Citations

Abstract Disclosure: J. Saini: None. R. Nathani: None. S. Singh: None. V. Fell: None. E. Atkinson: None. S. Achenbach: None. S. Khosla: None. I. Bancos: None. Background: Previous studies reported that both cortisol secretion and bone metabolism biomarkers follow a circadian pattern of secretion. Patients with mild autonomous cortisol secretion (MACS) demonstrate an increased risk of fractures. As most patients with MACS do not have increased cortisol production, we hypothesized that abnormal circadian cortisol secretion is associated with impaired bone metabolism. Objective: To compare the circadian secretory pattern of bone metabolism biomarkers in relation to cortisol circadian secretion in patients with MACS versus referent subjects. Methods: We conducted a pilot cross-sectional study of patients with MACS and referent subjects. MACS was diagnosed in patients with adrenal adenomas based on an abnormal 1 mg dexamethasone suppression test (cortisol >1.8 mcg/dL). Referent subjects with available abdominal imaging within 5 years and adrenal disorder were recruited from the community. Participants were admitted to the clinical research unit for blood sampling every 2 hours over 24h period. Measurements included total and free cortisol, calcium, parathyroid hormone (PTH), osteocalcin, amino-terminal propeptide type 1 collagen (PINP), and carboxy-terminal telopeptide of type 1 collagen (CTX). Subjects with disorders or medication affecting bone metabolism were excluded. Time periods of blood draw were categorized into the morning (6 to 12 hours), afternoon (14-18 hours) and night (20-2 hours). Delta (morning measurements/afternoon measurements) was calculated. Results: Subjects included 12 patients with MACS (median age 57, IQR 48-67, 83% women) and 10 referent subjects (median age 57, IQR 50-63, 80% women). The 24-hour area under the curve for total (10342 vs 9090 mcg/dL, p=0.468) and free cortisol (437 vs 329 mcg/dL, p=0.086) was no different between patients with MACS and referent subjects. However, the mean night total (6.7 vs 4.3 mcg/dL, p=0.056) and free cortisol (0.2 vs 0.1 mcg/dL, p=0.035) was higher in MACS vs referent subjects. The area under the curve for calcium, phosphorus, CTX, osteocalcin and PINP were similar between patients and referent subjects, however, the area under the curve for PTH was higher in patients vs referent subjects (mean 64179 vs 42602 pg/mL, p=0.021). Both delta total cortisol (mean 8.6 vs 5.5, p=0.01) and delta PTH (mean -1.5 vs 4.2, p=0.051) was higher in referent subjects vs patients with MACS. Conclusion: When compared to referent subjects, patients with MACS have similar 24-hour cortisol production but demonstrate an increase in night-time cortisol secretion and a blunting of diurnal cortisol (lower morning/afternoon cortisol). Patients with MACS have higher PTH production overall, as well as an abnormal diurnal PTH secretion. Noted abnormalities in PTH may contribute to the MACS-associated impairment in bone health. Presentation: Thursday, June 15, 2023

