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BACKGROUND: Pediatric patients with homozygous familial hypercholesterolemia (HoFH) have an increased risk of atherosclerotic cardiovascular disease and difficulty meeting low-density lipoprotein cholesterol (LDL-C) goals. In this post hoc analysis, we evaluated pooled safety and efficacy data from 3 studies in pediatric patients with HoFH treated with the PCSK9 (proprotein convertase subtilisin/kexin type 9) monoclonal antibody inhibitor evolocumab. METHODS: Patients with HoFH aged 10 to 17 years received treatment with open-label evolocumab 420 mg subcutaneously monthly or biweekly in the TAUSSIG, RAMAN, or HAUSER-OLE clinical studies. All patients received background statins with or without ezetimibe. Study duration ranged from 12 to 260 weeks. The primary end point was treatment-emergent adverse events per 100 patient-years. Efficacy end points were changes from baseline to week 12 in lipids and PCSK9. RESULTS: Of the 39 patients in the pooled analysis, 69.2% were males, median age was 13.0 years, and 79.5% (31/39) had genotyped HoFH with LDLR pathogenic variants. Overall, median exposure to evolocumab was 18.2 (Q1, Q3: 3.0, 18.5) months. Treatment-emergent adverse events with an exposure-adjusted patient incidence rate of ≥5% were upper respiratory tract infection (6.6%), influenza (5.2%), and acne (5.0%) per 100 patient-years. Exposure-adjusted patient incidence of serious treatment-emergent adverse events was 13.3% per 100 patient-years. Excluding 4 patients receiving lipoprotein apheresis, week 12 median percentage change from baseline in LDL-C was -2.9% (Q1, Q3: -21.7, 1.5); however, 42.9% (15/35) of patients achieved ≥15% reduction in LDL-C from baseline. Residual LDLR (LDL receptor) activity was not associated with a reduction in LDL-C. CONCLUSIONS: In this pooled data analysis from 3 studies in pediatric patients with HoFH, evolocumab was well tolerated, with no new safety signals reported. These safety findings are consistent with findings from previous studies of evolocumab. Patients showed marked variability in LDL-C reduction. Results from this pooled analysis support guidelines suggesting a trial of PCSK9 inhibitor therapy regardless of estimated residual LDLR function. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01624142, NCT03403374, and NCT02624869.
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Anticorpos Monoclonais Humanizados , Anticolesterolemiantes , LDL-Colesterol , Homozigoto , Hiperlipoproteinemia Tipo II , Inibidores de PCSK9 , Adolescente , Criança , Feminino , Humanos , Masculino , Fatores Etários , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticolesterolemiantes/uso terapêutico , Anticolesterolemiantes/efeitos adversos , Biomarcadores/sangue , LDL-Colesterol/sangue , Quimioterapia Combinada , Ezetimiba/uso terapêutico , Ezetimiba/efeitos adversos , Predisposição Genética para Doença , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Hiperlipoproteinemia Tipo II/genética , Hiperlipoproteinemia Tipo II/diagnóstico , Fenótipo , Pró-Proteína Convertase 9/genética , Inibidores de Serina Proteinase/efeitos adversos , Inibidores de Serina Proteinase/uso terapêutico , Fatores de Tempo , Resultado do Tratamento , Estudos Clínicos como AssuntoRESUMO
OBJECTIVES: Cancer morbidity and mortality can be reduced if the cancer is detected early. Cell-free DNA (cfDNA) fragmentomics emerged as a novel epigenetic biomarker for early cancer detection, however, it is still at its infancy and requires technical improvement. We sought to apply a single-strand DNA sequencing technology, for measuring genetic and fragmentomic features of cfDNA and evaluate the performance in detecting multiple cancers. METHODS: Blood samples of 364 patients from six cancer types (colorectal, esophageal, gastric, liver, lung, and ovarian cancers) and 675 healthy individuals were included in this study. Circulating tumor DNA mutations, cfDNA fragmentomic features and a set of protein biomarkers were assayed. Sensitivity and specificity were reported by cancer types and stages. RESULTS: Circular Ligation Amplification and sequencing (CLAmp-seq), a single-strand DNA sequencing technology, yielded a population of ultra-short fragments (<100â¯bp) than double-strand DNA preparation protocols and reveals a more significant size difference between cancer and healthy cfDNA fragments (25.84â¯bp vs. 16.05â¯bp). Analysis of the subnucleosomal peaks in ultra-short cfDNA fragments indicates that these peaks are regulatory element "footprints" and correlates with gene expression and cancer stages. At 98â¯% specificity, a prediction model using ctDNA mutations alone showed an overall sensitivity of 46â¯%; sensitivity reaches 60â¯% when protein is added, sensitivity further increases to 66â¯% when fragmentomics is also integrated. More improvements observed for samples representing earlier cancer stages than later ones. CONCLUSIONS: These results suggest synergistic properties of protein, genetic and fragmentomics features in the identification of early-stage cancers.
