Designing magnetic microcapsules for cultivation and differentiation of stem cell spheroids.

Human pluripotent stem cells (hPSCs) represent an excellent cell source for regenerative medicine and tissue engineering applications. However, there remains a need for robust and scalable differentiation of stem cells into functional adult tissues. In this paper, we sought to address this challenge by developing magnetic microcapsules carrying hPSC spheroids. A co-axial flow-focusing microfluidic device was employed to encapsulate stem cells in core-shell microcapsules that also contained iron oxide magnetic nanoparticles (MNPs). These microcapsules exhibited excellent response to an external magnetic field and could be held at a specific location. As a demonstration of utility, magnetic microcapsules were used for differentiating hPSC spheroids as suspension cultures in a stirred bioreactor. Compared to standard suspension cultures, magnetic microcapsules allowed for more efficient media change and produced improved differentiation outcomes. In the future, magnetic microcapsules may enable better and more scalable differentiation of hPSCs into adult cell types and may offer benefits for cell transplantation.

An Ultrathin Coating of Microcapsules Enhances the Function of Encapsulated Hepatocyte Spheroids.

Maintaining the differentiated phenotype and function of primary hepatocytes in vitro and in vivo represents a distinct challenge. Our paper describes microcapsules comprised of a bioactive polymer and overcoated with an ultrathin film as a means of maintaining the function of entrapped hepatocytes for at least two weeks. We previously demonstrated that heparin (Hep)-based microcapsules improved the function of entrapped primary hepatocytes by capturing and releasing cell-secreted inductive signals, including hepatocyte growth factor (HGF). Further enhancement of hepatic function could be gained by loading exogenous HGF into microcapsules. In this study, we demonstrate that an ultrathin coating of tannic acid (TA) further enhances endogenous HGF signaling for entrapped hepatocytes and increases by 2-fold the rate of uptake of exogenous HGF by Hep microcapsules. Hepatocytes in overcoated microcapsules exhibited better function and hepatic gene expression than in capsules without a TA coating. Our study showcases the potential application of ultrathin coatings to modulate the bioactivity of microcapsules and may enable the use of encapsulated hepatocytes for modeling drug toxicity or treating liver diseases.

Localization of Piezo 1 and Piezo 2 in Lateral Line System and Inner Ear of Zebrafish (Danio rerio).

Piezo proteins have been identified as mechanosensitive ion channels involved in mechanotransduction. Several ion channel dysfunctions may be associated with diseases (including deafness and pain); thus, studying them is critical to understand their role in mechanosensitive disorders and to establish new therapeutic strategies. The current study investigated for the first time the expression patterns of Piezo proteins in zebrafish octavolateralis mechanosensory organs. Piezo 1 and 2 were immunoreactive in the sensory epithelia of the lateral line system and the inner ear. Piezo 1 (28.7 ± 1.55 cells) and Piezo 2 (28.8 ± 3.31 cells) immunopositive neuromast cells were identified based on their ultrastructural features, and their overlapping immunoreactivity to the s100p specific marker (28.6 ± 1.62 cells), as sensory cells. These findings are in favor of Piezo proteins' potential role in sensory cell activation, while their expression on mantle cells reflects their implication in the maintenance and regeneration of the neuromast during cell turnover. In the inner ear, Piezo proteins' colocalization with BDNF introduces their potential implication in neuronal plasticity and regenerative events, typical of zebrafish mechanosensory epithelia. Assessing these proteins in zebrafish could open up new scenarios for the roles of these important ionic membrane channels, for example in treating impairments of sensory systems.

Piezo 1 and Piezo 2 in the Chemosensory Organs of Zebrafish (Danio rerio).

The ion channels Piezo 1 and Piezo 2 have been identified as membrane mechano-proteins. Studying mechanosensitive channels in chemosensory organs could help in understanding the mechanisms by which these channels operate, offering new therapeutic targets for various disorders. This study investigates the expression patterns of Piezo proteins in zebrafish chemosensory organs. For the first time, Piezo protein expression in adult zebrafish chemosensory organs is reported. In the olfactory epithelium, Piezo 1 immunolabels kappe neurons, microvillous cells, and crypt neurons, while Calretinin is expressed in ciliated sensory cells. The lack of overlap between Piezo 1 and Calretinin confirms Piezo 1's specificity for kappe neurons, microvillous cells, and crypt neurons. Piezo 2 shows intense immunoreactivity in kappe neurons, one-ciliated sensory cells, and multi-ciliated sensory cells, with overlapping Calretinin expression, indicating its olfactory neuron nature. In taste buds, Piezo 1 immunolabels Merkel-like cells at the bases of cutaneous and pharyngeal taste buds and the light and dark cells of cutaneous and oral taste buds. It also marks the dark cells of pharyngeal taste buds and support cells in oral taste buds. Piezo 2 is found in the light and dark cells of cutaneous and oral taste buds and isolated chemosensory cells. These findings provide new insights into the distribution of Piezo channels in zebrafish chemosensory organs, enhancing our understanding of their sensory processing and potential therapeutic applications.

