RESUMO
In recent years, exome sequencing (ES) has shown great utility in the diagnoses of Mendelian disorders. However, after rigorous filtering, a typical ES analysis still involves the interpretation of hundreds of variants, which greatly hinders the rapid identification of causative genes. Since the interpretations of ES data require comprehensive clinical analyses, taking clinical expertise into consideration can speed the molecular diagnoses of Mendelian disorders. To leverage clinical expertise to prioritize candidate genes, we developed PhenoApt, a phenotype-driven gene prioritization tool that allows users to assign a customized weight to each phenotype, via a machine-learning algorithm. Using the ability to rank causative genes in top-10 lists as an evaluation metric, baseline analysis demonstrated that PhenoApt outperformed previous phenotype-driven gene prioritization tools by a relative increase of 22.7%-140.0% in three independent, real-world, multi-center cohorts (cohort 1, n = 185; cohort 2, n = 784; and cohort 3, n = 208). Additional trials showed that, by adding weights to clinical indications, which should be explained by the causative gene, PhenoApt performance was improved by a relative increase of 37.3% in cohort 2 (n = 471) and 21.4% in cohort 3 (n = 208). Moreover, PhenoApt could assign an intrinsic weight to each phenotype based on the likelihood of its being a Mendelian trait using term frequency-inverse document frequency techniques. When clinical indications were assigned with intrinsic weights, PhenoApt performance was improved by a relative increase of 23.7% in cohort 2 and 15.5% in cohort 3. For the integration of PhenoApt into clinical practice, we developed a user-friendly website and a command-line tool.
Assuntos
Doenças Genéticas Inatas/genética , Perda Auditiva Neurossensorial/genética , Deficiência Intelectual/genética , Aprendizado de Máquina , Microcefalia/genética , Nistagmo Congênito/genética , Escoliose/genética , Estudos de Coortes , Biologia Computacional , Bases de Dados Genéticas , Exoma , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/patologia , Testes Genéticos , Genótipo , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/patologia , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/patologia , Microcefalia/diagnóstico , Microcefalia/patologia , Nistagmo Congênito/diagnóstico , Nistagmo Congênito/patologia , Fenótipo , Escoliose/diagnóstico , Escoliose/patologia , Software , Sequenciamento do ExomaRESUMO
Neuritin, also known as candidate plasticity gene 15 (CPG15), was first identified as one of the activity-dependent gene products in the brain. Previous studies have been reported that Neuritin induces neuritogenesis, neurite arborization, neurite outgrowth and synapse formation, which are involved in the development and functions of the central nervous system. However, the role of Neuritin in peripheral nerve injury is still unknown. Given the importance and necessity of Schwann cell dedifferentiation response to peripheral nerve injury, we aim to investigate the molecular mechanism of Neuritin steering Schwann cell dedifferentiation during Wallerian degeneration (WD) in injured peripheral nerve. Herein, using the explants of sciatic nerve, an ex vivo model of nerve degeneration, we provided evidences indicating that Neuritin vividly accelerates Schwann cell dedifferentiation. Moreover, we found that Neuritin promotes Schwann cell demyelination as well as axonal degeneration, phagocytosis, secretion capacity. In summary, we first described Neuritin acts as a positive regulator for Schwann cell dedifferentiation and WD after peripheral nerve injury.
