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INTRODUCTION: Healthcare workers in intensive care units often experience moral distress, depression, and stress-related symptoms. These conditions can lower staff retention and influence the quality of patient care. This study aimed to evaluate the prevalence of moral distress and psychological status among healthcare workers in a newly established paediatric intensive care unit (PICU) in Hong Kong. METHODS: A cross-sectional questionnaire survey was conducted in the PICU of the Hong Kong Children's Hospital; healthcare workers (doctors, nurses and allied health professionals) were invited to participate. The Revised Moral Distress Scale (MDS-R) Paediatric Version and Depression Anxiety and Stress Scale-21 items were used to assess moral distress and psychological status, respectively. Demographic characteristics were examined in relation to moral distress, depression, anxiety, and stress scores to identify risk factors for poor psychological outcomes. Correlations of moral distress with depression, anxiety, and stress were examined. RESULTS: Forty-six healthcare workers completed the survey. The overall median MDS-R moral distress score was 71. Nurses had a significantly higher median moral distress score, compared with doctors and allied health professionals (102 vs 47 vs 20). Nurses also had the highest median anxiety and stress scores (11 and 20, respectively). Moral distress scores were correlated with depression (r=0.445; P=0.002) and anxiety scores (r=0.417; P<0.05). Healthcare workers intending to quit their jobs had significantly higher moral distress scores (P<0.05). CONCLUSION: Among PICU healthcare workers, nurses had the highest level of moral distress. Moral distress was associated with greater depression, anxiety, and intention to quit. Healthcare workers need support and a sustainable working environment to cope with moral distress.
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Personal de Salud , Unidades de Cuidado Intensivo Pediátrico , Humanos , Niño , Estudios Transversales , Unidades de Cuidados Intensivos , Atención al Paciente , Encuestas y Cuestionarios , Principios Morales , Estrés Psicológico/epidemiología , Estrés Psicológico/etiologíaRESUMEN
Until now, most studies investigating the relationship between event segmentation and memory have used videos filmed from a third-person perspective, although people experience their lives from a first-person perspective. The present study aimed to determine whether visual perspective impacts events segmentation and further recall. Fifty-seven participants were recruited and assigned to either first- (1PP) or third-person perspective (3PP) condition, before segmenting videos of daily life activities. Our results showed that the although the number of event boundaries was higher in the 3PP condition than in the 1PP, no differences were observed for event segmentation qualitative abilities and organization. Memory of temporal order was better for events encoded in the 3PP than in the 1PP, while memory content was similar in both conditions. Higher event segmentation rates were correlated with a better recall of small actions and temporal order.
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Recuerdo Mental , Humanos , Estimulación Luminosa/métodos , Análisis de VarianzaRESUMEN
OBJECTIVE: The objective of this meta-analysis is to evaluate the impact of genetic polymorphisms on platinum-based chemotherapy (PBC)-induced ototoxicity. DATA SOURCES: Systematic searches of PubMed, Embase, Cochrane, and Web of Science were conducted from the inception of the databases to May 31, 2022. Abstracts and presentations from conferences were also reviewed. REVIEW METHODS: Four investigators independently extracted data in adherence to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Differences in the prevalence of PBC-induced ototoxicity between reference and variant (i) genotypes and (ii) alleles were analyzed. The overall effect size was presented using the random-effects model as an odds ratio (OR) with a 95% confidence interval (CI). RESULTS: From 32 included articles, 59 single nucleotide polymorphisms on 28 genes were identified, with 4406 total unique participants. For allele frequency analysis, the A allele in ACYP2 rs1872328 was positively associated with ototoxicity (OR: 2.61; 95% CI: 1.06-6.43; n = 2518). Upon limiting to cisplatin use only, the T allele of COMT rs4646316 and COMT rs9332377 revealed significant results. For genotype frequency analysis, the CT/TT genotype in ERCC2 rs1799793 demonstrated an otoprotective effect (OR: 0.50; 95% CI: 0.27-0.94; n = 176). Excluding studies using carboplatin or concomitant radiotherapy revealed significant effects with COMT rs4646316, GSTP1 rs1965, and XPC rs2228001. Major sources of variations between studies include differences in patient demographics, ototoxicity grading systems, and treatment protocols. CONCLUSION: Our meta-analysis presents polymorphisms that exert ototoxic or otoprotective effects in patients undergoing PBC. Importantly, several of these alleles are observed at high frequencies globally, highlighting the potential for polygenic screening and cumulative risk evaluation for personalized care.
