This cohort study evaluates the use of destruction techniques to treat actinic keratoses among Medicare beneficiaries between 2016 and 2023, both overall and by clinician type.

Importance:Recently, proteinuria has been accepted as a surrogate end point for clinical trials in focal segmental glomerulosclerosis (FSGS) ang IgA nephropathy. However, proteinuria has not been evaluated in Apolipoprotein L1 (APOL1)-mediated kidney disease (AMKD). Methods:Real world data (RWD) analysis of 128 patients of African ancestry with APOL1 high risk genotypes, without diabetes, enrolled in the Million Veteran Program (MVP; n=109) or the biorepository at Vanderbilt University (BioVU; n=19), who had urine albumin-creatinine ratio (UACR) >= 420 mg/g (PCR~0.9 g/g) with a concurrent GFR value. The main predictor was change in the log-UACR at 12 months. The primary outcome was annual GFR slope over 24 months. Secondary outcomes included a kidney composite of a sustained 30% GFR decline, end stage kidney disease (ESKD) or death and ESKD as a single outcome. Linear regression and Cox proportional hazards models were used to assess the effect of changes in UACR and the outcomes. Results:In the pooled analysis the mean age was 56.8 (SD 15.5) y, 116 were male (90.6%) and three patients had diagnosis of FSGS at baseline. Mean baseline eGFR was 46.8 (SD 16.1) mL/min/1.73m2, mean baseline UACR was 1240.8 (1107.7) mg/g, mean eGFR slope was 4.67[-6.00, -3.33] mL/min/1.73m2/year and the geometric mean percentage changes in the UACR at 12 months were -57.5% [-65.0%, -48.4%]. For every 1 unit of log (UACR) increment at 12 months, the annual eGFR slope decreased by -1.80 [-2.56, -1.03] mL/min/1.73m2 in the pooled analysis. For every 1 unit of log (UACR) increment at 12 months, the Cox regression showed a 61% increase in the risk of a kidney composite (p=0.002) and a 98% increase in the risk of ESKD (p<0.001). It was estimated that a 50% reduction of UACR at 12 months was associated with a 28% reduction in the kidney composite endpoint (adjusted hazard ratio [aHR]=0.72; 95% confidence interval [CI]:0.59-0.88; p=0.002), and a 38% reduction in the risk of ESKD (aHR=0.62; 95% CI:0.49-0.80; p<0.001). Conclusions and relevance:Changes in UACR at 12 months significantly modify the rate of decline of GFR over 24 months and clinically meaningful endpoints, supporting the use of UACR changes as surrogate endpoint in AMKD.

The segment anything model (SAM) was released as a foundation model for image segmentation. The promptable segmentation model was trained by over 1 billion masks on 11M licensed and privacy-respecting images. The model supports zero-shot image segmentation with various segmentation prompts (e.g., points, boxes, masks). It makes the SAM attractive for medical image analysis, especially for digital pathology where the training data are rare. In this study, we evaluate the zero-shot segmentation performance of SAM model on representative segmentation tasks on whole slide imaging (WSI), including (1) tumor segmentation, (2) non-tumor tissue segmentation, (3) cell nuclei segmentation. Core Results: The results suggest that the zero-shot SAM model achieves remarkable segmentation performance for large connected objects. However, it does not consistently achieve satisfying performance for dense instance object segmentation, even with 20 prompts (clicks/boxes) on each image. We also summarized the identified limitations for digital pathology: (1) image resolution, (2) multiple scales, (3) prompt selection, and (4) model fine-tuning. In the future, the few-shot fine-tuning with images from downstream pathological segmentation tasks might help the model to achieve better performance in dense object segmentation.

We sought to identify clinically relevant regulators of hair follicle inflammation by conducting a human genetic study of hidradenitis suppurativa (HS), a prevalent, understudied, inflammatory disease with limited effective treatments. We performed a GWAS with 6,300 cases and identified 12 independent risk loci. Epigenetic and transcriptomic analyses of HS risk variants defined cell-specific gene regulatory programs. We experimentally validated a coherent gene module defined by upregulated SOX9 , CXCR4 , and CD74 co-expression that maps to aberrant epithelial structures in the skin. Pharmacological inhibition of CXCR4 implicates CD74 mediated regulation of PI3K/AKT and NF-κB signaling to calibrate inflammation, proliferation and apoptosis in keratinocytes. We next used genome-wide methods to interrogate shared polygenic architecture and identified new clinically and mechanistically relevant disease associations, including another condition that involves aberrant hair follicle remodeling, male pattern hair loss. Our results point towards CXCR4-CD74 signaling in HS and hair follicle homeostasis and suggest CXCR4 blockade as a new therapeutic strategy in HS.

