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BACKGROUND: In early atherosclerosis, circulating LDLs (low-density lipoproteins) traverse individual endothelial cells by an active process termed transcytosis. The CANTOS trial (Canakinumab Antiinflammatory Thrombosis Outcome Study) treated advanced atherosclerosis using a blocking antibody for IL-1ß (interleukin-1ß); this significantly reduced cardiovascular events. However, whether IL-1ß regulates early disease, particularly LDL transcytosis, remains unknown. METHODS: We used total internal reflection fluorescence microscopy to quantify transcytosis by human coronary artery endothelial cells exposed to IL-1ß. To investigate transcytosis in vivo, we injected wild-type and knockout mice with IL-1ß and LDL to visualize acute LDL deposition in the aortic arch. RESULTS: Exposure to picomolar concentrations of IL-1ß induced transcytosis of LDL but not of albumin by human coronary artery endothelial cells. Surprisingly, expression of the 2 known receptors for LDL transcytosis, ALK-1 (activin receptor-like kinase-1) and SR-BI (scavenger receptor BI), was unchanged or decreased. Instead, IL-1ß increased the expression of the LDLR (LDL receptor); this was unexpected because LDLR is not required for LDL transcytosis. Overexpression of LDLR had no effect on basal LDL transcytosis. However, knockdown of LDLR abrogated the effect of IL-1ß on transcytosis rates while the depletion of Cav-1 (caveolin-1) did not. Since LDLR was necessary but overexpression had no effect, we reasoned that another player must be involved. Using public RNA sequencing data to curate a list of Rab (Ras-associated binding) GTPases affected by IL-1ß, we identified Rab27a. Overexpression of Rab27a alone had no effect on basal transcytosis, but its knockdown prevented induction by IL-1ß. This was phenocopied by depletion of the Rab27a effector JFC1 (synaptotagmin-like protein 1). In vivo, IL-1ß increased LDL transcytosis in the aortic arch of wild-type but not Ldlr-/- or Rab27a-deficient mice. The JFC1 inhibitor nexinhib20 also blocked IL-1ß-induced LDL accumulation in the aorta. CONCLUSIONS: IL-1ß induces LDL transcytosis by a distinct pathway requiring LDLR and Rab27a; this route differs from basal transcytosis. We speculate that induction of transcytosis by IL-1ß may contribute to the acceleration of early disease.
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Vasos Coronarios , Células Endoteliales , Interleucina-1beta , Lipoproteínas LDL , Ratones Noqueados , Receptores de LDL , Transducción de Señal , Transcitosis , Proteínas de Unión al GTP rab , Interleucina-1beta/metabolismo , Animales , Humanos , Receptores de LDL/genética , Receptores de LDL/metabolismo , Proteínas de Unión al GTP rab/metabolismo , Proteínas de Unión al GTP rab/genética , Células Endoteliales/metabolismo , Células Endoteliales/efectos de los fármacos , Lipoproteínas LDL/metabolismo , Vasos Coronarios/metabolismo , Vasos Coronarios/efectos de los fármacos , Células Cultivadas , Ratones Endogámicos C57BL , Caveolina 1/metabolismo , Caveolina 1/genética , Enfermedades de la Aorta/metabolismo , Enfermedades de la Aorta/genética , Enfermedades de la Aorta/patología , Modelos Animales de Enfermedad , Aorta Torácica/metabolismo , Aorta Torácica/efectos de los fármacos , Aterosclerosis/metabolismo , Aterosclerosis/genética , Aterosclerosis/patología , Masculino , RatonesRESUMEN
Background: Metabolic syndrome (MetS) is common following first-episode psychosis (FEP), contributing to substantial morbidity and mortality. The Psychosis Metabolic Risk Calculator (PsyMetRiC), a risk prediction algorithm for MetS following a FEP diagnosis, was developed in the United Kingdom and has been validated in other European populations. However, the predictive accuracy of PsyMetRiC in Chinese populations is unknown. Methods: FEP patients aged 15-35 y, first presented to the Early Assessment Service for Young People with Early Psychosis (EASY) Programme in Hong Kong (HK) between 2012 and 2021 were included. A binary MetS outcome was determined based on the latest available follow-up clinical information between 1 and 12 years after baseline assessment. The PsyMetRiC Full and Partial algorithms were assessed for discrimination, calibration and clinical utility in the HK sample, and logistic calibration was conducted to account for population differences. Sensitivity analysis was performed in patients aged >35 years and using Chinese MetS criteria. Findings: The main analysis included 416 FEP patients (mean age = 23.8 y, male sex = 40.4%, 22.4% MetS prevalence at follow-up). PsyMetRiC showed adequate discriminative performance (full-model C = 0.76, 95% C.I. = 0.69-0.81; partial-model: C = 0.73, 95% C.I. = 0.65-0.8). Systematic risk underestimation in both models was corrected using logistic calibration to refine PsyMetRiC for HK Chinese FEP population (PsyMetRiC-HK). PsyMetRiC-HK provided a greater net benefit than competing strategies. Results remained robust with a Chinese MetS definition, but worse for the older age group. Interpretation: With good predictive performance for incident MetS, PsyMetRiC-HK presents a step forward for personalized preventative strategies of cardiometabolic morbidity and mortality in young Hong Kong Chinese FEP patients. Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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Atherosclerosis results from the deposition and oxidation of LDL and immune cell infiltration in the sub-arterial space leading to arterial occlusion. Studies have shown that transcytosis transports circulating LDL across endothelial cells lining blood vessels. LDL transcytosis is initiated by binding to either scavenger receptor B1 (SR-B1) or activin A receptor-like kinase 1 on the apical side of endothelial cells leading to its transit and release on the basolateral side. HDL is thought to partly protect individuals from atherosclerosis due to its ability to remove excess cholesterol and act as an antioxidant. Apolipoprotein A1 (APOA1), an HDL constituent, can bind to SR-B1, raising the possibility that APOA1/HDL can compete with LDL for SR-B1 binding, thereby limiting LDL deposition in the sub-arterial space. To examine this possibility, we used in vitro approaches to quantify the internalization and transcytosis of fluorescent LDL in coronary endothelial cells. Using microscale thermophoresis and affinity capture, we find that SR-B1 and APOA1 interact and that binding is enhanced when using the cardioprotective variant of APOA1 termed Milano (APOA1-Milano). In male mice, transiently increasing the levels of HDL reduced the acute deposition of fluorescently labeled LDL in the atheroprone inner curvature of the aorta. Reduced LDL deposition was also observed when increasing circulating wild-type APOA1 or the APOA1-Milano variant, with a more robust inhibition from the APOA1-Milano. The results suggest that HDL may limit SR-B1-mediated LDL transcytosis and deposition, adding to the mechanisms by which it can act as an atheroprotective particle.
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Apolipoproteína A-I , Lipoproteínas HDL , Lipoproteínas LDL , Transcitosis , Animales , Humanos , Masculino , Ratones , Apolipoproteína A-I/metabolismo , Aterosclerosis/metabolismo , Células Endoteliales/metabolismo , Lipoproteínas HDL/metabolismo , Lipoproteínas LDL/metabolismo , Unión Proteica , Receptores Depuradores de Clase B/metabolismoRESUMEN
BACKGROUND: Extracellular vesicles (EVs) contain bioactive cargo including miRNAs and proteins that are released by cells during cell-cell communication. Endothelial cells (ECs) form the innermost lining of all blood vessels, interfacing with cells in the circulation and vascular wall. It is unknown whether ECs release EVs capable of governing recipient cells within these 2 separate compartments. Given their boundary location, we propose ECs use bidirectional release of distinct EV cargo in quiescent (healthy) and activated (atheroprone) states to communicate with cells within the circulation and blood vessel wall. METHODS: EVs were isolated from primary human aortic ECs (plate and transwell grown; ±IL [interleukin]-1ß activation), quantified, visualized, and analyzed by miRNA transcriptomics and proteomics. Apical and basolateral EC-EV release was determined by miRNA transfer, total internal reflection fluorescence and electron microscopy. Vascular reprogramming (RNA sequencing) and functional assays were performed on primary human monocytes or smooth muscle cells±EC-EVs. RESULTS: Activated ECs increased EV release, with miRNA and protein cargo related to atherosclerosis. EV-treated monocytes and smooth muscle cells revealed activated EC-EV altered pathways that were proinflammatory and atherogenic. ECs released more EVs apically, which increased with activation. Apical and basolateral EV cargo contained distinct transcriptomes and proteomes that were altered by EC activation. Notably, activated basolateral EC-EVs displayed greater changes in the EV secretome, with pathways specific to atherosclerosis. In silico analysis determined compartment-specific cargo released by the apical and basolateral surfaces of ECs can reprogram monocytes and smooth muscle cells, respectively, with functional assays and in vivo imaging supporting this concept. CONCLUSIONS: Demonstrating that ECs are capable of polarized EV cargo loading and directional EV secretion reveals a novel paradigm for endothelial communication, which may ultimately enhance the design of endothelial-based therapeutics for cardiovascular diseases such as atherosclerosis where ECs are persistently activated.
