Vierkant, Robert A.

Objective: To develop and validate 2 predictive models, the Diabetes Remission Index (DRI) and the Weight loss–adjusted DRI (W-DRI), for assessing type 2 diabetes (T2D) remission following metabolic and bariatric surgery (MBS). Background: MBS, including Roux-en-Y gastric bypass and sleeve gastrectomy, is highly effective in achieving T2D remission, but outcomes vary across populations. Predicting remission remains critical for individualized patient care and optimizing surgical outcomes. Existing tools focus on general outcomes, and a specific model incorporating weight loss data has been lacking. Methods: This multicenter, retrospective cohort study included patients with T2D and overweight/obesity (body mass index: ≥27 kg/m 2 ) who underwent Roux-en-Y gastric bypass or sleeve gastrectomy between 2008 and 2018. Institution 1 (I-1) data (n = 503) were used to develop and internally validate the models, whereas Institution 2 (I-2) data (n = 409) were used for external validation. The DRI model incorporated preoperative variables, and the W-DRI model, in addition, included postsurgical weight loss. Predictive accuracy was assessed using area under the Receiver Operating Characteristic curve [area under the curve (AUC)], calibration plots, and stratified analyses. Results: In I-1, 44.7% of patients achieved T2D remission, with a DRI model AUC of 0.80. In I-2, 52.6% achieved remission, with a model AUC of 0.78. Incorporating weight loss improved W-DRI predictive accuracy (AUC: 0.82 in I-1, 0.79 in I-2). Calibration plots demonstrated strong agreement between predicted and observed remission rates. An online DRI and W-DRI calculator is available through the Mayo Clinic webpage (https://newsnetwork.mayoclinic.org/dri-calculator/). Conclusions: The DRI and W-DRI models accurately predict T2D remission post-MBS, enabling personalized patient care and informed decision-making. Further validation across diverse populations is warranted.

Introduction: The lack of understanding about the genetic and molecular basis of young stroke (<55 years of age) has hindered development of diagnostic, management, and therapeutic approaches. Whole exome sequencing (WES) can be leveraged as a tool for studying etiological processes underlying stroke. At the time of study inception, this is the single largest WES study in this unique young stroke population to uncover elusive stroke etiologies. Methods: The Mayo Clinic TAPESTRY database is a research program conducting whole exome sequencing of 100,000 participants. Of these, 406 participants met the criteria for young stroke (18-54 years of age) based on ICD-9 and ICD-10 diagnostic codes. Controls were TAPESTRY participants without a stroke-related ICD diagnosis. Cases were matched for age, gender, and race for a 1:4 case-control ratio. Ischemic stroke etiology was classified using TOAST classification. To uncover genetic mechanisms, a gene centric approach was used to identify variants in our cohort. A list of 66 genes known to be associated with young stroke was curated based on existing genetic databases. Various filtration strategies were used to identify potentially damaging variants (graphic 1). Results: There were 406 cases (363 ischemic and 43 hemorrhagic; 291 female; age at stroke onset 39.8±10.4; 368 were White) and 3,857 controls. TOAST classification yielded 20 patients with large artery atherosclerosis, 58 cardioembolic, 10 small vessel disease, 148 other determined (58 patent foramen ovale, 50 dissection, 48 hypercoagulable state, 11 Moyamoya, 11 vasculitis, 10 fibromuscular dysplasia), and 165 undetermined etiologies. Several individuals had multiple competing etiologies. Of cerebral hemorrhages, there were 6 aneurysmal, 6 arteriovenous malformation, 5 hypertensive, 2 substance abuse, 3 trauma, and 21 other etiologies. Across the entire cohort, 35,054 variants were found within the 66 genes identified from the literature. Filtration identified 48 potentially damaging variants across 30 genes in 44 patients (20 cryptogenic and 21 other: 12 patent foramen ovale, 5 vasculitis, 4 dissection, 4 cardioembolic) that were absent in controls. Conclusion: WES is a powerful tool that can be used to uncover potential genetic mechanisms in the young stroke population. An improved understanding of etiologies would improve diagnostics and pave the way for new preventive and therapeutic approaches, thus improving the overall care of young stroke patients.

