language other than English are vulnerable to the consequences of medical communication barriers. Studies of Non-English Language Preferred (NELP) and English Language Preferred (ELP) patients have shown differences in rates of hospital admission and wait times, factors related to increased costs and lower patient satisfaction. However, few studies consider languages other than Spanish or account for the patient’s acuity level when they present to the Emergency Department (ED). This study investigates differences in care between NELP and ELP patients across three ED operational metrics: hospital admission rate, time from arrival to room, and time from arrival to disposition.

Methods: This retrospective cohort study used electronic health records from January 2020 to December 2020 from an urban academic medical center. Data extracted included age, gender, language preference, disposition, and Emergency Severity Index Score (ESI). NELP patients were languages were grouped into three language categories: Spanish, Chinese (Mandarin, Cantonese, Taishanese, Taiwanese, and Zhongshan-Chinese dialect), and Other (all remaining languages). The primary outcomes were hospital admission rate and times from arrival to the treatment room and arrival to disposition. Data was analyzed with chi-squared tests, logistic, and linear regressions.

Results: Of the 58,079 unique ED encounters in the study period, 26.4% (15,307) patients identified as NELP. Within NELP patient encounters, 75.0% preferred Spanish, 13.9% preferred Chinese, and 11.1% preferred another language. NELP patients had a higher admission rate than ELP (22.6% vs 20.0%, p<0.001), which after adjusting for age and acuity, demonstrated a 15% increased odds (p<0.001). NELP patients waited an average 5.4 minutes longer to be roomed (p<0.001) and 15.6 minutes longer until disposition (p<0.001). This discrepancy was greater for lower acuity patients, with ESI 5 Spanish and Chinese language-preferred patients waiting a longer average 50.4 and 90.6 minutes respectively ( p<0.001; p<0.05).

Conclusion: Even after adjusting for acuity level and age, NELP patients were at higher odds of admission and experienced disparate wait times, particularly at lower acuity levels. Decreased ED throughput not only affects patient experience but can delay treatment for more emergent patients. These disparities demonstrate opportunities to improve ED efficiency and the need to improve health equity.

Disparities in Emergency Department Admission Rates and Wait Times for Non-English Language Preferred Patients

Abstract Title
Implementation of a VA Addiction Hotline: Assessing the Impact of Addiction Hotline Intervention on Buprenorphine and Naloxone Prescribing Rates in the Emergency Department
Authors
Jennifer Diaz, Nathalie Dieujuste, Francis C. Averill, Cynthia Koh, Hemang Acharya, Zahir Basrai, Comilla Sasson, Manuel Celedon
Background
The opioid crisis in the United States resulted in over 81,000 deaths in 2022. The VeteransHealth Administration (VHA) has supported overdose education and naloxone distribution(OEND) programs and released clinical practice guidelines advocating for the use of medications for opioid use disorder. Despite increased awareness and allocation of resources, uptake of OEND programs has been variable within VHA, and buprenorphine for the treatment of opioid use disorder (OUD) remains underutilized. To improve naloxone and buprenorphine prescribing, we developed a daily telehealth addiction hotline service for VHA emergency
department (ED) providers to access an addiction specialist in real-time from 1:00 p.m. to 9:00p.m. PST. We evaluated naloxone and buprenorphine prescribing before and after implementing an addiction hotline in eight Southwest VHA facilities (SW VHA).
Methods
We reviewed VHA clinical dashboard quarterly performance data of ED naloxone and buprenorphine prescribing from October 1, 2021 through March 31st, 2024 (ten government fiscal year quarters). The dashboard reports a quarterly percentage of prescribing rates for naloxone (number of ED patients at risk for opioid-related overdose prescribed naloxone at discharge divided by the total number of at-risk ED patients) and buprenorphine (number of ED patients with untreated OUD receiving buprenorphine at discharge divided by the total number
of ED patients with untreated OUD). We conducted four paired sample t-tests evaluating the changes in trends for naloxone and buprenorphine prescribing from VHA EDs before implementation of the addiction hotline (October 1st, 2021 through December 31st, 2022) and after implementation (January 1st, 2023 through March 31st, 2024). The national VHA data was utilized as a control since the addiction hotline intervention occurred only in Southwest VHA
facilities.
Results
In the national (control) group, naloxone prescribing increased significantly between the pre- implementation period and the post-implementation period with a mean increase of 9.08 (SD=1.36, p<0.001), Cohen's d=6.66. The SW VHA (intervention) group also showed a significant increase of 13.47 (SD=9.29, p=0.032), Cohen's d=1.45. For buprenorphine, the control group displayed a significant increase of 0.73 (SD=0.19, p=0.001), Cohen's d=3.75. The intervention group showed a mean increase of 1.25 (SD=1.26), significant at only the one-tailed level (p=0.04), Cohen's d=0.99.
Conclusion
Naloxone and buprenorphine prescribing increased significantly both nationally and in SW VHA.A more pronounced increase was observed in SW VHA, indicating a potential positive impact from the addiction hotline. Further investigation is needed to evaluate the effect of a real-time clinician support service on naloxone and buprenorphine prescribing in the ED.