Abstract Disclosure: J. Saini: None. R. Nathani: None. S. Singh: None. K. Thangamuthu: None. M. Suresh: None. C. Zhang: None. A.L. Ebbehøj: None. M. Thomas: None. V. Fell: None. E. Atkinson: None. S. Achenbach: None. N. Stricker: None. I. Bancos: None. Introduction: While patients with overt Cushing syndrome are reported to have impaired cognition, the impact of milder, long-standing hypercortisolism on cognition is incompletely characterized. Objective: To determine the impact of MACS on cognition as compared to age, sex, and education-matched referent subjects. Methods: We conducted a single-center cross-sectional study of adults with MACS and referent subjects. MACS was defined as serum cortisol>1.8 mcg/dL after 1 mg dexamethasone suppression test (DST) in patients with adrenal incidentalomas. Referent subjects were included if they had abdominal imaging and had no adrenal disorders. Exclusion criteria were malignancy and exogenous glucocorticoid use within 1 year. All participants underwent a cognitive evaluation using the NIH Toolbox Cognition Battery between 1/2019 to 7/2022. NIH Toolbox assesses 8 cognitive domains using 7 tests and yields 3 composite scores: fluid cognition (executive function, episodic memory, cognitive flexibility, working memory, and processing speed), crystallized cognition (language and vocabulary), and total composite cognition (composite of all). Results are given in fully corrected T scores (adjusted for age, sex, race, and education) with an average of 50 and a standard deviation (SD) of 10. A subgroup analysis was performed based on DST cortisol. The Kruskal-Wallis test was used to compare scores between groups. Results: A total of 94 patients with MACS (median age 57.2 years, IQR 47.8-66.5, 70% women) and 94 referent subjects (median age 58 years, IQR 49.1-66.4, 70% women) were included. The median post-DST cortisol in patients with MACS was 3.3 mcg/dL (IQR, 2.4-6.2). The mean (SD) total composite T-score was lower in patients with MACS vs referent subjects (51 (9.1) vs 56.3 (9.3), P<0.001). Patients with MACS demonstrated lower mean fluid composite T-score when compared to referent subjects (49.5 (10.4) vs 56.9 (9.7), P<0.001). However, mean crystallized composite T-scores were similar in patients with MACS and referent subjects (52.3 (8.1) vs 53.9 (9.6), P=0.342). A subgroup analysis of patients with post-DST cortisol <3 mcg/dL (n=40) vs patients with post-DST cortisol >3 mcg/dL (n=54) did not show any differences in the total, fluid, or crystalized composite scores. Conclusion: Patients with MACS demonstrate lower cognitive performances than a referent group suggesting MACS has a subtle impact on cognitive functioning. The pattern of cognitive impairment in patients with MACS is similar to that seen with normal cognitive aging: impaired fluid cognitions and unaffected crystallized cognition). Cognitive performance did not differ based on the degree of MACS suggesting that in the absence of overt features of hypercortisolism, the degree of MACS is less important than the presence of MACS. Presentation: Thursday, June 15, 2023

Abstract Disclosure: L. Rahimi: None. A. Kittithaworn: None. R. Gregg Garcia: None. J. Saini: None. P. Dogra: None. E. Atkinson: None. S. Achenbach: None. A. Kattah: None. I. Bancos: None. Objective: Patients with mild autonomous cortisol secretion (MACS) have been reported to have a higher prevalence of chronic kidney disease (CKD), possibly due to the direct effect of hypercortisolism on kidney function and indirect effect of MACS-associated cardiovascular comorbidities, such as diabetes, hypertension, obesity, and dyslipidemia. Limited studies suggest improvement of kidney function following adrenalectomy in patients with MACS. In this study, we aimed to assess the factors associated and the degree and timing of change in kidney function post adrenalectomy in patients with MACS or nonfunctioning adrenal adenoma (NFA). Methods: We conducted a retrospective single-center study and included adult patients with MACS or NFA diagnosed based on a post-dexamethasone cortisol cutoff of 1.8 mcg/dL, who underwent adrenalectomy between 1999-2022. The change in estimated glomerular filtration rate (eGFR) before and up to 3.5 years after adrenalectomy was defined as the primary outcome. Demographics and comorbidities were included in univariable and multivariable analyses. Results: We included 155 (76.0%) patients with MACS and 49 (24.0%) patients with NFA treated with adrenalectomy. The proportion of women was high in both MACS and NFA (71.6% vs 69.4%, p=0.77), however, patients with MACS were older (median age 59.2 vs 54.6 years in NFA, p=0.05). The prevalence of hypertension was higher in MACS vs NFA (71.0% vs 53.1%, p=0.02), while the prevalence of diabetes (25.2% vs 28.6%, p=0.89), dyslipidemia (47.7% vs 46.9%, p=0.92), smoking (74.2% vs 68.9%, p=0.49) and obesity (median BMI 30.4 vs 31.8 kg/m2, p=0.35) was similar between the two groups. Prior to adrenalectomy, patients with MACS had lower eGFR (median 84.4 vs 89.2 ml/min/1.73m2, p=0.09) and a higher prevalence of CKD stage ≥ 3 (16.1% vs 8.2%, p= 0.16). In patients with MACS, after an initial decline of eGFR within 6 months post adrenalectomy (mean decrease 5.3 ml/min/1.73m2), eGFR increased by a mean of 4.9 points at 18-30 months, and by a mean of 8.1 points at 30-42 months post-adrenalectomy (p<0.01). Patients with NFA followed a similar eGFR change trend (p=NS). When comparing post-adrenalectomy delta eGFR in patients with MACS vs NFA, no significant differences were found. After adjusting for age, sex, pre-adrenalectomy eGFR, patient group, hypertension, antihypertensive therapy, and diabetes, there were still significant changes in eGFR over time. In a multivariable analysis, younger age (est -031, p<0.001) and lower pre-adrenalectomy eGFR (est-0.27, p=0.001) were associated with kidney function improvement post-adrenalectomy. Conclusion: Patients with MACS and NFA demonstrate improvement of eGFR over the 3.5 years of follow up post-adrenalectomy. The factors that are associated with improvement of eGFR are lower eGFR before surgery, younger age at time of adrenalectomy and longer follow up post adrenalectomy. Presentation: Friday, June 16, 2023