Medulloblastoma Spatial Transcriptomics Reveals Tumor Microenvironment Heterogeneity with High-Density Progenitor Cell Regions Correlating with High-Risk Disease.

The tumor microenvironment (TME) of medulloblastoma (MB) influences progression and therapy response, presenting a promising target for therapeutic advances. Prior single-cell analyses have characterized the cellular components of the TME but lack spatial context. To address this, we performed spatial transcriptomic sequencing on sixteen pediatric MB samples obtained at diagnosis, including two matched diagnosis-relapse pairs. Our analyses revealed inter- and intra-tumoral heterogeneity within the TME, comprised of tumor-associated astrocytes (TAAs), macrophages (TAMs), stromal components, and distinct subpopulations of MB cells at different stages of neuronal differentiation and cell cycle progression. We identified dense regions of quiescent progenitor-like MB cells enriched in patients with high-risk (HR) features and an increase in TAAs, TAMs, and dysregulated vascular endothelium following relapse. Our study presents novel insights into the spatial architecture and cellular landscape of the medulloblastoma TME, highlighting spatial patterns linked to HR features and relapse, which may serve as potential therapeutic targets.

Core items to be included in a definition of moderate psoriatic arthritis: literature review and expert opinion.

Evidence-based treatment recommendations for psoriatic arthritis (PsA) suggest that treatment should be individualised but acknowledge the difficulty of correctly defining levels of activity (mild, moderate and severe). The aim of this study was to define the parameters or disease characteristics that should be included in a future definition of moderate PsA. Mixed. methods: (1) literature review to identify previous assessment tools used to classify patients into mild, moderate and severe forms, and (2) survey of rheumatologists, and experts in PsA, to obtain their opinion on the degree of validation and applicability of published definitions and tools, and on the parameters that should be included in a future definition of moderate PsA. We propose eight domains/items to be included in a definition of moderate PsA: number of active joints and inflamed entheses, physician global assessment (by visual analogue scale), dactylitis, body surface area (BSA) affected by psoriasis, psoriasis in special locations, and absence of hip involvement. The Disease Activity Index for Psoriatic Arthritis (DAPSA) score would be supported as part of this definition, as would the Psoriatic Arthritis Impact of Disease (PsAID) index. This study proposes a set of items/domains to be included in a definition of moderate PsA based on literature and expert opinion, which can be the starting point for further development and validation studies of the proposed items.

Relationships Between Success Factors in Daily Disposable Multifocal Contact Lenses.

Purpose: To explore links between subjective comfort and vision in habitual multifocal soft contact lens (MFCL) wearers when refit with daily disposable MFCLs, to determine which factors are relevant for success with MFCLs and evaluate consistency between MFCLs of different designs. Patients and Methods: This work examined subjective measures in a randomised, participant masked, bilateral wear crossover study at five optometry practices. Fifty-eight habitual MFCL wearers wore stenfilcon A multifocal (stenA-MF; CooperVision Inc) and delefilcon A multifocal (delA-MF; Alcon) for two-weeks. Subjective ratings included satisfaction with comfort and vision and agreement questions. Results: Agreement with "I would like to wear this MFCL in the future" was taken to indicate success with each MFCL; agreement was significantly higher with stenA-MF. There was strong correlation between agreement responses for "I would like to wear this MFCL in the future" and "MFCL met my needs for vision" with both lenses (p<0.01). However, it was only with stenA-MF, which had higher agreement responses to both statements (p<0.05), that responses to these two statements correlated with satisfaction with end-of-day (EOD) comfort (p<0.01). These differences in correlations between the two lenses are seemingly driven by greater satisfaction with stenA-MF for near and intermediate vision (p<0.05). Conclusion: Subjective vision and comfort were only correlated when vision met the needs of most participants. Meeting participants' needs for vision correlated strongly with wanting to wear a MFCL. Results indicate that meeting vision needs is more important than meeting comfort needs when influencing whether presbyopic patients continue wearing MFCLs.

