Lay people are now able to obtain one-lead electrocardiograms (ECG) using smartwatches, which facilitates documentation of arrhythmias. The accuracy of smartwatch derived ECG intervals has not been validated in children though. Home-based monitoring of ECG intervals using a smartwatch could improve monitoring of children, e.g. when taking QTc prolonging medications. The aim of this study was to validate the ECG intervals measured by smartwatch in comparison to standard 12-lead ECGs in children and adolescents. Prospective study of children (age 5-17 years) at the outpatient clinic of a national pediatric heart center. Patients underwent a smartwatch ECG (ScanWatch, Withings) and a simultaneous standard 12-lead ECG. ECG intervals were measured both automatically and manually from the smartwatch ECG and the 12-lead ECG. Intraclass correlation coefficients and Bland-Altman plots were performed. 100 patients (54% male, median age 12.9 (IQR 8.7-15.6) were enrolled. The ICC calculated from the automated smartwatch and automated 12-lead ECG were excellent for heart rate (ICC 0.97, p < 0.001), good for the PR and QT intervals (ICC 0.86 and 0.8, p < 0.001), and moderate for the QRS duration and QTc interval (ICC 0.7 and 0.53, p < 0.001). When using manual measurements for the smartwatch ECG, validity was improved for the PR interval (ICC 0.93, p < 0.001), QRS duration (ICC 0.92, p < 0.001), QT (ICC 0.95, p < 0.001) and QTc interval (ICC 0.84, p < 0.001).
CONCLUSIONS: Automated smartwatch intervals are most reliable measuring the heart rate. The automated smartwatch QTc intervals are less reliable, but this may be improved by manual measurements.
BACKGROUND: In adults, smartwatch derived ECG intervals measured manually have previously been shown to be accurate, though agreement for automated QTc may be fair.
BACKGROUND: In children, automated smartwatch QTc intervals are less reliable than RR, PR, QRS and uncorrected QT interval. Accuracy of the QTc can be improved by peroforming manual measurements.

UNASSIGNED: To investigate the healing of the quadriceps tendon donor site after partial thickness graft harvesting through ultrasound imaging at a short-term follow-up of 6-month following anterior cruciate ligament reconstruction (ACLR) and to investigate the clinical outcomes.
UNASSIGNED: Between March 2019 and August 2020, 61 knees were retrospectively included in this study. Intraoperatively, the length, width and thickness of the harvested QT graft were measured. At a 6-month follow-up, patients were assessed by one of five radiologists, following the same protocol to calculate the defect volume, and patients performed a self-evaluation of pain on the Visual Analogue Scale, International Knee Documentation Committee (IKDC) and the Knee injury and Osteoarthritis Outcome Scores (KOOS).
UNASSIGNED: Intraoperatively, the QT grafts had a volume of 4635.4 ± 912.5 mm3. Postoperatively, ultrasound was performed at 6.5 ± 0.7 months, and the defect volume was 323.3 ± 389.2 mm3, representing a healing rate of 93% ± 9% of the donor site. At a minimum 6-month follow-up, IKDC was 61.6 ± 16 and KOOS was 70.2 ± 16.6. Age was significantly associated with the healing rate (β: -0.005; p = 0.032).
UNASSIGNED: At 6 months follow-up, the defect size of the QT donor site had healed by 93 ± 9% leaving a mean defect volume of 323.3 mm3 according to ultrasound measurements. This suggests that the QT has a high capacity for healing after graft harvesting, with 10 patients reaching full defect closure 6 months after surgery. The clinical relevance of these findings is that the quadriceps tendon donor site has high rates of healing, but surgeons should be aware of lower healing rates in older patients.
UNASSIGNED: Level IV, retrospective case series.