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Ácidos Nucleicos Livres , DNA Tumoral Circulante , Neoplasias , Humanos , Detecção Precoce de Câncer , Mutação , DNA Tumoral Circulante/genética , Neoplasias/diagnóstico , Neoplasias/genética , Biomarcadores Tumorais/genéticaRESUMO
Hippocampus oxidative stress is considered pathogenic in neurodegenerative diseases, such as Alzheimer disease (AD), and in neurodevelopmental disorders, such as Angelman syndrome (AS). Yet clinical benefits of antioxidant treatment for these diseases remain unclear because conventional imaging methods are unable to guide management of therapies in specific hippocampus subfields in vivo that underlie abnormal behavior. Excessive production of paramagnetic free radicals in nonhippocampus brain tissue can be measured in vivo as a greater-than-normal 1/T1 that is quenchable with antioxidant as measured by quench-assisted (Quest) MRI. Here, we further test this approach in phantoms, and we present proof-of-concept data in models of AD-like and AS hippocampus oxidative stress that also exhibit impaired spatial learning and memory. AD-like models showed an abnormal gradient along the CA1 dorsal-ventral axis of excessive free radical production as measured by Quest MRI, and redox-sensitive calcium dysregulation as measured by manganese-enhanced MRI and electrophysiology. In the AS model, abnormally high free radical levels were observed in dorsal and ventral CA1. Quest MRI is a promising in vivo paradigm for bridging brain subfield oxidative stress and behavior in animal models and in human patients to better manage antioxidant therapy in devastating neurodegenerative and neurodevelopmental diseases.-Berkowitz, B. A., Lenning, J., Khetarpal, N., Tran, C., Wu, J. Y., Berri, A. M., Dernay, K., Haacke, E. M., Shafie-Khorassani, F., Podolsky, R. H., Gant, J. C., Maimaiti, S., Thibault, O., Murphy, G. G., Bennett, B. M., Roberts, R. In vivo imaging of prodromal hippocampus CA1 subfield oxidative stress in models of Alzheimer disease and Angelman syndrome.
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Doença de Alzheimer/diagnóstico por imagem , Síndrome de Angelman/diagnóstico por imagem , Região CA1 Hipocampal/patologia , Estresse Oxidativo/fisiologia , Sintomas Prodrômicos , Aldeído-Desidrogenase Mitocondrial/genética , Aldeído-Desidrogenase Mitocondrial/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Síndrome de Angelman/patologia , Animais , Antioxidantes , Cálcio/metabolismo , Radicais Livres , Imageamento por Ressonância Magnética/métodos , Manganês , Memória/fisiologia , Camundongos Knockout , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismoRESUMO
Transmembrane protein 16A (TMEM16A), also called Ano1, is a Ca(2+) activated Cl(-) channel expressed widely in mammalian epithelia, as well as in vascular smooth muscle and some tumors and electrically excitable cells. TMEM16A inhibitors have potential utility for treatment of disorders of epithelial fluid and mucus secretion, hypertension, some cancers and other diseases. 4-Aryl-2-amino thiazole T16Ainh-01 was previously identified by high-throughput screening. Here, a library of 47 compounds were prepared that explored the 5,6-disubstituted pyrimidine scaffold found in T16Ainh-01. TMEM16A inhibition activity was measured using fluorescence plate reader and short-circuit current assays. We found that very little structural variation of T16Ainh-01 was tolerated, with most compounds showing no activity at 10 µM. The most potent compound in the series, 9bo, which substitutes 4-methoxyphenyl in T16Ainh-01 with 2-thiophene, had IC50 â¼1 µM for inhibition of TMEM16A chloride conductance.