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Antineoplásicos , Ototoxicidad , Humanos , Antineoplásicos/uso terapéutico , Ototoxicidad/tratamiento farmacológico , Platino (Metal) , Cisplatino , Polimorfismo de Nucleótido Simple , Proteína de la Xerodermia Pigmentosa del Grupo D/genética , Ácido Anhídrido Hidrolasas/genéticaRESUMEN
BACKGROUND: The prevalence of sleep-disordered breathing in children is underestimated due to impediments in detection and diagnosis. Consequently, delayed management may affect the quality of life and the growth and development of a child. Due to their patient demographic, orthodontists are optimally positioned to identify those at risk of sleep-disordered breathing and make referrals for investigation and management. This study aims to determine the prevalence of children at risk of sleep-disordered breathing in an Australian orthodontic population. METHODS: A 1-year retrospective study was conducted in an urban Western Australian private orthodontic practice with two branches in similar socioeconomic demographics. The responses of new patients to a modified paediatric sleep questionnaire and standard medical history form were recorded. RESULTS: In 1209 patients (4-18 years), 7.3% were at risk of sleep-disordered breathing. An association between sex and the potential risk of sleep-disordered breathing was found with 11% of males at risk of sleep-disordered breathing compared to 7% of females (P = 0.012). CONCLUSIONS: The relatively high prevalence of children at risk of sleep-disordered breathing presenting for orthodontic care presents an opportunity to identify at-risk individuals through routine use of the paediatric sleep questionnaire. This would facilitate early referral for diagnosis and management of sleep-disordered breathing.
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Calidad de Vida , Síndromes de la Apnea del Sueño , Masculino , Femenino , Niño , Humanos , Estudios Retrospectivos , Australia , Síndromes de la Apnea del Sueño/epidemiología , PrevalenciaRESUMEN
PURPOSE: Thyroid dysfunction in COVID-19 carries clinical and prognostic implications. In this study, we developed a prediction score (ThyroCOVID) for abnormal thyroid function (TFT) on admission amongst COVID-19 patients. METHODS: Consecutive COVID-19 patients admitted to Queen Mary Hospital were prospectively recruited during July 2020-May 2021. Thyroid-stimulating hormone (TSH), free thyroxine (fT4) and free triiodothyronine (fT3) were measured on admission. Multivariable logistic regression analysis was performed to identify independent determinants of abnormal TFTs. ThyroCOVID was developed based on a clinical model with the lowest Akaike information criteria. RESULTS: Five hundred and forty six COVID-19 patients were recruited (median age 50 years, 45.4% men, 72.9% mild disease on admission). 84 patients (15.4%) had abnormal TFTs on admission. Patients with abnormal TFTs were more likely to be older, have more comorbidities, symptomatic, have worse COVID-19 severity, higher SARS-CoV-2 viral loads and more adverse profile of acute-phase reactants, haematological and biochemical parameters. ThyroCOVID consisted of five parameters: symptoms (malaise), comorbidities (ischaemic heart disease/congestive heart failure) and laboratory parameters (lymphocyte count, C-reactive protein, and SARS-CoV-2 cycle threshold values). It was able to identify abnormal TFT on admission with an AUROC of 0.73 (95% CI 0.67-0.79). The optimal cut-off of 0.15 had a sensitivity of 75.0%, specificity of 65.2%, negative predictive value of 93.5% and positive predictive value of 28.1% in identifying abnormal TFTs on admission amongst COVID-19 patients. CONCLUSION: ThyroCOVID, a prediction score to identify COVID-19 patients at risk of having abnormal TFT on admission, was developed based on a cohort of predominantly non-severe COVID-19 patients.
