Period Of Rhythm Research Articles

Arterial hypertension and COVID-19 in Arctic rotating shift work: the impact of chronostructure disruptions on circadian blood pressure rhythm in relation to echocardiographic parameters

This study investigated the effects of chronostructure disruptions on circadian blood pressure (BP) rhythms and their association with echocardiographic parameters in men with arterial hypertension (AH) who contracted COVID-19 while engaged in rotating shift work in the Arctic. Methods – A random sample of 166 men with arterial hypertension (AH) was selected from the medical records database of patients treated at the hospital of the Medical Unit of Gazprom Dobycha Yamburg LLC in Yamburg (Nadymsky District, Russia, 68° 21’ 40” N) between June 2020 and March 2021. Randomization was achieved using a random number method. These patients underwent echocardiography (ECHO) and 24-hour ambulatory blood pressure monitoring (ABPM) before the COVID-19 pandemic (November 2019 to March 2020) and again in 2021. The group was then divided into those who had contracted COVID-19 (n=94) and those who had not (n=72). ABPM was performed using a BPLab v.3.2 device (BPlab, Russia). Chronobiological analysis was performed to identify the main hypertensive BP chronotypes (CT) based on the P. Cugini classification: “MESOR AH”, characterized by a 24-hour rhythm period (T); and “Aperiodic AH”, characterized by a predominance of oscillations with periods (T) of 4.0, 4.8, 6.0, and 8.0 hours within the circadian rhythm. Echocardiography (ECHO) was performed using a Philips CX 50 scanner (Netherlands). Results – Logistic regression analysis showed that the presence of the “Aperiodic AH” chronotype was associated with a threefold increase in the odds of contracting COVID-19, while a 1 g/m² increase in the left ventricular mass index (LVMI) increased these odds by a factor of 1.02. One year post-COVID-19, individuals with “Aperiodic AH”, in contrast to those with “MESOR AH”, exhibited increases in right atrial and inferior vena cava diameters, systolic pulmonary artery pressure, tricuspid regurgitation velocity, stroke volume, and cardiac output, as well as a more pronounced increase in left ventricular mass and LVMI. Associations were observed between structural alterations in the heart and parameters that reflect disruptions in the circadian BP rhythm. Conclusion — Within the context of Arctic rotating shift work, men with arterial hypertension (AH) exhibiting a disrupted chronostructure of the circadian BP rhythm, characterized by a predominance of irregular, short-term oscillations, and structural alterations in the heart, are more susceptible to COVID-19. This increased susceptibility is associated with more pronounced alterations in echocardiographic parameters following the infection.

A miR-219-5p-bmal1b negative feedback loop contributes to circadian regulation in zebrafish

MicroRNAs post-transcriptionally regulate gene expression and contribute to numerous life processes, including circadian rhythms. However, whether miRNAs contribute to zebrafish circadian regulation has not yet been investigated. Here, we showed that mature miR-219-5p, and its three pre-miRNAs, mir-219-1, mir-219-2, and mir-219-3, are rhythmically expressed primarily in Tectum opticum (TeO), Corpus cerebelli (CCe), and Crista cerellaris (CC) of the zebrafish brain. While mir-219-1 and mir-219-2 are regulated by the circadian clock through the E-like box, mir-219-3 is regulated by light via the D-box. Deleting mir-219-1, mir-219-2, or mir-219-3 individually or knocking down miR-219-5p all results in a shortened period of locomotor rhythms and up-regulation of bmal1b. RIP assays with Ago2 and miRNA pull-down assays show that miR-219-5p binds to bmal1b in the RISC. Cell transfection and in Vivo assays show that miR219-5p inhibits bmal1b through binding to its 3’UTR. Further, transcriptome analysis of miR-219-5p knockdown zebrafish adult brain reveals possible roles of miR-219-5p in phototransduction and neuroactive ligand-receptor interaction. Together, our findings demonstrate that mir-219-1, mir-219-2, and mir-219-3 are controlled directly by the circadian clock; and in turn, miR-219-5p contributes to circadian regulation by targeting bmal1b, highlighting a miR-219-5p-bmal1b negative feedback loop in the zebrafish circadian circuit.

