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Telomere-to-telomere (T2T) assemblies reveal new insights into the structure and function of the previously 'invisible' parts of the genome and allow comparative analyses of complete genomes across entire clades. We present here an open collaborative effort, termed the 'Ruminant T2T Consortium' (RT2T), that aims to generate complete diploid assemblies for numerous species of the Artiodactyla suborder Ruminantia to examine chromosomal evolution in the context of natural selection and domestication of species used as livestock.
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Ruminantes , Telômero , Telômero/genética , Animais , Ruminantes/genética , Evolução Molecular , Genoma/genética , Seleção Genética , Filogenia , DiploideRESUMO
Presence-absence variations (PAVs) are important structural variations, wherein a genomic segment containing one or more genes is present in some individuals but absent in others. While PAVs have been extensively studied in plants, research in cattle remains limited. This study identified PAVs in 173 Holstein bulls using whole-genome sequencing data and assessed their associations with 46 economically important traits. Out of 28,772 cattle genes (from the longest transcripts), a total of 26,979 (93.77%) core genes were identified (present in all individuals), while variable genes included 928 softcore (present in 95-99% of individuals), 494 shell (present in 5-94%), and 371 cloud genes (present in <5%). Cloud genes were enriched in functions associated with hormonal and antimicrobial activities, while shell genes were enriched in immune functions. PAV-based genome-wide association studies identified associations between gene PAVs and 16 traits including milk, fat, and protein yields, as well as traits related to health and reproduction. Associations were found on multiple chromosomes, illustrating important associations on cattle chromosomes 7 and 15, involving olfactory receptor and immune-related genes, respectively. By examining the PAVs at the population level, the results of this research provided crucial insights into the genetic structures underlying the complex traits of Holstein cattle.
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BACKGROUND: We recently identified ~ 10,000 correlated regions of systemic interindividual epigenetic variation (CoRSIVs) in the human genome. These methylation variants are amenable to population studies, as DNA methylation measurements in blood provide information on epigenetic regulation throughout the body. Moreover, establishment of DNA methylation at human CoRSIVs is labile to periconceptional influences such as nutrition. Here, we analyze publicly available whole-genome bisulfite sequencing data on multiple tissues of each of two Holstein cows to determine whether CoRSIVs exist in cattle. RESULTS: Focusing on genomic blocks with ≥ 5 CpGs and a systemic interindividual variation index of at least 20, our approach identifies 217 cattle CoRSIVs, a subset of which we independently validate by bisulfite pyrosequencing. Similar to human CoRSIVs, those in cattle are strongly associated with genetic variation. Also as in humans, we show that establishment of DNA methylation at cattle CoRSIVs is particularly sensitive to early embryonic environment, in the context of embryo culture during assisted reproduction. CONCLUSIONS: Our data indicate that CoRSIVs exist in cattle, as in humans, suggesting these systemic epigenetic variants may be common to mammals in general. To the extent that individual epigenetic variation at cattle CoRSIVs affects phenotypic outcomes, assessment of CoRSIV methylation at birth may become an important tool for optimizing agriculturally important traits. Moreover, adjusting embryo culture conditions during assisted reproduction may provide opportunities to tailor agricultural outcomes by engineering CoRSIV methylation profiles.
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Metilação de DNA , Epigênese Genética , Bovinos , Animais , Humanos , Ilhas de CpG , Variação GenéticaRESUMO
Acne vulgaris, rosacea, and hidradenitis suppurativa are enduring inflammatory skin conditions that frequently manifest with akin clinical attributes, posing a considerable challenge for their distinctive diagnosis. While these conditions do exhibit certain resemblances, they also demonstrate distinct underlying pathophysiological mechanisms and treatment modalities. Delving into both the molecular parallels and disparities among these three disorders can yield invaluable insights for refined diagnostics, effective management, and targeted therapeutic interventions. In this report, we present a comparative analysis of transcriptomic data across these three diseases, elucidating differentially expressed genes and enriched pathways specific to each ailment, as well as those shared among them. Specifically, we identified multiple zinc-binding proteins (SERPINA1, S100A7, S100A8, S100A9 and KRT16) as consistently highly upregulated genes across all three diseases. Our hypothesis suggests that these proteins could bind and sequester zinc, potentially leading to localized zinc deficiency and heightened inflammation. We identified high-dose dietary zinc as a promising therapeutic approach and confirmed its effectiveness through validation in an acne mouse model.
