Citations

Objective The aim of the study was to assess the applicability and safety of cervical cancer screening guidelines recommended by the American College of Obstetricians and Gynecologists (2016) and American Society for Colposcopy and Cervical Pathology (2019) for women with solid organ transplants (SOTs). Materials and Methods We analyzed data previously abstracted through December 2015 for 971 women (18–60 y) who received their first SOT at Mayo Clinic (Rochester, MN) from January 17, 1995, through December 31, 2011. Inclusion criteria were initial benign findings on cervical cytology after SOT and at least 1 subsequent cytologic screening. Results Of 415 women whose initial cytologic findings were benign, 310 met inclusion criteria. The cumulative incidence of abnormal cervical cytology among these 310 women was 4.3% (95% CI = 1.9%–6.7%) by 30 months and 11.2% (95% CI = 7.1%–15.4%) by 60 months after their initial benign results. Considering all women with SOT, 68.4% (284/415) had no documented abnormal cytologic findings within 60 months (26 had abnormality; 284 no abnormality; and 105 not assessed). In women with negative tests for human papillomavirus, high-grade squamous intraepithelial lesions were not documented on cytology with variable duration of follow-up. No cervical squamous cell carcinoma was identified. Conclusions Of women with initial benign cervical cytology after SOT, more than two thirds would have been eligible for extended-interval screening. Further study is needed, particularly regarding the role of high-risk human papillomavirus testing.

Anal cancer is rare in the general population but is steadily increasing in incidence over the past decade especially in women . Identification and screening of women with high risk facilitates detection of anal precancer and early-stage cancer, improves survival, and potentially uses less invasive therapies compared with the conventional chemoradiation treatments used for advanced cancers. No recently published guidelines currently describe details about screening women for anal squamous cell cancer (ASCC). The available evidence supports the existence of groups of women with higher prevalence of ASCC (e.g., women with human immunodeficiency virus, immune suppression, or previous lower-genital high-grade lesion or cancer) who would likely benefit from screening with some combination of anal cytology and human papillomavirus testing. Additional research is needed to establish the cost-effectiveness and the influence of screening on ASCC mortality rates.

ObjectiveDuring PREVENT (NCT01892345), eculizumab significantly reduced relapse risk versus placebo in patients with aquaporin‐4 immunoglobulin G‐positive neuromyelitis optica spectrum disorder (AQP4‐IgG+ NMOSD). We report an interim analysis of PREVENT's ongoing open‐label extension (OLE; NCT02003144) evaluating eculizumab's long‐term safety and efficacy.MethodsPatients who completed PREVENT could enroll in the OLE to receive eculizumab (maintenance dose = 1,200 mg/2 weeks, after a blinded induction phase). Safety and efficacy data from PREVENT and its OLE (interim data cut, July 31, 2019) were combined for this analysis.ResultsAcross PREVENT and the OLE, 137 patients received eculizumab and were monitored for a median (range) of 133.3 weeks (5.1–276.9 weeks), for a combined total of 362.3 patient‐years (PY). Treatment‐related adverse event (AE) and serious adverse event (SAE) rates were 183.5 in 100 PY and 8.6 in 100 PY, respectively. Serious infection rates were 10.2 in 100 PY in eculizumab‐treated patients versus 15.1 in 100 PY in the PREVENT placebo group. No patient developed a meningococcal infection. At 192 weeks (3.7 years), 94.4% (95% confidence interval [CI], 88.6–97.3) of patients remained adjudicated relapse‐free. The adjudicated annualized relapse rate was 0.025 (95% CI = 0.013–0.048) in all eculizumab‐treated patients versus 0.350 (95% CI = 0.199–0.616) in the PREVENT placebo group. During the OLE, 37% of patients (44 of 119 patients) stopped or decreased background immunosuppressive therapy use.InterpretationThis analysis demonstrates that eculizumab's long‐term safety profile in NMOSD is consistent with its established profile across other indications. This analysis also demonstrated the sustained ability of long‐term eculizumab treatment to reduce relapse risk in patients with AQP4‐IgG+ NMOSD. ANN NEUROL 2021;89:1088–1098