Reassessing the involvement of the CREB pathway in the circadian clock of Drosophila melanogaster

Circadian clocks are ubiquitous in almost all organisms on Earth and many key genes are highly conserved among species. In the mammalian suprachiasmatic nucleus, the cAMP response element binding protein (CREB) pathway is known to play a crucial role in conveying light-input to the transcription of clock genes. The fruit fly Drosophila melanogaster also expresses two Creb proteins, CrebA and CrebB, which have been associated with the circadian clock. For example, Drosophila Creb has been suggested to constitute a molecular link between neuronal excitability and clock gene transcription. In this study we subjected flies with clock cell specific CrebA or CrebB mutations to circadian behavioral and bioluminescence assays. Surprisingly, we found that neither loss of CrebA or CrebB did affect free-running locomotor behavior, rhythmic period oscillations in clock neurons, or light-dependent synchronization. In conclusion our findings question the conserved circadian role of the Creb pathway in Drosophila and encourage further studies to elucidate its potential function within insect circadian clocks.

O003 Higher central circadian temperature amplitude is associated with greater metabolite rhythmicity in humans

Abstract Introduction Robust circadian rhythms are essential for optimal health. The central circadian clock controls temperature rhythms, which are known to organize the timing of peripheral circadian rhythms in rodents. In humans, however, it is unknown whether temperature rhythms relate to the organization of circadian rhythms throughout the body. Methods We assessed core body temperature amplitude and the rhythmicity of 929 blood plasma metabolites across a 40-hour constant routine protocol, controlling for behavioral and environmental factors that mask endogenous temperature rhythms, in 23 healthy individuals (mean [±SD] age = 25.4±5.7 years, 5 females). Valid core body temperature data were available in 17/23 (mean [±SD] age = 25.6±6.3 years, 1 female). Results Individuals with higher core body temperature amplitude had a greater number of metabolites exhibiting circadian rhythms (R²=0.37, p=.009). Higher core body temperature amplitude was also associated with less variability in the free-fitted periods of metabolite rhythms within an individual (R²=0.47, p=.002). Discussion These findings indicate that a more robust central circadian clock is associated with greater organization of circadian metabolite rhythms in humans. Metabolite rhythms may therefore provide a window into the strength of the central circadian clock.

Abstract 4145826: Atrial Fibrillation Screening During Sinus Rhythm Periods by Interrelated Systems Dynamics Analysis

Background: Previous studies have shown that AF screening in at-risk populations can reduce stroke incidence. However, non-targeted screening approaches often result in high false positive rates, placing an unnecessary burden on the healthcare system. In contrast, artificial intelligence-guided screening has been demonstrated to increase diagnostic yield in large prospective clinical trials. This approach, however, requires recording an ECG and a large-scale dataset for model training. Heart rate variability (HRV) analysis has proven effective in deciphering key heart dynamics. By analyzing HRV as interrelated dynamic systems, it may be possible to facilitate targeted AF screening using wearable devices that measure heart rate. The Koopman operator, used for data-driven modeling of interrelated dynamic systems, has been shown to accurately predict complex phenomena in chaotic systems such as climate forecasting and drug adverse reaction prediction. This is achieved by utilizing common characteristics of the systems for most model parameters, with only a small fraction of the parameters being specific to a certain system. Methods: Long (>10 hour) records from 361 individuals (AFDB, LTAFDB) and healthy individuals' datasets from PhysioNet and THEW were analyzed for inter-beat intervals. The unified dataset was then split into 94 training, 17 validation, and 250 test set patients. Recordings from the training set were used to train both the common and specific parts of the interrelated dynamic systems model for each patient, along with a shared small neural network classifying patients into low and high risk for AF based on the unique (not shared between patients) singular values of the dynamic system model. Patient-specific dynamic system models were then fitted for the validation and test sets to calculate the patient dynamic singular values, which were used to classify patients into low and high risk for AF groups. Results: Atrial fibrillation occurred in 48 of 202 (23%) patients classified as low risk and 35 of 48 (72.9%) patients classified as high risk (odds ratio 8.63, 95% CI 4.23-17.64), yielding 72.9% sensitivity with 76.2% specificity. Conclusion: In this retrospective analysis, classification of the dynamic system model singular values identified patients at high risk for atrial fibrillation from sinus rhythm period.