Hormonal dynamics of matrotrophy vs. lecithotrophy in live-bearing fish reproduction.

We explored the relationship between gestational states, fecundity, and steroid hormone levels in three species of live-bearing fish with different maternal provisioning strategies. We studied two lecithotrophic species, Gambusia affinis and Xiphophorus couchianus, where embryos feed exclusively on yolk stored in the eggs, and one matrotrophic species, Heterandria formosa, which actively transfers nutrients to embryos through a follicular placenta. We measured water-borne cortisol, estradiol, and progesterone along with brood size (fecundity) and gestational stage(s). We examined the physiological costs of both maternal provisioning modes. Matrotrophy likely imposes energetic demands due to active nutrient transfer, while lecithotrophy may incur costs from carrying many large embryos. We hypothesized that fecundity, gestational stage, and hormones would covary differently in lecithotrophic vs. matrotrophic species. We found no relationships between hormones and fecundity or gestational stage in any species. However, in H. formosa, we found a positive relationship between estradiol levels and female mass, and a negative relationship between progesterone levels and female mass indicating a change in the circulating levels of both hormones as females grow. We observed differences in average hormone levels among species: the matrotrophic species had higher progesterone and lower estradiol compared to lecithotrophic species. Higher estradiol in lecithotrophic species may relate to egg yolk formation, while placental structures could play a role in progesterone production in matrotrophic species. Elevated cortisol in H. formosa suggests either higher energetic costs or a preparative role for reproduction. Our findings highlight progesterone's importance in maintaining gestation in matrotrophic species, like other placental species.

Síndrome de la arteria mesentérica superior (Síndrome de Wilkie): A propósito de un caso en una adolescente / Superior mesenteric artery syndrome (Wilkie syndrome): A case report in an adolescent

Introducción. El síndrome de la arteria mesentérica superior, también conocido como síndrome de Wilkie, es una entidad infrecuente en la que una reducción del ángulo o espacio aorto-mesentérico determina una compresión extrínseca con obstrucción del tercio distal del duodeno, demostrando síntomas y signos característicos de obstrucción intestinal. El pilar del tratamiento es el manejo médico conservador con repleción nutricional, con el objetivo de aumentar el grosor de la grasa retroperitoneal y con esto resolver la compresión duodenal. Caso clínico. Paciente de 16 años, con un curso crónico marcado por dolor abdominal, estreñimiento, distensión, pirosis y pérdida de peso. Inicialmente se trató como una enfermedad ácido-péptica, con pobre mejoría, por lo que se realizaron estudios imagenológicos con lo que se documentó una disminución del ángulo aortomesentérico. Resultado. Se instauró un manejo médico con un protocolo de repleción nutricional por vía oral, para lograr ganancia de peso y evitar la cirugía. Conclusión. Con base a los síntomas y hallazgos en imágenes diagnósticas se hizo el diagnóstico de síndrome de la arteria mesentérica superior, que es una causa de obstrucción intestinal con muy baja incidencia. Su presentación clínica incluye gran variedad de síntomas, entre los que destaca el dolor abdominal y la pérdida de peso. Es frecuente la confusión con otras enfermedades más frecuentes, como enfermedad ácido-péptica, reflujo gastrointestinal y malabsorción. Su diagnóstico requiere un alto índice de sospecha, por lo que es importante conocer esta entidad y considerarla en el estudio de pacientes con los síntomas mencionados.

Introduction. Superior mesenteric artery syndrome, also known as Wilkie syndrome, is a rare entity in which a reduction in the aorto-mesenteric angle or space determines extrinsic compression with obstruction of the distal third of the duodenum, demonstrating characteristic symptoms and signs of intestinal obstruction. The mainstay of treatment is conservative medical management with nutritional repletion, with the aim of increasing the thickness of the retroperitoneal fat and thereby resolving duodenal compression. Clinical case. A 16-year-old patient, with a chronic course marked by abdominal pain, constipation, bloating, heartburn and weight loss. Initially was treated as an acid-peptic disease, with poor improvement. Imaging studies were performed, which documented a decrease in the aorto-mesenteric angle. Conclusion. Based on the symptoms and findings on diagnostic images, the diagnosis of superior mesenteric artery syndrome was made, which is a cause of intestinal obstruction with a very low incidence. Its clinical presentation includes a wide variety of symptoms, among which abdominal pain and weight loss stand out. Confusion with other more common diseases is common, such as acid-peptic disease, gastrointestinal reflux and malabsorption. Its diagnosis requires a high index of suspicion, so it is important to know this entity and consider it in the study of patients with the aforementioned symptoms.

