Mara, Kristin C

OBJECTIVES: Protein binding of valproate is variable in ICU patients, and the total valproate concentration does not predict the free valproate concentration, even when correcting for albumin. We sought to quantify valproate free concentration among ICU patients, identify risk factors associated with an increasing free valproate concentration, and evaluate the association between free valproate concentration with potential adverse drug effect. DESIGN: Retrospective multicenter cohort study. SETTING: Two academic medical centers. PATIENTS: Patients greater than or equal to 18 years of age with concomitant free and total valproate concentrations collected in the ICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Two-hundred fifty-six patients were included in the study, with a median age of 56 years (42–70) and 65% of patients were male. The median total valproate concentration was 53 µg/mL (38–70 µg/mL), the free valproate concentration was 12 µg/mL (7–20 µg/mL), and the free fraction was 23.6% (17.0–33.9%). Therapeutic discordance between the free and total valproate concentration occurred in 70% of patients. On multivariable analysis, increased free valproate concentration was associated with higher total valproate concentration (per 5 µg/mL increase, increase 1.72 µg/mL, 95% CI, 1.48–1.96) and lower serum albumin (per 1 g/dL decrease, increase 4.60 µg/mL, 95% CI, 2.71–6.49). There was no association between free valproate concentration and adverse effects. CONCLUSIONS: The valproate total and free concentration was discordant in the majority of patients (70%). Increased valproate free concentration was associated with hypoalbuminemia and total valproate concentration. Clinical decisions based on total valproate concentration may be incorrect for many ICU patients. Prospective, controlled studies are needed to confirm these findings and their clinical relevance.

ABSTRACT Background Studies have found that women with endometriosis have a higher risk of female sexual dysfunction (FSD). Aim To evaluate the relationship between self-reported endometriosis and FSD utilizing validated surveys. Methods A cross-sectional analysis was conducted among sexually active women aged 18–90 who presented to 3 Mayo Clinic sites from 2015 to 2021. FSD was determined utilizing a combined endpoint of Female Sexual Function Index score ≤ 26.55 and Female Sexual Distress Scale-Revised score ≥ 11. Associations between history of endometriosis and FSD were evaluated by fitting 3 multivariable logistic models and were stratified by menopause status. In the first model, the association was adjusted for age, BMI, race/ethnicity, marital status, and education. The second model adjusted for the variables in Model 1 and hormone therapy, hormonal contraceptive use, self-reported history of abuse within the last year, and co-morbidities including the history of diabetes, heart disease, hypertension, osteoporosis, and stroke. The third model adjusted for the variables in Model 1, Model 2, and anxiety, depression, relationship satisfaction, and SSRI/SNRI use. Outcomes The outcomes included self-reported endometriosis and female sexual dysfunction determined utilizing a combined endpoint of Female Sexual Function Index score ≤ 26.55 and Female Sexual Distress Scale-Revised score ≥ 11. Results Of 7118 patients (mean age 51.3), 92.2% were white, 78.4% were peri- or postmenopausal, 8.7% reported endometriosis history, and 57.2% met the criteria for FSD. Women with endometriosis were more likely to be overweight or obese, be smokers, have had a history of heart disease and osteoporosis, have had anxiety and depressed mood, have had a hysterectomy and bilateral salpingo-oophorectomy, and have used hormone therapy. Compared to those without endometriosis, women with endometriosis were significantly more likely to have FSD only among premenopausal women (74.2% vs 57.4%). Similarly, in multivariable analysis the relationship was only seen for premenopausal women in all 3 models (Model 1: OR 2.74 (95% CI 1.43–5.27); Model 2: OR 2.55 (95% CI 1.30–5.04); Model 3: OR 2.30 (95% CI 1.13–4.68)). Clinical Implications These findings highlight the opportunity for healthcare practitioners to evaluate sexual function in premenopausal women with endometriosis. For peri and postmenopausal women with endometriosis, the risk of FSD was lower than for premenopausal women with endometriosis. Strengths and Limitations This study analyzed the association between endometriosis and FSD in women by menopause status using validated tools that included a measure of distress associated with sexual dysfunction. Limitations include its cross-sectional design which does not allow for determination of the direction of this association. Conclusion The risk for FSD associated with endometriosis depends on menopause status. Endometriosis increased the odds of FSD only in premenopausal women.