Background and Aims: Metabolic dysfunction–associated steatotic liver disease affects about a third of adults worldwide and is projected soon to be the leading cause of liver cirrhosis. It occurs when fat accumulates in hepatocytes and can progress to metabolic dysfunction–associated steatohepatitis, liver cirrhosis, and HCC. Metabolic dysfunction–associated steatotic liver disease pathogenesis is believed to involve a combination of genetic and environmental risk factors. Single nucleotide polymorphisms have been implicated, but non-syndromic monogenic causes are lacking. Approach and Results: We identified a novel genetic variant in a familial case of metabolic dysfunction–associated steatohepatitis and performed deep variant functional analysis, including protein modeling, dynamics, and cell-based assays to assess molecular mechanisms of dysfunction and altered cellular signaling. We analyzed exome sequencing data of 3904 individuals with steatotic liver disease (SLD) to identify additional cases and establish the link between specific gene variants and SLD diagnosis. We discovered and functionally validated the NM_000245.4:c.3505A>T; p.(Ile1169Phe) variant in the MET (mesenchymal-epithelial transition) kinase domain as a monogenic cause of SLD. Subsequently, we detected additional ultra-rare, previously uninterpreted, and likely deleterious variants in MET from screening sequencing data. Among individuals with confirmed SLD based on electronic record review, 1.1% (45/3904) had rare predicted deleterious MET variants. Eight of 45 (17.7%) individuals had predicted deleterious variants in the MET kinase domain confirmed to be functionally like the familial case variant. Conclusions: We report the first germline nonmalignant rare MET -driven disease, a monogenic form of SLD.

Abstract Background Benign breast disease (BBD) increases breast cancer (BC) risk progressively for women diagnosed with nonproliferative change, proliferative disease without atypia (PDWA), and atypical hyperplasia (AH). Leveraging data from 18 704 women in the Mayo BBD Cohort (1967-2013), we evaluated temporal trends in BBD diagnoses and how they have influenced associated BC risk over 4 decades. Methods BC risk trends associated with BBD were evaluated using standardized incidence ratios (SIRs) and age–period–cohort modeling across 4 eras—premammogram (1967-1981), precore needle biopsy (CNB) (1982-1992), transition to CNB (1993-2001), and CNB era (2002-2013). Results With a median follow-up of 15.8 years, 9.9% of women were diagnosed with BC (invasive and/or DCIS). From the premammogram era to the CNB era, we observed a significant increase in BC risk, rising from an SIR of 1.61 to 1.99. The proportion of proliferative BBD diagnoses (PDWA or AH) increased markedly over time (28.1%-49.7%), as did the proportion of DCIS events (11%-28%; χ2 P &lt; .001). Within specific BBD categories, the risk of invasive BC increased modestly. Conclusions Absolute risk of BC within BBD categories remained stable, but the relative risk of BC after BBD increased over time due to notable increases in higher risk BBD lesions, specifically PDWA and AH. These findings illustrate how evolving screening practices have changed the risk profile of BBD and should inform management strategies for patients with BBD in modern clinical settings.

Background: Controversy exists around the optimal timing of resection of nevus sebaceous (NS). The authors aim to determine optimal timing of NS resection and identify predictors of surgical outcomes and secondary intralesional neoplasms. Methods: Retrospective chart review of all patients with biopsy-proven NS diagnosis treated at the authors' institution between 1987 and 2024. Results: A total of 632 patients (317 females) underwent biopsy at a median age of 17 (interquartile range 11.7–36.9) years. Benign secondary intralesional neoplasms were found in 67 (10.6%) patients, with syringocystadenoma papilliferum being the most common. Malignant secondary intralesional neoplasms were diagnosed in 62 (9.8%) patients, with basal cell carcinoma being the most common. The incidence of secondary intralesional neoplasms was 3.9%, 24.4%, 36.05%, and 54%, in patients aged 0 to 20, 20 to 40, 40 to 60, and 60 to 80 years, respectively (P<0.001). Age and NS area were associated with an increased risk of developing benign and malignant intralesional neoplasms (P=0.01). Younger patients were more likely to need general anesthesia for excision (median age 10.42 versus 17 years, P<0.001). Surgical complications occurred in 10 cases, and 6 patients required unanticipated revision surgery. The risk of developing secondary intralesional neoplasms was similar across different NS anatomic regions (log-rank, P=0.09). Conclusion: Surgical excision of NS is safe and has an acceptable risk profile. The findings of this study support our historic practice of NS excision before puberty (before the accelerated growth phase) to reduce the risk of developing secondary intralesional neoplasms.