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Aterosclerosis , Vesículas Extracelulares , MicroARNs , Humanos , Células Endoteliales/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Vesículas Extracelulares/metabolismo , Comunicación Celular , Aterosclerosis/metabolismoRESUMEN
We report a fetus with prenatal ultrasound at 21 gestational weeks showing left cystic renal dysplasia with subcapsular cysts and echogenic parenchyma, right echogenic kidney with absent corticomedullary differentiation, and left congenital diaphragmatic hernia (CDH) with bowel herniation, with intestinal atresia (IA) found on postmortem examination. Whole genome sequencing of fetal blood DNA revealed a heterozygous pathogenic variant c.344 + 2 T>G in the HNF1B gene (NM_000458). Sanger sequencing of the parental samples suggested that it arose de novo in the fetus. HNF1B-associated disorders affect multiple organs with significant phenotypic heterogeneity. In pediatric and adult patients, renal cystic disease and cystic dysplasia are the dominant phenotypes. In prenatal settings, renal anomaly is also the most common presentation, typically with bilateral hyperechogenic kidneys. Our case presented with two uncommon extra-renal phenotypes of CDH and IA besides the typical bilateral cystic renal dysplasia. This association has been reported in fetuses with 17q12 microdeletion but not with HNF1B point mutation. Our case is the first prenatal report of such an association and highlights the possible causal relationship of HNF1B defects with CDH and IA in addition to the typical renal anomalies.
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Hernias Diafragmáticas Congénitas , Enfermedades Renales , Adulto , Femenino , Humanos , Embarazo , Feto/diagnóstico por imagen , Factor Nuclear 1-beta del Hepatocito/genética , Riñón/diagnóstico por imagen , Enfermedades Renales/diagnóstico por imagen , Enfermedades Renales/genética , FenotipoRESUMEN
Background: Total wrist replacement (TWR) is rarely done in the Asia-Pacific region. The aim of this study is to report the surgical outcomes and experience of TWR in patients with advanced arthritis. Methods: This is a retrospective review of all TWR patients in the Department of Orthopaedics and Traumatology, Prince of Wales Hospital, Hong Kong, which is a university tertiary centre, from January 2004 to March 2023. Recorded demographic parameters include gender, age upon surgery, pathology, types of implants and follow-up period. The surgical outcome parameters include range of motion, grip strength, wrist function assessment, radiological and clinical complications and any related secondary operations. Postoperative X-ray and clinical notes were reviewed. All wrist function assessments were performed by specialised occupational therapists according to protocol. Results: The study included a total of 12 wrists of 10 patients, all Chinese-Asian, with a mean age of 61.4 years at surgery. Larsen grade V arthritis constituted 50% and grade IV 16.7% of the patients, amongst which 33% had volar subluxation. The mean follow-up period was 97.4 months (21-205 months). The mean grip strength was 64.2% of the unaffected side. The mean postoperative Disabilities of Arm, Shoulder and Hand (DASH) score was 41.12% and patient-rated wrist/hand evaluation (PRWE) score 18.0. Complication incidence was 16.67% for loosening, 8.3% for metallosis and 8.3% for infection. One patient required conversion to total wrist arthrodesis due to metallosis. No patient suffered from dislocation, periprosthetic fracture and infection. Conclusions: TWR is an effective and safe alternative to total wrist arthrodesis with comparable outcomes. Our series outcomes are satisfactory and in line with literature. With meticulous soft tissue release and balancing, volar subluxation can also be corrected and may not be a contraindication. Level of Evidence: Level IV (Therapeutic).