BACKGROUND:Many patients will develop more than one skin cancer; however, most research to date has examined only case status. OBJECTIVE:Describe the frequency and timing of the treatment of multiple skin cancers in individual patients over time. METHODS:We conducted a longitudinal claims and electronic health record-based cohort study to examine the frequency of skin cancer multiplicity. We used a validated phenotype for counting individual skin cancers. RESULTS:Our combined cohort included 5,508,374 patients and 13,102,123 total skin cancers treated. Forty-three percent of patients treated for skin cancer were treated for more than one skin cancer, most within 2 years of the initial skin cancer. A subset of 3% of patients were treated for 10 or more skin cancers and contributed 22% of all skin cancers treated in the combined cohort. LIMITATIONS:High-quality data on skin cancer types were not available. Databases and health records are not designed to capture skin cancer multiplicity well. CONCLUSIONS:Nearly half of patients treated for skin cancer will develop at least one more. Better data formatting will allow for improved granularity in identifying individuals at high risk for multiple skin cancers and those unlikely to benefit from continued annual surveillance.

Importance:Nicotinamide supplementation has been studied as a chemopreventive medication for reducing skin cancer risk, but large-scale data are limited. Objective:To determine the clinical efficacy of nicotinamide supplementation for skin cancer prevention in the general population and among solid organ transplant recipients. Design, Setting, and Participants:A retrospective cohort study was conducted using electronic health record data (October 1, 1999, to December 31, 2024) from the Veterans Affairs Corporate Data Warehouse (CDW) of 33 822 patients. Analyses were conducted from January 17, 2025, to May 9, 2025. Patients who were exposed to nicotinamide were propensity score matched based on the number and year of skin cancers after which treatment with nicotinamide was initiated, age, sex, self-reported race, exposure to acitretin, exposure to field therapy, history of chronic lymphocytic leukemia, and history of solid organ transplant. The index date was the first prescription of nicotinamide filled within the VA system. Stratified Cox models were used to investigate the association of nicotinamide with skin cancer development. Exposures:Nicotinamide, 500 mg, twice daily for longer than 30 days as documented in the electronic health record. Main Outcomes and Measures:Time to the next skin cancer after baseline. Results:There were 12 287 patients (mean [SD] age, 77.2 [8.9] years; 241 women [2.0%]; 31 [0.3%] American Indian or Alaska Native, 3 [<0.1%] Asian, 13 [0.1%] Black or African American, 59 [0.5%] Native Hawaiian or other Pacific Islander, and 11 662 [94.9%] White individuals) exposed to oral nicotinamide, 500 mg, twice daily for longer than 30 days who were matched to 21 479 unexposed patients (mean [SD] age, 76.9 [8.7] years; 374 women [2.0%]; 49 [0.2%] American Indian or Alaska Native, 3 [<0.1%] Asian, 16 [0.1%] Black or African American, 88 [0.4%] Native Hawaiian or other Pacific Islander, and 20 517 [95.3%] White individuals). Within the matched dataset, there were 10 994 instances of basal cell carcinoma after nicotinamide exposure and 12 551 cutaneous squamous cell carcinoma (cSCC). A total of 1334 (3.9%) in the matched cohort were solid organ transplant recipients. Overall, there was a significant 14% reduction in skin cancer risk. When nicotinamide was initiated after a first skin cancer, the risk reduction rose to 54%, although this benefit declined with initiation following subsequent skin cancers. This risk reduction was seen for skin cancers overall, basal cell carcinoma, and cSCC, with the greatest risk reduction seen for cSCC. Among solid organ transplant recipients, no overall significant risk reduction was observed, although early nicotinamide use was associated with reduced cSCC incidence. Conclusions and Relevance:The results of this cohort study suggest that there is a decreased risk of skin cancer among patients treated with nicotinamide, with the greatest effect seen when initiated after the first skin cancer.