Assuntos
Desdiferenciação Celular , Neuropeptídeos , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Células de Schwann , Nervo Isquiático , Transdução de Sinais , Serina-Treonina Quinases TOR , Degeneração Walleriana , Células de Schwann/metabolismo , Células de Schwann/patologia , Degeneração Walleriana/metabolismo , Degeneração Walleriana/patologia , Animais , Serina-Treonina Quinases TOR/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Neuropeptídeos/metabolismo , Neuropeptídeos/genética , Nervo Isquiático/lesões , Nervo Isquiático/metabolismo , Nervo Isquiático/patologia , Proteínas Ligadas por GPI/metabolismo , Proteínas Ligadas por GPI/genética , Ratos , Traumatismos dos Nervos Periféricos/metabolismo , Traumatismos dos Nervos Periféricos/patologia , Ratos Sprague-Dawley , Axônios/metabolismo , Axônios/patologia , Masculino , Fagocitose , CamundongosRESUMO
Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) is associated with congenital absence of the uterus, cervix, and the upper part of the vagina; it is a sex-limited trait. Disrupted development of the Müllerian ducts (MD)/Wölffian ducts (WD) through multifactorial mechanisms has been proposed to underlie MRKHS. In this study, exome sequencing (ES) was performed on a Chinese discovery cohort (442 affected subjects and 941 female control subjects) and a replication MRKHS cohort (150 affected subjects of mixed ethnicity from North America, South America, and Europe). Phenotypic follow-up of the female reproductive system was performed on an additional cohort of PAX8-associated congenital hypothyroidism (CH) (n = 5, Chinese). By analyzing 19 candidate genes essential for MD/WD development, we identified 12 likely gene-disrupting (LGD) variants in 7 genes: PAX8 (n = 4), BMP4 (n = 2), BMP7 (n = 2), TBX6 (n = 1), HOXA10 (n = 1), EMX2 (n = 1), and WNT9B (n = 1), while LGD variants in these genes were not detected in control samples (p = 1.27E-06). Interestingly, a sex-limited penetrance with paternal inheritance was observed in multiple families. One additional PAX8 LGD variant from the replication cohort and two missense variants from both cohorts were revealed to cause loss-of-function of the protein. From the PAX8-associated CH cohort, we identified one individual presenting a syndromic condition characterized by CH and MRKHS (CH-MRKHS). Our study demonstrates the comprehensive utilization of knowledge from developmental biology toward elucidating genetic perturbations, i.e., rare pathogenic alleles involving the same loci, contributing to human birth defects.
Assuntos
Transtornos 46, XX do Desenvolvimento Sexual/genética , Anormalidades Congênitas/genética , Ductos Paramesonéfricos/anormalidades , Ductos Paramesonéfricos/crescimento & desenvolvimento , Mutação , Ductos Mesonéfricos/crescimento & desenvolvimento , Adulto , Proteína Morfogenética Óssea 4/genética , Proteína Morfogenética Óssea 7/genética , Códon sem Sentido , Feminino , Estudos de Associação Genética , Pleiotropia Genética , Proteínas Homeobox A10/genética , Proteínas de Homeodomínio/genética , Humanos , Fator de Transcrição PAX8/genética , Herança Paterna , Penetrância , Proteínas com Domínio T/genética , Fatores de Transcrição/genética , Proteínas Wnt/genética , Ductos Mesonéfricos/anormalidadesRESUMO
Cervical cancer is the fourth most common cancer in women, and its precise detection plays a critical role in disease treatment and prognosis prediction. Fluorodeoxyglucose positron emission tomography and computed tomography, i.e., FDG-PET/CT and PET/CT, have established roles with superior sensitivity and specificity in most cancer imaging applications. However, a typical FDG-PET/CT analysis involves the time-consuming process of interpreting hundreds of images, and the intense image screening work has greatly hindered clinicians. We propose a computer-aided deep learning-based framework to detect cervical cancer using multimodal medical images to increase the efficiency of clinical diagnosis. This framework has three components: image registration, multimodal image fusion, and lesion object detection. Compared to traditional approaches, our adaptive image fusion method fuses multimodal medical images. We discuss the performance of deep learning in each modality, and we conduct extensive experiments to compare the performance of different image fusion methods with some state-of-the-art (SOTA) object-detection deep learning-based methods in images with different modalities. Compared with PET, which has the highest recognition accuracy in single-modality images, the recognition accuracy of our proposed method on multiple object detection models is improved by an average of 6.06%. And compared with the best results of other multimodal fusion methods, our results have an average improvement of 8.9%.