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Artritis , Artroplastia de Reemplazo , Luxaciones Articulares , Humanos , Persona de Mediana Edad , Muñeca/cirugía , Resultado del Tratamiento , Artroplastia de Reemplazo/efectos adversos , Artritis/cirugía , Luxaciones Articulares/cirugía , Hong KongRESUMEN
In the search for new options for the pharmacological treatment of major depressive disorder, compounds with a rapid onset of action and high efficacy but lacking a psychotomimetic effect are of particular interest. In the present study, we evaluated the antidepressant potential of NitroSynapsin (NS) at behavioural, structural, and functional levels. NS is a memantine derivative and a dual allosteric N-methyl-d-aspartate receptors (NMDAR) antagonist using targeted delivery by the aminoadamantane of a warhead nitro group to inhibitory redox sites on the NMDAR. In a chronic restraint stress (CRS) mouse model of depression, five doses of NS administered on three consecutive days evoked antidepressant-like activity in the chronically stressed male C57BL/6J mice, reversing CRS-induced behavioural disturbances in sucrose preference and tail suspension tests. CRS-induced changes in morphology and density of dendritic spines in cerebrocortical neurons in the medial prefrontal cortex (mPFC) were also reversed by NS. Moreover, CRS-induced reduction in long-term potentiation (LTP) in the mPFC was found to be prevented by NS based on the electrophysiological recordings. Our study showed that NS restores structural and functional synaptic plasticity and reduces depressive behaviour to the level found in naïve animals. These results preliminarily revealed an antidepressant-like potency of NS.
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Depresión , Trastorno Depresivo Mayor , Ratones , Animales , Masculino , Depresión/tratamiento farmacológico , Corteza Prefrontal , Ratones Endogámicos C57BL , Plasticidad Neuronal/fisiología , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Modelos Animales de Enfermedad , Receptores de N-Metil-D-Aspartato/metabolismoRESUMEN
BACKGROUND: This study aimed to conduct a systematic review and meta-analysis on cognitive performances of patients with treatment-resistant schizophrenia (TRS) after clozapine treatment and to examine the potential effect of follow-up duration and clozapine dosage. METHODS: Five electronic databases were searched and studies were included if treatment-resistant schizophrenia patients were treated with clozapine and with baseline and follow-up cognitive functions assessments. Cognitive measures were categorised into six domains based on DSM-5-TR. Random-effect model analysis was used to pool the effect estimates. Moderator effects of clozapine dosage, follow up duration, duration of illness, age, years of education and change in positive symptoms severity were examined with meta-regression. FINDINGS: Nineteen articles were included with 50 cognitive measures reported. Systematic review found inconsistent results. Twelve cognitive measures were included for meta-analysis and found overall improvement of cognitive performances after clozapine treatment SMD = 0.11 [95 % CI 0.02, 0.20] (p = 0.021). Patients with younger age, more years of education and improvements in positive symptoms are more likely to improve in cognitive performances. Subgroup analysis found significant improvement in studies with follow-up periods of 6-months or longer but not for studies with shorter follow-up periods. CONCLUSION: Clozapine may improve some domains of cognitive function, particularly over a longer period. However, the overall inconsistent results suggest that more studies with larger sample size and standard cognitive function assessments would be needed to enhance our understanding of the impact of clozapine on the cognitive functions in the TRS patients.
