Comparison of electrogram characteristics in persistent atrial fibrillation.

INTRODUCTION: Multiple analysis techniques evaluate electrograms during atrial fibrillation (AF), but none have been established to guide catheter ablation. This study compares electrogram properties recorded from multiple right (RA) and left atrial (LA) sites. METHODS: Multisite LA/RA mapping (281 ± 176/239 ± 166 sites/patient) was performed in 42 patients (30 males, age 63 ± 9 years) undergoing first (n = 32) or redo-AF ablation (n = 10). All electrogram recordings were visually reviewed and artifactual signals were excluded leaving a total of 21 846 for analysis. Electrogram characteristics evaluated were cycle length (CL), amplitude, Shannon's entropy (ShEn), fractionation interval, dominant frequency, organizational index, and cycle length of most recurrent morphology (CLR ) from morphology recurrence plot analysis. RESULTS: Electrogram characteristics were correlated to each other. All pairwise comparisons were significant (p < .001) except for dominant frequency and CLR (p = .59), and amplitude and dominant frequency (p = .38). Only ShEn and fractionation interval demonstrated a strong negative correlation (r = -.94). All other pairwise comparisons were poor to moderately correlated. The relationships are highly conserved among patients, in the RA versus LA, and in those undergoing initial versus redo ablations. Antiarrhythmic drug therapy did not have a significant effect on electrogram characteristics, except minimum ShEn. Electrogram characteristics associated with ablation outcome were shorter minimum CLR , lower minimum ShEn, and longer mimimum CL. There was minimal overlap between the top 10 sites identified by one electrogram characteristic and the top 10 sites identified by the other 10 characteristics. CONCLUSION: Multiple techniques can be employed for electrogram analysis in AF. In this analysis of eight different electrogram characteristics, seven were poorly to moderately correlated and do not identify similar locations. Only some characteristics were predictive of ablation outcome. Further studies to consider electrogram properties, perhaps in combination, for categorizing and/or mapping AF are warranted.

Vein of Marshall chemical ablation decreases atrial fibrillation drivers detected by CARTOFINDER.

INTRODUCTION: This study sought to elucidate the impact of vein of Marshall (VOM) chemical ablation on atrial fibrillation (AF) drivers by investigating the changes in CARTOFINDER mappings before and after VOM chemical ablation in patients with persistent AF. METHODS: This study included 23 consecutive patients undergoing catheter ablation for long-persistent AF (>18 months). VOM chemical ablation was performed following pulmonary vein isolation. CARTOFINDER and AF cycle length (AFCL) maps were created in the left atrium (LA) before and after VOM chemical ablation. The LA was divided into 8 segments, and the number of focal activation points with 6 or more repetitions was counted in each segment. RESULTS: The number of focal activation points was largest in the LA appendage (LAA). After VOM chemical ablation, the number of focal activation points in the LA decreased significantly (37 [interquartile range, IQR: 19-55] vs. 15 [IQR: 7-21], p < .001), and median AFCL was significantly prolonged (159 [147-168] vs. 164 [150-173] ms, p < .001). In the assessment of each segment, significant decreases in focal activation points were observed in the inferior, lateral, and anterior segments and LAA. Among the focal activation points disappearing after chemical ablation, the number in the non-ethanol-affected area was significantly larger than that in the affected area (13 [8-25] vs. 4 [1-10], p < .001). CONCLUSIONS: VOM chemical ablation decreases AF drivers detected by CARTOFINDER. Mechanisms other than direct myocardial damage are considered to contribute the attenuation of AF drivers.

Is prolonged luteal phase a problem in lactating Holstein cows?

In this study, the main objective was to assess if long luteal phases could have other causes than pregnancy losses. We enrolled Holstein dairy cows ≥50 d in milk (DIM) from a commercial herd in Brazil from October 2016 to August 2017. All cows received an estradiol-based synchronization protocol, and, on the day of insemination (d 0), were randomly assigned either an artificial insemination (AI) or a placebo insemination (PBO) in a 3:1 ratio. An ultrasound was used to assess the presence of a CL on d17, 24, and 31, which, combined to the information from patches for the detection of estrus, was used to determine the length of the luteal phase following AI or PBO. Pregnancy was assessed by ultrasound on d 31 and cows that were pregnant were excluded from the analyses. The length of the estrous cycles was categorized as short (<17 d), normal (17-23 d), long (24-30 d), and very long (≥31 d). We compared the proportion of cows in each category between the AI and PBO groups using a cumulative ordinal mixed model. We define prolonged luteal phase as estrous cycles ≥24 d and tested its association with potential risk factors (parity, season, DIM, uterine size and position score, milk production, body condition score, and the presence of a corpus luteum (CL) at enrollment to the synchronization protocol) using mixed logistic regression models. Results are presented as odds ratio (OR) and 95% credible intervals (BCI). Data from 876 inseminations (AI: n = 616, PBO: n = 260) was collected. Overall, 12% of estrous cycles were short, 31% were normal, 19% were long, and 38% were very long. There was no difference in the odds of being in longer estrous cycle categories for the AI compared with the PBO group (OR = 0.92, 95% BCI = 0.76-1.10). Season and presence of a CL at enrollment were associated with prolonged luteal phase. In the AI group, there was a possible effect of early pregnancy losses on the lifespan of the CL, but not the PBO group, which led us to conclude that long and very long estrous cycles were not all caused by the embryonic loss. In fact, the high prevalence of cows with an extended CL lifespan in the present study suggests this could be an under- or miss-reported characteristic of high-producing lactating Holstein cows. This finding may have important repercussions in the understanding of the CL function physiology of lactating Holstein cows.

