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**Abstract:**



AMA Research Challenge 2023

Revealing the interactions of antihistamine with retinoic acid receptor beta (RARB) by molecular dynamics simulations and genome-wide meta-analysis.

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Background
Vitiligo is a common autoimmune condition characterized by patchy skin depigmentation, affecting nearly 3 million individuals in the United States with nearly half of cases in both adolescents and adults remaining undiagnosed [1,2]. This condition is often associated with other autoimmune and connective tissue comorbidities and mental health problems, further complicating patients' overall health and quality of life [3,4]. Recent studies have also suggested a potential correlation between vitiligo and an increased risk of obesity and renal diseases [3]. Renal disease patients often require dialysis or kidney transplant as part of their treatment and thus, these individuals may be at higher risk of systemic infections due to various factors, including vascular and catheter access and immunosuppression [5,6]. Due to the disrupted epidermal barrier composition and recovery in vitiligo patients, it is reasonable to hypothesize that these patients undergoing dialysis may be more susceptible to systemic infections [7,8]. However, there is a lack of research exploring the relationship between dialysis patients with vitiligo and their risk of infection. To address this knowledge gap, we conducted a retrospective analysis utilizing data from the United States Renal Data System (USRDS) to determine if vitiligo presents as a risk factor for increased risk of bacteremia, septicemia, cellulitis, herpes zoster, and conjunctivitis.

Methods
All end-stage renal disease (ESRD) patients in the USRDS who started dialysis between 2004 and 2019 were eligible for inclusion in the study. Those who were less than 18 years or greater than 100 years of age, or had missing or unknown data on age, race, sex, ethnicity, access type or dialysis type were excluded. The total sample size was 1,526,270. Infectious outcomes of interest included bacteremia, septicemia, cellulitis, herpes zoster, and conjunctivitis. Among those included in the sample, a diagnosis of vitiligo after the incident date of dialysis was determined. All statistical analysis was performed using SAS 9.4. Descriptive statistics on all variables were determined overall, by vitiligo status, and by each type of infection.

Results
A total of 676 subjects had a vitiligo diagnosis. Based on a simple logistic regression model, vitiligo was associated with an increased risk of bacteremia (adjusted relative risk = 1.28), septicemia (1.20), cellulitis (1.27), and herpes zoster (1.69) but not conjunctivitis (1.22). Controlling for demographics and clinical covariates, vitiligo was no longer significantly associated with septicemia.

Conclusion
These results indicate that vitiligo-ESRD patients may have an increased risk of bacteremia, cellulitis, and herpes zoster but not significantly associated with septicemia and conjunctivitis. These findings justify further research into tailored care plans for patients with vitiligo receiving dialysis and improved prevention and monitoring of infection in these patients.

1. Patel R, Pandya AG, Sikirica V, Gandhi K, Daniel SR, Anastassopoulos KP, Yamaguchi Y, Napatalung L, Baik R, Ezzedine K. Prevalence of Vitiligo among Children and Adolescents in the United States. Dermatology. 2023;239(2):227-234. doi: 10.1159/000528180. Epub 2023 Jan 11. PMID: 36630928; PMCID: PMC10210084.
2. Gandhi K, Ezzedine K, Anastassopoulos KP, Patel R, Sikirica V, Daniel SR, Napatalung L, Yamaguchi Y, Baik R, Pandya AG. Prevalence of Vitiligo Among Adults in the United States. JAMA Dermatol. 2022 Jan 1;158(1):43-50. doi: 10.1001/jamadermatol.2021.4724. PMID: 34787670; PMCID: PMC8600454.
3. Al Houssien AO, Al Houssien RO, Al Ajroush W, Al Kahtani HS. Chronic diseases among vitiligo patients. A case control study. Saudi Med J. 2017 Apr;38(4):400-404. doi: 10.15537/smj.2017.4.17551. PMID: 28397947; PMCID: PMC5447193.
4. Lee JH, Ju HJ, Seo JM, Almurayshid A, Kim GM, Ezzedine K, Bae JM. Comorbidities in Patients with Vitiligo: A Systematic Review and Meta-Analysis. J Invest Dermatol. 2023 May;143(5):777-789.e6. doi: 10.1016/j.jid.2022.10.021. Epub 2022 Nov 28. PMID: 36574529. 
5. Ramakrishna, P., & Rajni, T. (2014). Psychiatric morbidity and quality of life in vitiligo patients. Indian journal of psychological medicine, 36(3), 302–303. https://doi.org/10.4103/0253-7176.135385
6. Levey AS, Coresh J. Chronic kidney disease. The lancet. 2012;379 (9811):165-180. https://doi.org/10.1016/S0140-6736(11)60178-5
7. Suzuki M, Satoh N, Nakamura M, Horita S, Seki G, Moriya K. Bacteremia in hemodialysis patients. World J Nephrol. 2016 Nov 6;5(6):489-496. doi: 10.5527/wjn.v5.i6.489. PMID: 27872830; PMCID: PMC5099594.
8. Kovacs, D., et al., Altered epidermal proliferation, differentiation, and lipid composition: Novel key elements in the vitiligo puzzle. Sci Adv, 2022. 8(35): p. eabn9299.