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Neutrophils are essential for host defense against Staphylococcus aureus (S. aureus). The neuro-repellent, SLIT2, potently inhibits neutrophil chemotaxis, and might, therefore, be expected to impair antibacterial responses. We report here that, unexpectedly, neutrophils exposed to the N-terminal SLIT2 (N-SLIT2) fragment kill extracellular S. aureus more efficiently. N-SLIT2 amplifies reactive oxygen species production in response to the bacteria by activating p38 mitogen-activated protein kinase that in turn phosphorylates NCF1, an essential subunit of the NADPH oxidase complex. N-SLIT2 also enhances the exocytosis of neutrophil secondary granules. In a murine model of S. aureus skin and soft tissue infection (SSTI), local SLIT2 levels fall initially but increase subsequently, peaking at 3 days after infection. Of note, the neutralization of endogenous SLIT2 worsens SSTI. Temporal fluctuations in local SLIT2 levels may promote neutrophil recruitment and retention at the infection site and hasten bacterial clearance by augmenting neutrophil oxidative burst and degranulation. Collectively, these actions of SLIT2 coordinate innate immune responses to limit susceptibility to S. aureus.
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Infecciones Estafilocócicas , Staphylococcus aureus , Animales , Humanos , Ratones , Quimiotaxis de Leucocito , Inmunidad Innata , Neutrófilos , Infecciones Estafilocócicas/microbiologíaRESUMEN
PURPOSE OF REVIEW: The accumulation of LDL in the arterial intima is an initiating event in atherosclerosis. After decades of controversy, it is now clear that transcytosis of LDL across an intact endothelial monolayer contributes to its intimal deposition. We review recent observations in this field and address the question of whether LDL transcytosis can be manipulated therapeutically. RECENT FINDINGS: The development of a live-cell imaging method for studying transcytosis using total internal reflection fluorescence (TIRF) microscopy has catalyzed recent discoveries. LDL transcytosis is mediated by SR-BI and ALK1. Estrogen down-regulates SR-BI and inhibits LDL transcytosis, while the nuclear structural protein HMGB1 promotes LDL transcytosis. LDL transcytosis by ALK1 is independent of the receptor's kinase activity and is antagonized by BMP9, ALK1's canonical ligand. Inflammation stimulates LDL transcytosis. Identifying the function and mechanisms of LDL transcytosis may ultimately permit its therapeutic manipulation.
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Aterosclerosis , Lipoproteínas LDL , Humanos , Lipoproteínas LDL/metabolismo , Células Endoteliales/metabolismo , Transcitosis , Aterosclerosis/metabolismo , Endotelio Vascular/metabolismoRESUMEN
We report a case of maternally inherited autosomal dominant PLAG-1 related Silver Russell syndrome (SRS) in a fetus with IUGR and a mother who had growth and feeding problems in early life, dextrocardia and an atrio-ventricular septal defect. Amniocentesis was performed due to marked intra-uterine growth restriction (IUGR). The array was normal. Whole exome sequencing (WES) revealed a maternally inherited heterozygous likely pathogenic variant in PLAG1 (NM_002655.3): c.402delT p.(Gly135Aspfs*94). This variant has not been reported previously. PLAG1 pathogenic variants are associated with autosomal dominant Silver Russell syndrome, which fits with the clinical phenotypes of both fetus and mother. PLAG1 variants have previously been reported post-natally in Silver Russell syndrome, but the phenotype tends to be milder than in 11p15.5 methylation-related cases with fewer physical features. Although cardiac anomalies are uncommon in SRS, they have been previously reported. To our knowledge, dextrocardia has not been previously associated with SRS and there were no other potential causative genetic variants found. This report aims to highlight this rare type of SRS as a cause of IUGR.