Assuntos
Aprendizado Profundo , Neoplasias do Colo do Útero , Feminino , Fluordesoxiglucose F18 , Humanos , Processamento de Imagem Assistida por Computador/métodos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Tomografia por Emissão de Pósitrons/métodos , Neoplasias do Colo do Útero/diagnóstico por imagemRESUMO
PURPOSE: Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) is characterized by congenital absence of the uterus, cervix, and the upper part of the vagina in females. Whole-gene deletion and loss-of-function variants in TBX6 have been identified in association with MRKHS. We aimed to expand the spectrum of TBX6 variants in MRKHS and explore the biological effect of the variant alleles. METHODS: Rare variants in TBX6 were called from a combined multiethnic cohort of 622 probands with MRKHS who underwent exome sequencing or genome sequencing. Multiple in vitro functional experiments were performed, including messenger RNA analysis, western blotting, transcriptional activity assay, and immunofluorescence staining. RESULTS: We identified 16 rare variants in TBX6 from the combined cohort, including 1 protein-truncating variant reported in our previous study and 15 variants with unknown effects. By comparing the prevalence of TBX6 variants in the Chinese MRKHS cohort vs 1038 female controls, we observed a significant mutational burden of TBX6 in affected individuals (P = .0004, odds ratio = 5.25), suggesting a causal role of TBX6 variants in MRKHS. Of the 15 variants with uncertain effects, 7 were shown to induce a loss-of-function effect through various mechanisms. The c.423G>A (p.Leu141=) and c.839+5G>A variants impaired the normal splicing of TBX6 messenger RNA, c.422T>C (p.Leu141Pro) and c.745G>A (p.Val249Met) led to decreased protein expression, c.10C>T (p.Pro4Ser) and c.400G>A (p.Glu134Lys) resulted in perturbed transcriptional activity, and c.356G>A (p.Arg119His) caused protein mislocalization. We observed incomplete penetrance and variable expressivity in families carrying deleterious variants, which indicates a more complex genetic mechanism than classical Mendelian inheritance. CONCLUSION: Our study expands the mutational spectrum of TBX6 in MRKHS and delineates the molecular pathogenesis of TBX6 variants, supporting the association between deleterious variants in TBX6 and MRKHS.
Assuntos
Transtornos 46, XX do Desenvolvimento Sexual , Anormalidades Congênitas , Feminino , Humanos , Transtornos 46, XX do Desenvolvimento Sexual/genética , Ductos Paramesonéfricos/anormalidades , Vagina/anormalidades , RNA Mensageiro , Anormalidades Congênitas/genética , Proteínas com Domínio T/genéticaRESUMO
Müllerian anomaly (M.A.) is a group of congenital anatomic abnormalities caused by aberrations of the development process of the Müllerian duct. M.A. can either be isolated or be involved in Mendelian syndromes, such as Dandy-Walker syndrome, Holt-Oram syndrome and Bardet-Biedl syndrome, which are often associated with both uterus and kidney malformations. In this study, we applied a genotype-first approach to analyze the whole-exome sequencing data of 492 patients with M.A. Six potential pathogenic variants were found in five genes previously related to female urogenital deformities (PKD1, SON, SALL1, BMPR1B, ITGA8), which are partially overlapping with our patients' phenotypes. We further identified eight incidental findings in seven genes related to Mendelian syndromes without known association with reproductive anomalies (TEK, COL11A1, ANKRD11, LEMD3, DLG5, SPTB, BMP2), which represent potential phenotype expansions of these genes.
Assuntos
Anormalidades Múltiplas , Deformidades Congênitas das Extremidades Inferiores , Deformidades Congênitas das Extremidades Superiores , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Feminino , Genótipo , Humanos , Deformidades Congênitas das Extremidades Inferiores/genética , Ductos Paramesonéfricos/anormalidades , Ductos Paramesonéfricos/patologia , Deformidades Congênitas das Extremidades Superiores/genéticaRESUMO
BACKGROUND & AIMS: Genetic factors underlie a substantial proportion of paediatric liver diseases. Hereditary liver diseases have considerable genetic heterogeneity and variable clinical manifestations, which bring great challenges to clinical and molecular diagnoses. In this study, we investigated a group of paediatric patients with varying degrees of liver dysfunction using a hierarchical genetic testing strategy. METHODS: We first applied a panel encompassing 166 known causal genes of liver disease. We then used exome sequencing (ES) in those patients whose cases remained undiagnosed to identify the genetic aetiology of their symptoms. RESULTS: In total, we enrolled 131 unrelated paediatric patients with liver disease of Chinese Han ethnicity. We first applied targeted gene sequencing of 166 genes to all patients and yielded a diagnostic rate of 35.9% (47 of 131). Eighty-four patients who remained undiagnosed after target gene sequencing were subjected to ES. As a result, eight (8/84, 9.5%) of them obtained molecular diagnoses, including four patients suspected of abnormal bilirubin metabolism and four idiopathic cases. Non-typical genetic findings, including digenic inheritance and dual molecular diagnosis, were also identified. Through a comprehensive assessment of novel candidate variants of uncertain disease association, 11 patients of the remaining undiagnosed patients were able to obtain likely molecular diagnoses. CONCLUSIONS: Our study presents evidence for the diagnostic utility of sequential genetic testing in a cohort of patients with paediatric liver disease. Our findings expand the understanding of the phenotypic and mutational spectrum underlying this heterogeneous group of diseases.
