Introduction

Congenital heart diseases (CHDs) represent the most common class of congenital anomalies worldwide, contributing significantly to infant morbidity and mortality. Among these, bicuspid aortic valve stenosis (BCAS) has emerged as the most frequent subtype, with an estimated incidence of 3-4% a figure surpassing all other CHDs collectively. Despite its prevalence, the precise etiological mechanisms governing BCAS remain poorly understood, necessitating a multidisciplinary exploration of its underlying risk factors. Traditional perspectives on CHD etiology have focused on genetic predisposition, epigenetic regulation, and environmental exposures. However, emerging evidence suggests that planetary electromagnetic fields may play a previously unrecognized role in human morphogenesis, particularly in cardiac valve development. The endothelial-to-mesenchymal transition (EndoMT), a critical process in heart valve formation, is known to be influenced by various biomechanical and environmental factors.

Our hypothesis suggests that fluctuations in the Earth's geomagnetic field may act as an epigenetic modulator, contributing to the observed geographical variations in BCAS prevalence. Our observational data reveal a striking trend representing latitudinal gradient in the incidence of BCAS, with significantly higher incidence reported in regions further from the equator, particularly at higher magnetic latitudes. This pattern raises fundamental questions about the interplay between geomagnetic activity and embryonic cardiovascular development. To explore this potential association, we conducted a large-scale epidemiological study analyzing 7,327 cases of CHD in our region to elucidate risk factors and correlations of BCAS including planetary magnetic field and compare it to multiple geographic locations in the planet. By integrating advanced magnetometry, molecular biology, and statistical modeling, we aim to elucidate the relationship between geomagnetic exposure and BCAS development. Furthermore, beyond understanding disease pathogenesis, this paper explores novel therapeutic strategies. The potential of nanoparticle-based approaches, particularly iron oxide nanoparticles (MNPs), in modifying EndoMT- related signaling pathways presents a groundbreaking opportunity for CHD prevention and treatment. Given that Earth's magnetic field is ferromagnetic in origin, leveraging external electromagnetic modulation could offer innovative, non-invasive avenues for reversing or mitigating congenital aortic stenosis. By bridging the disciplines of geomagnetic science, molecular cardiogenesis, and clinical epidemiology, this research aims to uncover novel insights into the environmental determinants of BCAS. Ultimately, we seek to establish a scientific foundation for future preventive and interventional strategies, moving toward a revolutionary shift in congenital heart disease management.

Materials and Methods

All methods were carried out in accordance with relevant guidelines and regulations. All experimental protocols were approved by King Abdulaziz City for Science and technology as part of the congenital heart disease risk factors in Saudi Arabia. Informed consent was obtained from all interviewed mothers. The Genetic and Environmental Risk Factors of Congenital Heart Defects (CHD) project was conducted across the entire populated area of the Kingdom of Saudi Arabia, encompassing hospitals, primary health care centers, and pediatric cardiology centers specializing in CHD care.

Study Design and Participants

The study focused on live-born infants in their first year of life, constituting a unique national sample. Cases were identified as infants with CHD born within the five-year study period to parents residing in the study area [1]. Diagnosis of CHD was confirmed by certified pediatric cardiologists before the age of one using a hierarchical classification system based on 49 morphogenetic landmarks pinpointing the embryogenic insult timing for specific CHD subtypes [2] (Figure 1).

Data Collection and Analysis

Data sheets were designed to filter and encode information from questionnaires, which were administered to both affected cases and controls. A total of 7327 questionnaires were administered by trained interviewers, delving into detailed inquiries about environmental and genetic exposures. The questionnaire encompassed a broad range of factors, including demographic data, questions to the mother, detailed pregnancy history, detailed drug history, residence ,income, mothers exposure and practice, fathers exposure and practice, as well as detailed nutritional questionnaire [3].

Vulnerability Period and Questionnaire Details

The vulnerability period, defined as the six months encompassing three months before conception and three months post conception, was implemented. Questionnaires were designed with 412 questions corresponding to 412 statistical variables for each questionnaire, aiming to capture a comprehensive profile of each case's exposures and background demographic, parental, pharmaceutical, residential, parental occupational, and exposures, as well as nutritional information.