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Dextrocardia , Síndrome de Silver-Russell , Humanos , Femenino , Síndrome de Silver-Russell/diagnóstico , Síndrome de Silver-Russell/genética , Metilación de ADN , Herencia Materna , Retardo del Crecimiento Fetal/diagnóstico , Retardo del Crecimiento Fetal/genética , Fenotipo , Feto , Dextrocardia/genéticaRESUMEN
Rationale: Extracellular vesicles (EVs) contain bioactive cargo including microRNAs (miRNAs) and proteins that are released by cells as a form of cell-cell communication. Endothelial cells (ECs) form the innermost lining of all blood vessels and thereby interface with cells in the circulation as well as cells residing in the vascular wall. It is unknown whether ECs have the capacity to release EVs capable of governing recipient cells within two separate compartments, and how this is affected by endothelial activation commonly seen in atheroprone regions. Objective: Given their boundary location, we propose that ECs utilize bidirectional release of distinct EV cargo in quiescent and activated states to communicate with cells within the circulation and blood vessel wall. Methods and Results: EVs were isolated from primary human aortic endothelial cells (ECs) (+/-IL-1ß activation), quantified, and analysed by miRNA transcriptomics and proteomics. Compared to quiescent ECs, activated ECs increased EV release, with miRNA and protein cargo that were related to atherosclerosis. RNA sequencing of EV-treated monocytes and smooth muscle cells (SMCs) revealed that EVs from activated ECs altered pathways that were pro-inflammatory and atherogenic. Apical and basolateral EV release was assessed using ECs on transwells. ECs released more EVs apically, which increased with activation. Apical and basolateral EV cargo contained distinct transcriptomes and proteomes that were altered by EC activation. Notably, basolateral EC-EVs displayed greater changes in the EV secretome, with pathways specific to atherosclerosis. In silico analysis determined that compartment-specific cargo released by the apical and basolateral surfaces of ECs can reprogram monocytes and SMCs, respectively. Conclusions: The demonstration that ECs are capable of polarized EV cargo loading and directional EV secretion reveals a novel paradigm for endothelial communication, which may ultimately enhance our ability to design endothelial-based therapeutics for cardiovascular diseases such as atherosclerosis where ECs are persistently activated.
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Background: This study aims to look at the intermediate-term clinical, functional and radiological outcomes of patients with enchondroma in hand treated with osteoscopic-assisted curettage and artificial bone substitute or bone graft. The addition of osteoscopy allows direct visualisation of the bone cavity during and after curettage of tumour tissue without the need of creating a large opening in the bone cortex. This could lead to better clearance of tumour tissue and lower risk of iatrogenic fracture. Methods: A total of 11 patients who received surgery from December 2013 to November 2020 were retrospectively reviewed. All cases had histological diagnosis of enchondroma. Patients with a follow-up period of less than 3 months were excluded. The mean duration of follow-up was 20.9 months. For the clinical outcome, we measured the total active motion (TAM) and graded with Belsky score grip strength. For the functional outcome, the Quick Disabilities of the Arm, Shoulder and Hand Questionnaire (QuickDASH) score was used. For the radiological outcome, we evaluated the X-ray for bone cavity filling defect, new bone formation according to the system proposed by Tordai. Results: The mean TAM of patients was 257º. A total of 60% patients had Belsky score grading excellent, 40% patients had Belsky score grading good. The mean percentage of grip strength compared with the contralateral side was 86.2%. The mean QuickDASH score was 7.7. For the wound aesthetic rating by patients, 81.8% patients reported as excellent. For the radiological outcome, the postoperative X-ray of all patients showed bone filling defect less than 3 mm. The mean time to complete bone consolidation was 3.8 months. None of the patients showed any radiological signs of recurrence. Conclusions: Our study showed that patients with enchondromas in hand treated with this minimally invasive method demonstrated good functional and radiological outcome. Its application may also be extended into treating other benign bone lesions in hand. Level of Evidence: Level IV (Therapeutic).