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Acne Vulgar , Perfilação da Expressão Gênica , Hidradenite Supurativa , Rosácea , Zinco , Acne Vulgar/tratamento farmacológico , Acne Vulgar/genética , Zinco/uso terapêutico , Zinco/metabolismo , Rosácea/tratamento farmacológico , Rosácea/genética , Hidradenite Supurativa/tratamento farmacológico , Hidradenite Supurativa/genética , Animais , Camundongos , Humanos , Proteína A7 Ligante de Cálcio S100/metabolismo , Proteína A7 Ligante de Cálcio S100/genética , Calgranulina A/genética , Calgranulina A/metabolismo , Calgranulina B/genética , Calgranulina B/metabolismo , Transcriptoma , Proteínas S100/genética , Proteínas S100/metabolismo , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Modelos Animais de Doenças , Regulação para CimaRESUMO
During lactation, dairy cattle's digestive tract requires significant adaptations to meet the increased nutrient demands for milk production. As we attempt to improve milk-related traits through selective pressure, it is crucial to understand the biological functions of the epithelia of the rumen, small intestine, and colonic tissues in response to changes in physiological state driven by changes in nutrient demands for milk synthesis. In this study, we obtained a total of 108 transcriptome profiles from three tissues (epithelia of the colon, duodenum, and rumen) of five Holstein cows, spanning eight time points from the early, mid, late lactation periods to the dry period. On average 97.06% of reads were successfully mapped to the reference genome assembly ARS-UCD1.2. We analyzed 27,607 gene expression patterns at multiple periods, enabling direct comparisons within and among tissues during different lactation stages, including early and peak lactation. We identified 1645, 813, and 2187 stage-specific genes in the colon, duodenum, and rumen, respectively, which were enriched for common or specific biological functions among different tissues. Time series analysis categorized the expressed genes within each tissue into four clusters. Furthermore, when the three tissues were analyzed collectively, 36 clusters of similarly expressed genes were identified. By integrating other comprehensive approaches such as gene co-expression analyses, functional enrichment, and cell type deconvolution, we gained profound insights into cattle lactation, revealing tissue-specific characteristics of the gastrointestinal tract and shedding light on the intricate molecular adaptations involved in nutrient absorption, immune regulation, and cellular processes for milk synthesis during lactation.
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BACKGROUND: Sheep and goats have undergone domestication and improvement to produce similar phenotypes, which have been greatly impacted by structural variants (SVs). Here, we report a high-quality chromosome-level reference genome of Asiatic mouflon, and implement a comprehensive analysis of SVs in 897 genomes of worldwide wild and domestic populations of sheep and goats to reveal genetic signatures underlying convergent evolution. RESULTS: We characterize the SV landscapes in terms of genetic diversity, chromosomal distribution and their links with genes, QTLs and transposable elements, and examine their impacts on regulatory elements. We identify several novel SVs and annotate corresponding genes (e.g., BMPR1B, BMPR2, RALYL, COL21A1, and LRP1B) associated with important production traits such as fertility, meat and milk production, and wool/hair fineness. We detect signatures of selection involving the parallel evolution of orthologous SV-associated genes during domestication, local environmental adaptation, and improvement. In particular, we find that fecundity traits experienced convergent selection targeting the gene BMPR1B, with the DEL00067921 deletion explaining ~10.4% of the phenotypic variation observed in goats. CONCLUSIONS: Our results provide new insights into the convergent evolution of SVs and serve as a rich resource for the future improvement of sheep, goats, and related livestock.
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Cabras , Animais , Cabras/genética , Ovinos/genética , Evolução Molecular , Variação Estrutural do Genoma , Locos de Características Quantitativas , Genoma , Variação Genética , Domesticação , Fenótipo , Seleção Genética , Receptores de Proteínas Morfogenéticas Ósseas Tipo I/genéticaRESUMO
OBJECTIVE: Survey the current literature on artificial intelligence (AI) applications for detecting and classifying vocal pathology using voice recordings, and identify challenges and opportunities for advancing the field forward. DATA SOURCES: PubMed, EMBASE, CINAHL, and Scopus databases. REVIEW METHODS: A comprehensive literature search was performed following the Preferred Reporting Items for Systematic Reviews and Meta-analyses Extension for Scoping Reviews guidelines. Peer-reviewed journal articles in the English language were included if they used an AI approach to detect or classify pathological voices using voice recordings from patients diagnosed with vocal pathologies. RESULTS: Eighty-two studies were included in the review between the years 2000 and 2023, with an increase in publication rate from one study per year in 2012 to 10 per year in 2022. Seventy-two studies (88%) were aimed at detecting the presence of voice pathology, 24 (29%) at classifying the type of voice pathology present, and 4 (5%) at assessing pathological voice using the Grade, Roughness, Breathiness, Asthenia, and Strain scale. Thirty-six databases were used to collect and analyze speech samples. Fourteen articles (17%) did not provide information about their AI model validation methodology. Zero studies moved beyond the preclinical and offline AI model development stages. Zero studies specified following a reporting guideline for AI research. CONCLUSION: There is rising interest in the potential of AI technology to aid the detection and classification of voice pathology. Three challenges-and areas of opportunities-for advancing this research are heterogeneity of databases, lack of clinical validation studies, and inconsistent reporting.
