Citations

While published guidelines are useful in the care of patients with long-QT syndrome, it can be difficult to decide how to apply the guidelines to individual patients, particularly those with intermediate risk. We explored the diversity of opinion among 24 clinicians with expertise in long-QT syndrome. Experts from various regions and institutions were presented with 4 challenging clinical scenarios and asked to provide commentary emphasizing why they would make their treatment recommendations. All 24 authors were asked to vote on case-specific questions so as to demonstrate the degree of consensus or divergence of opinion. Of 24 authors, 23 voted and 1 abstained. Details of voting results with commentary are presented. There was consensus on several key points, particularly on the importance of the diagnostic evaluation and of β-blocker use. There was diversity of opinion about the appropriate use of other therapeutic measures in intermediate-risk individuals. Significant gaps in knowledge were identified.

Background We aimed to provide personalized risk estimates for cardiac events (CEs) and life‐threatening events in women with either type 1 or type 2 long QT. Methods and Results The prognostic model was derived from the Rochester Long QT Syndrome Registry, comprising 767 women with type 1 long QT (n=404) and type 2 long QT (n=363) from age 15 through 60 years. The risk prediction model included the following variables: genotype/mutation location, QTc‐specific thresholds, history of syncope, and β‐blocker therapy. A model was developed with the end point of CEs (syncope, aborted cardiac arrest, or long QT syndrome–related sudden cardiac death), and was applied with the end point of life‐threatening events (aborted cardiac arrest, sudden cardiac death, or appropriate defibrillator shocks). External validation was performed with data from the Mayo Clinic Genetic Heart Rhythm Clinic (N=467; type 1 long QT [n=286] and type 2 long QT [n=181]). The cumulative follow‐up duration among the 767 enrolled women was 22 243 patient‐years, during which 323 patients (42%) experienced ≥1 CE. Based on genotype‐phenotype data, we identified 3 risk groups with 10‐year projected rates of CEs ranging from 15%, 29%, to 51%. The corresponding 10‐year projected rates of life‐threatening events were 2%, 5%, and 14%. C statistics for the prediction model for the 2 respective end points were 0.68 (95% CI 0.65–0.71) and 0.71 (95% CI 0.66–0.76). Corresponding C statistics for the model in the external validation Mayo Clinic cohort were 0.65 (95% CI 0.60–0.70) and 0.77 (95% CI 0.70–0.84). Conclusions This is the first risk prediction model that provides absolute risk estimates for CEs and life‐threatening events in women with type 1 or type 2 long QT based on personalized genotype‐phenotype data. The projected risk estimates can be used to guide female‐specific management in long QT syndrome.

Background: Atrial fibrillation (AF) is an important modifiable and independent risk factor for stroke. AF is associated with 2-4% annual risk for first time stroke and about 8% annually for recurrent stroke. Anticoagulant therapy reduces the risk by 60%, while the relative risk reduction (RRR) obtained from antiplatelet therapy is only 20%. The effect is more robust for secondary than for primary prevention. Risk stratification schemes are utilized to assess an individual’s risk of future stroke and to determine the optimal antithrombotic or anticoagulation regimen for stroke prevention. Despite Warfarin’s superiority over antiplatelet therapy to reduce the risk of AF related systemic embolism, Warfarin is largely underutilized. The aim of this study was to determine the frequency and reasons behind withholding anticoagulation in patient with AF related cardioembolic stroke in our institution. Method: We extracted patients from our Get With The Guideline’s (GWTG) database who were admitted to Mayo Clinic AZ between January 2004 and December 2009. Two authors (TK and NL) independently identified all patients with the diagnosis of atrial fibrillation who were not prescribed Warfarin therapy upon discharge, then reviewed to identify the reason(s) why anticoagulation was not initiated. Factors such as discharge disposition (home, acute rehabilitation, long term nursing facility, hospice, other) and functional status (able to ambulate independently, with assistance, unable to ambulate, or not documented) were also assessed to help support the decision process. Results: From a total of 1295 patients, 305 with AF were identified. Patients who expired 48 (3.7%) from un-related causes were excluded. Of the 257 patients, 206 (80.2%) were anticoagulated and 51 (19.8%) were not anticoagulated. We found that in the anticoagulated group, patients discharged home were more likely to receive anticoagulation (89.2%), followed by those discharged to acute rehabilitation and skilled nursing facilities (77%). Those discharged to hospice were the least likely to receive anticoagulation (6.4%). In addition, patients with greater functional ability were also more likely to receive anticoagulation (independent 89.8%, vs. assisted 76.7%, vs. non-ambulatory 33.3%; p<0.0001). Reasons to withhold anticoagulation therapy at discharge included terminal illness/comfort measures only (40.0%); risk/discomfort due to bleeding (24%); risk of falls (13.0%); and patient refusal (9.0%). Discussion: Based on the results, we conclude that functional status and disposition at discharge are significant factors influencing the decision to anticoagulate after cardioembolic stroke attributed to AF.