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Canais de Cloreto/antagonistas & inibidores , Tiazóis/síntese química , Tiazóis/farmacologia , Animais , Anoctamina-1 , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Linhagem Celular , Espectroscopia de Prótons por Ressonância Magnética , Ratos , Ratos Endogâmicos F344 , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
Structure- and property-based drug design is an integral part of modern drug discovery, enabling the design of compounds aimed at improving potency and selectivity. However, building molecules using desktop modeling tools can easily lead to poor designs that appear to form many favorable interactions with the protein's active site. Although a proposed molecule looks good on screen and appears to fit into the protein site X-ray crystal structure or pharmacophore model, doing so might require a high-energy small molecule conformation, which would likely be inactive. To help scientists make better design decisions, we have built integrated, easy-to-use, interactive software tools to perform docking experiments, de novo design, shape and pharmacophore based database searches, small molecule conformational analysis and molecular property calculations. Using a combination of these tools helps scientists in assessing the likelihood that a designed molecule will be active and have desirable drug metabolism and pharmacokinetic properties. Small molecule discovery success requires project teams to rapidly design and synthesize potent molecules with good ADME properties. Empowering scientists to evaluate ideas quickly and make better design decisions with easy-to-access and easy-to-understand software on their desktop is now a key part of our discovery process.
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Desenho de Fármacos , Simulação de Acoplamento Molecular , Relação Quantitativa Estrutura-Atividade , Software , Desenho Assistido por Computador , Conformação Molecular , TYK2 Quinase/antagonistas & inibidores , TYK2 Quinase/químicaRESUMO
BACKGROUND: Ultrasound surveillance has become the new standard of care in stage III melanoma after the 2017 Multicenter Selective Lymphadenectomy Trial II (MSLT-II) demonstrated non-inferior 3-year survival compared with complete lymph node dissection. OBJECTIVE: We aimed to quantify diagnostic performance and adherence rates of ultrasound surveillance for melanoma locoregional metastasis, offering insights into real-world applicability. METHODS: Conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines, we systematically searched the Medline, Embase, Cochrane Library, CINAHL, Scopus, and Web of Science databases from inception until 11 October 2023. All primary studies that reported data on the diagnostic performance or adherence rates to ultrasound surveillance in melanoma were included. R statistical software was used for data synthesis and analysis. Sensitivity and specificity were aggregated across studies using the meta-analytic method for diagnostic tests outlined by Rutter and Gatsonis. Adherence rates were calculated as the ratio of patients fully compliant to planned follow-up to those who were not. RESULTS: A total of 36 studies including 18,273 patients were analysed, with a mean age of 56.6 years and a male-to-female ratio of 1:1.11. The median follow-up duration and frequency was 36 and 4 months, respectively. The pooled sensitivity of ultrasound examination was 0.879 (95% confidence interval [CI] 0.878-0.879) and specificity was 0.969 (95% CI 0.968-0.970), representing a diagnostic odds ratio of 224.5 (95% CI 223.1-225.9). Ultrasound examination demonstrated a substantial improvement in absolute sensitivity over clinical examination alone, with a number needed to screen (NNS) of 2.95. The overall adherence rate was 77.0% (95% CI 76.0-78.1%), with significantly lower rates in the United States [US] (p < 0.001) and retrospective studies (p < 0.001). CONCLUSION: Ultrasound is a powerful diagnostic tool for locoregional melanoma metastasis. However, the real applicability to surveillance programmes is limited by low adherence rates, especially in the US. Further studies should seek to address this adherence gap.