Inositol is an effective and safe treatment in polycystic ovary syndrome: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Metformin is the gold standard insulin sensitizer, which is widely used to treat insulin resistance in polycystic ovary syndrome (PCOS). However, metformin may induce gastrointestinal side effects. OBJECTIVE: Inositols have long been debated as a potential alternative for metformin in treating PCOS. Therefore, the present systematic review aimed to evaluate the efficacy and safety of inositols in treating PCOS. METHODS: The present systematic search was performed in CENTRAL, MEDLINE, and Embase from the inception until October 20th, 2021. Eligible randomized controlled trials (RCTs) included women diagnosed with PCOS and compared any inositols with metformin or placebo. Our primary outcome was cycle normalization, whereas secondary outcomes were body mass index (BMI), parameters of carbohydrate metabolism and clinical and laboratory hyperandrogenism. Results are reported as risk ratios or mean differences (MDs) with 95% confidence intervals (CIs). RESULTS: Twenty-six RCTs were identified, including data of 1691 patients (806 inositol, 311 with placebo, and 509 metformin groups). In patients treated with inositols, the risk (CI: 1.13; 2.85) of having a regular menstrual cycle was found by 1.79 higher than in the case of placebo. Moreover, the inositols showed non-inferiority compared to metformin in this outcome. In the case of BMI (MD = -0.45; CI: -0.89; -0.02), free testosterone (MD = -0,41, CI: -0.69; -0.13), total testosterone (MD = -20.39, CI: -40.12; -0.66), androstenedione (MD = -0.69, CI: -1,16; -0.22), glucose (MD = -3.14; CI: -5.75; -0.54) levels and AUC insulin (MD = -2081.05, CI: -2745.32; -1416.78) inositol treatment induced greater decrease compared to placebo. Inositol increased sex-hormone-binding globulin significantly compared to placebo (MD = 32.06, CI:1.27; 62.85). CONCLUSION: Inositol is an effective and safe treatment in PCOS. Moreover, inositols showed non-inferiority in most outcomes compared to the gold standard treatment; metformin. TRIAL REGISTRATION: PROSPERO registration number: CRD42021283275.

Detailed analysis of tachycardia cycle length aids diagnosis of the mechanism and location of atrial tachycardias.

AIMS: Although the mechanism of an atrial tachycardia (AT) can usually be elucidated using modern high-resolution mapping systems, it would be helpful if the AT mechanism and circuit could be predicted before initiating mapping. OBJECTIVE: We examined if the information gathered from the cycle length (CL) of the tachycardia can help predict the AT-mechanism and its localization. METHODS: One hundred and thirty-eight activation maps of ATs including eight focal-ATs, 94 macroreentrant-ATs, and 36 localized-ATs in 95 patients were retrospectively reviewed. Maximal CL (MCL) and minimal CL (mCL) over a minute period were measured via a decapolar catheter in the coronary sinus. CL-variation and beat-by-beat CL-alternation were examined. Additionally, the CL-respiration correlation was analysed by the RhythmiaTM system. : Both MCL and mCL were significantly shorter in macroreentrant-ATs [MCL = 288 (253-348) ms, P = 0.0001; mCL = 283 (243-341) ms, P = 0.0012], and also shorter in localized-ATs [MCL = 314 (261-349) ms, P = 0.0016; mCL = 295 (248-340) ms, P = 0.0047] compared to focal-ATs [MCL = 506 (421-555) ms, mCL = 427 (347-508) ms]. An absolute CL-variation (MCL-mCL) < 24 ms significantly differentiated re-entrant ATs from focal-ATs with a sensitivity = 96.9%, specificity = 100%, positive predictive value (PPV) = 100%, and negative predictive value (NPV) = 66.7%. The beat-by-beat CL-alternation was observed in 10/138 (7.2%), all of which showed the re-entrant mechanism, meaning that beat-by-beat CL-alternation was the strong sign of re-entrant mechanism (PPV = 100%). Although the CL-respiration correlation was observed in 28/138 (20.3%) of ATs, this was predominantly in right-atrium (RA)-ATs (24/41, 85.7%), rather than left atrium (LA)-ATs (4/97, 4.1%). A positive CL-respiration correlation highly predicted RA-ATs (PPV = 85.7%), and negative CL-respiration correlation probably suggested LA-ATs (NPV = 84.5%). CONCLUSION: Detailed analysis of the tachycardia CL helps predict the AT-mechanism and the active AT chamber before an initial mapping.

Assessing the utility of atrial fibrillation induction to risk stratify children with Wolff-Parkinson-White syndrome.