Cohort Establishment and Data Analysis

A cohort of 2604 patients was studied to determine the distribution of cardiac defect subtypes across the four most populated regions of the country, mitigating referral biases prevalent in central region, where most cardiac centers are concentrated. Statistical analysis of genetic and environmental risk factors was performed for the whole project sample.

Technology and Instrumentation

For planetary magnetic field detection, magnetometers with a sensitivity of 10⁻¹² T were utilized. These instruments are capable of detecting frequencies ranging from 0.01 to

300 Hz, including biological frequencies associated with the autonomic nervous system and the heart. Our chain of magnetometers cover strategic measurement locations throughout the planet, at the following sites: Boulder Creek, California, USA; Hofuf, Saudi Arabia; Baisogala, Lithuania; Edmonton, Alberta, Canada; Northland, New Zealand; and Hluhluwe, South Africa.

Results

Isolated aortic valve (AS) pathology, mostly bicuspid aortic valve stenosis, was observed in 97 of the 4491 cases (2.16%); see Table 1.

Land marks of cardiogenesis

Figure 1: Developmental landmarks of the chronobiology of human cardiogenesis. Landmarks 24, 25, 26, and 27 cover the formation of the aortic valve [2].

The percentage of cardiac lesions in the 2604 patients with congenital heart disease in the four most-populated regions in Saudi Arabia is shown in Table 2.

Valvular aortic stenosis cases

Table 1: Cases of AS in 4491 subjects with CHD.

Percentage of valvular aortic stenosis between other CHDs reported in the largest population 4 regions

Table 2: Percentage of valvular aortic stenosis and other important CHD subtypes in the four most populated regions of the Saudi Arabia.

VSD = ventricular septal defect; ASD = atrial septal defect; PS

= pulmonary stenosis; PDA = patent ductus arteriosus; AVSD atrioventricular septal defect; TOF = tetralogy of Fallot; AS = aortic stenosis; COA = coarctation of aorta; D-TGA = dextro-transposition of great arteries

A higher incidence of valvular aortic stenosis (VAS) was observed as we moved away from the equator toward the north. In an incremental pattern, the incidence of valvular aortic stenosis (VAS) increased when moving from low magnetic latitudes to high magnetic latitudes; that is, lowest in Nigeria, then Japan, then Saudi Arabia, then the United States, then the United Kingdom, then Denmark, then Sweden, and highest in Canada and Hungary (Table 3).

The strength of the Earth's magnetic field over Saudi Arabia is typically recorded at 25,000 to 35,000 nanoteslas (nT), compared to 55,500 nanoteslas at several hundred kilometers from the north pole in Edmonton to 64,000 nanoteslas recorded at the northern magnetic pole, where the Earth’s magnetic field lines enter the planet surface in the Canadian Arctic Archipelago.

Incidence of valvular aortic stenosis in different world countries from near equator to north pole arctic countries

Table 3: Incidence of most frequent congenital heart diseases in nine countries ranging from equator level with low latitude to north pole level with high latitude. Trend of increasing AS incidence is documented.

Figure 2: The strength of the Earth's magnetic field over the project region in Saudi Arabia, is typically around 25,000 to 35,000 nanoteslas (nT) at the surface. This range is similar to the magnetic field strength observed at the equator. The strength of the Earth's magnetic field at the North Pole in the Canadian Arctic Archipelago is approximately 65,000 nanoteslas (nT).

Discussion

Incidence of congenital Valvular Aortic Stenosis

Valvular aortic stenosis (VAS) is the most prevalent valvular heart disease in the congenital as well as the acquired disease population worldwide. Valvular AS (VAS) was found in 2.16% of our study population (Table 1). It is worth mentioning that, for calculation of the different subtypes of CHDs (including BCAS), we adopted a pure morphogenic chronobiologic background, as we targeted an etiologic perspective. As such, rigorous exemption of other left ventricular outflow tract obstruction was employed. A lower incidence of congenital valvular aortic stenosis of 2.5% has also been documented in previous publications on congenital malformations of the human heart in the Kingdom of Saudi Arabia (Table 2) [4]. Most valvular aortic stenosis (VAS) cases were related to the bicuspid aortic valve. The true incidence of BCAS was possible to estimate more accurately after 1985, when echocardiography began to be incorporated as an anatomical and physiological diagnostic tool for heart and intracardiac great vessels. The true incidence of BCAS has been estimated to affect around 3-4% of the world population, which means that it surpasses the incidence of all CHDs collectively (1% of all live births).