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Melanoma , Neoplasias Cutâneas , Ultrassonografia , Humanos , Melanoma/diagnóstico por imagem , Melanoma/patologia , Melanoma/diagnóstico , Neoplasias Cutâneas/diagnóstico por imagem , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/diagnóstico , Ultrassonografia/métodos , Ultrassonografia/estatística & dados numéricos , Sensibilidade e Especificidade , Metástase Linfática/diagnóstico por imagem , Estadiamento de Neoplasias , Cooperação do Paciente/estatística & dados numéricos , Excisão de Linfonodo/métodosRESUMO
Patient discharge summaries provide detailed medical information about individuals who have been hospitalized. To make a precise and legitimate assessment of the abundant data, a proper time layout of the sequence of relevant events should be compiled and used to drive a patient-specific timeline, which could further assist medical personnel in making clinical decisions. The process of identifying the chronological order of entities is called temporal relation extraction. In this paper, we propose a hybrid method to identify appropriate temporal links between a pair of entities. The method combines two approaches: one is rule-based and the other is based on the maximum entropy model. We develop an integration algorithm to fuse the results of the two approaches. All rules and the integration algorithm are formally stated so that one can easily reproduce the system and results. To optimize the system's configuration, we used the 2012 i2b2 challenge TLINK track dataset and applied threefold cross validation to the training set. Then, we evaluated its performance on the training and test datasets. The experiment results show that the proposed TEMPTING (TEMPoral relaTion extractING) system (ranked seventh) achieved an F-score of 0.563, which was at least 30% better than that of the baseline system, which randomly selects TLINK candidates from all pairs and assigns the TLINK types. The TEMPTING system using the hybrid method also outperformed the stage-based TEMPTING system. Its F-scores were 3.51% and 0.97% better than those of the stage-based system on the training set and test set, respectively.
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Registros Eletrônicos de Saúde , Informática Médica/métodos , Processamento de Linguagem Natural , Sumários de Alta do Paciente Hospitalar , Algoritmos , Mineração de Dados/métodos , Bases de Dados Factuais , Humanos , Reprodutibilidade dos Testes , Fatores de TempoRESUMO
INTRODUCTION: This study characterizes patients receiving evolocumab in clinical practice and assesses treatment effectiveness, safety and persistence outcomes across five countries. METHODS: This retrospective and prospective observational study enrolled patients initiated on evolocumab during August 2017 to July 2019 at 49 sites across Canada, Mexico, Colombia, Saudi Arabia and Kuwait. Medical records data were extracted within 6 months prior to (baseline) and every 3 months for 12 months post evolocumab initiation and reported as available. RESULTS: A total of 578 patients were enrolled (40.1% female, median age 60 [interquartile range (IQR) 51-68] years); 83.7% had atherosclerotic cardiovascular disease and/or familial hypercholesterolemia. Median low-density lipoprotein cholesterol (LDL-C) at baseline was 3.4 (IQR 2.7-4.2) mmol/L (131.5 [IQR 104.4-162.4] mg/dL), with 75.6% of patients receiving a statin (59.2% high intensity). Compared to baseline, the median lowest LDL-C was reduced by 70.2% and remained stable over 12 months of treatment. Guideline-recommended LDL-C thresholds < 1.8, < 1.4 and < 1.0 mmol/L (< 70, < 55 and < 40 mg/dL) were achieved by 75.3%, 63.6% and 47.4% of patients. LDL-C outcomes were consistent across high- and very high-risk patients. Background lipid-lowering therapy remained relatively stable. No serious treatment-emergent adverse events were reported, and persistence to evolocumab was 90.2% at 12 months. CONCLUSION: These findings provide real-world evidence that evolocumab use is in accordance with its international guideline-recommended place in dyslipidemia therapy, as well as confirmation of its effectiveness and safety in a heterogeneous population. Evolocumab can address a healthcare gap in the management of dyslipidemia by increasing the proportion of patients achieving LDL-C goals recommended to lower cardiovascular risk.