BACKGROUND: Wolff-Parkinson-White syndrome is associated with sudden cardiac death from rapid conduction through the accessory pathway in atrial fibrillation. Adult patients are at higher risk for sudden cardiac death if the shortest-pre-excited-RR-interval in atrial fibrillation (SPERRI) is ≤250 milliseconds (msec) during electrophysiologic study. Exclusive conduction through the atrioventricular node in atrial fibrillation is presumed to convey lower risk. The shortest-pre-excited-paced-cycle-length with atrial pacing has also served as a marker for risk stratification. OBJECTIVE: To determine accessory pathway characteristic of patients undergoing induction of atrial fibrillation during electrophysiologic study. METHODS: We reviewed 321 pediatric patients that underwent electrophysiologic study between 2010 and 2019. Induction of atrial fibrillation was attempted on patients while on isoproterenol and SPERRI was measured if atrial fibrillation was induced. Shortest-pre-excited-paced-cycle-length (SPPCL) was determined while on isoproterenol. RESULTS: Atrial fibrillation was induced in 233 (73%) patients. Of those, 104 (45%) patients conducted exclusively through the atrioventricular node during atrial fibrillation (Group A). The remaining 129 (55%) patients had some conduction through the accessory pathway (Group B). In Group A, SPPCL was 260 msec with 48 (46%) conducting through the accessory pathway at ≤250 msec. In Group B, SPPCL was 240 msec with 92 patients (71%) conducting at ≤250 msec (p < 0.05). In Group B, SPERRI was 250 msec and had a positive correlation with SPPCL (p < 0.001, R2 = 0.28). Almost half (46%) of those with exclusive conduction through the atrioventricular node in atrial fibrillation had rapid accessory pathway conduction with atrial pacing. CONCLUSION: Conduction in atrial fibrillation during electrophysiologic study on isoproterenol via the atrioventricular node may not exclude high-risk accessory pathways in pediatric patients.

Circuit Determinants of Ventricular Tachycardia Cycle Length: Characterization of Fast and Unstable Human Ventricular Tachycardia.

BACKGROUND: Fast ventricular tachycardias (VTs) have historically been attributed to shorter path lengths with smaller reentrant circuit dimensions in animal models. The relationship between the dimensions of the reentrant VT circuit and tachycardia cycle length (TCL) has not been examined in humans. This study aimed to analyze the determinants of the rate of human VT with comparison of circuit dimensions and conduction velocity (CV) across a wide range of both stable and unstable VTs delineated by high-resolution mapping. METHODS: Fifty-four VTs with complete circuit delineation (>90% TCL) by high-resolution multielectrode mapping were analyzed in 49 patients (men, 88%; age, 65 years [58-71 years]; nonischemic, 47%). Fast VT was defined as TCL <333 milliseconds (rate >180 bpm). Unstable VT was defined by hemodynamic deterioration with an intrinsic mean arterial pressure <60 mm Hg during a sustained episode. RESULTS: The median TCL of VT was 365 milliseconds (306-443 milliseconds), and 24 fast VTs were characterized. A wide range of CVs was observed within the entrance (0.03-0.55 m/s), common pathway (0.03-0.77 m/s), exit (0.03-0.53 m/s), and outer loop (0.17-1.13 m/s). There were no significant differences in the median dimensions of the isthmus and path length between fast and slow VTs and between unstable and stable VTs. The outer loop CV was the only circuit component that correlated with TCL in both ischemic cardiomyopathy (r=-0.5, P=0.006) and nonischemic cardiomyopathy (r=-0.45, P=0.028). The duration of the longest diastolic electrogram was inversely correlated with the dimensions of common pathway (length: r=-0.46, P=0.001, width: r=-0.3, P=0.047) and predictive of rapid VT termination by a single radiofrequency application (r=-0.41, P=0.023). CONCLUSIONS: Because of a wide spectrum of CV observed within the reentrant path during human VT, the dimensions of the circuit were not predictive of VT cycle length. For the first time, we demonstrate that the CV of the outer loop, rather than isthmus, is the principal determinant of the rate of VT. The size of the circuit was similar between fast and slow VTs and between unstable and stable VTs. Long, continuous electrograms were indicative of spatially confined isthmus dimensions, confirmed by rapid termination of VT during radiofrequency delivery.

Reproducibility and predictive value of a simple novel method to measure atrial fibrillation cycle length in persistent atrial fibrillation - FARS-AF study.