Assuntos
Exoma , Hepatopatias , Criança , Testes Genéticos , Humanos , Hepatopatias/diagnóstico , Hepatopatias/genética , Mutação , Sequenciamento do ExomaRESUMO
BACKGROUND: Early-onset scoliosis (EOS), defined by an onset age of scoliosis less than 10 years, conveys significant health risk to affected children. Identification of the molecular aetiology underlying patients with EOS could provide valuable information for both clinical management and prenatal screening. METHODS: In this study, we consecutively recruited a cohort of 447 Chinese patients with operative EOS. We performed exome sequencing (ES) screening on these individuals and their available family members (totaling 670 subjects). Another cohort of 13 patients with idiopathic early-onset scoliosis (IEOS) from the USA who underwent ES was also recruited. RESULTS: After ES data processing and variant interpretation, we detected molecular diagnostic variants in 92 out of 447 (20.6%) Chinese patients with EOS, including 8 patients with molecular confirmation of their clinical diagnosis and 84 patients with molecular diagnoses of previously unrecognised diseases underlying scoliosis. One out of 13 patients with IEOS from the US cohort was molecularly diagnosed. The age at presentation, the number of organ systems involved and the Cobb angle were the three top features predictive of a molecular diagnosis. CONCLUSION: ES enabled the molecular diagnosis/classification of patients with EOS. Specific clinical features/feature pairs are able to indicate the likelihood of gaining a molecular diagnosis through ES.
Assuntos
Predisposição Genética para Doença , Escoliose/diagnóstico , Escoliose/genética , Adolescente , Adulto , Idade de Início , Pré-Escolar , China/epidemiologia , Estudos de Coortes , Exoma/genética , Feminino , Humanos , Masculino , Estudos Retrospectivos , Escoliose/classificação , Escoliose/patologia , Sequenciamento do ExomaRESUMO
A rare autosomal recessive genetic disease is spinal muscular atrophy with respiratory distress type 1 (SMARD 1; OMIM #604320), which is characterized by progressive distal limb muscle weakness, muscular atrophy, and early onset of respiratory failure. Herein, we report the case of a 4-month-old female infant with SMARD type 1 who was admitted to our hospital owing to unexplained distal limb muscle weakness and early respiratory failure. This report summarizes the characteristics of SMARD type 1 caused by heterozygous variation in the immunoglobulin mu DNA binding protein 2 (IGHMBP2) gene by analyzing its clinical manifestations, genetic variation characteristics, and related examinations, aiming to deepen clinicians' understanding of the disease, assisting pediatricians in providing medical information to parents and improving the decision-making process involved in establishing life support.
RESUMO
OBJECTIVES: The project intended to analyze the impact of burden and related risk factors of late-onset colorectal cancer (LOCRC) and early-onset colorectal cancer (EOCRC) in China, thus offering essential references for optimizing prevention and control strategies. METHOD: Global Burden of Disease Study was employed to describe burden changes of EOCRC and LOCRC in China during 1990-2019, containing the numbers of incidence, deaths, prevalence, and disability-adjusted life years (DALYs), and to compare attributable deaths and DALYs risk factors in varying age and sex segments. RESULTS: The numbers and corresponding crude rates of incidence, deaths, prevalence, and DALYs of EOCRC and LOCRC in China during 1990-2019 demonstrated an upward trend across all age categories, with males being dramatically predominant. Overall, over time, the impact of a low-calcium diet and a low-fiber diet on mortality and DALY rates decreased, while the impact of other risk factors increased. In terms of gender, the risk factors affecting males changed greatly, with smoking, inadequate milk intake, and the low whole-grain diet being the main factors in 2019, while in 1990, the main factors were the low-calcium diet, smoking, and inadequate milk intake. CONCLUSION: The burden of colorectal cancer in China is concerning. Patients grouped by diagnostic age exhibit different characteristics, indicating the need for high-quality research in the future to achieve personalized medicine tailored to different population characteristics.