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Neoplasias Óseas , Sustitutos de Huesos , Condroma , Humanos , Sustitutos de Huesos/uso terapéutico , Estudios Retrospectivos , Neoplasias Óseas/diagnóstico por imagen , Neoplasias Óseas/cirugía , Neoplasias Óseas/patología , Mano/cirugía , Condroma/diagnóstico por imagen , Condroma/cirugíaRESUMEN
OBJECTIVE: To evaluate the local incidence of orofacial cleft (OFC) encountered in fetal morphology scan and prenatal diagnosis, genetic etiology of fetuses with or without other structural abnormalities, and their pregnancy outcomes. DESIGN: Retrospective cohort study. SETTING: Two maternal fetal medicine units, tertiary hospitals, Hong Kong. PARTICIPANTS: All pregnant women with antenatal diagnosis of fetal OFC between January 2016 and December 2020 (N = 66). RESULTS: OFC has an incidence of 0.13% among pregnancies in Hong Kong and 28.8% (19/66) were syndromic cleft that exhibited other fetal structural anomalies. There were 55 cases (84.6%) who opted for invasive prenatal diagnostic testing. Genetic defects were identified in 25.8% (17/66) of this cohort, including 14 pathogenic variants. The detection rate in the syndromic cases is 68.4% (13/19) which was significantly higher than 8.5% (4/47) among non-syndromic cases. Aneuploidies would be the most common cause, accounting for 9.1% (6/66). Chromosomal microarray analysis (CMA) provided an incremental diagnostic yield of 6.1% compared to conventional karyotyping. A total of 29 live births including 3 cases of a variant of uncertain significance and 26 cases without genetic abnormalities detected have continued pregnancy to birth. There were 87.5% (21/24) without detectable pathogenic genetic abnormality reported good long-term outcomes. The chance of OFC fetuses having a good long-term outcome was significantly higher if no genomic variant was detected (P < .001). CONCLUSIONS: Invasive prenatal tests with CMA should be offered to pregnancies with OFC regardless of the type. It has provided incremental diagnostic yield over conventional karyotyping and helped in prenatal and genetic counseling. A negative result in non-syndromic OFC favors couples to keep the pregnancy.
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INTRODUCTION: This study aimed to identify risk factors among maternal characteristics, obstetric history, and first trimester preeclampsia-specific biomarkers that were associated with subsequent development of gestational diabetes mellitus (GDM) and evaluate the performance of the prediction models. METHODS: This study was a secondary analysis of a prospective cohort study. The performance of the prediction models was assessed by area under the receiver operating characteristic curve (AUROC). RESULTS: A total of 837 (8.9%) cases of GDM and 8,535 (91.1%) unaffected cases were included. The AUROC of the prediction model combining maternal characteristics and obstetric history (0.735) was better than that of the model utilizing maternal characteristics (AUROC 0.708) and preeclampsia-specific biomarkers (AUROC 0.566). Among the preeclampsia-specific biomarkers, the mean arterial pressure (MAP) contributed to the increasing risk of GDM; however, its addition did not improve the AUROC of the model combining maternal characteristics and obstetric history (0.738). CONCLUSION: The first trimester prediction model for GDM with maternal characteristics and obstetric history achieves moderate predictability. The inclusion of MAP in the model combining maternal characteristics and obstetric history does not improve the screening performance for GDM. Future studies are needed to explore the effect of blood pressure control from early pregnancy on preventing GDM.
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Diabetes Gestacional , Preeclampsia , Biomarcadores , Diabetes Gestacional/diagnóstico , Femenino , Humanos , Preeclampsia/diagnóstico , Embarazo , Primer Trimestre del Embarazo , Estudios ProspectivosRESUMEN
Induction of labour is a common obstetrical procedure and is undertaken when the benefits of delivery are considered to outweigh the risks of continuation of pregnancy. However, more than one-fifth of induction cases fail to result in vaginal births and lead to unplanned caesarean deliveries, which compromise the birth experience and have negative clinical and resource implications. The need for accurate prediction of successful labour induction is increasingly recognised and many researchers have attempted to evaluate the potential predictability of different factors including maternal characteristics, Bishop score, various biochemical markers and ultrasound markers and derive predictive models to address this issue.