INTRODUCTION: Different methods are used for atrial fibrillation (AF) cycle length (CL) measurement with variable results. Previous studies of pulmonary vein (PV) CL measurement showed contradictory results on predicting PV isolation (PVI) efficacy. A novel simple method of measuring the average of 10 consecutive Fastest Atrial Repetitive Similar morphology signal (FARS10 )-CL to characterize local atrial activity rate was evaluated prospectively. METHODS: The intra-observer reproducibility of FARS10 -CL and traditional AF-CL measurement of continuously fragmented coronary sinus (CS) signals were tested. We prospectively enrolled 100 consecutive patients (62 ± 10 years, 72% male) undergoing wide antral PVI only ablation for persistent AF, measured PV-FARS10 -CLs, and evaluated long-term outcome. RESULTS: The Kendall area correlation between repeated traditional AF-CL measurements was -0.006 and between repeated FARS10 -CL measurements in the right and left atrial appendages, CS and PVs were 0.944, 0.859, 0.882, 0.675-0.955, respectively. Patients with recurrent atrial tachyarrhythmia had significantly longer fastest PV-FARS10 -CL (172 ± 41 vs. 156 ± 41 ms, p = .047). Patients with high burden of spontaneous low-voltage zone (LVZ) had significantly longer fastest PV-FARS10 -CL. Freedom from recurrent tachyarrhythmia at 24 months was 85% versus 59% in patients with fastest PV-FARS10 -CL ≤ 140 versus >140 ms, p = .0018, respectively. In multivariable analysis fastest PV-FARS10 -CL ≤ 140 ms was the only significant predictor of freedom from recurrent tachyarrhythmia. CONCLUSIONS: FARS10 -CL measurements have a high reproducibility in contrast to traditional AF-CL measurement of continuously fragmented CS signals. Patients with high burden of LVZ have longer fastest PV-FARS10 -CLs. Fastest PV-FARS10 -CL ≤ 140 ms is associated with a high success of wide antral PVI-only ablation approach in persistent AF.

Menstrual cycle characteristics and incident cancer: a prospective cohort study.

STUDY QUESTION: Are menstrual cycle characteristics throughout the reproductive lifespan associated with cancer risk? SUMMARY ANSWER: Irregular and long menstrual cycles throughout the reproductive lifespan were associated with increased risk of total invasive cancer, especially obesity-related cancers. WHAT IS KNOWN ALREADY: Long and irregular menstrual cycles have been associated with lower risk of pre-menopausal breast cancer and higher risk of endometrial cancer, but associations with other malignancies are less clear. STUDY DESIGN, SIZE, DURATION: Prospective cohort study. Prospective follow-up of 78 943 women participating in the Nurses' Health Study II between 1989 and 2015. PARTICIPANTS/MATERIALS, SETTING, METHODS: We followed 78 943 pre-menopausal women without cancer history who reported the usual length and regularity of their menstrual cycles at different ages (14-17, 18-22 and 29-46 years). Cancer diagnosis was confirmed through medical record review and classified as obesity-related (colorectal, gallbladder, kidney, multiple myeloma, thyroid, pancreatic, esophageal, gastric, liver, endometrial, ovarian and post-menopausal breast) or non-obesity-related. We fitted Cox proportional hazards models to estimate hazard ratios (HRs) and 95% CIs of the association between menstrual cycle characteristics and cancer incidence. MAIN RESULTS AND THE ROLE OF CHANCE: We documented 5794 incident cancer cases during 1 646 789 person-years of follow-up. After adjusting for BMI and other potential confounders, women reporting irregular cycles at age 29-46 years had an 11% (95% CI: 2-21%) higher risk of total invasive cancer than women reporting very regular cycles at the same age. This association was limited to obesity-related cancers, with a 23% (95% CI: 9-39%) higher risk and was strongest for endometrial cancer (HR = 1.39; 95% CI: 1.09-1.77). Findings were comparable for cycle characteristics earlier in life and for menstrual cycle length. Very irregular cycles at age 14-17 years were associated with significant increase in risk of colorectal cancer (HR = 1.36; 95% CI: 1.02-1.81). LIMITATIONS, REASONS FOR CAUTION: Our study might be subject to recall bias for findings pertaining to cycle characteristics in adolescence and early adulthood, as these were retrospectively reported. Generalizability to non-White women may be limited, as 96% of participants were White. WIDER IMPLICATIONS OF THE FINDINGS: Women with irregular or long menstrual cycles in mid-adulthood had a statistically significantly higher risk of developing cancer, especially obesity-related cancers. This association was not limited to gynecological cancers. Obesity-related cancers may need to be added to the spectrum of long-term health consequences of long or irregular cycles, possibly warranting targeted screening among women who experience long or irregular cycles in mid-adulthood. STUDY FUNDING/COMPETING INTEREST: This work was supported by grants U01 CA176726, U01 HL145386 and R01 HD096033 from the National Institutes of Health. The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

A prospective study of the association between SARS-CoV-2 infection and COVID-19 vaccination with changes in usual menstrual cycle characteristics.