Background and Aims: The impact of disease progression in NAFLD on liver outcomes remains poorly understood. We aimed to investigate NAFLD progression using longitudinal liver stiffness measurements (LSM) by serial magnetic resonance elastography (MRE) and the association with liver outcomes. Approach and Results: All adult patients with NAFLD who underwent at least two serial MREs for clinical evaluation at Mayo Clinic, Rochester, between 2007 and 2019 were identified from the institutional database. Progression and regression were defined based on LSM change of 19% above or below 19% of initial LSM, respectively, based on Quantitative Imaging Biomarker Alliance consensus. The association between change in LSM and liver‐related outcomes occurring after the last MRE was examined using time‐to‐event analysis. A total of 128 participants underwent serial MREs (53% female, median age 59 years). The median time between paired MREs was 3.4 (range 1–10.7) years. NAFLD progression (LSM = +0.61 kPa/year) was identified in 17 patients (13.3%). NAFLD regression (−0.40 kPa/year) occurred in 35 patients (27.3%). Stable LSM was noted in 76 participants (59.4%). In NAFLD without cirrhosis at baseline ( n = 75), cirrhosis development occurred in 14% of LSM progressors and 2.9% of non‐progressors ( p = 0.059) over a median 2.7 years of follow‐up from the last MRE. Among those with compensated cirrhosis at baseline MRE ( n = 29), decompensation or death occurred in 100% of LSM progressors and 19% of non‐progressors ( p < 0.001) over a median 2.5 years of follow‐up after the last MRE. Conclusions: Noninvasive monitoring of LSM by conventional MRE is a promising method of longitudinal NAFLD monitoring and risk estimation of liver‐related outcomes in NAFLD.

AbstractBackground and aimsNonalcoholic steatohepatitis (NASH) is associated with metabolic conditions that increase the risk of de novo malignancy following transplant. Patients often have more than one underlying liver disease, which could change the risk of de novo malignancy. This study assessed the incidence of NASH overlap and its effect on de novo malignancy in liver transplant recipients.MethodsData was analyzed from the United Network for Organ Sharing database for all liver transplant recipients from 1997 to 2017 for NASH alone or in combination with another liver disease.ResultsThere is an increasing prevalence of NASH overlap. Of the 98,679 patients included in the analysis, 1238 had a de novo malignancy identified (7.4% by 5 years post‐transplant). The cumulative incidence of de novo malignancy increases in primary sclerosing cholangitis (PSC)/NASH overlap after 5 years and was increased in alcohol‐related liver disease (ALD)/NASH through 10 years compared to ether disease alone. NASH overlaps with “other” diseases experience a cumulative incidence similar to NASH and not the “other” disease. An increased risk of de novo solid organ malignancy was associated with older age, male gender, previous malignancy, and multiorgan transplant.ConclusionThe prevalence of liver transplant recipients with NASH overlap is increasing. These patients may experience different long‐term outcomes than patients with either diagnosis alone. De novo malignancy risk can be influenced by multiple factors and metabolic comorbidities. Further study of patients with overlap diagnoses is important moving forward to guide individualized care and cancer screening programs.

Abstract Introduction Diabetes mellitus in kidney transplant recipients is a risk factor for cardiovascular events and premature death. Sodium‐glucose cotransporter 2 inhibitors (SGLT2i) are increasingly used in nontransplant populations to improve diabetes control and cardiovascular and renal benefits. Limited literature exists regarding the safety and efficacy of these agents in renal transplant recipients. Methods We retrospectively reviewed all kidney transplant recipients within our health system who were prescribed a SGLT2i after transplantation for diabetes. The safety, tolerability, and effectiveness of SGLT2i were analyzed. Results Thirty‐nine kidney transplant recipients were initiated on SGLT2i therapy, twenty‐seven of which remained on therapy for at least 1 year. Ten (25%) patients experienced an adverse event while on a SGLT2i, with urinary tract infections (UTI) being the most common. Seventeen patients (43%) discontinued the SGLT2i at the time of chart review, most commonly due to cost and kidney function decline. The median [IQR] hemoglobin A1c (HbA1c) at SGLT2i initiation of 8.4% [7.8–9.2] decreased to 7.5% [6.8–8.0%] after 3 months and 7.5% [6.5–7.9] after 12 months. No meaningful change in kidney function or tacrolimus exposure was observed. Conclusion SGLT2i may be a safe and effective treatment for diabetes in kidney transplant recipients. Cost is a barrier to SGLT2i therapy, and UTIs were the most frequently encountered adverse events in this cohort. More studies are needed to understand the safety profile and determine the effect of SGLT2i on diabetes‐related comorbidities among kidney transplant recipients.

Objective We characterize the most recent natural history of necrotizing enterocolitis (NEC), as this is an essential first step in guiding the prevention and treatment of this disease in the present day. Study Design We performed a retrospective cohort study of neonates who were born at 23 to 29 weeks' gestation and birth weight <1,500 g who received care from the Pediatrix Medical Group between 2004 and 2019. We assessed the incidence of medical and surgical NEC and the patterns of initial antibiotic treatment to develop a contemporary cohort for further analysis. Among patients discharged between 2015 and 2019, we characterized the stage-specific risk factors for patients diagnosed with medical or surgical NEC, as well as patterns of disease onset, progression, biomarkers, and outcomes. We used the same approach to characterize patients diagnosed with suspected NEC. Results Among 34,032 patients in the contemporary cohort, 1,150 (3.4%) were diagnosed with medical NEC and 543 (1.6%) were diagnosed with surgical NEC. The temporal pattern of disease onset was different for medical and surgical NEC, with gestational age– and birth weight–specific risk disparities emerging earlier in surgical NEC. Thirty-day mortality was much greater among surgical NEC patients (medical NEC 16.4% vs. surgical NEC 43.0%), as were rates of various in-hospital and long-term outcomes. Suspected NEC was diagnosed in 1,256 (3.7%) patients, among whom risk factors and disease onset, progression, and outcomes closely resembled those of medical NEC. Conclusion Analyzing data from a contemporary cohort enabled us to characterize the current, stage-specific natural history of NEC, including novel insights into suspected NEC. Future studies could leverage this cohort to characterize how specific patient characteristics, care processes, or biomarkers may influence or predict disease outcomes. Key Points