Objective: The pattern, rate, and natural history of bone flap resorption following cranioplasty with frozen, autologous bone flap has not been fully defined. The authors sought to quantify the progression and natural history of bone flap resorption. Methods: Patients who had craniectomy and delayed cranioplasty with stored, frozen bone flap between 2012 and 2022 were included in this study. Results: Ninety patients (63% male) were included, with a median age of 44.8 years (range: 4.2–84.4 y) at the time of autologous bone flap cranioplasty. Delayed, autologous cranioplasty occurred at a median time of 29.5 days (range: 2 d–10 y) from the index craniectomy. The median follow-up was 16.6 months (range: 3.4–85.4 mo). Radiographically quantifiable bone flap resorption occurred in 50 patients (56%). During the follow-up, the average percentage volume loss was 17%, with a nonlinear pattern of resorption. Following delayed, autologous cranioplasty, 11 patients had clinically significant bone flap resorption requiring secondary alloplastic cranioplasty at a median time of 13.8 months (range: 5.9–57.2 mo), with a mean percentage volume loss of 61%. Younger age was a risk factor for bone flap resorption (P < 0.05), whereas active smoking, presence of comorbidities, and number of days of bone flap storage were not risk factors for bone flap resorption. Penalized B-spline regression analysis showed that bone flap resorption followed a nonlinear pattern. Conclusion: Radiographically quantifiable bone flap resorption occurred in about 56% of patients following delayed autologous cranioplasty. Resorption followed a non-linear pattern. Young age is a risk factor for bone flap resorption.

Abstract Background Most breast biopsies are diagnosed as benign breast disease, with 1.5- to 4-fold increased breast cancer risk. Apart from pathologic diagnoses of atypical hyperplasia, few factors aid in breast cancer risk assessment of these patients. We assessed whether a 313–single nucleotide variation (formerly single-nucleotide polymorphism) polygenic risk score stratifies risk of benign breast disease patients. Methods We pooled data from 5 Breast Cancer Association Consortium case-control studies (mean age = 59.9 years), including 6706 participants with breast cancer and 8488 participants without breast cancer. Using logistic regression, we estimated breast cancer risk associations by self-reported benign breast disease history and strata of polygenic risk score, with median polygenic risk score category among women without benign breast disease as the referent. We assessed interactions and mediation of benign breast disease and polygenic risk score with breast cancer risk. Results Benign breast disease history was associated with increased breast cancer risk (odds ratio [OR] = 1.48, 95% confidence interval [CI] = 1.37 to 1.60; P &lt; .001). Polygenic risk score increased breast cancer risk, irrespective of benign breast disease history (Pinteraction = .48), with minimal evidence of mediation of either factor by the other. Women with benign breast disease and polygenic risk score in the highest tertile had more than twofold increased odds of breast cancer (OR = 2.73, 95% CI = 2.41 to 3.09), and those with benign breast disease and polygenic risk score in the lowest tertile experienced reduced breast cancer risk (OR = 0.79, 95% CI = 0.70 to 0.91) compared with the referent group. Women with benign breast disease and polygenic risk score in the highest decile had a 3.7-fold increase (95% CI = 3.00 to 4.61) compared with those with median polygenic risk score without benign breast disease. Conclusion Breast cancer risks are elevated among women with benign breast disease and increase progressively with polygenic risk score, suggesting that optimal combinations of these factors may improve risk stratification.