Axonal and Glial PIEZO1 and PIEZO2 Immunoreactivity in Human Clitoral Krause's Corpuscles.

Krause's corpuscles are typical of cutaneous mucous epithelia, like the lip vermillion or the glans clitoridis, and are associated with rapidly adapting low-threshold mechanoreceptors involved in gentle touch or vibration. PIEZO1 and PIEZO2 are transmembrane mechano-gated proteins that form a part of the cationic ion channels required for mechanosensitivity in mammalian cells. They are involved in somatosensitivity, especially in the different qualities of touch, but also in pain and proprioception. In the present study, immunohistochemistry and immunofluorescence were used to analyze the occurrence and cellular location of PIEZO1 and PIEZO2 in human clitoral Krause's corpuscles. Both PIEZO1 and PIEZO2 were detected in Krause's corpuscles in both the axon and the terminal glial cells. The presence of PIEZOs in the terminal glial cells of Kraus's corpuscles is reported here for the first time. Based on the distribution of PIEZO1 and PIEZO2, it may be assumed they could be involved in mechanical stimuli, sexual behavior, and sexual pleasure.

A retrospective study of deep learning generalization across two centers and multiple models of X-ray devices using COVID-19 chest-X rays.

Generalization of deep learning (DL) algorithms is critical for the secure implementation of computer-aided diagnosis systems in clinical practice. However, broad generalization remains to be a challenge in machine learning. This research aims to identify and study potential factors that can affect the internal validation and generalization of DL networks, namely the institution where the images come from, the image processing applied by the X-ray device, and the type of response function of the X-ray device. For these purposes, a pre-trained convolutional neural network (CNN) (VGG16) was trained three times for classifying COVID-19 and control chest radiographs with the same hyperparameters, but using different combinations of data acquired in two institutions by three different X-ray device manufacturers. Regarding internal validation, the addition of images from an external institution to the training set did not modify the algorithm's internal performance, however, the inclusion of images acquired by a device from a different manufacturer decreased the performance up to 8% (p < 0.05). In contrast, generalization across institutions and X-ray devices with the same type of response function was achieved. Nonetheless, generalization was not observed across devices with different types of response function. This factor was the key impediment to achieving broad generalization in our research, followed by the device's image-processing and the inter-institutional differences, which both reduced generalization performance to 18.9% (p < 0.05), and 9.8% (p < 0.05), respectively. Finally, clustering analysis with features extracted by the CNN was performed, revealing a substantial dependence of feature values extracted by the pre-trained CNN on the X-ray device which acquired the images.

Using Microfluidic Hepatic Spheroid Cultures to Assess Liver Toxicity of T-2 Mycotoxin.

The Fusarium fungi is found in cereals and feedstuffs and may produce mycotoxins, which are secondary metabolites, such as the T-2 toxin (T-2). In this work, we explored the hepatotoxicity of T-2 using microfluidic 3D hepatic cultures. The objectives were: (i) exploring the benefits of microfluidic 3D cultures compared to conventional 3D cultures available commercially (Aggrewell plates), (ii) establishing 3D co-cultures of hepatic cells (HepG2) and stellate cells (LX2) and assessing T-2 exposure in this model, (iii) characterizing the induction of metabolizing enzymes, and (iv) evaluating inflammatory markers upon T-2 exposure in microfluidic hepatic cultures. Our results demonstrated that, in comparison to commercial (large-volume) 3D cultures, spheroids formed faster and were more functional in microfluidic devices. The viability and hepatic function decreased with increasing T-2 concentrations in both monoculture and co-cultures. The RT-PCR analysis revealed that exposure to T-2 upregulates the expression of multiple Phase I and Phase II hepatic enzymes. In addition, several pro- and anti-inflammatory proteins were increased in co-cultures after exposure to T-2.

Alternative CNDOL Fockians for fast and accurate description of molecular exciton properties.