Assessment of Infection Risk in vitiligo patients undergoing dialysis for end-stage renal disease: A retrospective cohort study

This study introduces an advanced software tool designed for personalized diagnosis and comprehensive guidance in both the medical and surgical management of Androgenetic Alopecia (AGA). Developed through machine learning techniques, the software provides enhanced diagnostic accuracy and offers individualized follicular distribution guidance. The research is built upon a systematic review of 40 studies encompassing hair density measurements across multiple ethnicities. The software demonstrates good predictive accuracy in different scalp regions, with R2 values ranging from 0.42 to 0.67 and MAE values varying from 22.70 to 38.04 hairs/cm2. Compared to current clinical solutions, this software enables longitudinal response to treatment monitoring and delivers a personalized, data-driven diagnostic approach. It addresses existing gaps in the field by generating reliable predictions of normative scalp hair density, thereby assisting in tailored surgical planning and medical management. Future work aims to refine the model through real-world testing and integration of additional clinical variables.

Advanced Software for Personalized Diagnosis and Comprehensive Guidance in Medical and Surgical Management of Androgenetic Alopecia

Infection with SARS-COV-2 has shown the ability to damage nearly every organ system in the human body, including the largest organ - the skin. Granuloma annulare (GA) is a rare rash with unclear etiology that presents as annular, erythematous papules or plaques with central clearing. To our knowledge, there has only been one reported case of GA associated with COVID-19 vaccination published thus far. We present the cases of a 54-year-old female and a 66-year-old male who developed generalized GA and localized GA, respectively, following the administration of a COVID-19 vaccine, which worsened with subsequent boosters. This paper reviews the existing literature on GA associated with COVID-19 infection and vaccination, as well as the possible immunological mechanisms underlying the development of GA following vaccination. We especially note the striking similarities in disease morphology and temporal association with COVID-19 vaccination between our 54-year-old female and the first reported case of GA following COVID-19 vaccination. Despite the temporal association between COVID-19 vaccination and the development of GA, the exact causative relationship remains unclear. Further studies are needed to elucidate the underlying mechanisms and determine the true incidence and risk factors for GA associated with COVID-19 vaccination.

Granuloma Annulare Onset Following COVID-19 Vaccination

Background: 
Sunscreen use in people of color is less common than sunscreen use in people with lighter pigmentation, often due to low perceived risk. However, it is still recommended that people of color wear sunscreen to lower the risk of skin cancer, dyspigmentation and pigmentary disorders, and sunburns. Thus, public health efforts should be utilized to improve sunscreen use in people of color. TikTok, a popular social media platform, has been used by health professionals to disseminate educational information and for the purpose of public health outreach. This study looks at the discussion of sunscreen use in this population on this popular social media platform with the goal of understanding what information is being disseminated by and for this target population.

Objective: 
To understand the discussion of sunscreen-related topics on popular social media created for or by people of color.

Methods: 
The term “sunscreen” was searched on TikTok and the top 100 related hashtags were reviewed. Of these two hashtags, #SunscreenforBlackPeople and #Sunscreen for POC, were directed towards people of color. The top 50 videos for each of those hashtags were reviewed for content, creator characteristics including Fitzpatrick skin type and qualifications, and qualities of sunscreen discussed in the video. Analysis was performed to identify key themes in the videos.

Results: 
Most of the content creators discussing the topic of sunscreen for people of color were influencers without medical background. The majority of videos were focused on recommending or sampling different sunscreen brands. Common criteria for reviewing sunscreen brands included presence of “whitecasting”, the final finished look after sunscreen application, cost, and sunscreen density in regard to if the sunscreen feels heavy or lightweight. Only 5 of the top 50 videos contained an educational component. Educational topics included how much sunscreen to put on, importance of reapplication, and reasons to wear sunscreen. Additionally, few videos discussed reasons people of color should wear sunscreen. Of the reasons to wear sunscreen, most commonly discussed were anti-aging and prevention of hyperpigmentation.

