Citations

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 >3000 ng/mL should be considered.

Abstract Purpose There is a critical need for reliable diagnostic biomarkers as well as surrogate markers of disease progression in multiple system atrophy (MSA). Neurofilament light chain (NfL) has been reported to potentially meet those needs. We therefore sought to explore the value of NfL in plasma (NfL-p) in contrast to CSF (NfL-c) as diagnostic marker of MSA, and to assess NfL-p and NfL-c as markers of clinical disease progression. Methods Well-characterized patients with early MSA (n=32), Parkinson’s disease (PD, n=21), and matched controls (CON, n=15) were enrolled in a prospective, longitudinal study of synucleinopathies with serial annual evaluations. NfL was measured using a high sensitivity immunoassay, and findings were assessed by disease category and relationship with clinical measures of disease progression. Results Measurements of NfL-c were highly reproducible across immunoassay platforms (Pearson,r=0.99), while correlation between NfL-c and -p was only moderate (r=0.66). NfL was significantly higher in MSA compared to CON and PD; the separation was essentially perfect for NfL-c, but there was overlap, particularly with PD, for NfL-p. While clinical measures of disease severity progressively increased over time, NfL-c and -p remained at stable elevated levels within subjects across serial measurements. Neither change in NfL nor baseline NfL were significantly associated with changes in clinical markers of disease severity. Conclusions These findings confirm NfL-c as faithful diagnostic marker of MSA, while NfL-p showed less robust diagnostic value. The significant NfL elevation in MSA was found to be remarkably stable over time and was not predictive of clinical disease progression.

Abstract Importance and Objective Despite a decreasing incidence of cervical cancer in North America overall, disparities in screening and cervical cancer rates persist, especially in the postmenopausal age group. Methods We reviewed the literature regarding cervical cancer screening considerations for postmenopausal persons, with a focus on cervical cancer in postmenopausal persons, existing guidelines, screening methods, and gaps in care. Discussion and Conclusion Postmenopausal persons are an important population at risk because age 65 years in the United States and up to 70 years in some parts of Canada is a milestone for screening cessation if the criteria are met. Unfortunately, inadequate screening is common, with most women 65 years or older discontinuing (exiting) screening despite not meeting the criteria to do so. Screening cessation recommendations are nuanced, and if not all criteria are met, screening should be continued until they are. Cervical cancer screening should be stopped at the recommended age if adequate screening has occurred or at any age if life expectancy is limited or the patient has had a hysterectomy in the absence of high-grade preinvasive cervical lesions or cervical cancer. Human papillomavirus infection, which is causally linked to almost all cervical cancer cases, can persist or reactivate from a prior infection or can be newly acquired from sexual contact. With more persons aging with a cervix in place, the potential for cervical cancer has increased, and higher cancer rates may be observed if recommended screening is not adhered to. We propose an algorithm based on current cervical cancer screening guidelines to aid providers in identifying whether exit criteria have been met. Until adequate screening has been confirmed, cervical cancer screening should continue.

Abstract Androgen receptor (AR) inhibition by androgen deprivation and/or antiandrogen administration is the mainstay therapy for advanced prostate cancer. However, most prostate cancers ultimately become resistant to these therapies, indicating the importance of identifying mechanisms driving resistance to improve patient outcomes. Here we demonstrated that acute treatment with the antiandrogen enzalutamide (ENZ) decreased glutathione (GSH) production, increased lipid peroxidation, and induced ferroptosis in prostate cancer cells. Consistently, meta-analysis of transcriptomic data linked the androgen-AR axis to metabolism-related biological processes, including lipid metabolism. The cystine transporter gene SLC7A11 was a key AR target, and full-length AR (AR-FL) transactivated SLC7A11 transcription by directly occupying the SLC7A11 promoter and putative enhancer regions. AR variants (AR-V) preferentially bound the SLC7A11 enhancer and upregulated SLC7A11 expression, thereby conferring resistance to ferroptosis induced by ENZ treatment. However, this effect was abolished following downregulation of AR-Vs using the dual CBP/p300 and BET inhibitor NEO2734. These findings reveal ferroptosis induction as an anticancer mechanism of antiandrogens and SLC7A11 as a direct target gene of AR-FL and AR-Vs. AR-V-mediated SLC7A11 expression represents a mechanism coupling ferroptosis resistance to prostate cancer progression. Significance: Upregulation of SLC7A11 can be induced by androgen receptor variants to inhibit antiandrogen-induced prostate cancer cell ferroptosis and to drive castration resistance in prostate cancer.

Abstract Background Structural valve dysfunction in bioprosthetic heart valves necessitates redo replacement procedure that are associated with high mortality and morbidity. The transcatheter valve-in-valve (VIV) approach has emerged as a preferred option for patients requiring redo procedures due to structural valve degeneration. We report from India the first case of the simultaneous transcatheter dual VIV implantation (mitral valve and tricuspid valves) in a high-surgical-risk patient. Case summary A 57-year-old female was presented with a history of rheumatic heart disease, post-mitral valve as well as tricuspid valve replacement (perimount 33 mm) 11 years back. Bioprosthetic heart valve was chosen probably due to limited life expectancy and compliance issues with monitoring of international normalised ratio (INR). She now presented with progressive dyspnoea, oedema, and palpitations (New York Heart Association Class III) for the last 6 months. The patient was scheduled for transcatheter dual valve replacement simultaneously. The procedure was successful with a favourable outcome, short hospital stays, and early recovery. Discussion This is the first case of simultaneous transcatheter dual valve replacement reported from India, which is fluoroscopically guided and supported by TEE. It is a valuable and considerable option for patients with failing bioprosthesis valves who are at increased peri-operative risk.