BACKGROUND: Despite anecdotal reports, the impacts of SARS-CoV-2 infection or COVID-19 vaccination on menstrual health have not been systemically investigated. OBJECTIVE: This study aimed to examine the associations of SARS-CoV-2 infection and COVID-19 vaccination with menstrual cycle characteristics. STUDY DESIGN: This study prospectively observed 3858 premenopausal women in the Nurses' Health Study 3 living in the United States or Canada who received biannual follow-up questionnaires between January 2011 and December 2021 and completed additional monthly and quarterly surveys related to the COVID-19 pandemic between April 2020 and November 2021. History of positive SARS-CoV-2 test, COVID-19 vaccination status, and vaccine type were self-reported in surveys conducted in 2020 and 2021. Current menstrual cycle length and regularity "before COVID-19" were reported at baseline between 2011 and 2016, and current menstrual cycle length and regularity "after COVID-19" were reported in late 2021. Pre- to post-COVID change in menstrual cycle length and regularity was calculated between reports. Logistic or multinomial logistic regression models were used to assess the associations between SARS-CoV-2 infection and COVID-19 vaccination and change in menstrual cycle characteristics. RESULTS: The median age at baseline and the median age at end of follow-up were 33 years (range, 21-51) and 42 years (range, 27-56), respectively, with a median follow-up time of 9.2 years. This study documented 421 SARS-CoV-2 infections (10.9%) and 3527 vaccinations (91.4%) during follow-up. Vaccinated women had a higher risk of increased cycle length than unvaccinated women (odds ratio, 1.48; 95% confidence interval, 1.00-2.19), after adjusting for sociodemographic and behavioral factors. These associations were similar after in addition accounting for pandemic-related stress. COVID-19 vaccination was only associated with change to longer cycles in the first 6 months after vaccination (0-6 months: odds ratio, 1.67 [95% confidence interval, 1.05-2.64]; 7-9 months: odds ratio, 1.43 [95% confidence interval, 0.96-2.14]; >9 months: odds ratio, 1.41 [95% confidence interval, 0.91-2.18]) and among women whose cycles were short, long, or irregular before vaccination (odds ratio, 2.82 [95% confidence interval, 1.51-5.27]; odds ratio, 1.10 [95% confidence interval, 0.68-1.77] for women with normal length, regular cycles before vaccination). Messenger RNA and adenovirus-vectored vaccines were both associated with this change. SARS-CoV-2 infection was not associated with changes in usual menstrual cycle characteristics. CONCLUSION: COVID-19 vaccination may be associated with short-term changes in usual menstrual cycle length, particularly among women whose cycles were short, long, or irregular before vaccination. The results underscored the importance of monitoring menstrual health in vaccine clinical trials. Future work should examine the potential biological mechanisms.

Menstrual cycle length and adverse pregnancy outcomes among women in Project Viva.

BACKGROUND: Retrospective studies suggest that menstrual cycle length may be a risk marker of adverse pregnancy outcomes, but this evidence is susceptible to recall bias. OBJECTIVE: To evaluate the prospective association between menstrual cycle length and the risk of adverse pregnancy outcomes. METHODS: Secondary analysis of 2046 women enrolled in Project Viva at ~10 weeks of gestation and followed through delivery. The exposure was menstrual cycle length. The outcomes included gestational glucose tolerance (gestational diabetes/impaired glucose tolerance [GDM/IGT] and isolated hyperglycaemia), hypertensive disorders of pregnancy (gestational hypertension/preeclampsia), gestational weight gain, birthweight-for-gestational age z-scores (BWZ) categorised in tertiles, preterm birth and birth outcome (live birth and pregnancy loss). We used modified Poisson and multinomial logistic regression adjusted for age, race/ethnicity, parity, age at menarche and pre-pregnancy body mass index. RESULTS: Mean (SD) age at enrolment was 32.1 (4.9) years. Most women (74.3%) had a cycle length of 26-34 days (reference group), 16.2% reported short cycles (≤25 days), and 9.5% reported long/irregular cycles (≥35 days/too irregular to estimate). Compared with the reference group, women with short cycles had lower odds of GDM/IGT (odds ratio [OR] 0.50, 95% confidence interval [CI] 0.28, 0.89), whereas women with long/irregular cycles had higher odds (OR 1.72, 95% CI 1.04, 2.83). Additionally, women with short cycles had higher odds of having a newborn in the lowest tertile of BWZ (OR 1.45, 95% CI 1.06, 1.98). There was a U-shaped relation between cycle length and preterm birth with both short (relative risk [RR] 1.49, 95% CI 0.98, 2.27) and long/irregular (RR 2.04, 95% CI 1.30, 3.20) cycles, associated with a higher risk. CONCLUSIONS: Variation in menstrual cycle length may be a risk marker of GDM/IGT, lower birth size and preterm birth and flag women who may benefit from targeted monitoring and care before and during pregnancy.

New AMH cutoff values for warning of decreased ovarian response based on MCL characteristics in young women: a retrospective study using a propensity score-matching analysis.

BACKGROUND: Menstrual cycle length (MCL) and ovarian response varies widely among women of childbearing age. They are provided with anti-Mu¨llerian hormone (AMH) cutoffs for "normal" and "weakened" ovarian responses, which give an early warning of the onset of decreased ovarian response. METHODS: This was a retrospective study in women aged 21 to 35 years with MCLs of 21-35 days receiving in vitro fertilization (IVF) treatment at Center for Reproductive Medicine from October 2018 to October 2021. Intergroup variables were balanced using propensity score matching based on age and BMI, and each case patient (patients with MCLs of 21-25 days) was matched with three control patients (patients with MCLs of 26-35 days). A receiver operating characteristic curve was used to calculate the AMH cutoff values. RESULTS: We included 135 patients with MCLs of 21-25 days and 405 matched control patients with MCLs of 26-35 days who received IVF treatment. The case group had significantly fewer retrieved oocytes, lower AMH values and higher initial and total Gonadotropin (Gn) levels during controlled ovarian hyperstimulation than the control group. The ovarian response began to decrease when AMH was < 3.5 ng/ml in the case group and < 2.7 ng/ml in the control group. CONCLUSION: In young women with MCLs of 21-35 days, short MCL was negatively correlated with AMH values and the number of oocytes retrieved. In patients with MCLs of 21-25 days and 26-35 days, the AMH cutoff values corresponding to the onset of decreased ovarian response were 3.5 ng/ml and 2.7 ng/ml, respectively.