Introduction: Levels of type-B natriuretic peptide (BNP) adjusted for age and sex are a powerful predictor of mortality after the diagnosis of aortic stenosis (AS). Objective: To assess whether BNP activation (compared to normal values) affects mortality after aortic valve replacement (AVR). Methods: In 494 patients with AS, plasma level of BNP was measured pre-operatively at the time of Doppler-Echocardiography. BNP was normalized as BNPratio (BNP measured/BNP maximum normal value for age and sex) to evaluate the impact of BNP activation on post-operative outcomes. Results: Mean age was73±11 years and 300 (61%) patients were male. Mean aortic valve area was 0.82±0.20cm2, mean gradient 51±16mmHg, and mean Left Ventricular Ejection Fraction 59±15%. Incidence of hypertension was 65%, diabetes 27% and chronic kidney disease 22%. Median of BNP was 211 (interquartile: 87-508) and BNPratio 2.2 (1.0-5.2). After adjustment age, gender, body surface area, Charlson score index, presence of symptoms, creatinine, hemoglobin, systolic blood pressure, indexed aortic valve area and left ventricular ejection fraction, the BNPratio (log transformed) was a predictor of long-term mortality (p<0.0001) with an hazard ratio 1.34 (1.14-1.60). Moreover, stratification by BNPratio showed increasing long-term post-operative mortality with BNPratios>2 (Figure). Conclusions: BNP activation defined using BNPratios (normalized for age and sex) is a powerful independent predictor of long-term mortality after aortic valve replacement for AS. Furthermore, patients with a BNPratio>2 before aortic valve replacement incur excess mortality during follow-up in relation to the increasing BNPratio. These data support the use of the BNPratio to guide the timing of AVR.

Abstract There is a lack of large comparative study on the outcomes of reduced intensity conditioning (RIC) in acute myeloid leukemia (AML) transplantation using fludarabine/busulfan (FB) and fludarabine/melphalan (FM) regimens. Adult AML patients from Center for International Blood and Marrow Transplant Research who received first RIC allo-transplant between 2001 and 2015 were studied. Patients were excluded if they received cord blood or identical twin transplant, total body irradiation in conditioning, or graft-versus-host disease (GVHD) prophylaxis with in vitro T-cell depletion. Primary outcome was overall survival (OS), secondary end points were leukemia-free survival (LFS), nonrelapse mortality (NRM), relapse, and GVHD. Multivariate survival model was used with adjustment for patient, leukemia, and transplant-related factors. A total of 622 patients received FM and 791 received FB RIC. Compared with FB, the FM group had fewer transplant in complete remission (CR), fewer matched sibling donors, and less usage of anti-thymocyte globulin or alemtuzumab. More patients in the FM group received marrow grafts and had transplantation before 2005. OS was significantly lower within the first 3 months posttransplant in the FM group (hazard ratio [HR] = 1.82, P &lt; .001), but was marginally superior beyond 3 months (HR = 0.87, P = .05). LFS was better with FM compared with FB (HR = 0.89, P = .05). NRM was significantly increased in the FM group during the first 3 months of posttransplant (HR = 3.85, P &lt; .001). Long-term relapse was lower with FM (HR = 0.65, P &lt; .001). Analysis restricted to patients with CR showed comparable results. In conclusion, compared with FB, the FM RIC showed a marginally superior long-term OS and LFS and a lower relapse rate. A lower OS early posttransplant within 3 months was largely the result of a higher early NRM.