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A protocol to generate parameters for the AMOEBA polarizable force field for small organic molecules has been established, and polarizable atomic typing utility, Poltype, which fully automates this process, has been implemented. For validation, we have compared with quantum mechanical calculations of molecular dipole moments, optimized geometry, electrostatic potential, and conformational energy for a variety of neutral and charged organic molecules, as well as dimer interaction energies of a set of amino acid side chain model compounds. Furthermore, parameters obtained in gas phase are substantiated in liquid-phase simulations. The hydration free energy (HFE) of neutral and charged molecules have been calculated and compared with experimental values. The RMS error for the HFE of neutral molecules is less than 1 kcal/mol. Meanwhile, the relative error in the predicted HFE of salts (cations and anions) is less than 3% with a correlation coefficient of 0.95. Overall, the performance of Poltype is satisfactory and provides a convenient utility for applications such as drug discovery. Further improvement can be achieved by the systematic study of various organic compounds, particularly ionic molecules, and refinement and expansion of the parameter database.
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BACKGROUND: The extent of neck dissection for tongue SCC is unclear owing to the potential presence of occult level IV metastasis. We aim to assess the incidence of occult level IV nodal metastasis for tongue SCC patients treated in our centre over a 20 year period. METHODS: A retrospective analysis of data collected from 1999 to 2019 was performed. Patients diagnosed with oral tongue SCC treated primarily with surgery and a neck dissection fulfilled the inclusion criteria. RESULTS: A total of 124 patients were included in our study. Sixty-one patients were N0 with no occult level IV metastasis. About 17.3% of clinically node positive patients had level IV metastasis. Length of hospital stay and complication rates were comparable for patients who received levels I-III and I-IV neck dissections. CONCLUSION: Occult level IV metastasis in N0 tongue SCC patients are exceedingly rare, we would therefore suggest consideration for a level I-III neck dissection. In patients who are clinically node positive, a level I-IV neck dissection would be recommended.
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Carcinoma de Células Escamosas , Neoplasias da Língua , Humanos , Neoplasias da Língua/cirurgia , Neoplasias da Língua/patologia , Carcinoma de Células Escamosas/patologia , Estudos Retrospectivos , Incidência , Metástase Linfática , Esvaziamento Cervical , Língua/patologia , Estadiamento de NeoplasiasRESUMO
Effective virtual screening relies on our ability to make accurate prediction of protein-ligand binding, which remains a great challenge. In this work, utilizing the molecular-mechanics Poisson-Boltzmann (or Generalized Born) surface area approach, we have evaluated the binding affinity of a set of 156 ligands to seven families of proteins, trypsin ß, thrombin α, cyclin-dependent kinase (CDK), cAMP-dependent kinase (PKA), urokinase-type plasminogen activator, ß-glucosidase A, and coagulation factor Xa. The effect of protein dielectric constant in the implicit-solvent model on the binding free energy calculation is shown to be important. The statistical correlations between the binding energy calculated from the implicit-solvent approach and experimental free energy are in the range of 0.56-0.79 across all the families. This performance is better than that of typical docking programs especially given that the latter is directly trained using known binding data whereas the molecular mechanics is based on general physical parameters. Estimation of entropic contribution remains the barrier to accurate free energy calculation. We show that the traditional rigid rotor harmonic oscillator approximation is unable to improve the binding free energy prediction. Inclusion of conformational restriction seems to be promising but requires further investigation. On the other hand, our preliminary study suggests that implicit-solvent based alchemical perturbation, which offers explicit sampling of configuration entropy, can be a viable approach to significantly improve the prediction of binding free energy. Overall, the molecular mechanics approach has the potential for medium to high-throughput computational drug discovery.
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Simulação de Dinâmica Molecular , Proteínas/metabolismo , Animais , Desenho de Fármacos , Entropia , Humanos , Ligantes , Ligação Proteica , Proteínas/química , TermodinâmicaRESUMO
A general, transferable coarse-grain (CG) framework based on the Gay-Berne potential and electrostatic point multipole expansion is presented for polypeptide simulations. The solvent effect is described by the Generalized Kirkwood theory. The CG model is calibrated using the results of all-atom simulations of model compounds in solution. Instead of matching the overall effective forces produced by atomic models, the fundamental intermolecular forces such as electrostatic, repulsion-dispersion, and solvation are represented explicitly at a CG level. We demonstrate that the CG alanine dipeptide model is able to reproduce quantitatively the conformational energy of all-atom force fields in both gas and solution phases, including the electrostatic and solvation components. Replica exchange molecular dynamics and microsecond dynamic simulations of polyalanine of 5 and 12 residues reveal that the CG polyalanines fold into "alpha helix" and "beta sheet" structures. The 5-residue polyalanine displays a substantial increase in the "beta strand" fraction relative to the 12-residue polyalanine. The detailed conformational distribution is compared with those reported from recent all-atom simulations and experiments. The results suggest that the new coarse-graining approach presented in this study has the potential to offer both accuracy and efficiency for biomolecular modeling.