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Vaccination arguably remains the only long-term strategy to limit the spread of S. aureus infections and its related antibiotic resistance. To date, however, all staphylococcal vaccines tested in clinical trials have failed. In this review, we propose that the failure of S. aureus vaccines is intricately linked to prior host exposure to S. aureus and the pathogen's capacity to evade adaptive immune defenses. We suggest that non-protective immune imprints created by previous exposure to S. aureus are preferentially recalled by SA vaccines, and IL-10 induced by S. aureus plays a unique role in shaping these non-protective anti-staphylococcal immune responses. We discuss how S. aureus modifies the host immune landscape, which thereby necessitates alternative approaches to develop successful staphylococcal vaccines.
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BACKGROUND: Structural variations (SVs) have significant impacts on complex phenotypes by rearranging large amounts of DNA sequence. RESULTS: We present a comprehensive SV catalog based on the whole-genome sequence of 1060 pigs (Sus scrofa) representing 101 breeds, covering 9.6% of the pig genome. This catalog includes 42,487 deletions, 37,913 mobile element insertions, 3308 duplications, 1664 inversions, and 45,184 break ends. Estimates of breed ancestry and hybridization using genotyped SVs align well with those from single nucleotide polymorphisms. Geographically stratified deletions are observed, along with known duplications of the KIT gene, responsible for white coat color in European pigs. Additionally, we identify a recent SINE element insertion in MYO5A transcripts of European pigs, potentially influencing alternative splicing patterns and coat color alterations. Furthermore, a Yorkshire-specific copy number gain within ABCG2 is found, impacting chromatin interactions and gene expression across multiple tissues over a stretch of genomic region of ~200 kb. Preliminary investigations into SV's impact on gene expression and traits using the Pig Genotype-Tissue Expression (PigGTEx) data reveal SV associations with regulatory variants and gene-trait pairs. For instance, a 51-bp deletion is linked to the lead eQTL of the lipid metabolism regulating gene FADS3, whose expression in embryo may affect loin muscle area, as revealed by our transcriptome-wide association studies. CONCLUSIONS: This SV catalog serves as a valuable resource for studying diversity, evolutionary history, and functional shaping of the pig genome by processes like domestication, trait-based breeding, and adaptive evolution.
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Genoma , Variação Estrutural do Genoma , Animais , Sus scrofa/genética , Polimorfismo de Nucleotídeo Único , Suínos/genética , Mapeamento CromossômicoRESUMO
BACKGROUND: Domesticated pigs serve as an ideal animal model for biomedical research and also provide the majority of meat for human consumption in China. Porcine intramuscular fat content associates with human health and diseases and is essential in pork quality. The molecular mechanisms controlling lipid metabolism and intramuscular fat accretion across tissues in pigs, and how these changes in response to pig breeds, remain largely unknown. RESULTS: We surveyed the tissue-resident cell types of the porcine jejunum, colon, liver, and longissimus dorsi muscle between Lantang and Landrace breeds by single-cell RNA sequencing. Combining lipidomics and metagenomics approaches, we also characterized gene signatures and determined key discriminating markers of lipid digestibility, absorption, conversion, and deposition across tissues in two pig breeds. In Landrace, lean-meat swine mainly exhibited breed-specific advantages in lipid absorption and oxidation for energy supply in small and large intestinal epitheliums, nascent high-density lipoprotein synthesis for reverse cholesterol transport in enterocytes and hepatocytes, bile acid formation, and secretion for fat emulsification in hepatocytes, as well as intestinal-microbiota gene expression involved in lipid accumulation product. In Lantang, obese-meat swine showed a higher synthesis capacity of chylomicrons responsible for high serum triacylglycerol levels in small intestinal epitheliums, the predominant characteristics of lipid absorption in muscle tissue, and greater intramuscular adipcytogenesis potentials from muscular fibro-adipogenic progenitor subpopulation. CONCLUSIONS: The findings enhanced our understanding of the cellular biology of lipid metabolism and opened new avenues to improve animal production and human diseases. Video Abstract.