The genetically programmed rhythmic alteration of diurnal gene expression in the aged Arabidopsis leaves.

The circadian clock regulates the daily pattern of temporal gene expression. In Arabidopsis, aging is associated with a shortening of the endogenous period of circadian rhythms under circadian conditions. However, the functional link between the circadian clock and aging under diurnal conditions and its physiological relevance remain elusive. In this study, we investigate and characterize the effect of aging on the waveforms of rhythmic gene expression patterns under light/dark cycles. Our analysis revealed that the diurnal rhythmic patterns of core clock genes undergo significant rhythmic alteration with phase shift and change of waveforms in aged plants compared to younger plants. Transcriptomic analysis indicated that this age-dependent rhythmic alteration occurs not only in core clock genes but also globally. Due to the rhythmic alteration patterns of the diurnal rhythmic gene expression, aged plants experience subjectively a shorter day and longer night. We also observed that genetic mutants of core clock component genes exhibited broadly yet distinctively altered changes in diurnal rhythmic gene expression patterns as aging progresses. Collectively, our findings support that age-dependent rhythmic alteration of diurnal gene expression rhythms reprograms the timetable of daily gene expression, leading to the physiological changes required for plant senescence.

Experimental study on enhancing pedestrian efficiency and crowd safety with regular sound under open boundaries

Abstract We empirically investigated the impact of regular sound on planar pedestrian movement in open boundary environments, a rarely studied topic. Participants walked to regular sound with different tempos (70 BPM vs. 100 BPM) and types (monotone vs. periodic ‘tick-tack’ rhythm). We found that regular sounds at 100 BPM, close to the normal walking pace, improve pedestrian efficiency. They reduce passing time by 8.41% and increase average flow by 9.50%. This efficiency enhancement is lower compared to single-file experiment with periodic boundaries, where reaching a high-density jammed phase is easier. Additionally, this efficiency enhancement from sound is reduced by unstable step synchronization under open boundaries and turning behavior. Regular sound significantly improves crowd safety in turning areas, where congestion levels (Cls) and crowd danger (Cd) are highest. Cls decrease by 8.27% with the 100 BPM monotone, and Cd decreases by 19.1% with the 100 BPM periodic rhythm. Operationally, regular sounds at 100 BPM can be used to guide pedestrian flow smoothly and effectively in crowd management.

Two KaiABC systems control circadian oscillations in one cyanobacterium

The circadian clock of cyanobacteria, which predicts daily environmental changes, typically includes a standard oscillator consisting of proteins KaiA, KaiB, and KaiC. However, several cyanobacteria have diverse Kai protein homologs of unclear function. In particular, Synechocystis sp. PCC 6803 harbours, in addition to a canonical kaiABC gene cluster (named kaiAB1C1), two further kaiB and kaiC homologs (kaiB2, kaiB3, kaiC2, kaiC3). Here, we identify a chimeric KaiA homolog, named KaiA3, encoded by a gene located upstream of kaiB3. At the N-terminus, KaiA3 is similar to response-regulator receiver domains, whereas its C-terminal domain resembles that of KaiA. Homology analysis shows that a KaiA3-KaiB3-KaiC3 system exists in several cyanobacteria and other bacteria. Using the Synechocystis sp. PCC 6803 homologs, we observe circadian oscillations in KaiC3 phosphorylation in vitro in the presence of KaiA3 and KaiB3. Mutations of kaiA3 affect KaiC3 phosphorylation, leading to growth defects under both mixotrophic and chemoheterotrophic conditions. KaiC1 and KaiC3 exhibit phase-locked free-running phosphorylation rhythms. Deletion of either system (∆kaiAB1C1 or ∆kaiA3B3C3) alters the period of the cellular backscattering rhythm. Furthermore, both oscillators are required to maintain high-amplitude, self-sustained backscatter oscillations with a period of approximately 24 h, indicating their interconnected nature.