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COVID-19 , Triyodotironina , Proteína C-Reactiva , COVID-19/diagnóstico , COVID-19/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , SARS-CoV-2 , Pruebas de Función de la Tiroides , Glándula Tiroides , Tirotropina , TiroxinaRESUMEN
OBJECTIVE: To investigate the prognostic significance of videofluorographic swallowing study (VFSS)-confirmed oropharyngeal dysphagia in idiopathic inflammatory myopathies (IIMs). METHOD: We reviewed the medical records of patients who were diagnosed with IIM between 2009 and 2020 at Seoul St Mary's Hospital. All oropharyngeal dysphagia cases were limited to VFSS-confirmed dysphagia found during the initial diagnostic work-up for IIM. We described the findings on VFSS and the course of the dysphagic symptoms. Logistic regression and survival analyses were performed to evaluate the risk of pneumonia and mortality, respectively. RESULTS: We found 88 patients with IIM who met the criteria. Among them, 17 patients (19%) had oropharyngeal dysphagia. Except for two cases lost to follow-up and one deceased case, all of the patients with dysphagia (14 of 14) had swallowing function restored within 6 months. The risk of pneumonia within 3 months from the diagnosis of IIM was significant [odds ratio = 4.49, 95% confidence interval (CI) 1.07-18.88]. The median follow-up duration was 34 and 27 months for the groups without and with dysphagia, respectively. The survival analysis failed to demonstrate that the presence of oropharyngeal dysphagia increased the risk of death (hazard ratio = 0.77, 95% CI: 0.085-7.00). CONCLUSIONS: Oropharyngeal dysphagia found at the initial diagnosis of IIM improved within 3-6 months in nearly all cases. Furthermore, IIM patients who had oropharyngeal dysphagia at the initial diagnosis of IIM were not likely to have shorter survival, even if the risk of pneumonia was increased in the short term.
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Trastornos de Deglución , Miositis , Neumonía , Humanos , Deglución , Trastornos de Deglución/epidemiología , Trastornos de Deglución/etiología , Miositis/complicaciones , PronósticoRESUMEN
We aimed to evaluate the effectiveness of nasopharyngeal cancer (NPC) screening by comprehensive clinical follow-up and adjunctive Epstein-Barr virus (EBV) testing. In a prospective cohort study, 524 individuals with a first-degree family history of NPC were recruited at a university clinical center in Singapore. The cohort was evaluated at baseline and at 6 monthly intervals, with a complete head and neck examination including nasopharyngeal endoscopy. Blood was taken at baseline and at yearly intervals for EBV Viral Capsid Antigen (VCA) IgA, EBV Early Antigen (EA) IgA serology and serum cell-free EBV DNA. Nasopharyngeal biopsy was performed when any irregularity in the nasopharynx was observed, or when EBV markers were elevated. The mean duration of follow-up was 57.7 months, with an average of 8.6 clinical visits per participant. Five participants (0.96%) were identified to have NPC, giving a prevalence of 199 per 100,000 person-years of screening. Four of the five NPC cases identified had asymptomatic T1 disease, at an earlier stage compared to NPC patients diagnosed in the clinic during the same time period (p = 0.0297). All NPC cases identified had elevated EBV-EA IgA titers ≥1:10, with a specificity of 94.6% and a positive predictive value of 15.2%, outperforming EBV-VCA IgA and serum EBV DNA. Two NPC cases were biopsied only because of elevated EBV serology titers, with increasing EBV-EA IgA titers preceding the diagnosis of NPC. In conclusion, screening for NPC is effective in identifying early-stage disease. Adjunctive EBV-EA IgA testing improved the effectiveness of screening.
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Ácidos Nucleicos Libres de Células/sangre , Detección Precoz del Cáncer/métodos , Infecciones por Virus de Epstein-Barr/sangre , Neoplasias Nasofaríngeas/diagnóstico , Neoplasias Nasofaríngeas/virología , Adulto , Anciano , Estudios de Cohortes , ADN Viral/sangre , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/diagnóstico , Femenino , Herpesvirus Humano 4 , Humanos , Masculino , Persona de Mediana Edad , Carcinoma Nasofaríngeo/sangre , Carcinoma Nasofaríngeo/diagnóstico , Carcinoma Nasofaríngeo/virología , Neoplasias Nasofaríngeas/sangre , SingapurRESUMEN
INTRODUCTION: Obstetric anal sphincter injuries (OASIS) may be underdetected in primiparous women. This study evaluated the prevalence of OASIS in primiparous women after normal vaginal delivery or instrumental delivery using endoanal ultrasound (US) during postnatal follow-up. METHODS: This study retrospectively analysed endoanal US data collected during postnatal follow-up (6-12 months after vaginal delivery) at a tertiary hospital in Hong Kong. Offline analysis to determine the prevalence of OASIS was performed by two researchers who were blinded to the clinical diagnosis. Symptoms of faecal and flatal incontinence were assessed with the Pelvic Floor Distress Inventory. RESULTS: Of 542 women included in the study, 205 had normal vaginal delivery and 337 had instrumental delivery. The prevalence of OASIS detected by endoanal US was 7.8% (95% confidence interval [CI]=4.1%-11.5%) in the normal vaginal delivery group and 5.6% (95% CI=3.1%-8.1%) in the instrumental delivery group. Overall, 82.9% of women with OASIS on endoanal US did not show clinical signs of OASIS. Birth weight was significantly higher in the OASIS group (P=0.012). At 6 to 12 months after delivery, 5.5% of women reported faecal incontinence and 17.9% reported flatal incontinence, but OASIS was not associated with these symptoms. CONCLUSIONS: Additional training for midwives and doctors may improve OASIS detection.