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Metabolismo dos Lipídeos , Músculo Esquelético , Animais , China , Metabolismo dos Lipídeos/genética , Lipídeos , Músculo Esquelético/metabolismo , Obesidade/metabolismo , SuínosRESUMO
Understanding the genetic makeup of local sheep breeds is essential for their scientific conservation and sustainable utilization. The Liangshan semi-fine-wool sheep (LSS), a Chinese semi-fine-wool breed renowned for its soft wool, was analyzed using whole-genome sequencing data including 35 LSS, 84 sheep from other domestic breeds, and 20 Asiatic mouflons. We investigated the genetic composition of LSS by conducting analyses of the population structure, runs of homozygosity, genomic inbreeding coefficients, and selection signature. Our findings indicated that LSS shares greater genetic similarity with Border Leicester and Romney sheep than with Tibetan (TIB), Yunnan (YNS), and Chinese Merino sheep. Genomic analysis indicated low to moderate inbreeding coefficients, ranging from 0.014 to 0.154. In identifying selection signals across the LSS genome, we pinpointed 195 candidate regions housing 74 annotated genes (e.g., IRF2BP2, BVES, and ALOX5). We also found the overlaps between the candidate regions and several known quantitative trait loci related to wool traits, such as the wool staple length and wool fiber diameter. A selective sweep region, marked by the highest value of cross-population extended haplotype homozygosity, encompassed IRF2BP2-an influential candidate gene affecting fleece fiber traits. Furthermore, notable differences in genotype frequency at a mutation site (c.1051 + 46T > C, Chr25: 6,784,190 bp) within IRF2BP2 were observed between LSS and TIB and YNS sheep (Fisher's exact test, p < 2.2 × 10-16). Taken together, these findings offer insights crucial for the conservation and breeding enhancement of LSS.
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The failure of the Staphylococcus aureus (SA) IsdB vaccine trial can be explained by the recall of non-protective immune imprints from prior SA exposure. Here, we investigate natural human SA humoral imprints to understand their broader impact on SA immunizations. We show that antibody responses against SA cell-wall-associated antigens (CWAs) are non-opsonic, while antibodies against SA toxins are neutralizing. Importantly, the protective characteristics of the antibody imprints accurately predict the failure of corresponding vaccines against CWAs and support vaccination against toxins. In passive immunization platforms, natural anti-SA human antibodies reduce the efficacy of the human monoclonal antibodies suvratoxumab and tefibazumab, consistent with the results of their respective clinical trials. Strikingly, in the absence of specific humoral memory responses, active immunizations are efficacious in both naive and SA-experienced mice. Overall, our study points to a practical and predictive approach to evaluate and develop SA vaccines based on pre-existing humoral imprint characteristics.
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Staphylococcus aureus Resistente à Meticilina , Vacinas Antiestafilocócicas , Vacinas , Animais , Humanos , Camundongos , Imunização , Staphylococcus aureus , Ensaios Clínicos como AssuntoRESUMO
OBJECTIVE: To improve estimation of cochlear implant (CI) insertion depth in postoperative skull x-rays using synthesized information from preoperative CT scans. STUDY DESIGN: Retrospective cohort. SETTING: Tertiary referral center. PATIENTS: Ten adult cochlear implant recipients with preoperative and postoperative temporal bone computed tomography (CT)scans and postoperative skull x-ray imaging. INTERVENTIONS: Postoperative x-rays and digitally reconstructed radiographs (DRR) from preoperative CTs were registered using 3D Slicer and MATLAB to enhance localization of the round window and modiolus. Angular insertion depth (AID) was estimated in unmodified and registration-enhanced x-rays and DRRs in the cochlear view. Linear insertion depth (LID) was estimated in registered images by two methods that localized the proximal CI electrode or segmented the cochlea. Ground truth assessments were made in postoperative CTs. MAIN OUTCOME MEASURES: Errors of insertion depth estimates were calculated relative to ground truth measurements and compared with paired t t ests. Pearson correlation coefficient was used to assess inter-rater reliability of two reviewer's measurements of AID in unmodified x-rays. RESULTS: In postoperative x-rays, AID estimation errors were similar with and without registration enhancement (-1.3 ± 20.7° and -4.8 ± 24.9°, respectively; mean ± SD; p = 0.6). AID estimation in unmodified x-rays demonstrated strong interrater agreement (ρ = 0.79, p < 0.05) and interrater differences (-15.0 ± 35.3°) comparable to estimate errors. Registering images allowed measurement of AID in the cochlear view with estimation errors of 14.6 ± 30.6° and measurement of LID, with estimate errors that were similar between proximal electrode localization and cochlear segmentation methods (-0.9 ± 2.2 mm and -2.1 ± 2.7 mm, respectively; p = 0.3). CONCLUSIONS: 2D-3D image registration allows measurement of AID in the cochlear view and LID using postoperative x-rays and preoperative CT imaging. The use of this technique may reduce the need for postimplantation CT studies to assess these metrics of CI electrode position. Further work is needed to improve the accuracy of AID assessment in the postoperative x-ray view with registered images compared with established methods.