RESUMO
Background: Osteoporotic vertebral compression fractures (OVCF) appear to be more common as the population ages. Previous studies have found that percutaneous vertebroplasty (PVP) can achieve better short-term clinical outcomes than conservative treatment (CT) for OVCF. However, the long-term outcomes of PVP compared with CT for OVCF has been rare explored. This study was designed to explore the clinical outcomes of PVP or CT within 3 years after OVCF. Methods: This study reviewed the clinical outcomes of patients who underwent PVP or CT for OVCF in a single center from January 2015 to December 2019. The back pain visual analogue scale (VAS), Oswestry disability index (ODI) and satisfaction rate were compared between the two groups at baseline, 1 week, 1 month, 3 months, 6 months, 12 months, 24 months and 36 months after treatment. Outcomes: The baseline data including gender, age, bone mineral density, body mass index, back pain VAS, and ODI were not significantly different between the two groups. The back pain VAS and ODI of CT patients were significantly higher than those of PVP group at 1 week, 1 month, 3 months, 6 months and 12 months after treatment. The satisfaction rate in the PVP group were significantly higher than those in the CT group at 1 week, 1 month, 3 months and 6 months after treatment. Subsequently, the back pain VAS and ODI showed no significant difference between the two groups at 24 and 36 months. In addition, there was no significant difference in treatment satisfaction between the two groups at 36 months. There was no significant difference in the rate of new vertebral compression fractures between the two groups within 36 months after treatment. Conclusion: The clinical outcomes within 12 months after PVP and patient satisfaction rate within 6 months after PVP were significantly higher than CT. However, during 12 months to 36 months, this advantage generated by PVP was gradually diluted over time. Compared with CT, the long-term effect of PVP on OVCF should not be overestimated.
RESUMO
New vertebral compression fractures (NVCF) are common in patients with osteoporotic vertebral compression fractures (OVCF) who have undergone percutaneous vertebroplasty (PVP). We sought to develop a nomogram prediction model for better identification and prevention of NVCF within 3 years after PVP in patients with OVCF. The demographic, clinical, and imaging data of patients who underwent PVP for OVCF between January 2010 and December 2019 were reviewed. Multivariate logistic regression analysis was used to screen for risk factors for NVCF within 3 years after PVP. A nomogram prediction model was then developed and validated to visually predict NVCF. The samples in the model were randomly divided into training and validation sets at a ratio of 7:3. Twenty-seven percent of patients experienced NVCF in other segments within 3 years after PVP. Older age, lower bone mineral density (BMD), smoking, lack of anti-osteoporosis therapy, and postoperative trauma were risk factors for NVCF. The area under the receiver operating characteristic curve suggested good discrimination of this model: training set (0.781, 95% confidence interval: 0.731-0.831) and validation set (0.786, 95% confidence interval: 0.708-0.863). The calibration curve suggested good prediction accuracy between the actual and predicted probabilities in the training and validation sets. The DCA results suggested that, when the probability thresholds were 0.0452-08394 and 0.0336-0.7262 in the training and validation set, respectively, patients can benefit from using this model to predict NVCF within 3 years after PVP. In conclusion, this nomogram prediction model that included five risk factors (older age, lower BMD, smoking, postoperative minor trauma, and lack of anti-osteoporosis treatment can effectively predict NVCF within 3 years after PVP. Postoperative smoking cessation, standard anti-osteoporosis treatment, and reduction in incidental minor trauma are necessary and effective means of reducing the incidence of NVCF.
Assuntos
Fraturas por Compressão , Nomogramas , Fraturas por Osteoporose , Fraturas da Coluna Vertebral , Vertebroplastia , Humanos , Fraturas por Compressão/cirurgia , Fraturas por Compressão/etiologia , Fraturas da Coluna Vertebral/cirurgia , Fraturas da Coluna Vertebral/etiologia , Feminino , Masculino , Vertebroplastia/métodos , Fraturas por Osteoporose/cirurgia , Fraturas por Osteoporose/etiologia , Idoso , Fatores de Risco , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Densidade Óssea , Estudos RetrospectivosRESUMO
Leveraging protein structural information to evaluate pathogenicity has been hindered by the scarcity of experimentally determined 3D protein. With the aid of AlphaFold2 predictions, we developed the structure-informed genetic missense mutation assessor (SIGMA) to predict missense variant pathogenicity. In comparison with existing predictors across labeled variant datasets and experimental datasets, SIGMA demonstrates superior performance in predicting missense variant pathogenicity (AUC = 0.933). We found that the relative solvent accessibility of the mutated residue contributed greatly to the predictive ability of SIGMA. We further explored combining SIGMA with other top-tier predictors to create SIGMA+, proving highly effective for variant pathogenicity prediction (AUC = 0.966). To facilitate the application of SIGMA, we pre-computed SIGMA scores for over 48 million possible missense variants across 3,454 disease-associated genes and developed an interactive online platform (https://www.sigma-pred.org/). Overall, by leveraging protein structure information, SIGMA offers an accurate structure-based approach to evaluating the pathogenicity of missense variants.
