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1.
Am J Clin Dermatol ; 25(4): 513-525, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38635019

RESUMEN

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.


Asunto(s)
Melanoma , Neoplasias Cutáneas , Ultrasonografía , Humanos , Melanoma/diagnóstico por imagen , Melanoma/patología , Melanoma/diagnóstico , Neoplasias Cutáneas/diagnóstico por imagen , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/diagnóstico , Ultrasonografía/métodos , Ultrasonografía/estadística & datos numéricos , Sensibilidad y Especificidad , Metástasis Linfática/diagnóstico por imagen , Estadificación de Neoplasias , Cooperación del Paciente/estadística & datos numéricos , Escisión del Ganglio Linfático/métodos
2.
Arterioscler Thromb Vasc Biol ; 44(5): 1156-1164, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38545781

RESUMEN

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.


Asunto(s)
Anticuerpos Monoclonales Humanizados , Anticolesterolemiantes , LDL-Colesterol , Homocigoto , Hiperlipoproteinemia Tipo II , Inhibidores de PCSK9 , Adolescente , Niño , Femenino , Humanos , Masculino , Factores de Edad , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticolesterolemiantes/uso terapéutico , Anticolesterolemiantes/efectos adversos , Biomarcadores/sangre , LDL-Colesterol/sangre , Quimioterapia Combinada , Ezetimiba/uso terapéutico , Ezetimiba/efectos adversos , Predisposición Genética a la Enfermedad , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Hiperlipoproteinemia Tipo II/genética , Hiperlipoproteinemia Tipo II/diagnóstico , Fenotipo , Proproteína Convertasa 9/genética , Inhibidores de Serina Proteinasa/efectos adversos , Inhibidores de Serina Proteinasa/uso terapéutico , Factores de Tiempo , Resultado del Tratamiento , Estudios Clínicos como Asunto
3.
Cardiol Ther ; 12(4): 703-722, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37804438

RESUMEN

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.

4.
ANZ J Surg ; 92(12): 3259-3263, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36196806

RESUMEN

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.


Asunto(s)
Carcinoma de Células Escamosas , Neoplasias de la Lengua , Humanos , Neoplasias de la Lengua/cirugía , Neoplasias de la Lengua/patología , Carcinoma de Células Escamosas/patología , Estudios Retrospectivos , Incidencia , Metástasis Linfática , Disección del Cuello , Lengua/patología , Estadificación de Neoplasias
5.
Open Forum Infect Dis ; 8(12): ofab559, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-34901303

RESUMEN

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.

7.
Respir Med ; 187: 106547, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34340172

RESUMEN

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.


Asunto(s)
Anestesia General , Bronquios/diagnóstico por imagen , Bronquiectasia/diagnóstico por imagen , Tomografía Computarizada por Rayos X/métodos , Vigilia , Adolescente , Factores de Edad , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Dosis de Radiación , Adulto Joven
8.
ANZ J Surg ; 90(12): 2527-2531, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-33135832

RESUMEN

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.


Asunto(s)
Etnicidad , Glándula Tiroides , Femenino , Humanos , Masculino , Nativos de Hawái y Otras Islas del Pacífico , Nueva Zelanda/epidemiología , Estudios Retrospectivos , Glándula Tiroides/cirugía
9.
Expert Rev Respir Med ; 13(10): 969-979, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31408389

RESUMEN

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.


Asunto(s)
Bronquiectasia/terapia , Contaminación del Aire/efectos adversos , Contaminación del Aire/prevención & control , Antibacterianos/uso terapéutico , Antiinflamatorios no Esteroideos/uso terapéutico , Vacunas Bacterianas , Bronquiectasia/diagnóstico , Broncodilatadores/uso terapéutico , Niño , Ejercicio Físico , Expectorantes/uso terapéutico , Glucocorticoides/uso terapéutico , Humanos , Estilo de Vida , Nebulizadores y Vaporizadores , Estado Nutricional , Fenotipo , Radiografía Torácica , Terapia Respiratoria , Solución Salina Hipertónica/administración & dosificación , Tomografía Computarizada por Rayos X , Vacunas Virales
10.
Assessment ; 25(6): 744-758, 2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-27449054

RESUMEN

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.


Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad/psicología , Déficit de la Atención y Trastornos de Conducta Disruptiva/psicología , Trastornos de la Conducta Infantil/psicología , Trastorno de la Conducta/psicología , Problema de Conducta/psicología , Niño , Docentes , Femenino , Humanos , Masculino , Modelos Teóricos , Padres
12.
Invest Ophthalmol Vis Sci ; 58(7): 3286-3293, 2017 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-28666279

RESUMEN

Purpose: We identify noninvasive biomarkers that measure the severity of oxidative stress within retina layers in sodium iodate (SI)-atrophy vulnerable (C57BL/6 [B6]) and SI-atrophy resistant (129S6/SvEvTac [S6]) mice. Methods: At 24 hours after administering systemic SI to B6 and S6 mice we measured: (1) superoxide production in whole retina ex vivo, (2) excessive free radical production in vivo based on layer-specific 1/T1 values before and after α-lipoic acid (ALA) administration while the animal was inside the magnet (QUEnch-assiSTed MRI [QUEST MRI]), and (3) visual performance (optokinetic tracking) ± antioxidants; control mice were similarly assessed. Retinal layer spacing and thickness in vivo also were evaluated (optical coherence tomography, MRI). Results: SI-treated B6 mice retina had a significantly higher superoxide production than SI-treated S6 mice. ALA-injected SI-treated B6 mice had reduced 1/T1 in more retinal layers in vivo than in SI-treated S6 mice. Uninjected and saline-injected SI-treated B6 mice had similar transretinal 1/T1 profiles. Notably, the inner segment layer 1/T1 of SI-treated B6 mice was responsive to ALA but was unresponsive in SI-treated S6 mice. In both SI-treated strains, antioxidants improved contrast sensitivity to similar extents; antioxidants did not change acuity in either group. Retinal thicknesses were normal in both SI-treated strains at 24 hours after treatment. Conclusions: QUEST MRI uniquely measured severity of excessive free radical production within retinal layers of the same subject. Identifying the mechanisms underlying genetic vulnerabilities to oxidative stress is expected to help in understanding the pathogenesis of retinal degeneration.


Asunto(s)
Yodatos/toxicidad , Estrés Oxidativo/fisiología , Degeneración Retiniana/inducido químicamente , Análisis de Varianza , Animales , Antioxidantes/farmacología , Biomarcadores/metabolismo , Sensibilidad de Contraste/efectos de los fármacos , Sensibilidad de Contraste/fisiología , Radicales Libres/metabolismo , Imagen por Resonancia Magnética , Ratones , Ratones Endogámicos C57BL , Estrés Oxidativo/efectos de los fármacos , Degeneración Retiniana/metabolismo , Superóxidos/metabolismo , Agudeza Visual/efectos de los fármacos , Agudeza Visual/fisiología
13.
FASEB J ; 31(9): 4179-4186, 2017 09.
Artículo en Inglés | MEDLINE | ID: mdl-28592637

RESUMEN

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.


Asunto(s)
Enfermedad de Alzheimer/diagnóstico por imagen , Síndrome de Angelman/diagnóstico por imagen , Región CA1 Hipocampal/patología , Estrés Oxidativo/fisiología , Síntomas Prodrómicos , Aldehído Deshidrogenasa Mitocondrial/genética , Aldehído Deshidrogenasa Mitocondrial/metabolismo , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/genética , Péptidos beta-Amiloides/metabolismo , Síndrome de Angelman/patología , Animales , Antioxidantes , Calcio/metabolismo , Radicales Libres , Imagen por Resonancia Magnética/métodos , Manganeso , Memoria/fisiología , Ratones Noqueados , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo
14.
Auris Nasus Larynx ; 44(4): 417-421, 2017 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-27614778

RESUMEN

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.