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Implante Coclear , Implantes Cocleares , Adulto , Humanos , Raios X , Estudos Retrospectivos , Reprodutibilidade dos Testes , Implante Coclear/métodos , Cóclea/diagnóstico por imagem , Cóclea/cirurgia , Tomografia Computadorizada por Raios X/métodosRESUMO
KEY POINTS: Eustachian tube recanalization is a feasible procedure but additional studies are needed to determine its safety. Eustachian tube closure can result from different etiologies and can cause severe symptoms. Ureteral stents have appropriate shape and pliability for placement and long-term healing. Multidisciplinary team approach allows for simultaneous endonasal and otologic approaches.
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Tuba Auditiva , Humanos , Tuba Auditiva/cirurgia , Endoscopia/métodos , Nariz , Stents , Dilatação/métodosRESUMO
Plantar fasciitis is one of the most common foot conditions presenting to a foot and ankle specialist. Surgical treatment outcomes following plantar fasciotomy vary but short-term studies have reported excellent early pain relief and significant improvements in symptoms. This study evaluates patient reported pain scores collected pre- and post-op for patients who underwent percutaneous ultrasonic microtenotomy (PUT) plantar fasciotomy with PRP injection vs without the use of PRP. We compared pain visual analog scale (VAS) scores, for patients treated surgically by Orthopedic Surgery department of foot and ankle faculty members between December 2007 and December 2022. A total of 30 patients were identified that met inclusion and exclusion criteria. Our results showed that there was a significant decrease in pain VAS scores from pre-op visit (at least 1 month prior to operation) to post-op visit (at least 1 month following operation) for both groups, with a paired t test (p value <.0001). However, patients who received PRP had a statistically significant decrease in pain level compared to the group who did not receive PRP. Statistical analysis completed with a 2-sample t test (p-value <.0325). Our results found the mean time between the initial pre-op visit and last post-op follow-up visit was 19 months. The mean for time following surgical intervention was 10 months. The findings of our study suggest that the dual use of PUT and PRP to treat plantar fasciitis, could potentially lead to an improvement in pain reduction and longevity of pain relief.
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Fasciíte Plantar , Plasma Rico em Plaquetas , Humanos , Fasciotomia , Fasciíte Plantar/diagnóstico por imagem , Fasciíte Plantar/cirurgia , Estudos Retrospectivos , Resultado do Tratamento , Dor , Ultrassonografia de IntervençãoRESUMO
GPIHBP1 plays an important role in the hydrolysis of triglyceride (TG) lipoproteins by lipoprotein lipases (LPLs). However, Gpihbp1 knockout mice did not develop hypertriglyceridemia (HTG) during the suckling period but developed severe HTG after weaning on a chow diet. It has been postulated that LPL expression in the liver of suckling mice may be involved. To determine whether hepatic LPL expression could correct severe HTG in Gpihbp1 deficiency, liver-targeted LPL expression was achieved via intravenous administration of the adeno-associated virus (AAV)-human LPL gene, and the effects of AAV-LPL on HTG and HTG-related acute pancreatitis (HTG-AP) were observed. Suckling Gpihbp1-/- mice with high hepatic LPL expression did not develop HTG, whereas Gpihbp1-/- rat pups without hepatic LPL expression developed severe HTG. AAV-mediated liver-targeted LPL expression dose-dependently decreased plasma TG levels in Gpihbp1-/- mice and rats, increased post-heparin plasma LPL mass and activity, decreased mortality in Gpihbp1-/- rat pups, and reduced the susceptibility and severity of both Gpihbp1-/- animals to HTG-AP. However, the muscle expression of AAV-LPL had no significant effect on HTG. Targeted expression of LPL in the liver showed no obvious adverse reactions. Thus, liver-targeted LPL expression may be a new therapeutic approach for HTG-AP caused by GPIHBP1 deficiency.