AbstractAimsLong‐term lithium therapy (LTLT) has been associated with kidney insufficiency in bipolar disorder (BD). We aimed to investigate the risk factors of chronic kidney disease (CKD) development and progression among BD patients receiving LTLT.MethodsWe included adult patients with BD on LTLT (≥1 year) who were enrolled in the Mayo Clinic Bipolar Biobank, Rochester, Minnesota. We reviewed electronic medical records to extract information related to lithium therapy and kidney‐related data to assess changes in the estimated glomerular filtration rate (eGFR). CKD severity was assessed based on eGFR.ResultsAmong 154 patients who received LTLT, 41 patients (27%) developed CKD, of whom 20 (49%) patients continued lithium (continuers) and 19 (46%) discontinued it (discontinuers). The median time to stage 3 CKD development was 21.7 years from the start of Li treatment. Type‐2 diabetes mellitus and benzodiazepine use were independent predictors for CKD development in the survival analysis, after controlling for age. The subsequent CKD progression rate did not differ between continuers and discontinuers (mean GFR 48.6 vs. 44.1, p = 0.13) at the end of follow‐up duration (mean duration: 3.5 ± 4.4 years for continuers and 4.9 ± 5.3 years for discontinuers).ConclusionCKD was observed in one fourth of patients with BD receiving LTLT. There was no significant difference in the progression of CKD among Li continuers versus discontinuers, at the mean follow‐up duration of 4.2 years, after the CKD diagnosis. Progression of CKD could be influenced by existing comorbidities and may not necessarily be due to lithium alone.

Eosinophils protect against liver injury during orthotopic liver transplantation and other conditions of hepatic ischemia-reperfusion injury in mice.

AbstractBackgroundUnfortunately, some patients with long QT syndrome (LQTS) experience breakthrough cardiac events (BCEs) despite maximal therapy. Small studies have shown that refractory LQTS cases may benefit from intentional permanent atrial pacing (IPAP). As such, we sought to determine the genotype‐specific utilization and efficacy of IPAP in a single‐center LQTS registry.Methods and ResultsIn this retrospective study, electronic medical records from 1065 patients diagnosed with LQTS were used to identify individuals that received IPAP. Pre‐ and post‐IPAP heart rate, heart rate‐corrected QT (QTc) values, annual BCE rate, and IPAP‐related complications were compared between genotypes. BCEs were defined as LQTS‐associated syncope/seizures, sustained ventricular arrhythmia (VA)‐terminating ICD therapies, and sudden cardiac arrest/death.Overall, 52 out of 1065 LQTS patients received adjunctive IPAP therapy (77% female; median age 18.5 [interquartile range, 1–35.5] years; 73% with prior VA). Over an average IPAP follow‐up of 121 ± 82 months, the average heart rate increased from 65.8 ± 20.4 bpm to 78.9 ± 17.1 bpm; (p < .01) and the average QTc decreased from 533.4 ± 66.6 to 488.3 ± 52.4 ms; (p < .01). The mean BCE rate dropped from 0.88 to 0.19 per patient‐year (p = .01), driven by a marked decrease in the LQT2 cohort (1.01 BCE/year to 0.02 BCE/year; p = .003). No serious IPAP‐related complications were observed.ConclusionIn high‐risk LQTS patients, namely those with recalcitrant LQT2, IPAP appears to be a safe and efficacious adjunct therapy. The beneficial effects of IPAP may stem from attenuating the QTc and circumventing a pause‐dependent trigger. Whether IPAP might obviate the need for an ICD in some instances warrants further study.