Fibrillation cycle length predicts cardiovascular events in patients with long-standing persistent atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) is associated with an increased risk of heart failure (HF), stroke, and death. Although fibrillation cycle length (FCL) is used as a surrogate for atrial refractoriness, its impact on outcomes remains unclear. This study aimed to identify predictors of cardiovascular events, including FCL, in patients with long-standing persistent AF. METHODS: The study included 190 consecutive patients with long-standing persistent AF (mean age 74 years, 74% male). Patients with valvular AF or hemodialysis-dependent end-stage renal disease and those on anti-arrhythmic drugs were excluded. The primary composite outcome was occurrence of cardiovascular events (myocardial infarction, HF), cerebrovascular events (stroke, transient ischemic attack), and all-cause death. FCL was calculated by fast Fourier transformation analysis of fibrillation waves in the surface electrocardiogram. RESULTS: Over a median follow-up of 2.6 years, the primary outcome occurred in 31 patients (cardiovascular events, n = 18; cerebrovascular events, n = 8; all-cause death, n = 5). In multivariate analysis, longer FCL and history of HF were independent predictors of these outcomes. In a Cox proportional hazards model adjusted for age, sex, and history of HF, patients with an FCL > 160 ms (cut-off determined by receiver-operating characteristic curve analysis) were at increased risk of the outcome (hazard ratio 12.9; 95% confidence interval 4.99-44.10; p < 0.001). CONCLUSIONS: FCL was independently associated with cardiovascular outcomes in patients with long-standing persistent AF.

Identification of high priority focal activations in persistent atrial fibrillation using a novel mapping strategy.

Focal activation is believed to be an atrial fibrillation (AF) driver; however, little is known about whether all focal activations are necessary for AF persistence. The purpose of this study was to assess the electrical nature of focal activation and identify high-priority focal activations using a novel mapping system (CARTOFINDER). Thirty-five patients with persistent AF who underwent catheter ablation were assessed. Cycle length (CL) and CL standard deviation (CLSD) on unipolar recordings and voltage amplitude and electrogram morphologies on bipolar recordings were evaluated at all points of interest. The most frequent CL at each mapping site was defined as the dominant CL. We identified dominant focal activations (DFAs) that had a shorter dominant CL on the integrated CARTOFINDER map. The effect of elimination of DFAs on AF maintenance was assessed by the composite endpoint (termination to sinus rhythm, organization of the rhythm to atrial tachycardia, and AF CL slowing). In all, 450 focal activations were identified among 10,868 points, and 50.4% of focal activations were DFAs. Focal activations showed relatively long CL and regularity with short CLSD. Most focal activations showed an isoelectric baseline and were located outside of the fractionated electrogram area. Both DFAs and non-DFAs were typically observed in the normal voltage range. Elimination of DFAs was achieved in 19 (54.3%) patients, with a remarkable impact on AF maintenance (68.4% vs. 25.0%, p = 0.018). In conclusion, DFAs may play an important role in AF maintenance and could be an attractive therapeutic target for AF.

Characteristics of patients with atrial flutter and spontaneous 1:1 atrioventricular conduction with and without anti-arrhythmic drug treatment.

Atrial flutter (AFL) is a large reentrant circuit located in the right atrium. Anti-arrhythmic drugs (AADs) can provoke AFL with 1:1 atrioventricular conduction (AVC) to cause hemodynamic collapse. We elucidated the characteristics of patients with AFL exhibiting spontaneous 1:1 AVC. Fifteen patients (1:1 AFL group; 11 males, 52.4 ± 13.7 years old) who documented AFL with 1:1 AVC were enrolled and compared to 153 patients without 1:1 AVC (Control group; 137 males, 68.9 ± 11.2 years old). AFL cycle length during maximum AVC was significantly longer in the 1:1 AFL group than in the control group (274.7 ± 37.0 vs. 216.2 ± 25.6 ms, p < 0.001). Among 1:1 AVC group, 9 patients had AADs, and AFL cycle length was significantly longer during 1:1 AVC as compared with 2:1 AVC documented the other day (284.4 ± 41.3 vs. 233.3 ± 26.0 ms, p < 0.001), suggesting enhancement effect of the AADs during 1:1 AVC. Remaining 6 patients who did not take AADs, 2 patients showed enlargement of the tricuspid annulus and 3 patients developed 1:1 AVC during exercise. Multivariate analysis revealed that younger age and the use of AADs was independent risk factors for the development of 1:1 AFL group. Prolonged AFL cycle length associated with the class Ia/Ic AAD use, slower heart rate during sinus rhythm and younger age were important risk factors for the development of 1:1 AVC during AFL.