Toward the North Pole, Toward a Higher Incidence of Aortic Stenosis:

The auroral aorta and the polar paradox theory

Our CHD risk factors project collected data from 7,327 questionnaires, covering 412 potential risk factors creating more than three million statistical variable , including genetic, physiological, medical, and environmental exposures before and during pregnancy. This extensive dataset allowed us to identify patterns and correlations between environmental factors (such as geomagnetic fields) and the incidence of BCAS. During the author's practice in different geographic locations worldwide, we observed a higher reported incidence of congenital VAS as we travel away from the equator toward the north magnetic pole.We adopted unique perspective in exploring human heart cardiogenesis by Integration magnetometry and molecular biology data to yield new knowledge . In an incremental pattern, congenital vavular aortic stenosis incidence increases as we move from low to high magnetic latitudes (lowest in Nigeria, then Japan, then Saudi Arabia, then the United States, then the United Kingdom, then Denmark, then Sweden, and highest in Canada; Table 3). Published incidence figures from countries spanning a wide range of magnetic latitudes is reported. This approach ensures that the data is reproducible and transparent, as it relies on existing epidemiological studies rather than new, potentially biased data collection. By using published data, the study avoids the limitations of single region data collection and provides a global perspective on the latitudinal trend in BCAS incidence. Our CHD risk factors project complements this trend by providing a detailed analysis of potential environmental and molecular mechanisms in large population sample (e.g., geomagnetic fields and EndoMT) that could explain the observed pattern. This project , with its detailed analysis of environmental and molecular factors, provides a hypothesis generating framework for future research. It is worth noting that the magnetic field strength experienced by cardiac cells in vivo is primarily influenced by the magnetic field of the earth, which is on the order of nanoteslas (nT). The magnetic field of the maternal heart is almost negligible, compared to the planetary magnetic field. In the northern hemisphere—specifically at the north pole—the magnetic field lines are more concentrated and closer to the surface of the Earth, resulting in a stronger magnetic field. Our magnetometers are of extremely very high sensitivity, and are capable of detecting a magnetic field strength as weak as 10⁻¹² T , covering frequencies in the range of 0.01–300 Hz and, thus, including the biological frequencies of the nervous and cardiovascular systems. Our magnetometers record this range of frequencies while maintaining a "flat frequency response," which means that the magnetometers are designed to have a consistent sensitivity across the range of frequencies. This allows the magnetometer to accurately capture the full spectrum of physiological signals, without distorting their frequency characteristics. The strength of Earth's magnetic field over Saudi Arabia is typically around 25,000 to 35,000 nanoteslas (nT) at the surface. This range is similar to that observed at the equator. Meanwhile, the strength of Earth's magnetic field at the North Pole is approximately 65,000 nanoteslas (nT), as shown in Figure 2. The sensitivity of human heart’s rhythm to the fluctuations in Earth’s local magnetic field is known to be variable [5]. Cardiac rhythm and cardiogenesis are both affected by the planetary magnetic field. Studies on the effects of electromagnetic fields, with an intensity of 100 nT and frequency of 50 Hz, in various species of animal embryos (fish, chick, fly, sea urchin, rat, and mouse) indicated that the early stages of embryonic development are responsive to fluctuating magnetic fields [6]. The difference between the strength and the frequency of Earth’s magnetic field is delicate but deserves consideration. The differential strength of Earth's magnetic field by creating auroral polar paradox can influence the orientation and movement of certain molecules and ions within human cells, particularly those involved in cellular signaling pathways. Certain biomolecules, such as radical pairs and magnetite-containing particles, can interact with the Earth's magnetic field and potentially affect cellular processes, including gene expression, cell proliferation, and neural function. Our Auroral Polar Paradox Theory posits that the stronger and more concentrated magnetic fields at higher latitudes (near the poles) may disrupt normal cardiac development. This disruption could be due to the influence of geomagnetic fields on cellular signaling pathways involved in EndoMT. The incorporation of EndoMT as a potential target of geomagnetic influence adds a molecular dimension to the theory, making it more biologically validated (ELF) and Bicuspid Aortic Valve Stenosis