Increasing rates of infection by antibiotic resistant bacteria have led to a resurgence of interest in bacteriophage (phage) therapy. Several phage therapy studies in animals and humans have been completed over the last two decades. We conducted a systematic review of safety and toxicity data associated with phage therapy in both animals and humans reported in English language publications from 2008–2021. Overall, 69 publications met our eligibility criteria including 20 animal studies, 35 clinical case reports or case series, and 14 clinical trials. After summarizing safety and toxicity data from these publications, we discuss potential approaches to optimize safety and toxicity monitoring with the therapeutic use of phage moving forward. In our systematic review of the literature, we found some adverse events associated with phage therapy, but serious events were extremely rare. Comprehensive and standardized reporting of potential toxicities associated with phage therapy has generally been lacking in the published literature. Structured safety and tolerability endpoints are necessary when phages are administered as anti-infective therapeutics.

Introduction: Genetic studies of early-onset disease have been an effective strategy to identify novel pathways and drug targets relevant to later-onset disease. Few studies have investigated the role of common genetic variation in the etiology of early-onset ischemic stroke (IS). Methods: We performed a GWAS meta-analysis of 38 studies from 10 countries, comprised of 5,847 IS cases of European ancestry under age 60 and 32,533 controls. Results: We identified two genome-wide significant (p< 5 x 10 -8 ) loci (see Figure). The ABO locus has previously been associated with venous thrombosis and ischemic stroke in predominantly older adults, but the effect size of our top SNP (OR 1.18; p = 9.1 x 10 -12 ) is larger than the effect size for this same SNP in MEGASTROKE (OR: 1.05; p = 6.5 x 10 -5 ). The lead SNP at the BCL7A/MLXIP locus is a novel GWAS finding for stroke (OR 1.14, 95% CI 1.08-1.19; p = 1.7 x 10 -8 ) and is noteworthy because of prior reports linking SNPs in these genes to BMI and blood pressure. Conclusions: We identified a novel locus that is near variants associated with BMI and blood pressure. Further studies are needed to confirm this locus, examine subtype specificity, and determine its function. The larger effect size observed at the ABO in this early-onset IS sample compared to older-onset IS samples is consistent with a larger role for prothrombotic mechanisms in early-onset IS.

TSLP is a newly‐identified cytokine thought to be involved in airway inflammation. TSLP levels have been shown to significantly increase in airway smooth muscle (ASM) with chronic obstructive pulmonary disease and other inflammatory diseases. This study evaluated the expression of TSLP in human ASM cells and tissues exposed to cigarette smoke extract (CSE) or to pro‐inflammatory cytokines TNF‐α and IL‐13. In parallel studies, TSLP expression was evaluated in house dust mite sensitized mice with or without cigarette smoke exposure. The presence of TSLP and TSLP‐receptors were verified using Western blot analysis. Exposure to TNF‐α and IL‐13 (50 ng/mL each) for 24 hours resulted in increased TSLP and TSLP‐R expression. Simultaneous exposure to functional TSLP antibody blunted cytokine induced TSLP‐R expression. Interestingly, acute CSE (30 min) down‐regulated TSLP expression, while chornic exposure increased expression. Similarly, [Ca 2+ ] i responses of human ASM to histamine were blunted with chronic CSE exposure, effects reversed by TSLP and TSLP‐R antibodies. Sensitized mice demonstrated an increase in TSLP expression in whole lung samples. This effect was even further enhanced in dust mite sensitized mice exposed to chronic cigarette smoke. These results indicate a complex role for TSLP in ASM inflammation with or without cigarette smoke exposure. Supported by NIH grants HL088029, HL090595, RR024150, and the Flight Attendants Medical Research Institute (FAMRI). Additional funding from the Department of Anesthesiology, Mayo Clinic.