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Canal Anal/lesiones , Incontinencia Fecal/epidemiología , Laceraciones/epidemiología , Complicaciones del Trabajo de Parto/epidemiología , Adulto , Canal Anal/diagnóstico por imagen , Endosonografía , Incontinencia Fecal/etiología , Femenino , Hong Kong/epidemiología , Humanos , Laceraciones/etiología , Paridad , Parto , Embarazo , Prevalencia , Estudios RetrospectivosRESUMEN
BACKGROUND: When cell-free DNA (cfDNA) testing is used as a secondary screening tool following combined first-trimester screening (cFTS), cFTS is used to estimate the prior risk for chromosome abnormalities. This study aimed to assess the factors that are associated with common and atypical abnormalities following cFTS, including cFTS risk, advanced maternal age, increased nuchal translucency (NT) ≥3.5 mm, and abnormal levels of serum markers. METHODS: We reviewed a historical cohort of 1855 Chinese women carrying singleton pregnancies with a positive cFTS [at a threshold of 1:250 for trisomy (T) 21 or 1:180 for T18] in one public hospital over a five-year period. All chromosome abnormalities were confirmed by invasive prenatal diagnosis (IPD) with karyotyping, with or without array comparative genomic hybridization. Using multivariable binary logistic regression analysis, we determined the parameters that were associated with common and atypical abnormalities. RESULTS: Overall, the prevalence of common and atypical abnormalities was 6.2 and 1.2%, respectively, and the prevalence increased with the risk of T21 by cFTS. In pregnancies with a risk of T21 > 1 in 100, a high risk of both T21 and T18, an increased NT, or a pregnancy-associated plasma A (PAPP-A) level < 0.2 multiple of medians (MoM), the prevalence of common abnormalities was 12.2, 64.7, 25.5 and 33.8%, respectively, while that of atypical abnormalities was 1.6, 3.9, 4.2, and 7.4%, respectively. In the multivariable binary logistic regression analysis, out of these four factors, only two (increased NT and PAPP_A < 0.2 MoM) were significant predictors of common and atypical abnormalities, respectively. Of all positive cFTS pregnancies, 50.4% did not have any of these four factors, and the prevalence of common and atypical abnormalities was 1.1 and 0.6%, respectively. There were three atypical abnormalities, all of which were mosaicism, and they were detected among women with IPD alone. The ages of these women were ≥ 35 years. All three pregnancies were continued after proper counseling. After giving birth, only one child had mild abnormalities, while the other two were phenotypically normal. CONCLUSIONS: Our study identified factors associated with common and atypical abnormalities after cFTS. These factors can be used to estimate the prior risk for these abnormalities to help with post-cFTS counseling in terms of choosing between cfDNA testing and IPD.