Conclusions: 
The discussion of sunscreen for people of color is limited on TikTok. Of the top posts, few contained educational information and the majority were created by dermatologists. Given the popularity of TikTok and its use to promote other sources of health information, there is room to improve the outreach related to sunscreen on the popular social media platform. 


Analysis of Sunscreen-Related Posts Directed Toward People of Color (POC) on TikTok

Background 

Early melanoma detection has profound clinical impact with distant stages having a
32% 5-year relative survival rate. Traditionally, the automation of melanoma detection prior to biopsy has relied on broad-spectrum photography, thresholding in the frequency domain or analysis of electrical impedance. The advent of deep learning (DL) has enabled automation of dermoscopy.
However, most existing end-to-end DL approaches require annotated data, which is time-consuming to produce and cannot propose novel predictive markers. To address this, we utilized the Semantic Clustering by Adopting Nearest Neighbors (SCAN) algorithm, an unsupervised learning approach that decouples feature learning and clustering, enabling the automated detection of dermatoscopic features that predict disease.

Methods 

We employed the SCAN algorithm to analyze 7991 training and 2024 testing
dermatoscopic images of melanoma or benign nevi from the International Skin Imaging Collaboration dataset. Images are almost all Fitzpatrick type I-III. The model was trained to learn semantically meaningful features that were employed to build clusters of similar images.

Results 

The final clusters exhibited varying levels of homogeneity, with several clusters composed exclusively of one class (melanoma/benign nevi). Several highly predictive clusters for melanoma showed an absence of color uniformity, which is a Menzies method criterion to establish melanoma diagnosis. This indicates latent-space morphology congruent with established evidence-based practice.

Conclusion 

The application of the SCAN algorithm to dermatoscopic images presents a promising methodology for unsupervised learning in melanoma detection. Previous work has shown that AI models that offer explanations to clinicians, such as photos of similar lesions in that continuous area of the model’s latent space, boost physician satisfaction. The FDA approval process also prefers explainable paradigms to ensure model predictability spanning the input space. This study presents an unsupervised approach to melanoma detection via dermoscopy, which enables explainable AI and automated detection of features that predict disease. By providing explainability, the research addresses a key challenge in machine learning paradigms’ FDA approval pathway. Future research is warranted to see if analysis of nevi on dark skin (Fitzpatrick type >3) demonstrates alternate dermoscopic features, as has been previously reported in dermoscopic
literature.

End-to-End Semantic Clustering in Dermoscopy of Melanocytic Lesions

Alopecia areata (AA) is an autoimmune condition that leads to patchy, nonscarring hair loss. The etiology still remains unknown, and the condition can be debilitating for patients, impacting their psychosocial wellbeing. Various triggers have been reported ranging from genetic predispositions, infections, and environmental factors. Medications have also been thought to be an inciting factor in AA. Using the FDA adverse event reporting system (FAERS), all cases reporting AA as an adverse event were used to capture associated medications and patient characteristics. Descriptive statistics were conducted along with logistic regression analysis using patient sex as the primary outcome. There were 1,331 AA cases reported as an adverse event with medication use. With regards to the top 10 medications, 29.2% of AA cases were seen with docetaxel, 8.3% were with adalimumab, 4.7% with trastuzumab, 4.4% with cyclophosphamide, 4.3% with infliximab, 4.1% with carboplatin, 3.4% with dupilumab, 2.7% with levonorgestrel, 2.6% with etanercept, and 2.6% with from pertuzumab. Monoclonal antibodies accounted for 6 out of the top 10 drugs with the highest number of AA cases. Males were more likely to report AA when taking adalimumab (OR 1.79, p = 0.04) and dupilumab (OR 2.56, p = 0.03) compared to females. Individuals between 42-64 years old accounted for 46.7% of AA cases. Lastly, females in older age groups showed greater odds of experiencing AA compared to males (OR 1.03, p < 0.01). Based on the FAERS, there has been a steady rise in AA cases and monoclonal antibodies were the most frequently cited medication class tied to AA. Given the dearth of literature and many unanswered questions surrounding AA, our novel large dataset study highlights the most associated medications, identifies an increase in reported cases over the years, and captures age/sex related demographic trends. An awareness of notable medications and patient demographics adds granularity to the spectrum of potential AA triggers and may increase a provider’s index of suspicion to improve clinical outcomes in the future.