BACKGROUND: There has been a shift in the treatment of fistula-in-ano toward a focus on the preservation of continence while simultaneously eradicating the disease. The utilization of radially emitting diode laser catheters to ablate fistula tracks has been described since 2011, with heterogenous studies publishing success rates ranging from 20% to 89%. OBJECTIVE: Present the authors’ experience managing solitary transsphincteric fistulas of cryptoglandular origin with a radially emitting diode laser. DESIGN: Prospective nonrandomized single center trial with 12-month follow-up. SETTINGS: Quaternary referral academic health care center. PATIENTS: Forty-six adults with transsphincteric fistula-in-ano. INTERVENTIONS: All patients underwent radially emitting diode laser closure of fistula-in-ano. MAIN OUTCOME MEASURES: Clinical healing and fistula recurrence. RESULTS: Forty-six patients with a median age of 48 years (range, 26–85) underwent diode laser closure. Most were men (n = 28; 60%). Twenty-four patients (52%) had previous fistula repairs with a median of 1.5 (range, 1–7) repairs per patient. All were followed for 12 months. Successful closure after 1 laser treatment occurred in 43% of patients. Thirteen of 26 failure cases (50%) were able to undergo a delayed fistulotomy secondary to an anatomic change with the fistula becoming more superficial, moving out of the internal sphincter muscle after laser ablation, all of which healed. No patients experienced new or worsening (preexisting) fecal incontinence. Two patients (8%) continued treatment for abscesses/fistula branching. One patient (3%) experienced migration of the fistula from the base of the left labia to the introitus of the vagina and 1 experienced recurrence and worsening of their disease process with subsequent involvement of the coccyx (previous deep postanal space abscess). LIMITATIONS: Limitations to our study include its nonrandomized prospective nature, single center and surgeon experience, and small patient sample size. CONCLUSIONS: Radially emitting diode laser closure is a continence-preserving option to consider when treating transsphincteric fistula-in-ano. When the procedure fails, it does not fail poorly (open wounds, retracted flaps, incontinence, etc) and can be repeated. Complications can include abscess formation and fistula migration to adjacent anatomic locations (vagina). Even if unsuccessful, after treatment, the fistula can anatomically migrate distally, becoming more superficial and thus providing the opportunity to proceed with a delayed fistulotomy. See Video Abstract. CIERRE DE FÍSTULA ANAL TRANSESFINTÉRICA CON LÁSER DE DIODO DE EMISIÓN RADIAL ANTECEDENTES: Ha habido un cambio en el tratamiento de la fístula anal hacia un enfoque en la preservación de la continencia y al mismo tiempo en la erradicación de la enfermedad. La utilización de catéteres láser de diodo de emisión radial para extirpar los trayectos de las fístulas se describe desde el 2011 y estudios heterogéneos publican tasas de éxito que oscilan entre el 20 y el 89%. OBJETIVO: Presentar nuestra experiencia en el manejo de fístulas transesfinterianas solitarias de origen criptoglandular con láser de diodo de emisión radial. DISEÑO: Ensayo prospectivo, no aleatorizado, unicéntrico, con seguimiento de 12 meses. LUGARES: Centro de salud académico de referencia Cuaternario. PACIENTES: Cuarenta y seis adultos con fístula anal transesfintérica. INTERVENCIONES: Todos se sometieron a cierre de fístula anal con láser de diodo de emisión radial. MEDIDAS PRINCIPALES DEL RESULTADO: Curación clínica y recurrencia de la fístula. RESULTADOS: Cuarenta y seis pacientes con una mediana de edad de 48 años (rango, 26-85) se sometieron a cierre con láser de diodo. La mayoría eran hombres (n=28/60%). Veinticuatro (52%) habían tenido reparaciones previas de fístulas con una mediana de 1,5 (rango, 1-7) reparaciones por paciente. Todos fueron seguidos durante 12 meses. El cierre exitoso después de un tratamiento con láser se produjo en el 43%. Trece de 26 fracasos (50%) pudieron someterse a una fistulotomía tardía debido a un cambio anatómico en el que la fístula se volvió más superficial y salió del músculo del esfínter interno después de la ablación con láser, y todas sanaron. Ningún paciente experimentó incontinencia fecal nueva o que empeoró (preexistente). Dos (8%) continuaron tratamiento por abscesos/ramificación de fístulas. Una (3%) experimentó migración de la fístula desde la base de los labios izquierdos hasta el introito de la vagina y 1 experimentó recurrencia y empeoramiento de su proceso patológico con posterior afectación del cóccix (absceso previo en el espacio postanal profundo). LIMITACIONES: Las limitaciones de nuestro estudio incluyen su naturaleza prospectiva no aleatoria, la experiencia de un solo centro y del cirujano y el tamaño pequeño de la muestra de pacientes. CONCLUSIONES: El cierre con láser de diodo de emisión radial es una opción para preservar la continencia a considerar cuando se trata la fístula en el ano transesfintérica. Cuando el procedimiento fracasa, no fracasa mal (heridas abiertas, colgajos retraídos, incontinencia, etc.), y puede repetirse. Las complicaciones pueden incluir formación de abscesos y migración de fístulas a ubicaciones anatómicas adyacentes (vagina). Incluso si no tiene éxito, después del tratamiento la fístula puede migrar anatómicamente distal volviéndose más superficial y brindando así la oportunidad de proceder con una fistulotomía retrasada. (Traducción—Yesenia Rojas-Khalil)