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Dipeptídeos/química , Simulação por Computador , Modelos Moleculares , Conformação Molecular , Eletricidade Estática , TermodinâmicaRESUMO
BACKGROUND: There is a current lack of consensus amongst paediatric radiologists and respiratory paediatricians as to the correct CT definition of bronchiectasis in children. Using contemporary low-dose CT, our objectives were to determine the upper limit of normal for broncho-arterial ratio (BAR) in children and to evaluate the effect of age and general anaesthesia. METHODS: Measurements of 330 broncho-arterial ratios from 51 children (0-19 years) undergoing low-dose CT chest for non-respiratory indications were performed by 3 blinded observers (two radiologists, one respiratory physician) using four different methods. Inter-observer reliability, mean BAR and reference ranges (mean±2SD) were calculated. Correlation between age and BARs were examined. Mean BAR for CT under general anaesthesia and CT awake were compared. RESULTS: Inter-observer correlation was extremely high for all measurements (0.93-0.97). There was a weak positive correlation between age and BAR in the CT-awake group (r = 0.33, 95%CI: 0.03-0.57; p = 0.031) using the inner-bronchial wall to artery, short-axis measurement. CT under general anaesthesia showed significantly higher BAR compared to CT-awake [mean difference 0.13 (95%CI: 0.05-0.22; p = 0.004)]. For the CT-awake group, the mean BAR was 0.65 (range: 0.42 to 0.89), with no child having a BAR above 0.9. CONCLUSION: Using a standardised approach, we have shown that a broncho-arterial ratio above 0.9 in children undergoing awake CT is abnormal and suggests airway widening or radiological bronchiectasis. Children undergoing CT under anaesthesia have higher BARs than those undergoing awake CT. A weak positive correlation between broncho-arterial ratio and age was observed, hence, age-adjusted cut-offs for BAR warrant further study.
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Anestesia Geral , Brônquios/diagnóstico por imagem , Bronquiectasia/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Vigília , Adolescente , Fatores Etários , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Doses de Radiação , Adulto JovemRESUMO
We compared viral suppression rates between patients who continued tenofovir disoproxil fumarate (TDF)/lamivudine (3TC) vs switched to zidovudine (ZDV)/3TC in combination with a boosted protease inhibitor after failure of first-line efavirenz/TDF/3TC. We found higher rates of viral suppression with continued TDF/3TC compared with switching to ZDV/3TC.
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BACKGROUND: Significant health disparities exist between Maori and non-Maori patients in New Zealand. Maori patients treated medically for their thyroid disease are less likely to be euthyroid. The prevalence of thyroid disease and characteristics of Maori presenting for thyroid surgery has not been well studied. We aim to assess the differences in ethnic representation for thyroid surgery. METHODS: A retrospective analysis of cases performed between 2009 and 2019 at the Otolaryngology/Head and Neck Department in Waikato District Health Board (DHB) was completed. All patients who received a thyroid operation were included and divided into Maori and non-Maori groups. Clinical and operation notes were reviewed and the duration of presenting symptoms, weight, volume and diagnosis of the thyroid gland were assessed. RESULTS: A total of 93 patients were included in our study, of whom 71 patients were female and 22 male with 37 being Maori and 56 non-Maori. Maori patients had significantly higher rates of retrosternal extension, compressive symptoms, post-operative complications, delayed presentation and larger thyroid goitres when compared to non-Maori (P < 0.05). CONCLUSION: Our study confirms that there is a significant ethnic disparity for Maori patients requiring thyroid surgery. This highlights an additional poor health outcome for Maori compared to non-Maori patients.