CNDOL is an a priori, approximate Fockian for molecular wave functions. In this study, we employ several modes of singly excited configuration interaction (CIS) to model molecular excitation properties by using four combinations of the one electron operator terms. Those options are compared to the experimental and theoretical data for a carefully selected set of molecules. The resulting excitons are represented by CIS wave functions that encompass all valence electrons in the system for each excited state energy. The Coulomb-exchange term associated to the calculated excitation energies is rationalized to evaluate theoretical exciton binding energies. This property is shown to be useful for discriminating the charge donation ability of molecular and supermolecular systems. Multielectronic 3D maps of exciton formal charges are showcased, demonstrating the applicability of these approximate wave functions for modeling properties of large molecules and clusters at nanoscales. This modeling proves useful in designing molecular photovoltaic devices. Our methodology holds potential applications in systematic evaluations of such systems and the development of fundamental artificial intelligence databases for predicting related properties.

Pediatric Chordoma: A Tale of Two Genomes.

Little is known about the genomic alterations in chordoma, with the exception of loss of SMARCB1, a core member of the SWI/SNF complex, in poorly differentiated chordomas. A TBXT duplication and rs2305089 polymorphism, located at 6q27, are known genetic susceptibility loci. A comprehensive genomic analysis of the nuclear and mitochondrial genomes in pediatric chordoma has not yet been reported. In this study, we performed WES and mtDNA genome sequencing on 29 chordomas from 23 pediatric patients. Findings were compared with that from whole-genome sequencing datasets of 80 adult patients with skull base chordoma. In the pediatric chordoma cohort, 81% of the somatic mtDNA mutations were observed in NADH complex genes, which is significantly enriched compared with the rest of the mtDNA genes (P = 0.001). In adult chordomas, mtDNA mutations were also enriched in the NADH complex genes (P < 0.0001). Furthermore, a progressive increase in heteroplasmy of nonsynonymous mtDNA mutations was noted in patients with multiple tumors (P = 0.0007). In the nuclear genome, rare likely germline in-frame indels in ARID1B, a member of the SWI/SNF complex located at 6q25.3, were observed in five pediatric patients (22%) and four patients in the adult cohort (5%). The frequency of rare ARID1B indels in the pediatric cohort is significantly higher than that in the adult cohort (P = 0.0236, Fisher's exact test), but they were both significantly higher than that in the ethnicity-matched populations (P < 5.9e-07 and P < 0.0001174, respectively). Implications: germline ARID1B indels and mtDNA aberrations seem important for chordoma genesis, especially in pediatric chordoma.

Reduced precipitation can induce ecosystem regime shifts in lakes by increasing internal nutrient recycling.

Eutrophication is a main threat to continental aquatic ecosystems. Prevention and amelioration actions have been taken under the assumption of a stable climate, which needs reconsideration. Here, we show that reduced precipitation can bring a lake ecosystem to a more productive regime even with a decline in nutrient external load. By analyzing time series of several decades in the largest lake of the Iberian Peninsula, we found autocorrelated changes in the variance of state variables (i.e., chlorophyll and oxygen) indicative of a transient situation towards a new ecosystem regime. Indeed, exceptional planktonic diatom blooms have occurred during the last few years, and the sediment record shows a shift in phytoplankton composition and an increase in nutrient retention. Reduced precipitation almost doubled the water residence time in the lake, enhancing the relevance of internal processes. This study demonstrates that ecological quality targets for aquatic ecosystems must be tailored to the changing climatic conditions for appropriate stewardship.

Genome-wide association analyses using multilocus models on bananas (Musa spp.) reveal candidate genes related to morphology, fruit quality, and yield.

Bananas (Musa spp.) are an essential fruit worldwide and rank as the fourth most significant food crop for addressing malnutrition due to their rich nutrients and starch content. The potential of their genetic diversity remains untapped due to limited molecular breeding tools. Our study examined a phenotypically diverse group of 124 accessions from the Colombian Musaceae Collection conserved in AGROSAVIA. We assessed 12 traits categorized into morphology, fruit quality, and yield, alongside sequence data. Our sequencing efforts provided valuable insights, with an average depth of about 7× per accession, resulting in 187,133 single-nucleotide polymorphisms (SNPs) against Musa acuminata (A genome) and 220,451 against Musa balbisiana (B genome). Population structure analysis grouped samples into four and five clusters based on the reference genome. By using different association models, we identified marker-trait associations (MTAs). The mixed linear model revealed four MTAs, while the Bayesian-information and linkage-disequilibrium iteratively nested keyway and fixed and random model for circulating probability unification models identified 82 and 70 MTAs, respectively. We identified 38 and 40 candidate genes in linkage proximity to significant MTAs for the A genome and B genome, respectively. Our findings provide insights into the genetic underpinnings of morphology, fruit quality, and yield. Once validated, the SNP markers and candidate genes can potentially drive advancements in genomic-guided breeding strategies to enhance banana crop improvement.

