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IMPORTANCE: Protein binding of valproate varies among ICU patients, altering the biologically active free valproate concentration (VPAC). Free VPAC is measured at few laboratories and is often discordant with total VPAC. Existing equations to predict free VPAC are either not validated or are inaccurate in ICU patients. OBJECTIVES: We designed this study to derive and validate a novel equation to predict free VPAC using data from ICU patients and to compare its performance to published equations. DESIGN: Retrospective cohort study. SETTING: Two academic medical centers. PARTICIPANTS: Patients older than 18 years old with concomitant free and total VPACs measured in the ICU were included in the derivation cohort if admitted from 2014 to 2018, and the validation cohort if admitted from 2019 to 2022. MAIN OUTCOMES AND MEASURES: Multivariable linear regression was used to derive an equation to predict free VPAC. Modified Bland-Altman plots and the rate of therapeutic concordance between the measured and predicted free VPAC were compared. RESULTS: Demographics, median free and total VPACs, and valproate free fractions were similar among 115 patients in the derivation cohort and 147 patients in the validation cohort. The Bland-Altman plots showed the new equation performed better (bias, 0.3 [95% limits of agreement, –13.6 to 14.2]) than the Nasreddine (–9.2 [–26.5 to 8.2]), Kodama (–9.7 [–30.0 to 10.7]), Conde Giner (–7.9 [–24.9 to 9.1]), and Parent (–9.9 [–30.7 to 11.0]) equations, and similar to Doré (–2.0 [–16.0 to 11.9]). The Doré and new equations had the highest therapeutic concordance rate (73%). CONCLUSIONS AND RELEVANCE: For patients at risk of altered protein binding such as ICU patients, existing equations to predict free VPAC are discordant with measured free VPAC. A new equation had low bias but was imprecise. External validation should be performed to improve its precision and generalizability. Until then, monitoring free valproate is recommended during critical illness.

Abstract Objective Adverse childhood experiences (ACEs) are reported in more than half of the women in the United States and have been shown to negatively impact the menopause experience. The objective of this study was to evaluate the association between ACEs and age at natural menopause. Methods This is a cross-sectional study conducted among participants of the Data Registry on the Experiences of Aging, Menopause, and Sexuality (DREAMS). The registry included women who were seen for consultations in the women's health clinic at Mayo Clinic, Rochester, between May 2015 and December 2016. Only postmenopausal women were included in this analysis. Childhood adversity was assessed with the validated ACE questionnaire. Age at natural menopause was self-reported. The association between ACEs and age at menopause was evaluated using a multivariable linear regression model adjusting for multiple confounders. Results A total of 350 women were evaluated. The mean age was 59.2 years, and a majority were White (92.9%), married/partnered (82%), and educated (91.2% with at least some college education). Women with a history of at least four ACEs were estimated to reach natural menopause 1.3 years sooner than women with no ACE in multivariable analysis, but the results were not statistically significant (95% confidence interval, −3.2 to 0.6; P = 0.18). Conclusions Although stressful life experiences such as ACEs may negatively influence health for midlife women, this study did not find an association with the age at natural menopause.

Background: Data are controversial regarding nephrotoxicity risk with vancomycin plus piperacillin–tazobactam (VPT) compared to vancomycin alone or in combination with other beta-lactams (BLs) in acute care use. Furthermore, data are lacking on the incidence of acute kidney injury (AKI) with long-term use of VPT including outpatient parenteral antimicrobial therapy (OPAT). Methods: This retrospective study included 826 adult patients on an intravenous vancomycin plus BL for ⩾2 weeks, including cefepime, piperacillin/tazobactam, ertapenem, or meropenem, from August 2017 to January 2022. The primary outcome was incidence of AKI. Univariate and multivariable Cox proportional hazard regression analyses were conducted to adjust for confounding variables. A secondary analysis based on the propensity score (PS)-matched cohort was performed. Results: AKI occurred in 14.4% of patients in the VPT group ( n = 15/104) compared to 5.5% in the other BL group ( n = 40/722) ( p < 0.001). Average time to AKI from start of combination therapy was 9.4 (1.7–12.0) days in the VPT group and 10.9 (5–22.7) days in the other BL group ( p = 0.20). The median duration of vancomycin and BL in the overall cohort was approximately 1 month. Beyond BL selection, patient characteristics were not associated with AKI other than the receipt of concomitant acyclovir [hazard ratio (HR) 2.48 (95% confidence interval (CI): 1.33–4.65), p = 0.004]. In the PS-matched cohort, AKI occurred in 14.4% of patients in the VPT group ( n = 15/104) and 5.3% in the other BL group ( n = 11/208) ( p = 0.006). Receipt of VPT [HR: 2.55 (1.36–4.78), p = 0.004] and acyclovir [HR: 2.38 (1.19–4.74), p = 0.014) remained significantly associated with AKI in the multivariable model. Conclusion: Clinicians should exercise caution when using VPT for >2 weeks, including in the OPAT setting, even when no renal dysfunction is observed during the initial week of combination therapy.