The early embryonic heart regenerates by compensation of proliferating residual cardiomyocytes after cryoinjury.

The adult mammalian heart is non-regenerative because cardiomyocytes withdraw from the cell cycle shortly after birth. Embryonic mammalian hearts, in which cardiomyocytes are genetically ablated in a salt-and-pepper-like pattern, regenerate due to compensation by residual cardiomyocytes. To date, it remains unknown whether or how transmural ventricular defects at the looped heart stage regenerate after cryoinjury. We established a cryoablation model in stage 16 chick embryonic hearts. In hearts at 5 h post cryoinjury (hpc), cryoinjury-induced defects were approximately 200 µm in width in the primitive ventricle; thereafter, the defect was filled with mesenchymal cells accumulating between the epicardium and endocardium. The defect began to regress at 4 days post cryoinjury (dpc) and disappeared around 9 dpc. Immunohistochemistry showed that there were no isl1-positive cells in either the scar tissue or residual cardiomyocytes. BrdU incorporation into residual cardiomyocytes was transiently downregulated in association with upregulation of p27 (Kip1), suggesting that cell cycle arrest occurred at G1-to-S transition immediately after cryoinjury. Estimated cell cycle length was examined, and the results showed that the shortest cell cycle length was 18 h at stages 19-23; it increased with development due to elongation of the G2-M-G1 phase and 30 h at stages 27-29. The S phase length was constant at 6-8 h. The cell cycle length was elongated immediately after cryoinjury, and it reversed at 1-2 dpc. Cryoablated transmural defects in the early embryonic heart were restored by compensation by residual myocytes.

A prospective evaluation of the impact of individual RF applications for slow pathway ablation for AVNRT: Markers of acute success.

BACKGROUND: Catheter ablation is highly effective for atrioventricular nodal re-entrant tachycardia (AVNRT). Generally junctional rhythm (JR) is an accepted requirement for successful ablation however there is a lack of detailed prospective studies to determine the characteristics of JR and the impact on slow pathway conduction. METHODS: Multicentre prospective observational study evaluating the impact of individual radiofrequency (RF) applications in typical AVNRT (slow/fast). Characteristics of JR during ablation were documented and detailed testing was performed after every RF application to determine outcome. Procedural success was defined as ≤1 AV nodal echo. RESULTS: Sixty-seven patients were included (mean age 53 ± 18years, 57% female and a history of SVT 2.9 ± 4.7 years). RF (50w, 60°) ablation for AVNRT was applied in 301 locations with JR in 178 (59%). Successful slow pathway modification was achieved in 66 (99%) patients with slow pathway block in 30 (46%). Success was associated with JR in all patients. Success was achieved in six patients with RF < 10 s. There was no significant difference in the CL of JR during RF between effective (587 ± 150 ms) versus ineffective (611 ± 193 ms, p = .4) applications. Inadvertent junctional beat-atrial (JA) block with immediate termination of RF was observed in 19 (28%) patients with AVNRT no longer inducible in 14 (74%). Freedom from SVT was achieved in 66 (99%) patients at a mean follow up of 15 ± 6 months. CONCLUSION: In this prospective study, JR was required during RF for acute success in AVNRT. Cycle length of JR during RF was not predictive of success. Although unintended JA block during faster JR was associated with slow pathway block, this is a precursor to fast pathway block and should not be intentionally targeted.

Length of estradiol exposure >100 pg/ml in the follicular phase affects pregnancy outcomes in natural frozen embryo transfer cycles.