Sweetened caffeine drinking revealed behavioral rhythm independent of the central circadian clock in male mice

Caffeine consumption is associated with the evening chronotype, and caffeine administration in mice results in prolonged period of the circadian rhythm in locomotor activity. However, as caffeine is bitter, sweetened caffeine is preferred by humans and mice; yet, its impact on the circadian clock has not been explored. In this study, mice were provided with freely available sweetened caffeine to investigate its effects on behavioral rhythms and peripheral clocks. Mice that freely consumed sweetened caffeine shifted from nocturnal to diurnal activity rhythms. In addition to the light-dark entrained behavioral rhythm component, some animals exhibited free-running period longer than 24-h. Intraperitoneal administration of caffeine at the beginning of the light phase also acutely induced diurnal behavior. The behavioral rhythms with long period (26–30 h) due to sweetened caffeine were observed even in mice housed under constant light or with a lesioned central circadian clock located in the suprachiasmatic nucleus of the hypothalamus; however, the rhythmicity was unstable. PER2::LUCIFERASE rhythms in peripheral tissues, such as the kidney, as measured via in vivo whole-body imaging during caffeine consumption, showed reduced amplitude and desynchronized phases among individuals. These results indicate that consumption of sweetened caffeine induces diurnal and long-period behavioral rhythms irrespective of the central clock, causing desynchronization of the clock in the body.

Biological analysis method based on the relationship between athlete’s PSI rhythm and sports injury

Biorhythm is the law of cyclical changes in individual life activity characteristics as time changes. Biorhythm is an internal law of a biological organism, which comes from the changes that a biological organism is affected by changes in the external environment during natural activities, so its change law is similar to the cycle of the natural environment. Biological rhythms play an important role in mediating human body functions, vital activities, body temperature and other physiological reactions. The balance and stability of biological rhythms can ensure the healthy life activities of the human body. Disrupting the balance of biological rhythms may cause various kinds of human body. In this paper, the research of biological analysis method based on the relationship between athlete’s PSI (Physical, Sensitive, Intellectual) rhythm and sports injury is mainly introduced, and ideas and directions are intended to be provided for analyzing the relationship between athlete’s physical strength, emotion, intelligence and sports injury. This paper proposes a research strategy based on the biological analysis method of athlete’s PSI rhythm and sports injury, including measurement of biological rhythm, literature retrieval method, expert interview method, questionnaire survey method, clustering algorithm-based biological analysis method. A research experiment on the biological analysis method of the relationship between PSI rhythm and sports injury is conducted. The experimental results of this paper indicated that most sports injuries of athletes occur in the critical period of PSI rhythm, with an average incidence of 70.14%. Athletes’ training and competition can be avoided in this critical period as much as possible.

The specifics of percussion instruments treatment inthe jazz music from the 1950s

In the center of the author’s attention are the percussion instruments of jazz origin from the 1950s. The purpose of the paper consists in the analysis of the interpretative features developed within two main currents of jazz from this period, namely: West Coast Jazz and East Coast Jazz. The stylistic specificity of the cool style drummers stands out through the restrained way of expression – both in the accompanying and solo fragments. C. Hamilton was one of the first modern drummers who had the courage to abandon the jazz rhythms of the classical period. The performer created distinctive and memorable rhythmic patterns, later using them as accompaniment. Instead of using ride cymbals and high-hats in the accompaniment, C. Hamilton implemented the snare drum or tom-tom as the main voice. Therefore, each piece had individualized rhythmic patterns and its own coloring. The main style of East Coast jazz was hard bop, represented by great drummers such as Philly Joe Jones, Roy Brooks, Louis Hayes, Art Taylor, Roy Haynes, Roger Humphries, Elvin Jones, Lex Humphries, Max Roach, Art Blakey, Mickey Roker, Ben Riley, Jimmy Cobb, Frankie Dunlop, Billy Higgins.