Implementation of a VA Addiction Hotline: Assessing the Impact of Addiction Hotline
Intervention on Buprenorphine and Naloxone Prescribing Rates in the Emergency Department

Abstract Title 
CARDIOVASCULAR AUTONOMIC FUNCTION IN LONG COVID-19 INDIVIDUALS WITH AND WITHOUT DIABETES

Background
The objective of this study is to identify differences in the impact of cardiovascular autonomic (CAN) on long COVID individuals with and without diabetes. We examined associations with measures of CAN, using standardized cardiovascular autonomic reflex tests (CARTs) and heart rate variability (HRV), in long COVID individuals with and without diabetes.

Methods
We evaluated measures of CAN in a cross-sectional study in 47 adults with long COVID-19 with (N=32, mean age 61 years, 43% women, mean A1c 6.2%) and without type 2 diabetes mellitus (T2DM) (N=34, mean age 58 years, 65% women) and compared them with T2DM without COVID-19 (N=45, mean age 57 years, 42% women, mean A1c 7.8%). CAN was assessed with CARTs (30:15 ratio, E:I ratio, Valsalva ratio) and indices of HRV (standard deviation of the normal RR interval (SDNN), root mean square of the differences of successive RR intervals (RMSSD)). We used pairwise comparison and Analysis of Covariance (ANCOVA) both adjusted for age, sex, race, and body mass index (BMI) to compare the groups.
Results In a pairwise comparison higher heart rate (HR) and lower CAN measures (SDNN, RMSSD, Valsalva) were found in T2DM with COVID-19 compared to T2DM without COVID- 19. Lower HR and lower Valsalva were found in COVID-19 individuals without T2DM compared to T2DM without COVID-19. When comparing the three groups, lower Valsalva were found in COVID-19 individuals with and without T2DM compared to T2DM without COVID- 19.

Conclusion 
Data suggests that COVID-19 exacerbates CAN in individuals with T2D. COVID- 19 also impacts CAN in people without T2D at a magnitude similar to that of T2D participants. The role of long COVID-19 in the progression of CAN warrants further exploration.

Cardiovascular Autonomic Function in Long COVID-19 Individuals With and Without Diabetes