STUDY QUESTION: Do the length of follicular phase estradiol exposure and the total length of the follicular phase affect pregnancy and live birth outcomes in natural frozen embryo transfer (FET) cycles? SUMMARY ANSWER: An estradiol level >100 pg/ml for ≤4 days including the LH surge day is associated with worse pregnancy and live birth outcomes; however, the total length of the follicular phase is not associated with pregnancy and live birth outcomes. WHAT IS KNOWN ALREADY: An estradiol level that increases above 100 pg/ml and continues to increase is indicative of the selection and development of a dominant follicle. In programmed FET cycles, a limited duration of follicular phase estradiol of <9 days results in worse pregnancy rates, but a prolonged exposure to follicular phase estradiol for up to 4 weeks does not affect pregnancy outcomes. It is unknown how follicular phase characteristics affect pregnancy outcomes in natural FET cycles. STUDY DESIGN, SIZE, DURATION: This retrospective cohort study included infertile patients in an academic hospital setting who underwent their first natural frozen autologous Day-5 embryo transfer cycle in our IVF clinic between 01 January 2013 and 31 December 2018. Donor oocyte and gestational carrier cycles were excluded. PARTICIPANTS/MATERIALS, SETTING, METHODS: The primary outcomes of this study were pregnancy and live birth rates. Patients were stratified into two groups based on the cohorts' median number of days from the estradiol level of >100 pg/ml before the LH surge: Group 1 (≤4 days; n = 1052 patients) and Group 2 (>4 days; n = 839 patients). Additionally, patients were stratified into two groups based on the cohorts' median cycle day of LH surge: Group 1 (follicular length ≤15 days; n = 1287 patients) and Group 2 (follicular length >15 days; n = 1071 patients). A subgroup analysis of preimplantation genetic testing for aneuploidies (PGT-A) embryo transfer cycles was performed. Logistic regression analysis, adjusted a priori for patient age, number of embryos transferred, and use of PGT-A, was used to estimate the odds ratio (OR) with a 95% CI. MAIN RESULTS AND THE ROLE OF CHANCE: In the length of elevated estradiol analysis, the pregnancy rate per embryo transfer was statistically significantly lower in patients with an elevated estradiol to surge of ≤4 days (65.6%) compared to patients with an elevated estradiol to surge of >4 days (70.9%; OR 1.30 (95% CI 1.06-1.58)). The live birth rate per embryo transfer was also statistically significantly lower in patients with an elevated estradiol to surge of ≤4 days (46.6%) compared to patients with an elevated estradiol to surge of >4 days (52.0%; OR 1.23 (95% CI 1.02-1.48)). In the follicular phase length analysis, the pregnancy rate per embryo transfer was similar between patients with a follicular length of ≤15 days (65.4%) and patients with a follicular length of >15 days (69.0%; OR 1.12 (95% CI 0.94-1.33)): the live birth rate was also similar between groups (45.5% vs 51.5%, respectively; OR 1.14 (95% CI 0.97-1.35)). In all analyses, once a pregnancy was achieved, the length of the follicular phase or the length of elevated oestradiol >100 pg/ml no longer affected the pregnancy outcomes. LIMITATIONS, REASONS FOR CAUTION: The retrospective design of this study is subject to possible selection bias in regard to which patients at our clinic were recommended to undergo a natural FET compared to a fresh embryo transfer or programmed FET. To decrease the heterogeneity of our study population, we only included patients who had blastocyst embryo transfers; therefore, it is unknown whether similar results would be observed in patients with cleavage-stage embryo transfers. The retrospective nature of the study design did not allow randomized to a specific ovarian stimulation or ovulation trigger protocol. However, all patients were managed with the standardized protocols at a single center, which strengthens the external validity of our results when compared to a study that only evaluates one specific stimulation protocol. WIDER IMPLICATIONS OF THE FINDINGS: Our observations provide cycle-level characteristics that can be applied during a natural FET cycle to help optimize embryo transfer success rates. Physicians should consider the parameter of number of days that oestradiol is >100 pg/ml prior to the LH surge when determining whether to proceed with embryo transfer in a natural cycle. This cycle-specific characteristic may also help to provide an explanation for some failed transfer cycles. Importantly, our findings should not be used to determine whether to recommend a natural or a programmed FET cycle for a patient, but rather, to identify natural FET cycles that are not optimal to proceed with embryo transfer. STUDY FUNDING/COMPETING INTEREST(S): No financial support, funding, or services were obtained for this study. The authors do not report any potential conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

Cycle length statistics during human atrial fibrillation reveal refractory properties of the underlying substrate: a combined in silico and clinical test of concept study.

AIMS: The treatment of atrial fibrillation beyond pulmonary vein isolation has remained an unsolved challenge. Targeting regions identified by different substrate mapping approaches for ablation resulted in ambiguous outcomes. With the effective refractory period being a fundamental prerequisite for the maintenance of fibrillatory conduction, this study aims at estimating the effective refractory period with clinically available measurements. METHODS AND RESULTS: A set of 240 simulations in a spherical model of the left atrium with varying model initialization, combination of cellular refractory properties, and size of a region of lowered effective refractory period was implemented to analyse the capabilities and limitations of cycle length mapping. The minimum observed cycle length and the 25% quantile were compared to the underlying effective refractory period. The density of phase singularities was used as a measure for the complexity of the excitation pattern. Finally, we employed the method in a clinical test of concept including five patients. Areas of lowered effective refractory period could be distinguished from their surroundings in simulated scenarios with successfully induced multi-wavelet re-entry. Larger areas and higher gradients in effective refractory period as well as complex activation patterns favour the method. The 25% quantile of cycle lengths in patients with persistent atrial fibrillation was found to range from 85 to 190 ms. CONCLUSION: Cycle length mapping is capable of highlighting regions of pathologic refractory properties. In combination with complementary substrate mapping approaches, the method fosters confidence to enhance the treatment of atrial fibrillation beyond pulmonary vein isolation particularly in patients with complex activation patterns.

Fourier analysis using the number of COVID-19 daily deaths in the US.

Fourier analysis can provide policymakers useful information for analysing the pandemic behaviours. This paper proposes a Fourier analysis approach for examining the cycle length and the power spectrum of the pandemic by converting the number of deaths due to coronavirus disease 2019 in the US to the frequency domain. Policymakers can control the pandemic by using observed cycle length whether they should strengthen their policy or not. The proposed Fourier method is useful for analysing waves in other medical applications.