Dose selection for investigations of intrinsic and extrinsic factors of pharmacokinetic variability as well as safety is a challenging question in the early clinical stage of drug development. The dose of an investigational product is chosen considering the compound information available to date, feasibility of the assessments, regulatory requirements, and the intent to maximize information for later regulatory submission. This review selected 37 programs as case examples of recently approved drugs to explore the doses selected with focus on studies of drug interaction, renal and hepatic impairment, food effect and concentration-QTc assessment.The review found that regulatory agencies may consider alternative approaches if justified and safe as illustrated in these examples. It is thus recommendable to use the first in human trial as an opportunity to assess QT-prolongation and drug interactions using probes or endogenous markers while maximizing the DDI potential, increasing sensitivity and ensuring safety. Early understanding of dose proportionality assists dose finding and simple and fast to conduct DDI study designs are advantageous. Single dose impairment studies despite non-proportional/time-dependent PK are often acceptability.Overall, the early understanding of the drug\'s safety profile is essential to ensure the safety of doses selected while preventing clinical trials with unnecessary exposure when using high doses or multiple doses. The information collected in this retrospective survey is a good reminder to tailor the early clinical program to the profile and needs of the molecule and consider regulatory opportunities to streamline the development path.

OBJECTIVE: The first aim of this study was to assess the predictive power of Tend interval (Te) and non-invasive hemodynamic markers, based on bioimpedance in decompensated chronic heart failure (CHF). The second one was to verify the possible differences in repolarization and hemodynamic data between CHF patients grouped by level of left ventricular ejection fraction (LVEF). Finally, we wanted to check if repolarization and hemodynamic data changed with clinical improvement or worsening in CHF patients.
METHODS: Two hundred and forty-three decompensated CHF patients were studied by 5 min ECG recordings to determine the mean and standard deviation (TeSD) of Te (first study). In a subgroup of 129 patients (second study), non-invasive hemodynamic and repolarization data were recorded for further evaluation.
RESULTS: Total in-hospital and cardiovascular mortality rates were respectively 19 and 9%. Te was higher in the deceased than in surviving subjects (Te: 120 ± 28 vs. 100 ± 25 ms) and multivariable logistic regression analysis reported that Te was related to an increase of total (χ2: 35.45, odds ratio: 1.03, 95% confidence limit: 1.02-1.05, p < 0.001) and cardiovascular mortality (χ2: 32.58, odds ratio: 1.04, 95% confidence limit: 1.02-1.06, p < 0.001). Subjects with heart failure with reduced ejection fraction (HFrEF) reported higher levels of repolarization and lower non-invasive systolic hemodynamic data in comparison to those with preserved ejection fraction (HFpEF). In the subgroup, patients with the NT-proBNP reduction after therapy showed a lower rate of Te, heart rate, blood pressures, contractility index, and left ventricular ejection time in comparison with the patients without NT-proBNP reduction.
CONCLUSIONS: Electrical signals from ECG and bioimpedance were capable of monitoring the patients with advanced decompensated CHF. These simple, inexpensive, non-invasive, easily repeatable, and transmissible markers could represent a tool to remotely monitor and to intercept the possible worsening of these patients early by machine learning and artificial intelligence tools.

UNASSIGNED: Sickle cell disease, a common genetic disorder in African Americans, manifests an increased risk of sudden death, the basis of which is incompletely understood. Prolongation of heart rate-corrected QT (QTc) interval on the electrocardiogram, a standard clinical measure of cardiac repolarization, may contribute to sudden death by predisposing to torsades de pointes ventricular tachycardia.
UNASSIGNED: We established a cohort study of 293 adult and 121 pediatric sickle cell disease patients drawn from the same geographic region as the Jackson Heart Study (JHS) cohort, in which significant correlates of QT duration have been characterized and quantitatively modeled. Herein, we establish clinical and laboratory correlates of QTc duration in our cohort using stepwise multivariate linear regression analysis. We then compared our adult sickle cell disease data to effect-size predictions from the published JHS statistical model of QT interval duration.
UNASSIGNED: In adult sickle cell disease, gender, diuretic use, QRS duration, serum ALT levels, anion gap, and diastolic blood pressure show positive correlation; hemoglobin levels show inverse correlation; in pediatric sickle cell disease, age, hemoglobin levels, and serum bicarbonate and creatinine levels show inverse correlation. The mean QTc in our adult sickle cell disease cohort is 7.8 milliseconds longer than in the JHS cohort, even though the JHS statistical model predicts that the mean QTc in our cohort should be > 11 milliseconds shorter than in the much older JHS cohort, a differential of > 18 milliseconds.
UNASSIGNED: Sickle cell disease patients have substantial QTc prolongation relative to their age, driven by factors some overlapping, in adult and pediatric sickle cell disease, and distinct from those that have been defined in the general African American community.