Title: Comparison of Glimepiride dosing and blood sugar levels in Type 2 Diabetes Mellitus - A Meta-Analysis
Author: Sheema Khan, Master of Science Clinical Research, 2019
Thesis Directed by: Dr. Andrew Bean, PhD, Dean of Graduate College
Background: Glimepiride, a sulfonylurea drug, is widely used to manage blood glucose in Type 2 Diabetes Mellitus (T2DM). Recommended dosages range from 1 to 8 mg daily, typically administered alongside Metformin. Dose escalation, though common, poses risks of hypoglycemia and cardiovascular concerns.
Objective: To conduct a meta-analysis of randomized clinical trials comparing the efficacy of 2 mg versus 4 mg Glimepiride as add-on therapy with Metformin in T2DM patients aged 18 and above. Primary outcome measured was change in HbA1c levels; secondary outcomes included BMI, Fasting Plasma Glucose (FPG), lipid levels, lipid subtypes, and frequency of hypoglycemic episodes.
Methods: Fifty-one RCTs were initially identified from databases such as PubMed and Scopus, with 11 studies meeting inclusion criteria (2 mg group: 693 subjects; 4 mg group: 666 subjects). Comprehensive meta-analysis using "Comprehensive Meta-Analysis (CMA)" software was performed, utilizing difference in means and standardized difference in means to assess outcomes.
Results: Both 2 mg and 4 mg doses of Glimepiride significantly reduced HbA1c levels, with the 2 mg dose showing a greater reduction. Subgroup analyses indicated significant heterogeneity among studies. FPG reduction was statistically significant for both doses, while BMI changes and lipid levels did not show significant associations with dose. Hypoglycemia risk was lower with the 2 mg dose compared to 4 mg.
Conclusion: The meta-analysis supports the efficacy of both Glimepiride doses in reducing HbA1c levels, with the 2 mg dose demonstrating superior results. Significant associations were observed between FPG reduction and Glimepiride dose, while other outcomes showed mixed results. These findings suggest potential benefits of initiating treatment with the 2 mg dose to minimize hypoglycemia risk and achieve effective glycemic control in T2DM patients.
Limitations: Limitations include the lack of direct comparative studies between 2 mg and 4 mg doses and high heterogeneity among included trials. Larger randomized trials are recommended to validate these findings and guide clinical practice.

Comparison of Glimepiride dosing and blood sugar levels in Type 2 Diabetes Mellitus - A Meta-Analysis

Background
The CDC reports that the prevalence of obesity in US adults has risen to nearly 42%. The underlying mechanisms of obesity, insulin resistance, and the metabolic syndrome are not well characterized. This study aims to identify how adipose cellular senescence affects metabolic outcomes in the context of obesity and aging. 
Senescent cells have a proclivity to aggregate in adipose and act on neighboring tissues through the release of markers dictated by their senescence-associated secretory phenotypes. It is theorized that inflammatory cytokines may contribute to the pathogenesis of cardiometabolic disease. Furthermore, a high volume of adipocytes may be associated with increased immune cells and fat oxidation, contributing to the development of insulin resistance.
Methods
The ongoing clinical trial in the Musi lab will enroll 160 subjects to account for a dropout rate of approximately 25%. 120 subjects will complete the study. Based on their baseline characteristics they will be divided in the following groups:

Younger Lean (n=24) Group, age 18-30 years, BMI 18.5-24.9 kg/m²
Older Lean (n=24) Group, age ≥ 65 years, BMI 18.5-24.9 kg/m²
Older Obese (n=72) Group, age ≥ 65 years, BMI 30-39.9 kg/m²

Subjects will be enrolled and studied at Cedars Sinai Medical Center in Los Angeles, California (n=120 completers). We will recruit patients of any sex, race, and ethnic background. All subjects will be nondiabetic (fasting plasma glucose < 126 mg/dl, 2-h glucose during oral glucose tolerance test <200 mg/dl, and A1c <6.5%), community-dwelling, and sedentary (≤1.5 h of exercise per week).

Exclusion criteria include history of diabetes, participation in structured exercise >1.5h per week, chronic inflammatory / neurologic / autoimmune / pulmonary disorders, GI or heart disease, use of anti-arrhythmic or weight altering medications, smoking/alcohol use, previous bariatric surgery, and use of/allergy to senolytic agents.

All subjects will undergo initial screening, OGTT analysis, DXA/cardiopulmonary testing, insulin clamp and adipose/skin biopsy (which will be used for sn RNA-seq analyses of senescence). The older obese cohort will be further randomized into three arms: lifestyle intervention (n=24), senolytics (n=24), or placebo (n=24). They will undergo repeat adipose biopsies, snRNA-seq, and metabolic/physiologic assessment after respective 10-week interventions

Conclusion
Characterizing the relationship between adipose senescence and metabolic outcomes will provide greater insight into the underlying mechanism of insulin resistance. While preliminary murine data are promising, assessing these hypotheses in human subjects will reveal the degree to which senolytic agents can improve metabolic function. Furthermore, this study study may help us gain better understanding of the aging process and identify potential molecular targets for prevention of metabolic disease.

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