Asunto(s)
Variación Anatómica , Endoscopía , Pólipos Nasales/cirugía , Procedimientos Quirúrgicos Otorrinolaringológicos , Senos Paranasales/anatomía & histología , Rinitis/cirugía , Sinusitis/cirugía , Enfermedad Crónica , Bases de Datos Factuales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pólipos Nasales/complicaciones , Pólipos Nasales/diagnóstico por imagen , Senos Paranasales/diagnóstico por imagen , Cuidados Posoperatorios , Pronóstico , Estudios Retrospectivos , Rinitis/complicaciones , Rinitis/diagnóstico por imagen , Sinusitis/complicaciones , Sinusitis/diagnóstico por imagen , Tomografía Computarizada por Rayos X
15.
Nat Commun ; 7: 11473, 2016 05 05.
Artículo en Inglés | MEDLINE | ID: mdl-27145901

RESUMEN

Viruses encode secreted and cell-surface expressed proteins essential to modulate host immune defenses and establish productive infections. However, to date there has been no systematic study of the extracellular interactome of any human virus. Here we utilize the E3 proteins, diverse and rapidly evolving transmembrane-containing proteins encoded by human adenoviruses, as a model system to survey the extracellular immunomodulatory landscape. From a large-scale protein interaction screen against a microarray of more than 1,500 human proteins, we find and validate 51 previously unidentified virus-host interactions. Our results uncover conserved strategies as well as substantial diversity and multifunctionality in host targeting within and between viral species. Prominent modulation of the leukocyte immunoglobulin-like and signalling lymphocyte activation molecule families and a number of inhibitory receptors were identified as hubs for viral perturbation, suggesting unrecognized immunoregulatory strategies. We describe a virus-host extracellular interaction map of unprecedented scale that provides new insights into viral immunomodulation.


Asunto(s)
Adenovirus Humanos/inmunología , Inmunomodulación/inmunología , Mapas de Interacción de Proteínas/inmunología , Proteínas Virales/inmunología , Células A549 , Adenovirus Humanos/metabolismo , Adenovirus Humanos/fisiología , Animales , Células CHO , Línea Celular Tumoral , Células Cultivadas , Cricetulus , Espacio Extracelular/inmunología , Espacio Extracelular/metabolismo , Células HEK293 , Células HeLa , Interacciones Huésped-Patógeno/inmunología , Humanos , Células Jurkat , Células K562 , Unión Proteica , Proteoma/inmunología , Proteoma/metabolismo , Proteínas Virales/metabolismo
16.
J Enzyme Inhib Med Chem ; 31(6): 1362-8, 2016 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26796863

RESUMEN

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 ∼1 µM for inhibition of TMEM16A chloride conductance.


Asunto(s)
Canales de Cloruro/antagonistas & inhibidores , Tiazoles/síntesis química , Tiazoles/farmacología , Animales , Anoctamina-1 , Espectroscopía de Resonancia Magnética con Carbono-13 , Línea Celular , Espectroscopía de Protones por Resonancia Magnética , Ratas , Ratas Endogámicas F344 , Espectrometría de Masa por Ionización de Electrospray
17.
J Comput Aided Mol Des ; 29(6): 511-23, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25921252

RESUMEN

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.


Asunto(s)
Diseño de Fármacos , Simulación del Acoplamiento Molecular , Relación Estructura-Actividad Cuantitativa , Programas Informáticos , Diseño Asistido por Computadora , Conformación Molecular , TYK2 Quinasa/antagonistas & inhibidores , TYK2 Quinasa/química
18.
J Am Med Inform Assoc ; 22(2): 340-9, 2015 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-25665706

RESUMEN

OBJECTIVE: The primary objective was to evaluate time, number of interface actions, and accuracy on medication reconciliation tasks using a novel user interface (Twinlist, which lays out the medications in five columns based on similarity and uses animation to introduce the grouping - www.cs.umd.edu/hcil/sharp/twinlist) compared to a Control interface (where medications are presented side by side in two columns). A secondary objective was to assess participant agreement with statements regarding clarity and utility and to elicit comparisons. MATERIAL AND METHODS: A 1 × 2 within-subjects experimental design was used with interface (Twinlist or Control) as an independent variable; time, number of clicks, scrolls, and errors were used as dependent variables. Participants were practicing medical providers with experience performing medication reconciliation but no experience with Twinlist. They reconciled two cases in each interface (in a counterbalanced order), then provided feedback on the design of the interface. RESULTS: Twenty medical providers participated in the study for a total of 80 trials. The trials using Twinlist were statistically significantly faster (18%), with fewer clicks (40%) and scrolls (60%). Serious errors were noted 12 and 31 times in Twinlist and Control trials, respectively. DISCUSSION: Trials using Twinlist were faster and more accurate. Subjectively, participants rated Twinlist more favorably than Control. They valued the novel layout of the drugs, but indicated that the included animation would be valuable for novices, but not necessarily for advanced users. Additional feedback from participants provides guidance for further development and clinical implementations. CONCLUSIONS: Cognitive support of medication reconciliation through interface design can significantly improve performance and safety.