Cone-Beam Computed Tomography for the Evaluation of Dental Pulp Chamber Volume: Implications for Clinics and Teaching.

The dental pulp chamber volume is a fundamental measurement in the field of endodontics, but also in forensic sciences, teaching and training, or tissue engineering. This study evaluates the precision of cone-beam computed tomography (CBCT) in comparison with computed micro-tomography (micro-CT) in evaluating the pulp chamber volume of the upper central incisors ex vivo. The intra-operator and inter-operator errors were evaluated, and the results for the two techniques were compared with those of a T-test for paired samples. The intra-operator and inter-operator errors were >0.05, indicating adequate reproducibility in each operator and no significant differences between their measurements. On the other hand, no significant differences between the two measurement techniques were found. The present results demonstrate that CBCT is a precise, feasible, and reproducible technique for the evaluation of the dental pulp chamber volume ex vivo. The results provided with this method are useful for different medical domains but also for the teaching and training of undergraduate and postgraduate students. Furthermore, the findings of this study carry significant clinical implications, as the accurate assessment of the pulp chamber volume is critical in the diagnosis and treatment of various endodontic conditions. The ability of CBCT to provide reliable 3D dental anatomy measurements can enhance the planning of endodontic treatments by allowing for a better understanding of the internal tooth morphology. Additionally, the precision and reproducibility of CBCT in assessing the pulp chamber volume can contribute to improved clinical outcomes and reduced complications during endodontic procedures. These findings further support the increasingly vital role of CBCT in modern clinical practice and underscore its value as an indispensable tool in the field of dentistry.

A Dye Uptake Assay to Measure Large-Pore Channel Activity in Trypanosoma cruzi.

Large-pore channels allow the exchange of ions and molecules between the intra- and extracellular compartments. These channels are structures formed by several protein families with little or no evolutionary linkages that include connexins (Cxs), pannexins (Panxs), innexins (Inxs), CALHM1, and LRRC8 proteins. Recently, we have described the unnexins (Unxs) proteins expressed in Trypanosoma cruzi (T. cruzi) that also is like to form large-pore channels at the plasma membrane. In this chapter, we describe a dye uptake method for evaluating the unnexin-formed channel function in T. cruzi, as well as the methods for evaluating their participation in the transformation of trypomastigotes into amastigotes. These methods can facilitate understanding the role of large-pore channels in the parasite's biology.

Global Safety Assessment of Adverse Events of Special Interest Following 2 Years of Use and 772 Million Administered Doses of mRNA-1273.

Background: Large-scale use of mRNA COVID-19 vaccines during the pandemic was associated with enhanced safety monitoring to ensure accurate and timely review of safety. We reviewed the mRNA-1273 (original strain) safety profile following 2 years of use (>772 million administered doses), primarily focusing on predefined safety topics (ie, adverse events of special interest [AESIs]) proposed in advance of COVID-19 vaccine use. Methods: Cumulative mRNA-1273 safety data were included from spontaneous adverse event (AE) cases reported to Moderna's global safety database between 18 December 2020 and 17 December 2022. Reporting rates of AESIs were calculated per 1 million doses of mRNA-1273 administered. Observed-to-expected (OE) ratios were computed by comparing observed rates of AESIs with the background/expected rate for these events to evaluate potential associations with mRNA-1273. Results: There were 658 759 identified case reports associated with 2 517 669 AEs. Most AEs were nonserious (83.4%; 2 098 954/2 517 669). Overall 0.7% (17 751/2 517 669) were fatal. AESIs represented 13.7% of all AEs (344 921/2 517 669), with reporting rates for most AESIs below the expected background incidence. Exceptions included anaphylaxis (OE ratio 3 days after vaccination, 2.09; 95% CI, 1.93-2.25) and, among individuals aged 12 to 40 years, myocarditis (OE ratio 7 days after any dose, 3.89 [3.50-4.32]; among men after dose 2, 8.57 [6.88-10.68]) and pericarditis (OE ratio 7 days after vaccination, 3.47; 2.89-4.16). Conclusions: This safety analysis of mRNA-1273 identified evidence of increased risk for anaphylaxis, myocarditis, and pericarditis but not for other AESIs identified for enhanced monitoring ahead of COVID-19 vaccine use.