Background: Type 1 long QT syndrome (LQT1) is caused by loss-of-function variants in the KCNQ1 -encoded K v 7.1 potassium channel α-subunit that is essential for cardiac repolarization, providing the slow delayed rectifier current. No current therapies target the molecular cause of LQT1. Methods: A dual-component suppression-and-replacement (SupRep) KCNQ1 gene therapy was created by cloning a KCNQ1 short hairpin RNA and a short hairpin RNA-immune KCNQ1 cDNA modified with synonymous variants in the short hairpin RNA target site, into a single construct. The ability of KCNQ1-SupRep gene therapy to suppress and replace LQT1-causative variants in KCNQ1 was evaluated by means of heterologous expression in TSA201 cells. For a human in vitro cardiac model, induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs) were generated from 4 patients with LQT1 (KCNQ1-Y171X, -V254M, -I567S, and -A344A/spl) and an unrelated healthy control. CRISPR-Cas9 corrected isogenic control iPSC-CMs were made for 2 LQT1 lines (correction of KCNQ1-V254M and KCNQ1-A344A/spl). FluoVolt voltage dye was used to measure the cardiac action potential duration (APD) in iPSC-CMs treated with KCNQ1-SupRep. Results: In TSA201 cells, KCNQ1-SupRep achieved mutation-independent suppression of wild-type KCNQ1 and 3 LQT1-causative variants (KCNQ1-Y171X, -V254M, and -I567S) with simultaneous replacement of short hairpin RNA-immune KCNQ1 as measured by allele-specific quantitative reverse transcription polymerase chain reaction and Western blot. Using FluoVolt voltage dye to measure the cardiac APD in the 4 LQT1 patient-derived iPSC-CMs, treatment with KCNQ1-SupRep resulted in shortening of the pathologically prolonged APD at both 90% and 50% repolarization, resulting in APD values similar to those of the 2 isogenic controls. Conclusions: This study provides the first proof-of-principle gene therapy for complete correction of long QT syndrome. As a dual-component gene therapy vector, KCNQ1-SupRep successfully suppressed and replaced KCNQ1 to normal wild-type levels. In TSA201 cells, cotransfection of LQT1-causative variants and KCNQ1-SupRep caused mutation-independent suppression and replacement of KCNQ1 . In LQT1 iPSC-CMs, KCNQ1-SupRep gene therapy shortened the APD, thereby eliminating the pathognomonic feature of LQT1.

Background and Aims Electronic health record (EHR)‐based research allows the capture of large amounts of data, which is necessary in NAFLD, where the risk of clinical liver outcomes is generally low. The lack of consensus on which International Classification of Diseases (ICD) codes should be used as exposures and outcomes limits comparability and generalizability of results across studies. We aimed to establish consensus among a panel of experts on ICD codes that could become the reference standard and provide guidance around common methodological issues. Approach and Results Researchers with an interest in EHR‐based NAFLD research were invited to collectively define which administrative codes are most appropriate for documenting exposures and outcomes. We used a modified Delphi approach to reach consensus on several commonly encountered methodological challenges in the field. After two rounds of revision, a high level of agreement (>67%) was reached on all items considered. Full consensus was achieved on a comprehensive list of administrative codes to be considered for inclusion and exclusion criteria in defining exposures and outcomes in EHR‐based NAFLD research. We also provide suggestions on how to approach commonly encountered methodological issues and identify areas for future research. Conclusions This expert panel consensus statement can help harmonize and improve generalizability of EHR‐based NAFLD research.

Context.— Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a recently emerged, currently pandemic virus, and the etiologic agent of coronavirus disease 2019 (COVID-19). Clinical testing for antibodies to SARS-CoV-2 has rapidly become widespread, but data regarding the interlaboratory performance of these serologic assays are limited. Objective.— To describe the development and initial results of the College of American Pathologists (CAP) SARS-CoV-2 Serology Survey. Design.— Members from the CAP Microbiology and Diagnostic Immunology and Flow Cytometry Committees formed a working group to support development of a new proficiency testing survey for anti–SARS-CoV-2 antibody assays. Supplemental questions in the survey assessed the state of SARS-CoV-2 serologic testing among participating laboratories as of July 2020. Results were analyzed for agreement by immunoglobulin (Ig) isotype tested, assay manufacturer, and methodology. Results.— A total of 4125 qualitative results were received from 1110 laboratories participating in the first survey. Qualitative agreement for assays measuring anti–SARS-CoV-2 total antibodies or IgG was greater than 90% for all 3 samples in the survey. Qualitative agreement for IgM and IgA for the negative sample was greater than 95%, but lacked consensus for the other 2 samples. Conclusions.— These initial data suggest overall excellent agreement and comparable performance for most qualitative anti–SARS-CoV-2 IgG and total antibody assays across all participating clinical laboratories, regardless of specific target antigen or assay methodology.