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Hipertrigliceridemia , Pancreatite , Receptores de Lipoproteínas , Animais , Humanos , Camundongos , Ratos , Doença Aguda , Dependovirus/genética , Dependovirus/metabolismo , Hipertrigliceridemia/genética , Hipertrigliceridemia/terapia , Lipase Lipoproteica/genética , Lipase Lipoproteica/metabolismo , Fígado/metabolismo , Pancreatite/genética , Pancreatite/terapia , Pancreatite/metabolismo , Receptores de Lipoproteínas/genética , Receptores de Lipoproteínas/metabolismo , Triglicerídeos/metabolismoRESUMO
Hallux valgus (HV) is a common condition in which the first ray is deformed, leading to pain and altered joint mechanics. A variety of radiographic measurements are used to evaluate HV. Little is known about measurements used in the assessment of HV on lateral radiographs compared to anteroposterior (AP) radiographs. The primary aim of this study was to correlate lateral measurements with AP measurements pre and postoperatively. The secondary aim was to correlate lateral measurements with patient-reported outcome measures (PROMs) pre and postoperatively. One hundred eighty-three patients were initially enrolled in the study. Two fellowship-trained musculoskeletal radiologists independently performed all measurements. On AP radiographs, hallux valgus angle (HVA) and intermetatarsal angle (IMA) were measured. On lateral radiographs, sagittal IMA, Meary's angle, and sagittal first ray length were measured. Measurements were recorded at baseline and 6, 12, and 24 months postoperatively. Intraclass correlation coefficients (ICCs) were used for inter-reader analysis. ICCs were moderate to very strong among readers. There were significant but weak correlations between lateral measurements and AP measurements. For at least 1 timepoint, IMA correlated with sagittal IMA, sagittal first ray length, and Meary's angle. HVA only correlated with sagittal first ray length. These correlations were all weak in magnitude. There were a few significant but weak correlations between the measurements in the study and PROMs. This study showed that sagittal IMA, sagittal first ray length, and Meary's angle are not predictive of AP measurements or patient outcomes and are not useful in preoperative assessment of HV.
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Joanete , Hallux Valgus , Ossos do Metatarso , Humanos , Hallux Valgus/diagnóstico por imagem , Hallux Valgus/cirurgia , Estudos Prospectivos , Pé , Medidas de Resultados Relatados pelo Paciente , Estudos Retrospectivos , Ossos do Metatarso/cirurgiaRESUMO
We describe an unusual case of glomangiopericytoma presenting as a mass filling the middle ear, enveloping the ossicles, and extending into the mastoid antrum without bony destruction. Management involved three surgeries and stereotactic radiosurgery, which achieved short-term local control with no evidence of disease on MRI imaging 12 months after radiation. Facial nerve function and hearing were preserved. This is the first report to our knowledge of a glomangiopericytoma presenting as a primary temporal bone lesion. Treatment with surgery and stereotactic radiosurgery for residual or recurrent disease is a reasonable approach to achieve local control and functional preservation. Laryngoscope, 134:1426-1430, 2024.
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Otopatias , Neoplasias de Cabeça e Pescoço , Radiocirurgia , Humanos , Audição , Radiocirurgia/métodos , Orelha Média/diagnóstico por imagem , Resultado do TratamentoRESUMO
IMPORTANCE: The prevalence of multidrug-resistant Staphylococcus aureus is of global concern, and vaccines are urgently needed. The iron-regulated surface determinant protein B (IsdB) of S. aureus was investigated as a vaccine candidate because of its essential role in bacterial iron acquisition but failed in clinical trials despite strong immunogenicity. Here, we reveal an unexpected second function for IsdB in pathogen-host interaction: the bacterial fitness factor IsdB triggers a strong inflammatory response in innate immune cells via Toll-like receptor 4 and the inflammasome, thus acting as a novel pathogen-associated molecular pattern of S. aureus. Our discovery contributes to a better understanding of how S. aureus modulates the immune response, which is necessary for vaccine development against the sophisticated pathogen.