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Aberraciones Cromosómicas/embriología , Trastornos de los Cromosomas/diagnóstico , Pruebas Genéticas/estadística & datos numéricos , Pruebas de Detección del Suero Materno/estadística & datos numéricos , Primer Trimestre del Embarazo/sangre , Adulto , Pueblo Asiatico/genética , Biomarcadores/sangre , Ácidos Nucleicos Libres de Células/análisis , China/epidemiología , Trastornos de los Cromosomas/embriología , Trastornos de los Cromosomas/epidemiología , Hibridación Genómica Comparativa , Femenino , Pruebas Genéticas/métodos , Humanos , Cariotipificación , Modelos Logísticos , Edad Materna , Pruebas de Detección del Suero Materno/métodos , Medida de Translucencia Nucal , Embarazo , Proteína Plasmática A Asociada al Embarazo/análisis , Estudios Retrospectivos , Factores de Riesgo , Adulto JovenRESUMEN
OBJECTIVE: The aim was to investigate prevalence and degree of ocular and oral involvement in patients with primary Sjögren's syndrome (PSS). METHOD: We analysed 134 participants from the Korean Initiative of PSS cohort who completed a 2 year follow-up oral and ocular sign test. The severity of keratoconjunctivitis sicca (KCS) was determined with the Schirmer I test value (STV) [abnormal (AB) ≤ 5 mm/5 min; normal (N) > 5 mm/5 min]. Salivary gland dysfunction (SGD) was determined by unstimulated whole salivary (UWS) flow rate [moderate to severe (MS) < 0.1 mL/min; mild (Mi) ≥ 0.1 mL/min]. Subgroups were divided into three groups according to STV and severity of SGD: AB-STV/MS-SGD, AB-STV/Mi-SGD, and N-STV/MS-SGD groups. We analysed the changes in STV and SGD during the follow-up period. RESULTS: Among the 134 participants enrolled in this study, 105 (78%) were placed in the AB-STV/MS-SGD group, 16 (12%) in the AB-STV/Mi-SGD, and 13 (10%) in the N-STV/MS-SGD at the 2 year follow-up. The AB-STV/Mi-SGD group was younger than the other two groups, and had a lower Xerostomia Inventory score and lower level of ß2-microglobulin. Participants in the N-STV/MS-SGD group had less hyperimmunoglobulinaemia, rheumatoid factor (RF), and antinuclear antibodies (ANAs). Patients and those with positive RF or ANA ≥ 1:320 at baseline were more likely to have abnormal STV at the 2 year follow-up. CONCLUSIONS: Patients with PSS and positive RF or ANA ≥ 1:320 at baseline may benefit from regular ophthalmology examinations, even if they do not have KCS at baseline or dry eye symptoms.
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Queratoconjuntivitis Seca , Síndrome de Sjögren/complicaciones , Xerostomía , Adulto , Factores de Edad , Anticuerpos Antinucleares/sangre , Estudios de Cohortes , Femenino , Humanos , Queratoconjuntivitis Seca/diagnóstico , Queratoconjuntivitis Seca/etiología , Queratoconjuntivitis Seca/inmunología , Masculino , Persona de Mediana Edad , Prevalencia , República de Corea/epidemiología , Factor Reumatoide/sangre , Índice de Severidad de la Enfermedad , Síndrome de Sjögren/diagnóstico , Síndrome de Sjögren/epidemiología , Evaluación de Síntomas , Xerostomía/diagnóstico , Xerostomía/etiología , Xerostomía/inmunologíaRESUMEN
INTRODUCTION: Congenital long QT syndrome (LQTS) is a genetically transmitted cardiac channelopathy that can lead to sudden cardiac death. This study aimed to report the clinical and genetic characteristics of all young patients diagnosed with LQTS in the only tertiary paediatric cardiology centre in Hong Kong. METHODS: This is a retrospective review of all paediatric and young adult patients diagnosed at our centre with LQTS from January 1997 to December 2016. The diagnosis of LQTS was established with a corrected QT interval (QTc) ≥480 ms, Schwartz score of >3 points, or the presence of a pathogenic mutation. RESULTS: Fifty-nine patients (33 males) from 52 families were included, with a mean age of 8.17 years (range, 0.00-16.95 years) at presentation. Five patients had concomitant congenital heart diseases. The mean follow-up duration was 5.33 ± 4.65 years. The mean QTc in the cohort was 504 ± 47 ms. They presented with syncope and convulsion (49%), cardiac arrest (10%), bradycardia and neonatal atrioventricular block (12%). Fifteen (25%) patients were asymptomatic at diagnosis. Thirty-eight (64.4%) patients were confirmed to have a pathogenic mutation for LQTS genes. Forty-five (76.3%) patients received beta blocker therapy. Thirteen (22.0%) patients required implantable cardioverter defibrillator. There was no mortality in the study period. The 1-, 5-, and 10-year breakthrough cardiac event-free rates were 93.0%, 80.7%, and 72.6%, respectively. CONCLUSION: Identification of the disorder, administration of beta blockers, and lifestyle modification can prevent subsequent cardiac events in LQTS. Genotyping in patients with LQTS is essential in guiding medical therapy and improving prognosis.