AbstractObjectiveTo examine the efficacy and safety of a new fractional, ablative erbium:glass fiber (Er:glass) laser (2910 nm) at improving clinical signs of photodamaged skin.Materials and MethodsThirty‐seven healthy participants aged 38–75 years with photodamaged skin were enrolled into two treatment groups. Group A (n = 14) received up to four laser treatments with mild settings, and focal facial subunits were treated with deeper settings. Group B (n = 23) received a single treatment using deeper settings. Following treatment, pain scores and severity and duration of skin responses (erythema, edema, and pinpoint bleeding) were assessed. Primary outcome was the improvement in participant and investigator Global Aesthetic Improvement Scale (GAIS) at 3‐month follow‐up. Secondary outcomes were participant satisfaction with treatment and whether they would repeat treatment.ResultsThirty‐five participants completed the study (n = 1 lost to follow up in each group). Both groups had similar mean participant and investigator GAIS scores of 3/5 corresponding to “Improvement.” All but two patients (both from Group A) reported improvement, satisfaction with treatment, and would repeat treatment. Posttreatment skin responses were mild‐to‐moderate, lasting up to 5 days. There was no scarring or dyspigmentation.ConclusionThe 2910 nm Er:glass laser provided improvement in photoaging with high patient satisfaction.

Importance People who smoked cigarettes may experience respiratory symptoms without spirometric airflow obstruction. These individuals are typically excluded from chronic obstructive pulmonary disease (COPD) trials and lack evidence-based therapies. Objective To define the natural history of persons with tobacco exposure and preserved spirometry (TEPS) and symptoms (symptomatic TEPS). Design, Setting, and Participants SPIROMICS II was an extension of SPIROMICS I, a multicenter study of persons aged 40 to 80 years who smoked cigarettes (>20 pack-years) with or without COPD and controls without tobacco exposure or airflow obstruction. Participants were enrolled in SPIROMICS I and II from November 10, 2010, through July 31, 2015, and followed up through July 31, 2021. Exposures Participants in SPIROMICS I underwent spirometry, 6-minute walk distance testing, assessment of respiratory symptoms, and computed tomography of the chest at yearly visits for 3 to 4 years. Participants in SPIROMICS II had 1 additional in-person visit 5 to 7 years after enrollment in SPIROMICS I. Respiratory symptoms were assessed with the COPD Assessment Test (range, 0 to 40; higher scores indicate more severe symptoms). Participants with symptomatic TEPS had normal spirometry (postbronchodilator ratio of forced expiratory volume in the first second [FEV 1 ] to forced vital capacity >0.70) and COPD Assessment Test scores of 10 or greater. Participants with asymptomatic TEPS had normal spirometry and COPD Assessment Test scores of less than 10. Patient-reported respiratory symptoms and exacerbations were assessed every 4 months via phone calls. Main Outcomes and Measures The primary outcome was assessment for accelerated decline in lung function (FEV 1 ) in participants with symptomatic TEPS vs asymptomatic TEPS. Secondary outcomes included development of COPD defined by spirometry, respiratory symptoms, rates of respiratory exacerbations, and progression of computed tomographic–defined airway wall thickening or emphysema. Results Of 1397 study participants, 226 had symptomatic TEPS (mean age, 60.1 [SD, 9.8] years; 134 were women [59%]) and 269 had asymptomatic TEPS (mean age, 63.1 [SD, 9.1] years; 134 were women [50%]). At a median follow-up of 5.76 years, the decline in FEV 1 was −31.3 mL/y for participants with symptomatic TEPS vs −38.8 mL/y for those with asymptomatic TEPS (between-group difference, −7.5 mL/y [95% CI, −16.6 to 1.6 mL/y]). The cumulative incidence of COPD was 33.0% among participants with symptomatic TEPS vs 31.6% among those with asymptomatic TEPS (hazard ratio, 1.05 [95% CI, 0.76 to 1.46]). Participants with symptomatic TEPS had significantly more respiratory exacerbations than those with asymptomatic TEPS (0.23 vs 0.08 exacerbations per person-year, respectively; rate ratio, 2.38 [95% CI, 1.71 to 3.31], P < .001). Conclusions and Relevance Participants with symptomatic TEPS did not have accelerated rates of decline in FEV 1 or increased incidence of COPD vs those with asymptomatic TEPS, but participants with symptomatic TEPS did experience significantly more respiratory exacerbations over a median follow-up of 5.8 years.

Human pluripotent stem cells (hPSCs) are capable of unlimited proliferation and can undergo differentiation to give rise to cells and tissues of the three primary germ layers. While directing lineage selection of hPSCs has been an active area of research, improving the efficiency of differentiation remains an important objective. In this study, we describe a two-compartment microfluidic device for co-cultivation of adult human hepatocytes and stem cells. Both cell types were cultured in a 3D or spheroid format. Adult hepatocytes remained highly functional in the microfluidic device over the course of 4 weeks and served as a source of instructive paracrine cues to drive hepatic differentiation of stem cells cultured in the neighboring compartment. The differentiation of stem cells was more pronounced in microfluidic co-cultures compared to a standard hepatic differentiation protocol. In addition to improving stem cell differentiation outcomes, the microfluidic co-culture system described here may be used for parsing signals and mechanisms controlling hepatic cell fate.