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Etnicidade , Glândula Tireoide , Feminino , Humanos , Masculino , Havaiano Nativo ou Outro Ilhéu do Pacífico , Nova Zelândia/epidemiologia , Estudos Retrospectivos , Glândula Tireoide/cirurgiaRESUMO
Introduction: Bronchiectasis is increasingly recognized as a major cause of morbidity and mortality worldwide. It affects children of all ethnicities and socioeconomic backgrounds and represents a far greater burden than cystic fibrosis (CF). Bronchiectasis often begins in childhood and the radiological changes can be reversed, when mild, with optimal management. As there are limited pediatric studies in this field, current treatment approaches in children are based largely upon adult and/or CF studies. The recent establishment of bronchiectasis registries will improve understanding of pediatric bronchiectasis and increase capacity for large-scale research studies in the future. Areas covered: This review summarizes the current management of bronchiectasis in children and highlights important knowledge gaps and areas for future research. Current treatment approaches are based largely on consensus guidelines from international experts in the field. Studies were identified through searching Medline via the Ovid interface and Pubmed using the search terms 'bronchiectasis' and 'children' or 'pediatric' and 'management' or 'treatments'. Expert opinion: Bronchiectasis is heterogeneous in nature and a one-size-fits-all approach has limitations. Future research should focus on advancing our understanding of the aetiopathogenesis of bronchiectasis. This approach will facilitate development of targetted therapeutic interventions to slow, halt or even reverse bronchiectasis in childhood.
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Bronquiectasia/terapia , Poluição do Ar/efeitos adversos , Poluição do Ar/prevenção & controle , Antibacterianos/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Vacinas Bacterianas , Bronquiectasia/diagnóstico , Broncodilatadores/uso terapêutico , Criança , Exercício Físico , Expectorantes/uso terapêutico , Glucocorticoides/uso terapêutico , Humanos , Estilo de Vida , Nebulizadores e Vaporizadores , Estado Nutricional , Fenótipo , Radiografia Torácica , Terapia Respiratória , Solução Salina Hipertônica/administração & dosagem , Tomografia Computadorizada por Raios X , Vacinas ViraisRESUMO
The authors examined life stress and self-efficacy as predictors of time to relapse for 113 adults with comorbid major depressive disorder and alcohol and/or substance dependence in a randomized clinical trial comparing 2 psychotherapy interventions (integrated cognitive- behavioral therapy and 12-step facilitation therapy). Life stress, self-efficacy, and substance use were assessed at treatment entry, 12 weeks (mid-treatment), and 24 weeks (end of treatment). Time to relapse was defined as the number of days from treatment initiation until first alcohol and/or drug use. Half of the sample relapsed within the study period of 24 weeks. There was no significant difference between treatment groups. Individuals experiencing life stressors were more likely to relapse early than those not experiencing life stressors. Lower self-efficacy also predicted earlier relapse. Chronic stress levels and self-efficacy were stable across time for most individuals. In contrast, acute stress events occurred at differing times, and survival analyses provided evidence of heightened relapse risk in the month following acute stressors. The interaction of self-efficacy and life stress was not significant. The results highlight the significance of life stress and self-efficacy as predictors of early relapse.