Higher central circadian temperature amplitude is associated with greater metabolite rhythmicity in humans

Robust circadian rhythms are essential for optimal health. The central circadian clock controls temperature rhythms, which are known to organize the timing of peripheral circadian rhythms in rodents. In humans, however, it is unknown whether temperature rhythms relate to the organization of circadian rhythms throughout the body. We assessed core body temperature amplitude and the rhythmicity of 929 blood plasma metabolites across a 40-h constant routine protocol, controlling for behavioral and environmental factors that mask endogenous temperature rhythms, in 23 healthy individuals (mean [± SD] age = 25.4 ± 5.7 years, 5 women). Valid core body temperature data were available in 17/23 (mean [± SD] age = 25.6 ± 6.3 years, 1 woman). Individuals with higher core body temperature amplitude had a greater number of metabolites exhibiting circadian rhythms (R2 = 0.37, p = .009). Higher core body temperature amplitude was also associated with less variability in the free-fitted periods of metabolite rhythms within an individual (R2 = 0.47, p = .002). These findings indicate that a more robust central circadian clock is associated with greater organization of circadian metabolite rhythms in humans. Metabolite rhythms may therefore provide a window into the strength of the central circadian clock.

The role of N6-methyladenosine RNA methylation in the crosstalk of circadian clock and neuroinflammation in rodent suprachiasmatic nuclei.

N6-methyladenosine (m6A) is the most abundant epitranscriptomic mark that regulates the fate of RNA molecules. Recent studies have revealed a bidirectional interaction between m6A modification and the circadian clock. However, the precise temporal dynamics of m6A global enrichment in the central circadian pacemaker have not been fully elucidated. Our study investigates the relationship between FTO demethylase and molecular clocks in primary cells of the suprachiasmatic nucleus (SCN). In addition, we examined the effects of lipopolysaccharide (LPS) on Fto expression and the role of FTO in LPS-induced reactive oxygen species (ROS) production in primary SCN cell culture. We observed circadian rhythmicity in the global m6A levels, which mirrored the rhythmic expression of the Fto demethylase. Silencing FTO using siRNA reduced the mesor of Per2 rhythmicity in SCN primary cells and extended the period of the PER2 rhythm in SCN primary cell cultures from PER2::LUC mice. When examining the immune response, we discovered that exposure to LPS upregulated global m6A levels while downregulating Fto expression in SCN primary cell cultures. Interestingly, we found a loss of circadian rhythmicity in Fto expression following LPS treatment, indicating that the decrease of FTO levels may contribute to m6A upregulation without directly regulating its circadian rhythm. To explore potential protective mechanisms against neurotoxic inflammation, we examined ROS production following LPS treatment in SCN primary cell cultures pretreated with FTO siRNA. We observed a time-dependent pattern of ROS induction, with significant peak at 32 h but not at 20 h after synchronization. Silencing the FTO demethylase abolished ROS induction following LPS exposure, supporting the hypothesis that FTO downregulation serves as a protective mechanism during LPS-induced neuroinflammation in SCN primary cell cultures.