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Antagonistas Adrenérgicos beta/uso terapéutico , Desfibriladores Implantables , Cardiopatías Congénitas/epidemiología , Síndrome de QT Prolongado/congénito , Adolescente , Adulto , Niño , Preescolar , Electrocardiografía , Femenino , Estudios de Seguimiento , Hong Kong/epidemiología , Humanos , Lactante , Recién Nacido , Síndrome de QT Prolongado/genética , Síndrome de QT Prolongado/terapia , Masculino , Pronóstico , Estudios Retrospectivos , Síncope/epidemiología , Adulto JovenRESUMEN
The hallmark function of αß T cell antigen receptors (TCRs) involves the highly specific co-recognition of a major histocompatibility complex molecule and its carried peptide. However, the molecular basis of the interactions of TCRs with the lipid antigen-presenting molecule CD1c is unknown. We identified frequent staining of human T cells with CD1c tetramers across numerous subjects. Whereas TCRs typically show high specificity for antigen, both tetramer binding and autoreactivity occurred with CD1c in complex with numerous, chemically diverse self lipids. Such extreme polyspecificity was attributable to binding of the TCR over the closed surface of CD1c, with the TCR covering the portal where lipids normally protrude. The TCR essentially failed to contact lipids because they were fully seated within CD1c. These data demonstrate the sequestration of lipids within CD1c as a mechanism of autoreactivity and point to small lipid size as a determinant of autoreactive T cell responses.
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Antígenos CD1/inmunología , Autoantígenos/inmunología , Autoinmunidad/inmunología , Glicoproteínas/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Linfocitos T/inmunología , Presentación de Antígeno/inmunología , Humanos , Lípidos/inmunología , Activación de Linfocitos/inmunologíaAsunto(s)
Fibromatosis Abdominal/complicaciones , Neoplasias Peritoneales/complicaciones , Peritonitis/diagnóstico , Peritonitis/etiología , Anciano , Diagnóstico Diferencial , Fibromatosis Abdominal/patología , Fibromatosis Abdominal/cirugía , Humanos , Yeyuno/cirugía , Leucocitosis/etiología , Masculino , Neoplasias Peritoneales/patología , Neoplasias Peritoneales/cirugía , Tomografía Computarizada por Rayos XRESUMEN
Rett syndrome (RTT) is an X-linked, neurodevelopmental disorder caused primarily by mutations in the methyl-CpG-binding protein 2 (MECP2) gene, which encodes a multifunctional epigenetic regulator with known links to a wide spectrum of neuropsychiatric disorders. Although postnatal functions of MeCP2 have been thoroughly investigated, its role in prenatal brain development remains poorly understood. Given the well-established importance of microRNAs (miRNAs) in neurogenesis, we employed isogenic human RTT patient-derived induced pluripotent stem cell (iPSC) and MeCP2 short hairpin RNA knockdown approaches to identify novel MeCP2-regulated miRNAs enriched during early human neuronal development. Focusing on the most dysregulated miRNAs, we found miR-199 and miR-214 to be increased during early brain development and to differentially regulate extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase and protein kinase B (PKB/AKT) signaling. In parallel, we characterized the effects on human neurogenesis and neuronal differentiation brought about by MeCP2 deficiency using both monolayer and three-dimensional (cerebral organoid) patient-derived and MeCP2-deficient neuronal culture models. Inhibiting miR-199 or miR-214 expression in iPSC-derived neural progenitors deficient in MeCP2 restored AKT and ERK activation, respectively, and ameliorated the observed alterations in neuronal differentiation. Moreover, overexpression of miR-199 or miR-214 in the wild-type mouse embryonic brains was sufficient to disturb neurogenesis and neuronal migration in a similar manner to Mecp2 knockdown. Taken together, our data support a novel miRNA-mediated pathway downstream of MeCP2 that influences neurogenesis via interactions with central molecular hubs linked to autism spectrum disorders.