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Transtorno Depressivo Maior/epidemiologia , Transtorno Depressivo Maior/terapia , Autoeficácia , Estresse Psicológico/epidemiologia , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Temperança , Adulto , Comorbidade , Transtorno Depressivo Maior/psicologia , Feminino , Humanos , Masculino , Psicoterapia , Estresse Psicológico/psicologia , Transtornos Relacionados ao Uso de Substâncias/terapia , Inquéritos e QuestionáriosRESUMO
The externalizing spectrum may explain covariation among externalizing disorders observed in childhood and adulthood. Few prospective studies have examined whether externalizing spectrum might manifest differently across time, reporters, and gender during childhood. We used a multitrait, multimethod model with parent and teacher report of attention-deficit/hyperactivity disorder (ADHD) symptoms, oppositional defiant disorder (ODD) symptoms, and conduct disorder (CD)symptoms from kindergarten to Grade 5 in data from the Fast Track Project, a large multisite trial for children at risk for conduct problems ( n = 754). The externalizing spectrum was stably related to ADHD, ODD, and CD symptoms from kindergarten to Grade 5, with similar contributions from parents and teachers. Configural, metric, and scalar invariance were largely supported across time, suggesting that the structure of the externalizing spectrum is stable over time. Configural and partial metric invariance were supported across gender, but scalar invariance was not supported, with intercepts consistently higher for males than for females. Overall, our findings confirm other research that the externalizing spectrum can be observed early in development as covariation between ADHD, ODD, and CD, and extend that work to show that it is relatively consistent across time and reporter, but not consistent across gender.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Transtornos de Deficit da Atenção e do Comportamento Disruptivo/psicologia , Transtornos do Comportamento Infantil/psicologia , Transtorno da Conduta/psicologia , Comportamento Problema/psicologia , Criança , Docentes , Feminino , Humanos , Masculino , Modelos Teóricos , PaisRESUMO
PURPOSE: To determine what proportion of primary open angle glaucoma (POAG) in Tasmania, Australia is familial. METHODS: Between 1994 and 1996 an audit of Tasmanian patients diagnosed with glaucoma was performed. Identified probands along with their family members were invited to participate. Family history of POAG was noted and pedigrees constructed. Each participant underwent a detailed examination, including visual acuity, intraocular pressure measurement, gonioscopy, optic disc assessment and visual field testing. Participants were classified as normal, suspect or POAG. Data from 467 participants in the Twins Eye Study in Tasmania (TEST) were used as a reference for the general population. RESULTS: Of 2062 participants examined, 1700 were classified as POAG. A total of 1014 participants (59.6%) belonged to families in which other members were affected (familial glaucoma). Six hundred and fifty-six of these 1014 familial cases (64.8%) had a first-degree relative affected. The number of affected members in the family groups varied from two to 29. Six hundred and eighty-eight participants had no known family history of POAG (sporadic glaucoma). There were significantly more POAG patients with a family history of POAG compared to the TEST population (chi2 = 161.81, P < 0.0001), and for a person with POAG the odds ratio of having a positive family history was 4.1 (95% confidence interval: 3.2-5.2). CONCLUSION: Approximately 60% of POAG in Tasmania is familial. This percentage is higher than most previous reports of familial glaucoma and emphasizes the importance of genetics in POAG, with major implications for screening and future research.
Assuntos
Família , Glaucoma de Ângulo Aberto/genética , Prontuários Médicos , Idoso , Idoso de 80 Anos ou mais , Feminino , Glaucoma de Ângulo Aberto/epidemiologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Tasmânia/epidemiologiaRESUMO
OBJECTIVE: The role of anatomical variants of the paranasal sinuses in the aetiology of chronic rhinosinusitis (CRS) is not well understood. Furthermore, the effect of anatomical variants on long-term outcomes has not been described. This study aims to assess the effects of anatomical variants of the middle meatus on patients with limited and diffuse CRS. METHODS: A database analysis was conducted for patients with limited sinusitis (undergoing anterior FESS) and patients with diffuse sinusitis (undergoing complete FESS) between 2009 and 2013. Intergroup comparisons were made for symptom scores, CT scans, revision surgery, re-referrals following discharge and number of clinic follow-ups. RESULTS: A total of 86 patients were included in the study: 40 anterior FESS, 25 CRSwNP and 21 CRSsNP. Following surgery, anterior FESS symptom scores reduced by 4.6±0.8 on average, while the CRSwNP and CRSsNP group reduced by 5.7±1.1 and 5.9±1.3 respectively. Patients undergoing anterior FESS required fewer clinic follow-ups than CRSwNP (Δ 2.7±0.9, P<0.001) and CRSsNP (Δ 3.3±0.6, P<0.001). Patients with fewer anatomical variants (0-2) required more follow-up (5.2±0.6) than those with higher numbers of variants (3+) (3.8±0.3, P=0.05). No significant differences were seen between groups for revision surgery, repeat CT and re-referral rates. CONCLUSION: Limited surgery for local disease demonstrated comparable symptom improvement to patients with extensive disease receiving extensive surgery. Patients with greater numbers of anatomical variants are associated with localised sinus disease who typically require less postoperative care after receiving limited surgery.