Since 2015, concentration-QTc (C-QTc) analysis has been used to exclude the possibility that a drug has a concerning effect on the QTc interval. This has enabled the replacement of the designated thorough QT (TQT) study with serial electrocardiograms (ECGs) in routine clinical pharmacology studies, such as the first-in-human (FIH) study. The E14 revision has led to an increased proportion of FIH studies with the added objective of QT evaluation, with the intention of replacing the TQT study. With the more recent revision of the S7B/E14 Q&A document in February 2022, nonclinical assays/studies can be brought into the process of regulatory decisions at the time of marketing application. If the hERG (human ether-a-go-go-related gene) and the non-rodent in vivo study are conducted according to the described best practices and are negative, the previous requirement that a QTc effect of >10 milliseconds must be excluded in healthy subjects at plasma concentrations 2-fold above what can be seen in patients can be reduced to covering the concentrations seen in patients. For drugs that cannot be safely given in high doses to healthy subjects, ECG evaluation is often performed at the therapeutic dose in patients. If a QTc effect of >10 milliseconds can be excluded, an argument can be made that the drug should be considered as having a low likelihood of proarrhythmic effects due to delayedrepolarization, if supported by negative best practices hERG and in vivo studies. In this article, we describe what clinicians involved in early clinical development need to understand in terms of the hERG and in vivo studies to determine whether these meet best practices and therefore can be used in an integrated clinical/nonclinical QT/QTc risk assessment.

UNASSIGNED: An association between excessively prolonged QT and ventricular arrhythmia in patients with ST-elevation myocardial infarction has been described; however, the QT dynamics, characterization, and long-term predictive value are not well known.
UNASSIGNED: To characterize QT interval dynamics in patients undergoing ST elevation myocardial infarction (STEMI) and determine its association with mortality.
UNASSIGNED: A retrospective analysis of 4,936 consecutive patients, hospitalized for STEMI between 01/2013-12/2021. Patients with less than three electrocardiograms (ECGs) during index hospitalization were excluded. Baseline demographics, cardiovascular history, clinical risk factors, treatment measures, laboratory results, and mortality data were retrieved from the hospital\'s electronic medical records.
UNASSIGNED: We included 1,054 patients and 5,021 ECGs in our cohort with a median follow-up of 6 years [interquartile range (IQR) 4.3-7.4 years]. The QT was longer in women in comparison to men (428.6 ms ± 33.4 versus 419.8 ms ± 32.52, P-value = 0.001). QT prolongation was greater in females, elderly patients, and patients with STEMI caused by occlusion of the left anterior descending (LAD) coronary artery. We determined QT cutoff to be 445 ms. This value of QT divided our cohort upon arrival into a long QT group (217 patients, 26% of the cohort) and a \"normal\" QT group (835 patients, 74% of the cohort). The long QT group experienced an increase in combined short and long terms all-cause mortality. The QT upon arrival, on day 2 of hospitalization, and before discharge from the hospital, correlated with long-term mortality.
UNASSIGNED: QT duration is often prolonged during STEMI; this prolongation is associated with increased mortality and adverse events. Gender is an important mediator of QT dynamics.

This thorough QT/QTc (TQT) study was conducted to evaluate the risk of QT prolongation for verinurad when combined with allopurinol. Verinurad is a novel, urate anion exchanger 1 inhibitor that reduces serum urate levels by promoting urinary excretion of uric acid. It is co-administered with a xanthine oxidase inhibitor.
The TQT study (NCT04256629) was a randomized, placebo-controlled, double-blind, three-period, crossover study, conducted in healthy volunteers. A total of 24 participants received single doses of verinurad 24 mg extended release, 40 mg immediate release formulation (both co-administered with allopurinol 300 mg), and matching placebos. The primary endpoint was baseline- and placebo-adjusted Fridericia-corrected QTcF interval (ΔΔQTcF) at the concentration of interest. A prespecified linear mixed-effects concentration-QTc model was used to estimate the primary endpoint. Time-matched 12-lead digital electrocardiograms and plasma concentrations were measured at baseline and up to 48 h after dose in each participant.
Estimated ΔΔQTcF at the highest clinically relevant scenario (76 ng/mL) was -2.7 msec (90% confidence interval [CI]: -4.6, -0.8). Furthermore, the upper 90% ΔΔQTcF CI was estimated to be below 10 msec at all observed verinurad concentrations. Supratherapeutic verinurad dose was used to achieve exposures eightfold higher than the highest clinically relevant exposure, thus waiving the need for positive control.
As the effect on ΔΔQTcF was below the threshold for regulatory concern (10 msec) at the supratherapeutic exposure, it can be concluded that verinurad and allopurinol treatment does not induce QTcF prolongation at the highest clinically relevant exposures.