Abstract Objective Adrenal adenomas are commonly encountered in clinical practice. To date, population-based data on their impact on cognition, mental health, and sleep are lacking. We aimed to study possible associations between adrenal adenomas and dementia, psychiatric or sleep disorders. Design Population-based cohort study, Olmsted County, MN, 1995-2017. Methods Patients with adrenal adenoma and absent overt hormone excess were age- and sex-matched 1:1 to a referent person without adrenal adenoma. Outcomes were baseline and incident diagnoses of dementia, psychiatric or sleep disorders, assessed using ICD codes. Results Of 1004 patients with adrenal adenomas, 582 (58%) were women, and median age at diagnosis was 63 years. At baseline, and after adjusting for age, sex, education, BMI, and tobacco use, patients with adenoma had higher odds of depression (adjusted odds ratio, aOR: 1.3, 95% CI, 1.1-1.6), anxiety (aOR: 1.4, 95% CI, 1.1-1.8), and substance abuse (aOR: 2.4, 95% CI, 1.7-3.4) compared to referents. During a median follow-up of 6.8 years, and after adjusting for age, sex, socioeconomic status, BMI, tobacco, and substance abuse, patients demonstrated a higher risk of psychiatric and sleep disorders [adjusted hazard ratio (95% CI)]: depression [1.7 (1.3-2.2)], anxiety [1.4, CI (1.1-1.7)], insomnia [1.4 (1.0-1.9)], sleep-related breathing disorders [1.5 (1.1-1.9)], hypersomnias [2.1 (1.0-4.2)], parasomnias [2.1 (1.0-4.2)], and sleep-related movement disorders [1.5 (1.0-2.1)], but not dementia. Conclusions Patients with adenomas demonstrate a higher incidence of psychiatric and sleep disorders, possibly due to the underlying subtle increase in cortisol secretion.

Significance Statement Accurate diagnosis of a patient's underlying cause of CKD can influence management and ultimately overall health. The single-arm, interventional, prospective Renasight Clinical Application, Review, and Evaluation study assessed the utility of genetic testing with a 385 gene kidney disease panel on the diagnosis and management of 1623 patients with CKD. Among 20.8% of patients who had positive genetic findings, half resulted in a new or reclassified diagnosis. In addition, a change in management because of genetic testing was reported for 90.7% of patients with positive findings, including treatment changes in 32.9%. These findings demonstrate that genetic testing has a significant effect on both CKD diagnosis and management. Background Genetic testing in CKD has recently been shown to have diagnostic utility with many predicted implications for clinical management, but its effect on management has not been prospectively evaluated. Methods Renasight Clinical Application, Review, and Evaluation RenaCARE (ClinicalTrials.gov NCT05846113) is a single-arm, interventional, prospective, multicenter study that evaluated the utility of genetic testing with a broad, 385 gene panel (the Renasight TM test) on the diagnosis and management of adult patients with CKD recruited from 31 US-based community and academic medical centers. Patient medical history and clinical CKD diagnosis were collected at enrollment. Physician responses to questionnaires regarding patient disease categorization and management were collected before genetic testing and 1 month after the return of test results. Changes in CKD diagnosis and management after genetic testing were assessed. Results Of 1623 patients with CKD in 13 predefined clinical disease categories (ages, 18–96; median, 55 years), 20.8% ( n =338) had positive genetic findings spanning 54 genes. Positive genetic findings provided a new diagnosis or reclassified a prior diagnosis in 48.8% of those patients. Physicians reported that genetic results altered the management of 90.7% of patients with a positive genetic finding, including changes in treatment plan, which were reported in 32.9% of these patients. Conclusions Genetic testing with a CKD-focused 385 gene panel substantially refined clinical diagnoses and had widespread implications for clinical management, including appropriate treatment strategies. These data support the utility of broader integration of panels of genetic tests into the clinical care paradigm for patients with CKD. Clinical Trial registry name and registration number ClinicalTrials.gov, NCT05846113.