A Cross-Sectional Analysis of Medications Used by Patients Reporting Alopecia Areata on the FDA Adverse Event Reporting System

Objective: To determine the effect of video and direct laryngoscopy on first-pass success rates for out-of-hospital orotracheal intubation.
Methods: MEDLINE, Embase, and Cochrane databases were searched from inception to January 2023. Out-of-hospital studies comparing video and direct laryngoscopy on either first-pass or overall intubation success were included. A random effects meta-analysis was performed with a primary outcome of first-pass success stratified by clinician type and laryngoscope blade geometry. The secondary outcomes were overall intubation success stratified by clinician type, and intubation time. All hypotheses and subgroup analyses were determined a priori.
Results: Twenty-five studies involving 35,489 intubations met inclusion criteria. Substantial heterogeneity (>75%) precluded reporting point estimates for nearly all analyses. For our primary outcome, video laryngoscopy was associated with improved first-pass success in 3/5 physician studies, 4/6 critical care paramedic/registered nurse studies, and 7/10 paramedic studies. Video laryngoscope devices with Macintosh blade geometry were associated with improved first-pass success in 7/10 studies, while devices with hyperangulated geometry were associated with improved first-pass success in 3/7 studies. Overall intubation success was greater with video laryngoscopy in 2/6 studies in the physician subgroup and 9/10 studies in the paramedic subgroup. Video laryngoscopy was not associated with overall intubation success among critical care paramedics/nurses (OR = 1.89, 0.96 to 3.72, I2 = 34%). Lastly, 4/5 studies found video laryngoscopy to be associated with longer intubation times.
Conclusions: We found substantial heterogeneity among out-of-hospital studies comparing video laryngoscopy to direct laryngoscopy on first-pass success, overall success, or intubation time. This heterogeneity was not explained with stratification by study design, clinician type, video laryngoscope blade geometry, or leave-one-out meta-analysis. A majority of studies showed that video laryngoscopy was associated with improved first pass success in all subgroups, but only for paramedics and not physicians when looking at overall success. This improvement was more common in studies that used Macintosh blades than those that used hyperangulated blades. Future research should explore the heterogeneity identified in our analysis with an emphasis on differences in training, clinical milieu, and specific video laryngoscope devices.


Out-of-Hospital Video Laryngoscopy: Should We Be Convinced?
A Systematic Review & Meta-Analysis

Background:
As we navigate the post-COVID era, it is essential to confront the health challenges that arose from our changed lifestyles. The World Health Organization (WHO) predicts that by 2025, one out of five adults globally will be obese. Researchers have identified a connection between obesity and mild cognitive impairment. Cognitive impairment is a major public health issue with rising costs for governments and communities. This study aims to evaluate the impact of obesity on cognitive function 

Methods:
A systematic review was undertaken, following the PRISMA 2020 guidelines. Initially, 1250 potentially eligible studies were discovered, out of which 12 duplicates were removed. A thorough assessment of titles and abstracts, 35 full-text articles carefully reviewed, and ultimately, 21 eligible studies incorporated. The search encompassed databases such as PubMed, ScienceDirect, and Google Scholar, focusing on the most recent 20-year period. Articles involving animal models were omitted, and only those freely available in the English Language were examined for inclusion.

Results: 
Based on the literature reviewed, obesity is significantly associated with an increased risk of cognitive impairment in younger and middle-aged individuals but not in older age. Older people with obesity may have a reduced risk of incident dementia. Studies show that obese individuals aged ≥65 years had lower risk ratios for incident dementia compared to normal-weight individuals (0.83 and 0.88, respectively). Another study indicates lower cognitive function in obese school children compared to healthy ones. 

Conclusion:
Obesity is a complex, multifactorial, but preventable disease. Evidence indicates that obesity is associated with cognitive impairment, increasing the risk of dementia later in life. Pathophysiological mechanisms, such as neural integrity reduction and inflammation, contribute to cognitive decline. Addressing obesity through public health interventions may help prevent cognitive impairment. More research is needed to understand the association fully, especially regarding body weight and dementia risk in older age. The lack of a universally accepted cognitive test approach hinders early detection of mild cognitive impairment.


Investigating Obesity-Related Cognitive Decline

Background
Type 2 diabetes mellitus (T2DM) may be a long-term sequela of Mycobacterium tuberculosis (M.tb) infection by mechanisms yet to be fully unraveled. Using the 2011-2012 NHANES, we evaluated (i) the association between latent tuberculosis infection (LTBI) and T2DM among adults (≥20 years old), and (ii) the extent to which this association is mediated by insulin resistance and β-cell failure.