Assuntos
Biologia Computacional , Mutação de Sentido Incorreto , Virulência , Proteínas/genética , MutaçãoRESUMO
The damage of islet cells caused by oxidative stress is closely related to diabetes. The aim of this study is to investigate the protective effect of saponins isolated from polygonatum sibiricum (PSS) on pancreas injury by using in vitro and in vivo models. The oxidative stress model of RIN-m5F cells induced by H2O2 was established. We found that PSS could decrease the apoptosis of RIN-m5F cells under oxidative stress. After PSS treatment, ROS and MDA levels in cells significantly decreased. Moreover, the levels of SOD and GSH were significantly increased. PSS could increase the insulin secretion level of cells under oxidative stress. The expression level of intracellular Bcl-2 increased, and the expression levels of Bax, caspase-3, caspase-8, and caspase-9 decreased significantly. In addition, the type 2 diabetes mouse model was established. The results showed that PSS had a protective effect on the injury of the pancreas in T2DM mice. PSS can relieve oxidative stress and high glucose-mediated pancreas cytotoxicity. PSS may be a promising candidate for diabetes intervention and functional foods.
Assuntos
Diabetes Mellitus Tipo 2 , Ilhotas Pancreáticas , Polygonatum , Saponinas , Camundongos , Animais , Peróxido de Hidrogênio/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Saponinas/farmacologia , Saponinas/metabolismo , Estresse Oxidativo , Ilhotas Pancreáticas/metabolismo , ApoptoseRESUMO
STUDY DESIGN: A systematic review and meta-analysis of randomized controlled trials. OBJECTIVE: The aim of this study was to determine the effect of chewing gum on postoperative abdominal pain, nausea, and hospital stays after posterior spinal fusions (PSFs) in patients with adolescent idiopathic scoliosis (AIS). SUMMARY OF BACKGROUND DATA: Chewing gum had been extensively reported to improve bowel motility and is recommended to hasten bowel recovery following gastrointestinal surgery. However, there is no conclusive evidence regarding the effect of chewing gum on postoperative abdominal pain, nausea, and hospital stays after PSFs in AIS patients. METHODS: A comprehensive literature search was performed for relevant randomized controlled trials using PubMed, Cochrane Central Register of Controlled Trials, Web of Science, and Embase. Studies were selected to compare the use of chewing gum versus standard care in the management of postoperative abdominal pain and nausea in AIS patients undergoing PSFs. Hospital stays were also investigated. The study was conducted using the checklist for PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses). RESULTS: Three randomized controlled trials were included in the systematic review and the meta-analysis. No significant effect of chewing gum was highlighted concerning the postoperative abdominal pain scores at 24 and 48 hours [24 h: mean difference (MD)=0.45, 95% CI=-0.97 to 0.07, P =0.09; 48 h: MD=-0.24, 95% CI=-0.79 to 0.32, P =0.41]. No significant difference regarding the postoperative nausea scores was found at 24 and 48 hours (24 h: MD=0.26, 95% CI=-0.27 to 0.79, P =0.34; 48 h: MD=0.06, 95% CI=-0.36 to 0.48, P =0.77). No significant difference regarding hospital stays was found (MD=0.13, 95% CI=-0.02 to 0.28, P =0.09). CONCLUSIONS: Based on the current studies, chewing gum does not have a significant effect on postoperative abdominal pain, nausea, or hospital stays after PSFs in AIS patients. As the effect of chewing gum in reducing postoperative abdominal pain exhibits a tendency towards statistical significance ( P =0.09), the effect of chewing gum in spinal surgery merits further studies with larger sample size.