ObjectivesMicrovascular free tissue transfer is routinely used for reconstructing midface defects in patients with malignancy, however, studies regarding reconstructive outcomes in invasive fungal sinusitis (IFS) are lacking. We aim to describe outcomes of free flap reconstruction for IFS defects, determine the optimal time to perform reconstruction, and if anti‐fungal medications or other risk factors of an immunocompromised patient population affect reconstructive outcomes.MethodsRetrospective review of reconstruction for IFS (2010–2022). Age, BMI, hemoglobin A1c, number of surgical debridements, and interval from the last debridement to reconstruction were compared between patients with delayed wound healing versus those without. Predictor variables for delayed wound healing and the effect of time on free flap reconstruction were analyzed.ResultsTwenty‐seven patients underwent free flap reconstruction for IFS. Three patients were immunocompromised from leukemia and 21 had diabetes mellitus (DM). Patients underwent an average of four surgical debridements for treatment of IFS. The interval from the last IFS debridement to flap reconstruction was 5.58 months (±5.5). Seven flaps (25.9%) had delayed wound healing. A shorter interval of less than 2 months between the last debridement for IFS and reconstructive free flap procedure was associated with delayed wound healing (Fisher Exact Test p = 0.0062). Other factors including DM, BMI, HgA1c, and bone reconstruction were not associated with delayed wound healing.ConclusionPatients with maxillectomy defects from IFS can undergo microvascular‐free flap reconstruction with good outcomes while on anti‐fungal medication. Early reconstruction in the first 2 months after the last IFS debridement is associated with delayed wound healing.Level of Evidence4 Laryngoscope, 134:1642–1647, 2024

Background Studies during the COVID-19 pandemic have demonstrated an association between COVID-19 virus infection and the development of acute ischemic stroke, particularly large vessel occlusion (LVO). Studying the characteristics and immunohistochemistry of retrieved stroke emboli during mechanical thrombectomy for LVO may offer insights into the pathogenesis of LVO in COVID-19 patients. We examined retrieved COVID-19 emboli from the STRIP, EXCELLENT, and RESTORE registries and compared their characteristics to a control group. Methods We identified COVID-positive LVO patients from the STRIP, RESTORE, and EXCELLENT studies who underwent mechanical thrombectomy. These patients were matched to a control group controlling for stroke etiology based on Trial of Org 10172 in Acute Stroke Treatment criteria. All clots were stained with Martius Scarlet Blue (MSB) along with immunohistochemistry for interleukin-6 (IL-6), C-reactive protein (CRP), von Willebrand factor (vWF), CD66b, fibrinogen, and citrullinated Histone H3. Clot composition was compared between groups. Results Nineteen COVID-19-positive patients and 38 controls were included. COVID-19-positive patients had a significantly higher percentage of CRP and vWF. There was no difference in IL-6, fibrin, CD66b, or citrullinated Histone H3 between groups. Based on MSB staining, there was no statistically significant difference regarding the percentage of red blood cells, white blood cells, fibrin, and platelets. Conclusions Our study found higher concentrations of CRP and vWF in retrieved clots of COVID-19-positive stroke patients compared to COVID-19-negative controls. These findings support the potential role of systemic inflammation as indicated by elevated CRP and endothelial injury as indicated by elevated vWF as precipitating factors in thrombus development in these patients.