ImportanceNicotinamide metabolites have recently been implicated in increased risk of major cardiovascular events (MACE). Supportive data about clinical risk of MACE for nicotinamide users is lacking.ObjectiveTo determine whether nicotinamide use results in an increase of MACE.Design, Setting, and ParticipantsThis study used retrospective electronic health record data of 2 patient cohorts, the Vanderbilt University Medical Center (VUMC) and Million Veteran Program (MVP). The risk of MACE in patients exposed to nicotinamide was compared with the risk of MACE in unexposed patients. In the VUMC cohort, patients were either exposed to nicotinamide based on keyword entry for nicotinamide or niacinamide and manual review of medical records or were unexposed but had documented recommendation for use. In the MVP cohort, those exposed to nicotinamide were matched via propensity scores to those who were not exposed. Data were collected from January 1989 to February 2024, and data were analyzed from March to December 2024.ExposuresThe primary exposure for the VUMC cohort was a confirmed exposure to nicotinamide on medical record review. The primary exposure for the MVP cohort was medication entry for nicotinamide or niacinamide.Main Outcomes and MeasuresThe primary outcome was development of MACE based on a validated phenotype.ResultsOf 13 108 included patients, 11 926 (91.0%) were male, and the mean (SD) age was 66.8 (11.5) years. In the VUMC cohort, 1228 patients were exposed to nicotinamide and 253 were unexposed; in the MVP cohort, 4063 were exposed and 7564 were not. A total of 5291 had exposure to nicotinamide. Neither cohort had significant differences in mean age, sex, race, or ethnicity between the nicotinamide exposed and unexposed groups. There was no difference in the cumulative incidence of MACE after nicotinamide exposure in either the VUMC cohort or MVP cohorts. In adjusted cause-specific models stratified by history of prior MACE, there was no significant association between nicotinamide exposure and the primary outcome of MACE in either the VUMC cohort (no prior MACE: hazard ratio [HR], 2.02; 95% CI, 0.81-5.05; prior MACE: HR, 0.46; 95% CI, 0.22-0.95) or MVP cohort (no prior MACE: HR, 1.07; 95% CI, 0.75-1.17; prior MACE: HR, 1.04; 95% CI, 0.53-2.06).Conclusions and RelevanceIn this retrospective cohort study of 13 108 adults from 2 different patient populations, there was no increased risk of MACE in patients with nicotinamide exposure.

Cases for a disease can be defined broadly using diagnostic codes, or narrowly using gold-standard confirmation that often is not available in large administrative datasets. These different definitions can have significant impacts on the results and conclusions of studies. We conducted this study to assess how using melanoma phecodes versus histologic confirmation for invasive or in situ melanoma impacts the results of a genome-wide association study (GWAS) using the Million Veteran Program. Melanoma status was determined three ways: (1) by the presence of two or more phecodes, (2) histologically-confirmed invasive melanoma, and (3) histologically-confirmed melanoma in situ. We conducted a GWAS for variants with minor allele frequencies of 1% or greater. There were 45,665 cases in the phecode cohort, 5364 cases in the confirmed invasive melanoma cohort, and 4792 cases in the confirmed melanoma in situ cohort. There were 20,457 variants significant at the genome-wide level in the phecode cohort, 2582 in the invasive melanoma cohort, and 1989 in the melanoma in situ cohort. Most of the variants identified in the phecode cohort did not replicate in the histologically-confirmed cohorts. The different case definitions led to large differences in sample size and variants associated at the genome-wide level. Unvalidated and imprecise case definitions can lead to less accurate results. Investigators should use validated phenotypes when gold-standard definitions are not available.

Background:African Americans are at increased risk for chronic kidney disease (CKD) in part due to Apolipoprotein L1 gene (APOL1) high-risk genotypes. Recently, a study from West Africa reported an association between monoallelic genotypes and risk of CKD and focal segmental glomerulosclerosis (FSGS). We here study the association of biallelic and monoallelic genotypes with CKD, proteinuria, and FSGS in participants in a hospital-based cohort in the Southeastern United States. Methods:We conducted a case-control study of African Ancestry participants from the Vanderbilt University Medical Center Biobank (n=23, 857). The primary outcome was CKD defined as: persistent GFR < 60 ml/min, end stage kidney disease (ESKD), biopsy-proven FSGS or urine protein-to-creatinine ratio of >700 mg/g or albumin-to-creatinine ratio of >420 mg/g. Secondary outcomes were proteinuria and FSGS outcomes separately. The primary exposure was APOL1 monoallelic genotype (1 copy of a risk allele versus none). APOL1 biallelic genotypes was studied as a secondary exposure. Sequential logistic regression models were performed adjusting for potential confounders. Results:Among 23,857 participants, 5,784 had CKD, 1,533 had proteinuria, and 80 had biopsy-proven FSGS, 44.5% had one risk allele (monoallelic) and 13.6% had two risk alleles (biallelic). Biallelic carriers had higher odds of CKD than those with one or no risk alleles (adjusted odds ratio ( aOR ), 1.72; 95% confidence interval [CI], 1.57-1.89), proteinuria aOR = 2.02 (95% CI, 1.77-2.31), and FSGS aOR = 17.48 (95%CI 10.53-29.02). Monoallelic carriers (G0/G1 or G0/G2) had a small increase in odds of CKD ( aOR = 1.08, 95% CI 1.00-1.16, p=0.04), which was driven by the G0/G2 genotype ( aOR = 1.11, 95% CI 1.01-1.23, p=0.03). Monoallelic carriers (G0/G1 or G0/G2) had higher odds of proteinuria ( aOR = 1.23; 95% CI, 1.09-1.39) and G0/G1 had higher odds of FSGS (14 cases) ( aOR = 2.83; 95% CI, 1.18-6.79). Conclusions:In our study, monoallelic APOL1 genotypes were associated with 23% higher odds of proteinuria and 3-fold higher odds of FSGS for G0/G1. A modest increase odd for CKD of 8%, which may reflect CKD phenotypic heterogeneity. Our study supports the observations from a West Africa cohort in a US based cohort and adds the association of APOL1 monoallelic genotypes with proteinuria.