Abstract The reduced-intensity conditioning regimen, fludarabine and melphalan, is frequently used in allogeneic hematopoietic stem cell transplantation (HSCT). Melphalan and the active metabolite of fludarabine, F-ara-A, are excreted via the kidneys. Existing methods to assess clearance in this setting are based on serum creatinine, which has known limitations for glomerular filtration rate (GFR) estimation in patients with malignancy. Measured GFR (mGFR) may better predict drug dosing to mitigate toxicity and increase the chances of successful engraftment. The primary objective of this study was to assess the association between mGFR and risk for nonrelapse mortality (NRM) in patients who have undergone allogeneic HSCT receiving conditioning with fludarabine and melphalan. In the 109 included patients, mGFR &lt;65 mL/min/1.73 m2 predicted a significantly higher rate of overall NRM (hazard ratio [HR], 2.13; 95% confidence interval [CI], 1.03-4.35; P = 04) and 1-year incidence of infection (HR, 2.63; 95% CI, 1.54-4.55; P &lt; .001) in addition to a significantly lower 2-year survival (P = .019). Kidney function estimated via estimated GFR (eGFR) and estimated creatinine clearance did not correlate with posttransplant outcomes. These results suggest that mGFR is a promising approach for assessing clearance in patients who have undergone allogeneic HSCT and may be preferred to standard creatinine-based eGFR strategies.

Objective: To determine if gastrointestinal (GI) symptoms can predict deep endometriosis (DE) of the posterior pelvic compartment on magnetic resonance imaging (MRI). Methods: Patients with suspected endometriosis undergoing endometriosis protocol MRI at an academic center between 9/1/2015 and 7/31/2018 were identified. Presenting GI symptoms were collected via a standardized survey instrument prospectively at initial presentation. MRI and interdisciplinary conference notes were reviewed to identify posterior compartment DE (rectosigmoid, uterosacral ligaments, posterior cul de sac, and pelvic side walls). Associations between symptoms and DE were evaluated. Results: A total of 104 patients met inclusion criteria, and 89 (85.6%) presented with at least one GI symptom. Posterior compartment DE was identified on MRI in 47 patients (45.2%). The GI symptom that most strongly predicted DE was a bowel movement resulting in pain relief (OR 3.36, 95% CI 1.31–8.61, p = 0.012), with sensitivity, specificity, positive and negative predictive values 0.42, 0.82, 0.67, and 0.63, respectively. Other GI symptoms such as nausea, vomiting, rectal bleeding, change in frequency of bowel movements, and pain exacerbation by bowel movements did not significantly correlate to having DE. Of the 15 patients with no GI symptoms, 5 were found to have posterior compartment DE. Conclusion: In patients with suspected endometriosis, those who noted that bowel movements relieved their pain had more than three times the odds of having DE of the posterior compartment on MRI. Preoperative evaluation with MRI may be of value in these patients; however, lack of gastrointestinal symptoms does not exclude the possibility of posterior compartment DE.

Objective: To determine whether there are differences in asthma management provided in the retail clinic setting versus in the primary care setting, and whether it would increase the number of well controlled asthmatics as determined by ACT score of 20 or greater, and less than or equal to 1 ED or hospital visit due to asthma, within 6 months. Methods: All asthma patients with an asthma control test (ACT) of 19 or less, received a new or updated asthma action plan (AAP) at the visit. If the patient presented to the retail clinic during an asthma exacerbation or with any asthma symptoms, they were not given an ACT and received usual care. Asthma quality data was retrospectively collected for primary care patients seen in the 6-months prior to as well as up to 6 months after the patient’s enrollment visit. Results: There was no significant difference in the number of admissions between locations in either the pre-implementation period or the post-implementation period for either the pediatric or adult cohort. There was a significant improvement in the percentage of pediatric and adult patients with at least 1 ACT in the post-implementation compared to pre-implementation for both retail clinic and primary care sites. The percentage of pediatric and adult patients with at least 1 AAP increased in the post-implementation compared to pre-implementation for both retail clinic and primary care sites. Conclusion: Retail clinics may be able to provide asthma management with similar outcomes to primary care settings.