Background: Underweight patients may be at an increased risk of bleeding while receiving venous thromboembolism (VTE) prophylaxis. Additional evidence is needed to identify patient-specific factors associated with bleeding. The objective of the study was to describe the incidence and identify risk factors associated with bleeding in low-weight (⩽ 60 kg) adult patients receiving subcutaneous unfractionated heparin (SQH) for VTE prophylaxis. Methods: This was a single-center, retrospective, nested case–control study of low-weight patients receiving SQH for VTE prophylaxis for ⩾ 48 hours. Cases, patients with clinically relevant bleeding while receiving SQH, and controls, patients without a bleeding event, were matched in a 1:3 ratio for age, sex, primary service (surgical or medical), and time at risk of bleeding on SQH to determine factors associated with bleeding. Results: A total of 3761 patients met the inclusion criteria, of which 38 cases of clinically relevant bleeding were identified. The bleeding incidence was 1% at hospital day 6 and 2.8% at hospital day 14. Most patients in this study (69%) received SQH 5000 units three times daily. ICU admission at SQH start was associated with bleeding, OR 2.97 (95% CI 1.21–7.29). Conclusion: Bleeding in low-weight patients on prophylactic SQH was uncommon. Patients admitted to the ICU at time of SQH start may be at a higher risk of bleeding. Further studies are needed to detect additional risk factors associated with bleeding and investigate the effects of reduced dosing in this population.

AbstractBackgroundInfertility has been linked with an increased risk of sexual dysfunction in reproductive-aged women, with longer periods of infertility associated with a greater risk.AimThe study’s aim was to examine whether a history of infertility treatment in women is linked to sexual dysfunction during midlife.MethodsThe cross-sectional study was conducted among sexually active women, between the ages of 45 and 65 years, who sought consultation at the women’s health clinics at a US tertiary care center. History of infertility treatment was assessed with a single question that asked participants if they were treated for infertility in the past. The association between a history of infertility treatment and sexual dysfunction—which was diagnosed by a combination of Female Sexual Function Index score ≤26.55 and Female Sexual Distress Scale–Revised score ≥11—was assessed in a multivariable logistic regression model that adjusted for multiple confounders.OutcomesThe primary outcome was sexual dysfunction in midlife women.ResultsThe analysis included 5912 women, with a mean age of 54.1 years. Nearly 16% of women reported receiving treatment for infertility. More than half the women (55%) had sexual dysfunction: 56.3% of those with previous fertility treatments and 54.4% of those without any fertility treatment (P = .3). Receiving treatment for infertility in the younger years did not significantly increase the odds of sexual dysfunction in midlife in univariate (odds ratio, 1.08; 95% CI, 0.94-1.24; P = .3) and multivariable analyses (odds ratio, 1.11; 95% CI, 0.96-1.29; P = .17).Clinical ImplicationsWhile infertility is known to be predictive of sexual dysfunction in women during their reproductive years, there was no association between a history of infertility treatment and sexual dysfunction in midlife women in the current study.Strengths and LimitationsThe study used validated questionnaires accounting for sexual complaints and distress and adjusted for multiple confounding factors. Limitations include the selection bias introduced by the study of women presenting for evaluation of sexual dysfunction, which may have been a result of factors stronger than the influence of infertility. Other limitations include the study’s cross-sectional nature with suboptimal racial and ethnic representation.ConclusionAlthough infertility is commonly associated with female sexual dysfunction in women of reproductive age, the association was not present in midlife women in the current study.

Abstract Purpose With the implementation of a new electronic health record (EHR) system across Mayo Clinic, a project was approved to standardize and converge 9 region-specific large-volume infusion pump (LVP) drug libraries for Baxter SIGMA Spectrum pumps. Summary The objectives of the project were to (1) develop recommendations for identified variances in practice, (2) consolidate regional drug libraries into a converged enterprise library, (3) improve the drug library management process, and (4) maintain or exceed previous Dose Error Reduction System (DERS) compliance for infusions administered. Harmonization efforts with infusion pumps decreased the number of drug libraries maintained, reduced content maintenance time, and increased readiness for smart infusion pump–EHR interoperability. Seven of the 8 regions for which change in DERS compliance was assessed showed improved compliance relative to baseline in the 30-day postwashout period. Furthermore, when comparing pre- and postimplementation DERS compliance, the number of regions meeting the minimum compliance rate of 95% increased from 5 to 6 regions. Conclusion The project improved the drug library management process, allowed for DERS compliance to be accurately compared across regions, and ensured that patients across the enterprise receive the same standard of care with the administration of intravenous medications.

Abstract Posaconazole therapeutic drug monitoring (TDM) is widely utilized to assess therapeutic efficacy and safety; however, clinical effects of very high serum concentrations are unknown. A retrospective review of 90 patients receiving posaconazole for treatment or prophylaxis of invasive fungal infections with serum concentrations ≥3000 ng/mL from 1/1/2019 to 4/30/2021 evaluated the incidence and type of adverse drug reactions (ADRs). Symptomatic ADRs were very common in patients with posaconazole concentrations of ≥5000 ng/mL and 3000–4999 ng/mL (80% vs. 58.8%; P = 0.31). Posaconazole TDM should be performed for both treatment and prophylaxis indications and dose decrease for serum concentrations &gt;3000 ng/mL should be considered.