Assuntos
Escoliose , Fusão Vertebral , Humanos , Adolescente , Goma de Mascar , Complicações Pós-Operatórias , Escoliose/cirurgia , Ensaios Clínicos Controlados Aleatórios como Assunto , Dor Pós-Operatória/etiologia , Dor Pós-Operatória/prevenção & controle , Náusea , Dor Abdominal/etiologia , Dor Abdominal/prevenção & controleRESUMO
Importance: Currently, the diagnostic yield of exome sequencing (ES) and chromosomal microarray analysis (CMA) for short stature cohorts is uncertain. Despite previous studies reporting the widespread use of ES and CMA, a definitive diagnostic yield has not been established. Objective: To investigate the diagnostic yield of ES and CMA in short stature. Data Sources: A systematic literature search was conducted using relevant keywords in 3 databases (PubMed, Embase, and Web of Science) in February 2023. Study Selection: Eligible studies for meta-analysis were those that had at least 10 participants with short stature who were diagnosed using either ES or CMA and the number of diagnosed patients was reported. Of 5222 identified studies, 20 were eventually included in the study. Data Extraction and Synthesis: Two independent investigators extracted relevant information from each study, which was then synthesized using proportional meta-analysis to obtain the overall diagnostic yield of ES and CMA. Main Outcomes and Measures: The primary outcome measure was to determine the overall diagnostic yield of ES and CMA. A subgroup meta-analysis was also performed to assess if the diagnostic yield varied depending on whether ES was used as a first-tier or last-resort test. Additionally, a meta-regression was carried out to investigate how the diagnostic yield varied over time. Results: Twenty studies were included, comprising 1350 patients with short stature who underwent ES and 1070 patients who completed CMA. The overall diagnostic yield of ES among the cohorts and CMA among the cohorts was found to be 27.1% (95% CI, 18.1%-37.2%) and 13.6% (95% CI, 9.2%-18.7%), respectively. No statistically significant difference was observed between the first-tier (27.8%; 95% CI, 15.7%-41.8%) and last-resort groups (25.6%; 95% CI, 13.6%-39.6%) (P = .83) or in the percentage of positively diagnosed patients over time. No statistically significant difference was observed between the first-tier (27.8%; 95% CI, 15.7%-41.8%) and last-resort groups (25.6%; 95% CI, 13.6%-39.6%) (P = .83) or in the percentage of positively diagnosed patients over time. Conclusion and Relevance: This systematic review and meta-analysis provides high-level evidence supporting the diagnostic efficacy of ES and CMA in patients with short stature. The findings serve as a solid reference for clinicians when making informed decisions about recommending these genetic tests.
Assuntos
Testes Genéticos , Patologia Molecular , Humanos , Sequenciamento do Exoma , Análise em MicrossériesRESUMO
BACKGROUND: Burkholderia pseudomallei (B. pseudomallei) is a short, straight, medium-sized Gram-negative bacterium that mostly exists alone, without a capsule or spores, has more than three flagella at one end, and actively moves. B. pseudomallei confers high morbidity and mortality, with frequent granulocytopenia in B. pseudomallei sepsis-related deaths. However, mortality may be related to hemophagocytic lymphohistiocytosis (HLH) secondary to B. pseudomallei infection. CASE SUMMARY: A 12-year-old female was referred from a local hospital to the pediatric intensive care unit with suspected septic shock and fever, cough, dyspnea, and malaise. After admission, supportive symptomatic treatments including fluid resuscitation, anti-infective therapy, mechanical ventilation, and a vasoactive drug maintenance cycle were carefully initiated. The patient became unconscious, her blood pressure could not be maintained even under the exposure of vasoactive drugs, and she experienced cardiorespiratory arrest. The patient died due to ineffective high-quality in-hospital cardiopulmonary resuscitation. A subsequent bone marrow smear examination revealed extensive phagocytosis, and the blood culture was positive for B. pseudomallei. Family history revealed a sibling death from B. pseudomallei sepsis 5 years earlier. CONCLUSION: The higher mortality rate in patients with B. pseudomallei sepsis may be related to secondary HLH after infection, wherein multiorgan dysfunction syndrome may be directly related to infection or immune damage caused by secondary HLH. Patients with B. pseudomallei can be asymptomatic and can become an infective source.