Using bio-impedance to deduce some hemodynamic parameters combined with some short-term ECG temporal dispersion intervals, and measuring myocardial depolarization, intraventricular conduction, and repolarization. A total of 65 in-hospital patients (M/F:35/30) were enrolled, 39 with HFrEF and 26 HFpEF, in New York Heart Association (NYHA) class IV. Stroke volume (SVI), cardiac indexes (CI), left ventricular ejection fraction (LVEFBIO), end diastolic volume (LV-EDV), and other systolic and diastolic parameters were noninvasively obtained at enrollment and at hospital discharge. At the same time, QR, QRS, QT, ST, Tpeak-Tend (Te) interval mean, and standard deviation (SD) from 5 min ECG recordings were obtained. At baseline, HFrEF patients reported significantly lower SVI (p < 0.05), CI (p < 0.05), and LVEF (p < 0.001) than HFpEF patients; moreover, HFrEF patients also showed increased LV-EDV (p < 0.05), QR, QRS, QT, ST, and Te means (p < 0.05) and standard deviations (p < 0.05) in comparison to HFpEF subjects. Multivariable logistic regression analysis reported a significant correlation between hospital mortality and Te mean (odds ratio: 1.03, 95% confidence limit: 1.01−1.06, p: 0.01). Fifty-seven percent of patients were considered responders to optimal medical therapy and, at discharge, they had significantly reduced NT-proBNP, (p < 0.001), heart rate (p < 0.05), and TeSD (p < 0.001). LVEF, obtained by transthoracic echocardiography, and LVEFBIO were significantly related (r: 0.781, p < 0.001), but these two parameters showed a low agreement limit. Noninvasive hemodynamic and ECG-derived parameters were useful to highlight the difference between HFrEF and HFpEF and between responders and nonresponders to the optimal medical therapy. Short-period bioimpedance and electrocardiographic data should be deeply evaluated to determine possible advantages in the therapeutic and prognostic approach in severe CHF.

OBJECTIVE: The purpose of this study was to evaluate the differences in the patient-reported functional outcomes, and graft failure in revision ACL reconstruction using quadriceps tendon (QT), Hamstring tendon (HT) and bone-patellar tendon-bone (BPTB) autografts.
METHODS: Between 2010 and 2020, 97 patients who underwent revision ACL reconstruction (40 patients received a QT, 26 an HT and 31 a BPTB graft) met the inclusion criteria. Pre-injury and at 2-year postoperatively patients were evaluated for patient-reported functional outcomes; Lysholm knee score, Tegner activity level and VAS (visual analogue scale) for pain; and graft failure. Patient-reported outcomes and graft failure were compared between the QT, HT and BPTB groups. The patients with graft failure were not included for outcome analysis at 2-years of follow-up.
RESULTS: All three revision groups with QT, HT and BPTB autograft did not differ significantly in terms of age, sex, time from injury to surgery, concomitant injuries and single-stage or double-stage procedures (n.s.). No significant difference was found in the pre-injury patient-reported outcome; Lysholm knee score, Tegner activity and VAS for pain (n.s.) between the three groups. At the 2-year follow-up functional outcomes improved in all three groups and all the patients returned to pre-injury activity level; however, no significant difference was found in functional outcomes at the 2-year follow-up between the three groups (n.s.). Graft failure occurred in 4 (10%), 5 (19%) and 3 (10%) patients of QT, HT and BPTB groups, respectively. However, the rate of failure did not differ significantly between groups.
CONCLUSIONS: All three autografts (QT, HT and BPTB) demonstrated satisfactory patient-reported outcomes in revision ACL reconstruction. Compared with QT and BPTB grafts, HT graft showed a higher tendency for failure rates. With the increasing incidence of revision ACL reconstruction, surgeons should be aware of all the available graft options. The findings of this study will assist the surgeons in the graft selection for revision ACL reconstruction.
METHODS: Level III.