Asunto(s)
Recursos Audiovisuales , Quimioterapia Asistida por Computador , Eficiencia , Conciliación de Medicamentos/métodos , Interfaz Usuario-Computador , Actitud hacia los Computadores , Presentación de Datos , Bases de Datos como Asunto , Humanos , Encuestas y Cuestionarios
19.
Health Psychol ; 34(1): 83-8, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24467255

RESUMEN

OBJECTIVE: Physical and sociocognitive lifestyle activities promote aspects of cognitive function in older adults. Very little is known about the relation between these lifestyle activities and cognitive function in young adults. One aspect of cognitive function that is critical for everyday function is episodic memory. The present study examined the relationship between lifestyle activities and episodic memory in younger and older adults. METHOD: Participants were 62 younger (mean age = 24 years) and older adults (mean age = 74 years). The augmented Victoria Longitudinal Study Activities Questionnaire was used to quantify level of engagement in physical activity, sociocognitive activity, and TV viewing. Episodic memory was assessed using the old-new face recognition paradigm in which memory for younger and older faces was tested. RESULTS: Compared to younger adults, older adults reported being less physically and sociocognitively active while engaging in more passive behaviors such as TV viewing. A positive association was observed between physical activity and episodic memory for young adults but not for older adults. Interestingly, TV viewing was negatively associated with episodic memory in older adults but not younger adults. No relationship was found between sociocognitive activity and episodic memory for either younger or older adults. Although the own-age effect was observed for older adults, face age did not interact with lifestyle activities. CONCLUSION: The positive cognitive benefits of physical activity extend to younger adults; however, the interplay between physical activity and cognition may differ across the life span. Furthermore, TV viewing may be particularly detrimental to cognitive performance later in life.


Asunto(s)
Envejecimiento/psicología , Cognición/fisiología , Cara , Memoria Episódica , Actividad Motora/fisiología , Conducta Social , Televisión/estadística & datos numéricos , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Envejecimiento/fisiología , Femenino , Humanos , Estilo de Vida , Estudios Longitudinales , Masculino , Adulto Joven
20.
Lancet HIV ; 1(2): e77-e84, 2014 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-25473651

RESUMEN

BACKGROUND: Reincarceration in prison or jail correlates with non-sustained HIV viral suppression, but HIV treatment outcomes in released prisoners who are reincarcerated have not recently been systematically assessed despite advances in antiretroviral treatment (ART) potency, simplicity, and tolerability. METHODS: In a retrospective cohort of reincarcerated inmates with HIV in Connecticut (2005-12), we used longitudinally linked demographic, pharmacy, and laboratory databases to examine correlates of viral suppression. The primary outcome was viral suppression on reincarceration, defined as viral load lower than 400 RNA copies per mL. FINDINGS: Of 497 prisoners and jail detainees with HIV, with 934 reincarcerations, individuals were mostly unmarried, uninsured, and black men prescribed a protease-inhibitor-based ART regimen. During the median 329 days (IQR 179-621) between prison release and reincarceration, the proportion of incarceration periods with viral suppression decreased significantly from 52% to 31% (mean HIV-RNA increased by 0·4 log10; p<0·0001), lower than Connecticut's HIV-infected prison population and those prescribed ART nationally. 158 (51%) of 307 individuals with viral suppression on release had viral suppression on reincarceration. Viral suppression on reincarceration was associated with increasing age (adjusted odds ratio [aOR] 1·04, 95% CI 1·01-1·07), being prescribed non-nucleoside reverse transcriptase inhibitor-based regimens (1·63, 1·14-2·34), and having higher levels of medical or psychiatric comorbidity (1·16, 1·03-1·30). INTERPRETATION: Identification of individuals most at risk for recidivism and loss of viral suppression might mitigate the risk that repeated reincarceration poses to systems of public health and safety. FUNDING: Bristol-Myers Squibb Virology, Patterson Trust, and National Institute on Drug Abuse.

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