Machine learning workflow for edge computed arrhythmia detection in exploration class missions

Deep-space missions require preventative care methods based on predictive models for identifying in-space pathologies. Deploying such models requires flexible edge computing, which Open Neural Network Exchange (ONNX) formats enable by optimizing inference directly on wearable edge devices. This work demonstrates an innovative approach to point-of-care machine learning model pipelines by combining this capacity with an advanced self-optimizing training scheme to classify periods of Normal Sinus Rhythm (NSR), Atrial Fibrillation (AFIB), and Atrial Flutter (AFL). 742 h of electrocardiogram (ECG) recordings were pre-processed into 30-second normalized samples where variable mode decomposition purged muscle artifacts and instrumentation noise. Seventeen heart rate variability and morphological ECG features were extracted by convoluting peak detection with Gaussian distributions and delineating QRS complexes using discrete wavelet transforms. The decision tree classifier’s features, parameters, and hyperparameters were self-optimized through stratified triple nested cross-validation ranked on F1-scoring against cardiologist labeling. The selected model achieved a macro F1-score of 0.899 with 0.993 for NSR, 0.938 for AFIB, and 0.767 for AFL. The most important features included median P-wave amplitudes, PRR20, and mean heart rates. The ONNX-translated pipeline took 9.2 s/sample. This combination of our self-optimizing scheme and deployment use case of ONNX demonstrated overall accurate operational tachycardia detection.

Circadian Gating of Thyroid Hormone Action in Hepatocytes.

Thyroid hormones, thyroxin (T4) and the biologically active triiodothyronine (T3), play important roles in liver metabolic regulation, including fatty acid biosynthesis, beta-oxidation, and cholesterol homeostasis. These functions position TH signaling as a potential target for the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD). Elevated T3 levels in the circulation are associated with increased hepatic lipid turnover, which is also under the control of the circadian clock system. In this study, we developed a cell system to study the impact of hepatocyte circadian rhythms on the metabolic response to T3 treatment under control and steatotic conditions. Synchronized AML-12 circadian reporter hepatocytes were treated with T3 at different circadian phases and metabolic conditions. T3 treatment increased metabolic activity in a dose-independent fashion and had no significant effect on circadian rhythms in AML-12 cells. T3 had marked time-of-treatment-dependent effects on metabolic transcript expression. Steatosis induction altered metabolic transcript expression in AML-12 cells. In this condition, the circadian rhythm period was lengthened, and this effect was independent of T3. Under steatotic conditions, T3 had marked time-of-treatment dependent effects on metabolic transcript expression, which differed from those observed under control conditions. These findings reveal a time-of-day-dependent response of hepatocytes to T3, which is further modulated by the metabolic state. Our data suggest that time has a strong influence on liver TH action, which might be considered when treating MASLD.

The contribution of circadian clock to the biological processes.

All organisms have various circadian, behavioral, and physiological 24-h periodic rhythms, which are controlled by the circadian clock. The circadian clock controls various behavioral and physiological rhythms. In mammals, the primary circadian clock is present in the suprachiasmatic nucleus of the hypothalamus. The rhythm of the circadian clock is controlled by the interaction between negative and positive feedback loops, consisting of crucial clock regulators (including Bmal1 and Clock), three cycles (mPer1, mPer2, and mPer3), and two cryptochromes (Cry1 and Cry2). The development of early mammalian embryos is an ordered and complex biological process that includes stages from fertilized eggs to blastocysts and undergoes important morphological changes, such as blastocyst formation, cell multiplication, and compaction. The circadian clock affects the onset and timing of embryonic development. The circadian clock affects many biological processes, including eating time, immune function, sleep, energy metabolism, and endocrinology, therefore, it is also crucial for overall health, growth and development after birth. This review summarized the effects of the circadian clock in the body's physiological activities. A new strategy is proposed for the prevention of malformations or diseases by regulating the circadian clock or changing circadian rhythms.