Objective: To investigate patterns and trends of co-prescriptions of stimulants and sedatives within the last 6 years at a tertiary care center. Method: Patients 18 years of age and older who were dispensed at least one stimulant prescription from an institutional pharmacy between 1/1/2015 and 7/1/2021 were included. Prescription data for any co-prescribed sedative/hypnotic were collected. Results: Both the number of stimulant dispenses and the number of patients with stimulant dispenses increased significantly with yearly incidence rate ratios of 1.115 (95% CI [1.110, 1.119]) and 1.090 (95% CI [1.084, 1.096]), respectively. The number of patients with a stimulant dispensed who also had a benzodiazepine or “Z-drug” sedative-hypnotic dispensed at any point in the search timeframe increased significantly with incidence rate ratios of 1.077 and 1.092, respectively. The number of stimulant dispenses, number of patients with stimulant dispenses, and number of patients with a stimulant dispensed who also had both a benzodiazepine and Z-drug dispensed at any point in the search timeframe increased significantly more in Non-White than in White patients. Conclusions: The results confirm previous findings of increases in dispensing of stimulants over the past 6 years and report increased polypharmacy of stimulants and sedative-hypnotics.

AbstractBackground: Liver transplant (LT) recipients with untreated hepatitis C (HCV) are at risk for cirrhosis graft failure. The advent of direct acting antiviral agents (DAA) has improved outcomes in HCV.Aims: We aim to examine liver transplant outcomes and allograft fibrosis development/progression after sustained virologic response (SVR).Methods: We performed a retrospective cohort study of 226 consecutive liver transplant recipients with HCV from 2007 to 2018. The cohort was split into transplants pre (Group A) and post (Group B) 2014 to reflect the introduction of DAAs. Fibrosis was monitored with liver biopsy and non‐invasive imaging.Results: Group B had significantly improved HCV treatment rates and earlier SVR compared to Group A, with a cumulative incidence rate of SVR at 2 years of 86.7% versus 15.4% (HR = .11, p < .001). Prior to achieving SVR, Group A demonstrated worsening of fibrosis stage per year (+.21, p < .001) whereas Group B showed minimal change on protocol annual biopsy (−.02, p = .80). After SVR, most patients were followed non‐invasively and demonstrated stable or improved fibrosis stage over time. Patients undergoing transient elastography showed regression in fibrosis stage per year (−.19, p < .001).Conclusion: HCV patients undergoing LT after 2014 had higher rates of SVR and improved clinically relevant transplant outcomes, namely less graft loss and death relating to HCV. Fibrosis progression halted or improved after SVR in both cohorts, suggesting that LT recipients with SVR do not require fibrosis monitoring even with established fibrosis prior to SVR.

Abstract Introduction Obstructive Sleep Apnea (OSA) in children and adolescents is commonly discussed amongst dental specialists. Physical attributes such as a high and narrow palate, dolichofacial appearance, and retrognathic mandible are reported to increase pediatric risk for OSA. Previous research states rapid maxillary expansion decreases AHI in children with OSA and may be an effective treatment option. Current literature does not report a consistent method of measuring a maxillary transverse deficiency nor does it report a numerical maxillary threshold deficiency that requires expansion in pediatric patients with OSA. Our aims are to compare two different orthodontic diagnostic methods for measuring the maxillary transverse dimension and to assess whether patients diagnosed with mild, moderate, or severe OSA have a numerical threshold for maxillary deficiency. Methods Participants were ages 7-17 years old (average 11.7 years) with no history of orthodontic treatment, craniofacial syndromes, craniosynostosis forms, or nasal abnormalities. Those with and without adenoids and tonsils were included. Participants presented to the Mayo Clinic Sleep Center for their polysomnogram. Their dentition was scanned, and a digital model was rendered. The maxillary transverse dimension was measured via two different methods: McNamara’s Analysis and Andrew’s Six Elements of Orofacial Harmony. Results There were 65 participants: 31 diagnosed with OSA (13 Mild, 4 Moderate, 5 Severe, and 9 Other) and 34 without (controls). Patients in the Other category were diagnosed based on clinical findings. No statistical difference was found between the maxillary transverse measurements of patients with versus without OSA or between the OSA categories. Patients with OSA were more likely to have permanent teeth (61.3% vs 32.4%, p=0.019), tonsils removed (54.8% vs 26.5%, p=0.020), and to have snored during the PSG (83.9% vs 55.9%, p=0.048). Conclusion Conclusions based on this pilot study should be interpreted carefully due to limited sample sizes. No statistically significant differences of the maxillary transverse dimension were found between those with and without OSA using either diagnostic method. No numerical maxillary deficiency threshold was found. Maxillary expansion should not be recommended based on OSA diagnosis alone. Referral to a dental specialist is recommended based on dental needs. Support (if any) Support was provided by Mayo Clinic CTSA grant UL1TR002377.