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Parto Obstétrico , Fibronectinas , Cesárea , Parto Obstétrico/métodos , Femenino , Humanos , Trabajo de Parto Inducido/métodos , Embarazo , UltrasonografíaRESUMEN
Background: Low-pass genome sequencing (GS) detects clinically significant copy number variants (CNVs) in prenatal diagnosis. However, detection at improved resolutions leads to an increase in the number of CNVs identified, increasing the difficulty of clinical interpretation and management. Methods: Trio-based low-pass GS was performed in 315 pregnancies undergoing invasive testing. Rare CNVs detected in the fetuses were investigated. The characteristics of rare CNVs were described and compared to curated CNVs in other studies. Results: A total of 603 rare CNVs, namely, 597 constitutional and 6 mosaic CNVs, were detected in 272 fetuses (272/315, 86.3%), providing 1.9 rare CNVs per fetus (603/315). Most CNVs were smaller than 1 Mb (562/603, 93.2%), while 1% (6/603) were mosaic. Forty-six de novo (7.6%, 46/603) CNVs were detected in 11.4% (36/315) of the cases. Eighty-four CNVs (74 fetuses, 23.5%) involved disease-causing genes of which the mode of inheritance was crucial for interpretation and assessment of recurrence risk. Overall, 31 pathogenic/likely pathogenic CNVs were detected, among which 25.8% (8/31) were small (<100 kb; n = 3) or mosaic CNVs (n = 5). Conclusion: We examined the landscape of rare CNVs with parental inheritance assignment and demonstrated that they occur frequently in prenatal diagnosis. This information has clinical implications regarding genetic counseling and consideration for trio-based CNV analysis.
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INTRODUCTION: Fetal pleural effusion may require in utero shunting which is associated with procedure-related complications. OBJECTIVE: To evaluate the efficacy and complications of the newly designed Somatex shunt in treating fetal pleural effusion. METHODS: Consecutive cases with primary fetal pleural effusion who were treated with the Somatex shunt between 2018 and 2019 were evaluated. Perinatal outcomes and complications were retrospectively analyzed. RESULTS: There were 6 cases of unilateral and 1 case of bilateral pleural effusion, and hence a total of 8 pleuroamniotic shunting procedures were performed. The median gestational age at diagnosis and shunting was 20.7 and 22.6 weeks, respectively. All 8 procedures were successful, achieving complete in utero drainage. All but one were live births (85.7%) with a median gestational age of 38 weeks. The single case of in utero death occurred 4.7 weeks after successful shunting, and no cause could be identified after autopsy. The rates of preterm birth and premature rupture of membranes were 33.3% (2/6) and 16.7% (1/6), respectively. Four of the 8 procedures (50%) had minor shunt-related complications such as dislodgement and entrapment, occurring at a median of 7.7 weeks after shunting. None of the shunts became blocked. CONCLUSIONS: The Somatex shunt is effective in relieving fetal pleural effusions with good survival rate. Overall, it was a safe instrument, though minor shunt complications occurred.
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Derrame Pleural , Nacimiento Prematuro , Estudios de Cohortes , Femenino , Edad Gestacional , Humanos , Lactante , Recién Nacido , Derrame Pleural/diagnóstico por imagen , Derrame Pleural/cirugía , Embarazo , Estudios RetrospectivosRESUMEN
OBJECTIVE: To investigate changes in the median nerve, retinaculum, and carpal tunnel on ultrasound after successful endoscopic carpal tunnel release (ECTR). MATERIALS AND METHODS: This prospective study involved 37 wrists in 35 patients (5 male, 30 female; mean age ± standard deviation [SD], 56.9 ± 6.7 years) with primary carpal tunnel syndrome (CTS). An in-house developed scoring system (0-3) was used to gauge the clinical improvement after ECTR. Ultrasound was performed before ECTR, and at 1, 3, and 12 months post-ECTR. Changes in the median nerve, flexor retinaculum, and carpal tunnel morphology on ultrasound after ECTR were analyzed. Ultrasound parameters for different clinical improvement groups were compared. RESULTS: All patients improved clinically after ECTR. The average clinical improvement score ± SD at 12 months post-ECTR was 2.2 ± 0.7. The median nerve cross-sectional area proximal and distal to the tunnel decreased at all time intervals post-ECTR but remained swollen compared to normal values. Serial changes in the median nerve caliber and retinacular bowing after ECTR were more pronounced at the tunnel outlet than at the tunnel inlet. The flexor retinaculum had reformed in 25 (68%) of 37 wrists after 12 months. CONCLUSION: Postoperative changes in median nerve and retinaculum parameters were most pronounced at the tunnel outlet. Even in patients with clinical improvement after ECTR, nearly all ultrasound parameters remain abnormal at one year post-ECTR. These ultrasound parameters should not necessarily be relied upon to diagnose persistent CTS after ECTR.