ABSTRACT Infections due to nontuberculous mycobacteria (NTM) continue to increase in prevalence, leading to problematic clinical outcomes. Omadacycline (OMC) is an aminomethylcycline antibiotic with FDA orphan drug and fast-track designations for pulmonary NTM infections, including Mycobacteroides abscessus (MAB). This multicenter retrospective study across 16 U.S. medical institutions from January 2020 to March 2023 examined the long-term clinical success, safety, and tolerability of OMC for NTM infections. The cohort included patients aged ≥18 yr, who were clinically evaluable, and` had been treated with OMC for ≥3 mo without a previous diagnosis of cystic fibrosis. The primary outcome was 3 mo clinical success, with secondary outcomes including clinical improvement and mortality at 6- and 12 mo, persistence or reemergence of infection, adverse effects, and reasons for OMC utilization. Seventy-five patients were included in this analysis. Most patients were female (48/75, 64.0%) or Caucasian (58/75, 77.3%), with a median (IQR) age of 59 yr (49–67). Most had NTM pulmonary disease (33/75, 44.0%), skin and soft tissue disease (19/75, 25.3%), or osteomyelitis (10/75, 13.3%), and Mycobacterium abscessus (60/75, 80%) was the most commonly isolated NTM pathogen. The median (IQR) treatment duration was 6 mo ( 4 – 14 ), and the most commonly co-administered antibiotic was azithromycin (33/70, 47.1%). Three-month clinical success was observed in 80.0% (60/75) of patients, and AEs attributable to OMC occurred in 32.0% (24/75) of patients, leading to drug discontinuation in 9.3% (7/75).

Abstract Background The racial, ethnic and sex compositions of a study population may impact the clinical performance of a biomarker. In a prospective clinical study to evaluate biomarkers for asthmatic and allergic conditions in a large medical center in the upper Midwest, a largely White-alone patient population was encountered. Using several outreach strategies, potential eligible patients were contacted to enroll in a biomarker clinical study and to provide blood specimens. The patient demographics between the eligible candidates and the enrolled participants were compared. The analysis was carried out to understand the likelihood of enrollment in different race, ethnicity, and sex groups; and to identify factors that contribute to selection biases in enrolled cohorts. Methods Patients with eligible asthma and allergic conditions were selected based on relevant diagnostic codes in their electronic medical records, verified by clinical research coordinator. In accordance with Institutional Review Board approval, eligible patients were contacted via their electronic healthcare portal or with a phone call. The study information was also posted in an internal classified ad as an additional outreach strategy. Interested participants were then contacted a second time to complete consent. Upon consent, participants were considered as “enrolled”. Demographics information including sex, race, ethnicity, and age were de-identified for comparison analysis. Results Among all eligible patients, a disproportionally low representation of Blacks, Asians, and Hispanics (“non-White” groups) was observed, relative to regional demographics (22.2% non-White groups, 2021 census) and higher asthma and allergy prevalence in the non-White groups. In eligible adult patients (>18 years old) with asthma, only 13.4% were from non-White racial and ethnic groups. In eligible pediatric asthma patients, a larger proportion at 24.1% were from American Indian, Asian, Black, or Hispanic groups. In patients with allergic conditions, 10.3% of the adult patients were from non-White only groups, compared to 21.9% in pediatric patients. Among all eligible patients, White-alone patients were more likely to enroll in the study compared to their counterparts from non-White groups, further skewing the racial and ethnic distribution in the enrolled cohorts. As a result, less than 10% of enrolled adult patients were from non-White background in both allergy and asthma cohorts. Among the enrolled pediatric asthma and allergy patients, 16.9% and 10.3% respectively were from non-White groups. We also identified sex and age dependent enrollment behavior across different study cohorts. In adult groups, there were more female eligible patients (allergy: 66.7% female; asthma: 66.7% female) than male patients. Female adult patients were significantly more likely to participate, thus constituting 79.6% and 75.8% of the enrolled allergy and asthma cohorts. In the pediatric groups, male patients represented a larger share of eligible patients (allergy: 58.6%; asthma 64.7%). Female pediatric patients were still more likely to participate in the study. Hence, male and female enrolled patients were closer to equal distribution (allergy: 50.0% male; asthma 59.7% male). Conclusion The non-even distribution of demographics in eligible patients contributed to biased distribution in enrolled patients. Existing outreach approaches were not effective in reversing enrollment rates in underrepresented racial and ethnic groups.