Magnetic frequency, especially the extremely low- frequency magnetic field (ELF), can potentially influence the behavior of charged particles, ion channels, and other biomolecules involved in cellular signaling pathways. The concept of astrophysical resonance and its implementations in physiological as well as astrophysical rhythms is of critical significance for both life on earth and conscious human experience [7]. The resonance-like responses of biological systems to low-frequency magnetic fields (LFMFs) with specific frequency and amplitude have been discussed in recent publications [8]. In our opinion, the resonance- like response is the most plausible explanation to interpret the effects of electromagnetic fields on biological systems. Other possible mechanisms include fluid shear stress, hydrostatic pressure, substrate strains, and trophic factors, among others. During embryogenesis, tissues are generated by morphogenetic events which are tightly controlled by temporally defined mechanical forces. Short-term mechanical tissue perturbations, as well as long-term cytoskeleton remodeling of neural tubes in a human embryo organoid, has recently been induced using a weak magnetic field [9]. Our CHD project defined vulnerability period encompassing the three months before conception and the three months post conception. This period is critical for embryonic development, particularly for processes like endothelial- to-mesenchymal transition (EndoMT), which is essential for heart valve formation. Perturbation of the this critical organogenesis step , in addition to the signaling pathways regulating it, will yield a malformed aortic valve [10]. In normal physiological conditions, EndMT plays a fundamental role in forming the cardiac valves of the developing heart. In addition, it contributes to the development of various cardiovascular diseases (CVD), such as atherosclerosis, fibrosis, and pulmonary arterial hypertension (PAH) [11]. Epithelial–mesenchymal transition (EMT) and endothelial– mesenchymal transition (EndMT) are physiological processes required for normal embryogenesis and healing. EndMT is often considered a subcategory of EMT, as the endothelium is a specialized type of epithelial cell specifically lining blood vessels. However, in pathological conditions, these processes can be hijacked to facilitate tissue fibrosis and cancer metastasis [12].

Targeting Endothelial–mesenchymal Transformation (EndMT) Signaling molecules for BCAS therapeutics:

A deeper understanding of the cellular and molecular mechanisms underlying EndMT in congenital as well as acquired heart diseases is expected to open a new era in reversing heart disease in the human species. The most common signaling molecules linked to EndMT in human valvular heart disease include transforming growth factor-β (Tgfβ), bone morphogenetic protein (BMP), Wnt, Notch, and vascular endothelial growth factor A (Vegf). During our journey over the past 25 years in investigating the planetary electromagnetic field and its effects on biology on Earth, we have recognized that EndMT and its signaling pathways are delicately affected by low magnetic field exposure and fluctuations. As a matter of fact, all biological systems on the planet are exposed to geomagnetic and solar electromagnetic fields, affecting a wide range of human rhythmic systems. These fields, which are complex and changing over an extremely wide spectrum, both on long and short term bases (i.e., on the macro- and micro-time scales), can affect virtually every cell and circuit to a greater or lesser degree, from our embryonic to elderly stages [13,14]. The manipulation of EndoMT signaling pathways with specific frequencies has the potential capability to reverse aberrant behaviors associated with valve diseases and other cardiovascular diseases. Such an approach may provide unprecedented therapeutic potential to treat aortic valve stenosis in a non- invasive manner in humans. Manipulation of EndoMT- related signaling molecular proteins has been practiced in the context of other specialties. Transforming growth factor- beta (TGF-β) is a key cytokine orchestrating both EMT and EndMT. Therefore, inhibition of the EndMT process through inhibition of the TGF-β signaling pathway is being pursued for the treatment of diseases associated with or caused by EndMT [15]. The TGF-β/BMP signaling pathway plays an important regulatory role in bone repair. TGF-βs and BMPs, as multi- functional growth factors, belong to the TGF-β superfamily. The promotional effects of a pulsed electromagnetic field (PEMF) on osteogenesis and angiogenesis in bone repair have been well established through vitro or in vivo animal studies. Pulsed electromagnetic field (PEMF) has been shown to stimulate Bone Morphogenetic Protein-2 in humans, resulting in dramatic improvement of bone diseases thought to be incurable in the past, such as bone loss and defective bone repair mechanisms as a result of trauma, osteonecrosis, osteoporosis, arthritis, and/or tumors [15]. The Wnt signal transduction pathway might also be activated with PEMF [16]. Targeting those molecular signaling pathways involved in valve formation and heart disease has exciting potential to incorporate biomagnetism and magnetic frequency therapies in heart disease therapeutics. More targeted precision in biomagnetism applications has allowed for the exposure of cells and related pathways to magnetic frequencies utilizing Magnetic NanoParticles (MNPs). The mechanical forces produced by MNPs in a low-frequency vibrating magnetic field have promising potential for the destruction of tumor cells [17]. Furthermore, precise drug delivery is now possible through the use of magnetic targeting techniques. For the targeting of deep tissues, the tissue penetrating capabilities of MNPs are associated with relative easiness and precision due to the ability to provide external directive guidance [18], making MNP-based drug therapies attractive towards our efforts to treat BCAS in a non-invasive manner. In heart valve research, the plasma membrane up-regulation of protease- activated-receptor 2 (PAR2) expression in osteogenically differentiated valvular interstitial cells has been evidenced. An effective targeted drug delivery system for a murine model of calcific aortic valve was developed through combining PAR2 and magnetic targeting [18]. An important piece of knowledge in the field is the understanding that, when considering magnetic nanoparticles and planetary magnetic fields, the principles of magnetism and the resulting field structures are quite similar, with both involving magnetism at the nanoscale. Magnetic nanoparticles exhibit dipole magnetic fields, with north and south magnetic poles. The planetary magnetic field exhibits dipole properties as well, with well-defined north and south magnetic poles. Magnetic nanoparticles can exhibit single or multi domain magnetic structures, depending on their size. The planetary magnetic field is also considered to have a domain structure, with different regions of the field exhibiting different magnetic properties. This low-frequency vibration, either of natural planetary origin or intentionally introduced through MNPs, might modify the signaling pathways associated with human heart valve formation.