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Sistema de Señalización de MAP Quinasas , Proteína 2 de Unión a Metil-CpG/metabolismo , MicroARNs/metabolismo , Neurogénesis/fisiología , Animales , Encéfalo/embriología , Encéfalo/metabolismo , Diferenciación Celular/genética , Línea Celular , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Femenino , Humanos , Células Madre Pluripotentes Inducidas/citología , Células Madre Pluripotentes Inducidas/metabolismo , Masculino , Proteína 2 de Unión a Metil-CpG/genética , Ratones , MicroARNs/genética , Neurogénesis/genética , Neuronas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Interferente Pequeño/genética , Síndrome de Rett/genética , Síndrome de Rett/metabolismo , Síndrome de Rett/patología , Transducción de SeñalRESUMEN
The risk factors for atypical femur fracture in patients exposed to bisphosphonates for at least 1 year were examined. Prolonged and continuous use of bisphosphonates, long-term use of glucocorticoids, and a higher body mass index were associated with increased risk of atypical femur fracture. INTRODUCTION: The purpose of the present study is to determine whether rheumatoid arthritis (RA) and other clinical factors are associated with an increased risk of bisphosphonate (BP)-related atypical femur fracture (AFF). METHODS: A retrospective nested case-control study of patients who had taken BPs for at least 1 year was conducted. Patients with AFF were identified by reviewing surgical and radiographic records. Three controls with no history of AFFs were randomly selected and age- and sex-matched to each patient with AFFs. Cox proportional hazard models were used to analyze the independent contribution of risk factors to BP-related AFF. RESULTS: Among the 35,104 patients prescribed BPs for at least 1 year, 43 females (mean age, 68 years) suffered AFFs (0.12%). Patients with AFFs were exposed to BPs for a mean of 7.3 years. Patients with AFFs were exposed to BPs for longer than those without AFFs and continued treatment without a drug holiday. More patients with AFF than controls had taken glucocorticoids and disease-modifying anti-rheumatic drugs. Multivariate Cox regression analyses estimated that long-term use of glucocorticoids, prolonged exposure to BP without cessation, and every 1 kg/m2 increase in the body mass index (BMI) increased the hazard ratio for AFFs by 3.0, 5.2, and 1.2, respectively. CONCLUSIONS: Prolonged and continuous use of BPs, long-term use of glucocorticoids, and a higher BMI increase the risk of AFFs. Switching long-term BP and glucocorticoid users to other bone-protective agents should be considered.
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Conservadores de la Densidad Ósea/efectos adversos , Difosfonatos/efectos adversos , Fracturas del Fémur/inducido químicamente , Absorciometría de Fotón/métodos , Anciano , Densidad Ósea/efectos de los fármacos , Conservadores de la Densidad Ósea/administración & dosificación , Conservadores de la Densidad Ósea/uso terapéutico , Difosfonatos/administración & dosificación , Difosfonatos/uso terapéutico , Esquema de Medicación , Femenino , Fracturas del Fémur/diagnóstico por imagen , Fracturas del Fémur/fisiopatología , Glucocorticoides/efectos adversos , Humanos , Persona de Mediana Edad , Osteoporosis Posmenopáusica/tratamiento farmacológico , Radiografía , Estudios Retrospectivos , Factores de RiesgoRESUMEN
We recently reported the presence of anti-aquaporin 5 (AQP5) immunoglobulin G (IgG) in patients with primary Sjögren syndrome (SS) with a sensitivity of 0.73 and a specificity of 0.68. The aim of this study was to identify functional epitopes for the anti-AQP5 autoantibodies detected in control subjects and patients with SS. Recognition of epitopes by anti-AQP5 autoantibodies in sera ( n = 13 for control and n = 24 for SS) or purified IgG ( n = 1 for control and n = 3 for SS) was evaluated by indirect immunofluorescence (IIF) assay performed in the presence or absence of peptides corresponding to the second transmembrane helix and extracellular loops A, C, and E of AQP5. Functional epitopes were determined by measuring the effects of purified IgG and neutralizing peptides on transepithelial osmotic permeability (PfT) of MDCK cells expressing AQP5. In the IIF assay, 89% of SS samples were inhibited by at least 1 peptide, while only half of control samples were inhibited by any peptide. Overall, SS samples were inhibited by peptides corresponding to extracellular loops A, C, and E by 40% to 50%, whereas control samples were inhibited only by peptides corresponding to loop E by <20%. A cyclized peptide (E1) mimicking loop E was most frequently recognized and best differentiated between the SS and control samples. Incubation of MDCK-AQP5 cells with SS but not with control IgG, significantly decreased PfT, which was reversed by neutralization of IgG binding to any of the extracellular loops. In conclusion, the anti-AQP5 autoantibodies detected in control and SS groups showed differences in fine specificity to the functional epitopes of AQP5. The prevalent recognition of functional epitopes by anti-AQP5 autoantibodies from SS patients suggests that anti-AQP5 autoantibodies act as mediators of glandular hypofunction and are a potential therapeutic target in SS.