RESUMO
Type 2 diabetes mellitus (T2DM) is a systemic metabolic disorder characterized by insulin deficiency and insulin resistance. Recently, it has become a significant threat to public health. Polygonatum sibiricum saponin (PSS) has potential hypoglycemic effects, but its specific mechanism needs further study. In this study, PSS significantly decreased the level of blood glucose, water intake, and the organ index in diabetic mice. Meanwhile, PSS effectively reduced the content of total triglyceride (TG), total cholesterol (TCHO), low-density lipoprotein cholesterol (LDL-C), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) in the blood, and increased the content of high-density lipoprotein cholesterol (HDL-C). This suggests that PSS could reduce the content of blood lipids and initially improve the damage of hepatocytes. We found that PSS alleviated hepatic insulin resistance, repaired islet beta cells, and enabled insulin to play its biological role normally. It also improved oral glucose tolerance and abated serum lipopolysaccharide (LPS) and glycosylated hemoglobin (HbA1c) levels in T2DM mice. Furthermore, studies have found that PSS increased the content of phosphorylated protein kinase B (AKT), thereby promoting the effect of glucose transporter 4 (GLUT-4), and activating glycogen synthase kinase 3beta (GSK-3ß) and glycogen synthase (GS) proteins to promote hepatic glycogen synthesis. Finally, we found that PSS could promote the growth of beneficial bacteria such as Bifidobacterium and Lactobacillus, reduce the growth of harmful bacteria such as Enterococcus and Enterobacter, and preliminarily improve the composition of important bacteria in the intestine. These studies indicate that PSS has an excellent hypoglycemic effect, which provides a potential new treatment for T2DM and guidance for more in-depth research.
Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Resistência à Insulina , Polygonatum , Camundongos , Animais , Hipoglicemiantes/farmacologia , Hipoglicemiantes/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Glicogênio/metabolismo , Fígado/metabolismo , Insulina , Glicemia/metabolismo , Colesterol/metabolismoRESUMO
Background: In recent years, miRNAs have become a research hotspot, which is related to the occurrence and development of a variety of malignant tumors, but there are few studies in neuroblastoma. In this study, the differentially expressed microRNAs (miRNAs) in neuroblastoma were identified and analyzed using bioinformatics, and their biological functions and related signaling pathways were examined. Methods: The neuroblastoma miRNA chip GSE121513 was obtained from the Gene Expression Omnibus (GEO) database and the data of 95 neuroblastoma samples and normal fetal adrenal neuroblastoma samples were analyzed to screen the differential miRNAs. The target genes of the differentially expressed miRNAs were predicted using |log fold change (FC)| ≥4. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses were performed to construct a protein-protein interaction network and identify the core target genes. Results: A total of 91 differentially expressed miRNAs were identified (P<0.05, |logFC| ≥1), including 52 upregulated and 39 downregulated miRNAs. The target genes of the differential miRNAs (P<0.05, |logFC| ≥4) were pretested, and 602 target genes were obtained. Functional analysis showed that these genes were mainly located in the extracellular matrix region of proteins, and were involved in the negative regulation of cytoplasmic translation, mRNA 3'-untranslated region (UTR) binding, and binding to nucleic acid to inhibit the activity of translation factors. They were also involved in RNA degradation, adhesion pathways, and the phosphatidylinositol-3-kinase (PI3K)-Akt signaling pathway. Ten key target genes were identified via protein interaction network screening. Conclusions: The differential miRNAs may be related to the occurrence of neuroblastoma were screened.
RESUMO
Congenital contractural arachnodactyly (CCA) is a rare autosomal dominant disorder of connective tissue characterized by crumpled ears, arachnodactyly, camptodactyly, large joint contracture, and kyphoscoliosis. The nature course of CCA has not been well-described. We aim to decipher the genetic and phenotypic spectrum of CCA. The cohort was enrolled in Beijing Jishuitan Hospital and Peking Union Medical College Hospital, Beijing, China, based on Deciphering disorders Involving Scoliosis and COmorbidities (DISCO) study (http://www.discostudy.org/). Exome sequencing was performed on patients' blood DNA. A recent published CCA scoring system was validated in our cohort. Seven novel variants and three previously reported FBN2 variants were identified through exome sequencing. Two variants outside of the neonatal region of FBN2 gene were found. The phenotypes were comparable between patients in our cohort and previous literature, with arachnodactyly, camptodactyly and large joints contractures found in almost all patients. All patients eligible for analysis were successfully classified into likely CCA based on the CCA scoring system. Furthermore, we found a double disease-causing heterozygous variant of FBN2 and ANKRD11 in a patient with blended phenotypes consisting of CCA and KBG syndrome. The identification of seven novel variants broadens the mutational and phenotypic spectrum of CCA and may provide implications for genetic counseling and clinical management.