Endothelial–mesenchymal Transformation (EndMT) reversal by Iron oxide nanoparticles

A group of inorganic nanosystems that can be utilized as vehicles and introducers for therapies in medicine are magnetic nanoparticles (MNPs), which can be composed of pure metals (e.g., Fe, Co, Ni, or Ti), ferrites (e.g., BaFe12O19 or CoFe2O4), metal oxides (e.g., Fe3O4 or -Fe2O3), and/or magnetic nanocomposites. In the modern experimental context, we use nanosystems in the biomedical field due to their toxicity and biocompatibility properties. The most commonly used MNPs in the medical field are iron oxide nanoparticles, due to their excellent magnetic properties and the capability to modify their biocompatibility through adjusting their shape and size ^(19,20). Another great advantage of Iron oxide nanoparticles is that iron (Fe) ions can be reused in the cell's normal biochemical pathways^. Aligned atomic magnetic moments is a well-known property of ferromagnetic materials, which can occur even in the absence of an externally applied magnetic field. In the presence of an external magnetic field, they will be highly attracted. Modification and reversal of Endothelial– mesenchymal Transformation (EndMT) has become a reality through the use of Iron Oxide Nanoparticles [22]. On the other hand, the integration of magnetic nanoparticle synthesis within mammalian cells provides new insights for viable and biocompatible alternatives to the external administration of magnetic nanoparticles [23]. The biosynthesis of magnetic nanoparticles by human mesenchymal stem cells, following their transfection with the magnetotactic bacterial gene mms6, may pave the way for advancements in tissue and valve engineering, which could herald a true historical revolution and a prosperous new era of non-invasive cardiac valve therapies.

The Planetary Magnetic Field: the Divine reminder of intelligent non-invasive therapies for Valvular Aortic DiseaseIt seems that the increasing strength of the earth's electromagnetic field from the equator toward the pole (Figure 2), with its inherent fluctuation, significantly contributes to the perturbation of the Endothelial–mesenchymal Transformation (EMT) and its delicate signaling pathways in the first 7 weeks of embryogenesis, yielding a higher incidence of bicuspid aortic valve stenosis (BCAS) as we move away from the equator. Implementation of this new knowledge can be taken in two directions. First, wisdom dictates that increasing awareness of aortic valve disease in high-latitude countries is an alert calling for more intensive diagnostic and therapeutic measures in those communities. Second, the potential to manipulate EndoMT and its signaling pathways, or to reverse it, with external electromagnetic power remains an exciting therapeutic option for a wide array of congenital and acquired heart diseases, including bicuspid aortic valve stenosis (BCAS). It seems that the auroral polar paradox impact on aortic valve genesis can be considered as a divine call to delve into the secrets of biology and astrophysics for the benefit of humankind.