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Acuaporina 5/antagonistas & inhibidores , Epítopos/inmunología , Síndrome de Sjögren/inmunología , Secuencia de Aminoácidos , Autoanticuerpos/inmunología , Técnica del Anticuerpo Fluorescente Indirecta , Humanos , Inmunoglobulina G/inmunología , Péptidos/inmunologíaRESUMEN
OBJECTIVES: Fatigue is a common clinical manifestation in patients with primary Sjögren's syndrome (pSS). The aims of this study were to investigate the association between fatigue severity and other clinical characteristics in pSS patients and to determine the factors contributing to fatigue. METHOD: We analysed 257 participants from the Korean Initiative of pSS (KISS), a prospective pSS cohort. Fatigue was assessed according to the fatigue domain of the European League Against Rheumatism (EULAR) Sjögren's Syndrome Patient-Reported Index (ESSPRI). Health-related quality of life (HRQoL) was evaluated using the EuroQol-5 dimensions (EQ-5D) questionnaire. Multiple linear regression analysis was used to estimate the effect of each variable on fatigue severity. RESULTS: The median total ESSPRI score was 5 [interquartile range (IQR) 4-6]. Thirty-four per cent of patients reported a fatigue score > 5. Younger and premenopausal patients presented with more fatigue (p = 0.013 and p < 0.001, respectively). Higher Xerostomia Inventory (XI) scale (p < 0.001) and Ocular Surface Dryness Index (OSDI) (p < 0.001) scores were observed in patients with a fatigue score > 5. Pain, xerostomia, and age were determined to be significantly associated with fatigue severity after adjusting for depression/anxiety, OSDI score, and the presence of fibromyalgia using a multivariate general linear model. The ESSPRI fatigue score was correlated with the EQ-5D by time trade-off (TTO) values and visual analogue scale (VAS) scores. CONCLUSIONS: In Korean patients with pSS, younger age, xerostomia, and pain were correlated significantly with fatigue, and fatigue was associated with HRQoL.
Asunto(s)
Fatiga/etiología , Síndrome de Sjögren/complicaciones , Factores de Edad , Estudios de Cohortes , Fatiga/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Dolor/etiología , Calidad de Vida , República de Corea/epidemiología , Síndrome de Sjögren/epidemiología , Xerostomía/etiologíaRESUMEN
INTRODUCTION: In Hong Kong, universal combined first-trimester screening for Down's syndrome was started as a 'free service' in July 2010. Non-invasive prenatal testing was available as a self-financed item in August 2011. This study aimed to determine whether the introduction of non-invasive prenatal testing as a contingent approach influenced the indications for invasive prenatal diagnosis and the consequent prenatal detection of Down's syndrome. METHODS: This historical cohort study was conducted at the Prenatal Diagnosis Clinic of Queen Elizabeth Hospital in Hong Kong. We compared the indications for invasive prenatal diagnosis and prenatal detection of Down's syndrome in singleton pregnancies 1 year before and 2 years following the availability of non-invasive prenatal testing as a contingent test after a positive aneuploidy test. All pregnant women who attended our hospital for counselling about universal Down's syndrome screening between August 2010 and July 2013 were recruited. RESULTS: A total of 16 098 women were counselled. After the introduction of non-invasive prenatal testing, the invasive prenatal diagnosis rate for a positive aneuploidy screening reduced from 77.7% in 2010-11 to 68.8% in 2012-13. The new combined conventional plus non-invasive prenatal testing strategy was associated with a lower false-positive rate (6.9% in 2010-11 vs 5.2% in 2011-12 and 4.9% in 2012-13). There was no significant increase in invasive prenatal diagnosis for structural anomalies over the years. There was no significant trend in the overall prenatal detection rate of Down's syndrome (100% 1 year before vs 89.1% 2 years after introduction of non-invasive prenatal testing). Four (2.6%) of 156 women who underwent non-invasive prenatal testing for a screen-positive result had a high-risk result for trisomy 21, which was subsequently confirmed by invasive prenatal diagnosis. There were no false-negative cases. CONCLUSION: The introduction of non-invasive prenatal testing as a contingent approach reduced the invasive prenatal diagnosis rate for a positive aneuploidy screening without affecting the invasive prenatal diagnosis rate for structural anomalies or the overall detection rate of fetal Down's syndrome.