Impact of catheter ablation on erectile dysfunction in atrial fibrillation patients

Abstract Background Previous studies suggested a consequential link between impaired diastolic function, which could be related to atrial fibrillation (AF), and a heightened susceptibility to erectile dysfunction (ED). No data exists regarding the correlation between restoration of sinus rhythm and ED. Objective This study investigates the influence of cardiac ablation on the need for phosphodiesterase-5 inhibitors (PDEF5i) medications in patients with atrial fibrillation. Methods We retrospectively investigated by chart review 220 consecutive male patients with erectile dysfunction who underwent AF catheter ablation and performed at least one follow-up visit afterward between 2019 and 2022. Exclusion criteria were considered patients older than 85 years old and those assuming non-selective beta-blockers or antidepressant medications. Patients were monitored for arrhythmia at quarterly office visits, ECGs, 7-day Holter monitoring, and event recorders during the first year. The Chi-Square test was utilized to statistically analyze the correlation between the achievement of sinus rhythm post-ablation and the discontinuation of ED medications. Results During follow-up 182 (82.7%) pts remained in sinus rhythm after one year (Group 1). Among these, 141 (77.4%) reported withdrawal of ED medication and a marked improvement in their overall sexual health and satisfaction. Whereas among the 38 (17.3%) who did not maintain stable sinus rhythm during follow-up (Group 2), only 2 (5.2%) reported a reduction in ED medication. A statistically significant difference was observed when comparing the two groups (p<0.001, OR 0,016, 95%, 0,003 - 0,061). Moreover, patients maintaining sinus rhythm for more than six months exhibited a higher tendency to stop ED medications compared to those with shorter periods of sinus rhythm or with recurrent AF episodes. Conclusion Our findings suggest a strong association between the achievement of sinus rhythm through cardiac ablation and a reduction PDEF5i in patients affected by ED medications in AF patients. This highlights the potential dual benefits of cardiac ablation in improving quality of life and in improving sexual health.

Extended period rhythm outcomes of posterior box isolation of left atrium during pan-spectrum of atrial fibrillation catheter ablation in 4 randomized clinical trials

Abstract Background Catheter-based electrical posterior box isolation (POBI) in addition to circumferential pulmonary vein isolation (CPVI) did not improve rhythm outcome of atrial fibrillation (AF) catheter ablations (AFCA). We analyzed the long-term rhythm outcomes of previously conducted our 4 randomized controlled trials (RCTs) comparing CPVI vs. additional POBI by intention to treat. Methods We analyzed 575 AF patients who were included in 4 RCTs (PAF [paroxysmal AF], PEACEFUL [persistent to paroxysmal AF]; POBI [persistent and long-standing persistent AF]; and RILI [repeat procedures] trials) comparing the usefulness of additional POBI after further long-term protocol-based rhythm follow-up. We compared the primary endpoint as clinical recurrence after index procedure and major adverse cardiac event, and the secondary endpoint as procedure time, procedure-related complication rate, recurrence as atrial tachycardia (AT), and cardioversion or repeat procedure rates. We also conducted Cox regression analysis to evaluate the efficacy of POBI. Results After a median follow-up of 48months, there was no significant difference in the clinical recurrence (42.9% vs. 41.3%; log-rank P=0.855) and major adverse cardiac event (4.5% vs. 3.7%; log-rank P=0.675). Procedure time was significantly longer (p=0.003) and AT recurrence rate was higher (6.6% vs. 12.6%; log-rank P=0.014) in the additional POBI group. In patients who experienced clinical recurrence, there were no significant differences in the rates of cardioversion (33.9% vs. 46.6%, P=0.059) or the need for a repeat procedure (30.4% vs. 31.7%, P=0.955) between the two groups. Catheter-based POBI did not improve AFCA outcomes (HR 1.07 [0.81~1.40], P=0.655), regardless of paroxysmal, persistent to paroxysmal, persistent AFs, or the 2nd procedures. In the redo mapping after RCTs (n=64), PV reconnection rate did not differ, but reentrant AT was more common in POBI than in CPVI alone group (46.7% vs. 10.7%, P=0.007), while extra-PV trigger was more common in CPVI alone than in POBI group (29% vs. 3.0%, P=0.012). Conclusions Additional-POBI to CPVI did not improve long-term rhythm outcomes. Additional-POBI to CPVI is related to the increase of AT recurrence and the decrease of extra-PV trigger.