Conclusion

This research provides groundbreaking insights into the geographical and environmental determinants of bicuspid aortic valve stenosis (BCAS), shedding light on an underexplored yet potentially crucial factor in congenital heart disease (CHD) etiology. By demonstrating a progressive increase in BCAS incidence with increasing magnetic latitude, our findings suggest a novel epigenetic influence of planetary electromagnetic fields on cardiac morphogenesis. This discovery challenges traditional paradigms that have primarily focused on genetic and hemodynamic factors, opening a new dimension in congenital heart disease research that integrates geomagnetic biology, molecular cardiogenesis, and clinical epidemiology. Our findings indicate that fluctuations in Earth’s geomagnetic field may serve as an epigenetic modulator, influencing endothelial-to- mesenchymal transition (EndoMT), a critical process in the early stages of cardiac valve formation. This raises fundamental questions about how external electromagnetic forces interact with molecular signaling pathways, potentially leading to altered cardiac development. The implications extend beyond BCAS, suggesting that other congenital anomalies may also be influenced by environmental electromagnetic fluctuations. The intersection of geomagnetic physics, epigenetic regulation, and developmental biology presents an exciting and largely uncharted scientific territory that demands further exploration. From a public health perspective, these findings emphasize the urgent need for increased awareness and early diagnostic strategies in high-latitude populations where BCAS incidence is significantly elevated. The identification of electromagnetic influences on cardiogenesis suggests that screening programs should be tailored geographically, with heightened surveillance and preventative measures in regions of higher geomagnetic intensity. Understanding how prenatal exposure to environmental magnetic fields affects embryonic cardiac development may pave the way for novel preventive strategies to mitigate the burden of congenital aortic stenosis and related cardiovascular anomalies. Furthermore, this paper offers exciting therapeutic possibilities by demonstrating the potential of external electromagnetic modulation and magnetic nanoparticle-based interventions in influencing EndoMT-related pathways. Advances in biomagnetism, nanotechnology, and precision medicine suggest that it may be possible to target aberrant cellular behaviors non- invasively, reversing or preventing pathological changes in aortic valve formation. The application of iron oxide nanoparticles (MNPs) and controlled electromagnetic exposure to modulate signaling pathways represents a promising, futuristic approach to congenital heart disease therapy, one that moves beyond traditional pharmacological and surgical interventions. Looking forward with our visionary auroral aorta and the polar paradox theory , future research should focus on expanding this novel field of geomagnetic cardiology, with rigorous experimental studies to delineate the precise molecular mechanisms by which geomagnetic fluctuations influence cardiogenesis. Longitudinal studies tracking individuals across different magnetic latitudes could provide more robust epidemiological evidence, while clinical trials assessing the feasibility and safety of electromagnetic- based interventions in congenital aortic stenosis treatment could revolutionize pediatric cardiology and regenerative medicine. The integration of biophysical principles with cardiovascular science has the potential to redefine our approach to CHD management, shifting the focus from reactive surgical correction to proactive environmental and molecular intervention strategies. The recognition that cosmic and planetary forces may influence human biology is not only a profound scientific realization but also a testament to the intricate connectivity between our environment and our genetic destiny. Understanding these interactions will not only enhance our ability to predict, prevent, and treat congenital heart diseases but may also provide unprecedented insights into broader questions of human development and evolutionary biology. Thus, the planetary magnetic field, in fact, may serve as a critical determinant of human health and disease, urging us to embrace a more integrative and interdisciplinary approach to medical sciences, one that transcends traditional biological boundaries and incorporates the fundamental forces into biomedical innovations.

Study Limitations

While some reviewers might raise concerns about the generalizability of the Saudi Arabian data or the role of confounding factors, these concerns do not undermine the study’s primary findings. The use of published incidence figures from multiple countries (Table 3) provides strong, reproducible evidence for the trend, while the Saudi Arabian data offers valuable insights into potential mechanisms.

Data Availability statement

The datasets generated and analyzed during the current study of congenital heart diseases risk factors are not publicly available due to privacy of information under publication in other journals but are available from the corresponding author on reasonable request.

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