Objective: Few studies have examined peripartum maternal outcomes in systemic lupus erythematosus (SLE). Using a de-identified electronic health record (EHR) cohort of individuals with and without SLE, we compared rates of peripartum maternal outcomes including maternal infections, blood transfusions, hospital length of stay, and SLE flares. Methods: We identified deliveries among individuals with SLE and individuals without autoimmune disease using a previously validated algorithm. Peripartum maternal infection was assessed up to 6 weeks postpartum. Using Chi-square and Mann-Whitney U tests, we compared peripartum outcomes in SLE and control deliveries. We performed mixed effects models to estimate the association of SLE case status with peripartum outcomes. We assessed for SLE flares up to 6 months postpartum using chart review of rheumatology notes and the 2009 revised SELENA Flare Index. We evaluated SLE medications prescribed during pregnancy and at time of delivery on peripartum outcomes. Results: We identified 185 deliveries to 142 individuals with SLE and 468 deliveries to 241 control individuals without autoimmune diseases. Mean length of hospital stay was longer for individuals with SLE compared to controls (3.1 +/- 2.0 vs. 2.4 +/- 1.0 days, p < 0.001). In a mixed effects model, peripartum infection was significantly associated with SLE case status (OR = 6.18, 95 % CI 2.73 - 13.98, p < 0.01), Cesarean section (OR = 5.00, 95 % CI 2.16 - 11.57, p < 0.01), and age at delivery (OR = 0.92, 95 % CI 0.86 - 0.99, p = 0.03) after adjusting for race. Transfusion was also significantly associated with SLE case status (OR = 9.05, 95 % CI 3.24-25.32, p < 0.01) and Black race (OR = 6.64, 95 % CI 1.47 - 30.02, p = 0.01) after adjusting for Cesarean section and age at delivery. We observed a postpartum flare rate of 32 % among individuals with SLE with 13 % characterized as mild, 41 % moderate, and 46 % severe. Antimalarial use in the postpartum period was associated with lower flare rate (43 % vs. 63 %, p = 0.04). Conclusions: Individuals with SLE have increased rates of blood transfusions, longer hospital stays, and more frequent infections compared to control individuals in the peripartum period. We observed a postpartum flare rate of 32 %, and antimalarial use was associated with lower flare rate. Our findings demonstrate that the peripartum period remains a high-risk time for individuals with SLE with an ongoing need for close monitoring.

This cohort study describes the use of the Skin and UV Neoplasia Transplant Risk Assessment Calculator tool for transplant recipients.

Acitretin is a retinoid used for severe chronic psoriasis [1] and chemoprevention of keratinocyte carcinomas [2]. It is generally contraindicated in patients with end stage renal disease (ESRD) on hemodialysis (HD) based on a single study showing acitretin to not be dialyzed [3]. However, there are scenarios where the benefits of acitretin use may outweigh the potential risks. Therefore, we conducted this study to report the safety outcomes of ESRD patients on HD receiving acitretin. We identified 24 ESRD patients on HD taking acitretin from Duke and Vanderbilt University Medical Centers. 11 patients were on acitretin and then started HD, and 13 were on HD and then started acitretin. There were statistically significant increases in alkaline phosphatase (ALP) and total bilirubin. Despite recommendations to monitor lipids during acitretin therapy, we found no significant changes. 6 patients developed adverse effects commonly associated with acitretin. While 15 patients discontinued acitretin, only 2 of these cases were due to its adverse effects. Interestingly, adverse effects were seen only among those already on HD when acitretin was started. There were 11 admissions and 3 mortalities while on acitretin and 4 mortalities within 6 months after discontinuing acitretin. However, no admissions or mortalities were attributed to acitretin. The overall mortality in our cohort of 29% was similar to that observed in hemodialysis patients of 30% [4]. Based off these preliminary findings, acitretin may safely be used in patients receiving HD with close monitoring of ALP and bilirubin.