The Free-Running Circasemilunar Period Is Determined by Counting Circadian Clock Cycles in the Marine Midge Clunio Marinus.

Semilunar rhythms are found in numerous marine organisms, but the molecular mechanism and functional principles of endogenous circasemilunar clocks remain elusive. Here, we explore the connection between the free-running circasemilunar clock and the circadian clock in the marine midge Clunio marinus with three different chronobiological assays. First, we found that the free-running circasemilunar period of the adult emergence rhythm in C. marinus changes linearly with diel T-cycle length, supporting a day-counting mechanism. Second, under LD 6:6, periods of circasemilunar and circadian emergence were comparable to those under LD 12:12, indicating that the circasemilunar counter in C. marinus relies on endogenous circadian oscillations rather than external T-cycles. Finally, when desynchronizing the circadian clock with constant light, the free-running circasemilunar emergence rhythm disappeared as well, suggesting that it requires a synchronized circadian clock. These results oppose the long-held view that C. marinus' free-running circasemilunar clock operates independently of the circadian clock. In a broader evolutionary context, our results strengthen the idea that the circasemilunar clocks of dipterous insects are based on different functional principles compared to the circasemilunar or circalunar clocks of marine annelids and algae. These divergent clock principles may indicate multiple evolutionary origins of circasemilunar and circalunar clocks.

MULTIFOCAL ATRIAL TACHYCARDIA AND HYPERTROPHIC CARDIOMYOPATHY IN THREE PATIENTS WITH COSTELLO SYNDROME

Abstract Introduction Costello syndrome is a rare disease, caused by mutation of the HRAS gene, associated with intellectual disability, growth retardation, facial dimorphisms. Cardiac abnormalities, mainly cardiac hypertrophy and multifocal atrial tachycardia, are present in 1/3 of patients. Clinical Cases From 2019 to 2023, 3 newborns with Costello syndrome came under our observation. M.M. showed respiratory distress, hypotonia and dysmorphic notes; genetic analysis highlighted the pathogenic variant c.64C>A (p.Gln22Lys). On the echocardiogram, septal hypertrophic cardiomyopathy was found with left outflow obstruction and mitral insufficiency. Therapy with propranolol was undertaken. Holter ECG never revealed arrhythmias. At the last check–up, SIV hypertrophy, continent mitral valve, free left ventricular outflow. The second patient, O.L., arrived at 10 days of age following a run of supraventricular tachycardia. He had bilateral clubfoot and facial dimorphisms. The echocardiogram was normal. On Holter ECG atrial tachycardia interrupted by rare sinus beats. Therapy with flecainide was undertaken, without benefit. Subsequently, was undertaken amiodarone, then associated with digitalis. She was discharged with satisfactory control of the average ventricular rate, but later due to the appearance of chaotic atrial arrhythmia, propranolol was added; on the Holter ECG in triple therapy, periods of sinus rhythm alternating with short episodes of atrial tachycardia were observed. Genetic analysis revealed the pathogenic variant c.34G>A, p.(Gly12Ser) of the HRAS gene. The third patient, F.A., presented atrial tachycardia. Flecainide therapy had transient benefit. Subsequently propranolol was added, without benefit. Therapy with amiodarone was initiated. Transesophageal electrophysiological study demonstrated multifocal atrial tachycardia, unresponsive to overdrive pacing. Partial control of the average ventricular rate was achieved in triple therapy. On the echocardiogram, mild concentric hypertrophy and dysplastic pulmonary valve. Genetic testing detected the c.35G>C, p(Gly12Ala) variant of the HRAS gene. Conclusions Costello syndrome requires cardiac monitoring for the possible presence of multifocal atrial tachycardia and hypertrophic cardiomyopathy. Arrhythmia, which can also occur independently of hypertrophy, can be self–limited in the first months of life with aggressive pharmacological treatment but can persist or worsen in ¼ of patients.