Methods
T2DM was assessed by fasting plasma glucose and HbA1c; homoeostasis model assessment 2 (HOMA2) was used to estimate β-cell function (HOMA2-B) and insulin resistance (HOMA2-IR); while LTBI status was ascertained by interferon-γ release assay. Quintile and probit regression models were used to examine associations between LTBI and, respectively, HOMA2 indices, and prevalent T2DM. Mediation analyses using the counterfactual framework were then performed to quantify the contribution of each of β-cell dysfunction and insulin resistance to the association of LTBI with T2DM. Analyses were adjusted for sociodemographic, behavioral and clinical confounders.

Results
The analytic sample included 2,235 adults. Compared to TB uninfected individuals, those with LTBI were older [median (IQR): 60 (46, 69) vs. 44 (30, 61) years old], and more frequently male [58.5% vs. 48.9%]. LTBI was associated with increased insulin resistance [adjusted mean difference (AMD) (95% CI) in median: 0.08 (0.01, 0.22); p=0.048] but not β-cell function [AMD in median: -2.6 (-9.4, 4.3); p=0.46]. Similarly, T2DM was more prevalent among those with LTBI [adjusted prevalence (95% CI): 18.3 (13.1, 23.5)%] than peers without TB [11.2 (9.7, 12.9)%], corresponding to an adjusted absolute risk difference of 7.4 (2.3, 13.4)%. In mediation analyses, insulin resistance and β-cell function mediated 22.7 (12.2, 68.9)% and 2.7 (-1.4, 9.7)%, respectively, of the total effect of the association between LTBI and T2DM.

Conclusion
Definitive prospective studies examining incident T2DM following tuberculosis are warranted. Notwithstanding, our findings suggest infection with M.tb may be a novel risk factor for T2DM, likely driven by an increase in insulin resistance.

Insulin resistance, and not β-cell impairment, mediates association between latent tuberculosis infection and type II diabetes mellitus among US adults.

Background
There is a higher burden of diabetes related lower extremity amputation in the Lower Rio Grande Valley area of Texas compared to the Texas average. Hispanics have a higher proportion of this complication in the region. Yet, there is a dearth of research on factors associated with the risk of diabetes associated amputation in Hispanic populations. This study evaluates factors associated with diabetic related amputations in Hispanic patients with diabetic foot ulcer in the Rio Grande Valley area of Texas.

Methods
Our study was a retrospective study using patients’ medical records. Subjects were categorized based on whether they had at least one amputation (outcome) during the period of analyses. Baseline demographic, lifestyle, and metabolic characteristics of participants were determined. Characteristics of interest were insulin use, neuropathy, nephropathy, peripheral arterial disease, hypertension, history of cerebrovascular accident, smoking status, osteomyelitis, previous history of diabetic foot ulcer, previous history of amputation, hyperlipidemia, and glycated hemoglobin levels. Chi-square tests were used to analyze the association between these characteristics and amputation status. Logistic regression modeling was used to estimate the odds ratios for amputation and their 95% confidence intervals by each of the independent variables. We adjusted for age and gender in our multivariable analyses. Statistical analyses were carried out using Stata software.

Results
This study included 120 subjects, all of whom had diabetic foot ulcer. Sixty (50%) of the study subjects had diabetic foot amputation and the rest did not. The variables found to be significantly associated with amputation were peripheral arterial disease (p = 0.006), osteomyelitis (p < 0.0001), previous history of amputation (p < 0.0001), and hyperlipidemia (p = 0.013). However, previous diabetic ulcer, neuropathy, nephropathy, hypertension, smoking status, the use of insulin, retinopathy, and levels of hemoglobin A1c were not significantly associated with amputation.

Conclusion
Diabetic foot amputations have untold effects on the lives of affected individuals, and the broader society. Thus, factors promoting this event should be readily prevented and managed. In the studied population, peripheral arterial disease, osteomyelitis, previous amputation, and hyperlipidemia were significantly linked to diabetic foot amputations. Hence, while more research is required, medical professionals should actively seek out and adequately manage diabetic Hispanic patients with these risk factors to prevent this complication.

Next from AMA Research Challenge 2023

Assessment of Infection Risk in vitiligo patients undergoing dialysis for end-stage renal disease: A retrospective cohort study

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