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1.
Artigo em Inglês | MEDLINE | ID: mdl-31530447

RESUMO

Thyroid disease can significantly impact the pregnant woman and her child. Human and animal studies have firmly linked overt hypothyroidism and overt hyperthyroidism to miscarriage, preterm delivery and other adverse pregnancy outcomes. Overt hypothyroidism and overt hyperthyroidism affect 1% of all pregnancies. Treatment is widely available, and if detected early, results in decreased rates of adverse outcomes. Universal screening for thyroid disease in pregnancy can identify patients with thyroid disease requiring treatment, and ultimately decrease rates of complications. Universal screening is cost-effective compared to the currently accepted practice of targeted screening and may even be cost-saving in some healthcare systems. Targeted screening, which is recommended by most professional associations, fails to detect a large proportion of pregnant women with thyroid disease. In fact, an increasing number of providers are performing universal screening for thyroid disease in pregnancy, contrary to society guidelines. Limited evidence concerning the impact of untreated and treated subclinical disease and thyroid autoimmunity has distracted from the core rationale for universal screening - the beneficial impact of detecting and treating overt thyroid disease. Evidence supporting universal screening for overt disease stands independently from that of subclinical and autoimmune disease. The time to initiate universal screening is now.

2.
J Grad Med Educ ; 11(4 Suppl): 141-145, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31428271

RESUMO

Background: Ethiopia has experienced tremendous growth in medical education beginning in the early 2000s. Research shows a need for emphasis on empathy and compassionate care in this setting. In the United States, the Communication Assessment Tool (CAT) is a widely used, validated survey measuring provider-patient interactions. Objective: The goal of this study was to translate, culturally adapt, and pilot the CAT to allow it to be used with trainees and patients in Ethiopia. Methods: Bilingual experts translated the CAT into Tigrigna, the primary language of the Tigray region in northern Ethiopia, followed by focus group discussions, back translation, and review by the original author of the CAT. The translated tool was administered to the patients of resident physicians in 6 specialties at Ayder Referral Hospital between December 2016 and February 2017. Results: Our translation of the CAT into Tigrigna had semantic, idiomatic, and experiential equivalence. Of 1024 patients recruited, 1002 (98%) completed interviews using the CAT. Mean score was 3.09; 3% of all scores were excellent and 54% were good. Cronbach's alpha score for the full survey was 0.942, demonstrating high reliability. Conclusions: The translated CAT in Tigrigna can be used to assess communication skills in Ethiopian residents. Both mean score and percentage of excellent scores were considerably lower than scores in other countries, suggesting that there may be opportunities for improvement in residents' communication skills.

3.
Nat Commun ; 10(1): 1144, 2019 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-30850633

RESUMO

Despite intense interests in developing blood measurements of Alzheimer's disease (AD), the progress has been confounded by limited sensitivity and poor correlation to brain pathology. Here, we present a dedicated analytical platform for measuring different populations of circulating amyloid ß (Aß) proteins - exosome-bound vs. unbound - directly from blood. The technology, termed amplified plasmonic exosome (APEX), leverages in situ enzymatic conversion of localized optical deposits and double-layered plasmonic nanostructures to enable sensitive, multiplexed population analysis. It demonstrates superior sensitivity (~200 exosomes), and enables diverse target co-localization in exosomes. Employing the platform, we find that prefibrillar Aß aggregates preferentially bind with exosomes. We thus define a population of Aß as exosome-bound (Aß42+ CD63+) and measure its abundance directly from AD and control blood samples. As compared to the unbound or total circulating Aß, the exosome-bound Aß measurement could better reflect PET imaging of brain amyloid plaques and differentiate various clinical groups.


Assuntos
Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/química , Encéfalo/patologia , Exossomos/química , Neurônios/patologia , Fragmentos de Peptídeos/química , Placa Amiloide/patologia , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/sangue , Técnicas Biossensoriais , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Estudos de Casos e Controles , Linhagem Celular Tumoral , Exossomos/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Técnicas Analíticas Microfluídicas , Neurônios/metabolismo , Neurônios/ultraestrutura , Fragmentos de Peptídeos/sangue , Placa Amiloide/diagnóstico por imagem , Placa Amiloide/metabolismo , Tomografia por Emissão de Pósitrons , Agregados Proteicos , Soroalbumina Bovina/química , Soroalbumina Bovina/metabolismo , Ressonância de Plasmônio de Superfície , Células THP-1 , Tetraspanina 30/química , Tetraspanina 30/metabolismo
4.
Conf Proc IEEE Eng Med Biol Soc ; 2018: 1050-1053, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30440571

RESUMO

Mapping the brain alterations post stroke and post intervention is important for rehabilitation therapy development. Previous work has shown changes in functional connectivity based on resting-state fMRI, structural connectivity derived from diffusion MRI and perfusion as a result of brain-computer interface-assisted motor imagery (MI-BCI) and transcranial direct current stimulation (tDCS) in upper-limb stroke rehabilitation. Besides functional connectivity, regional amplitude of local low-frequency fluctuations (ALFF) may provide complementary information on the underlying neural mechanism in disease. Yet, findings on spontaneous brain activity during resting-state in stroke patients after intervention are limited and inconsistent. Here, we sought to investigate the different brain alteration patterns induced by tDCS compared to MI-BCI for upper-limb rehabilitation in chronic stroke patients using resting-state fMRI-based ALFF method. Our results suggested that stroke patients have lower ALFF in the ipsilesional somatomotor network compared to controls at baseline. Increased ALFF at contralesional somatomotor network and alterations in higher-level cognitive networks such as the default mode network (DMN) and salience networks accompany motor recovery after intervention; though the MI-BCI alone group and MI-BCI combined with tDCS group exhibit differential patterns.

5.
Contemp Clin Trials ; 73: 145-151, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30243810

RESUMO

OBJECTIVE: Pregnancy of unknown location (PUL) is not a diagnosis but a transient state used to classify a woman when she has a positive pregnancy test without definitive evidence of an intra-uterine or extra-uterine pregnancy on transvaginal ultrasonography. Management of a persisting PUL varies substantially, including expectant or active management. Active management can include uterine cavity evacuation or systemic administration of methotrexate. To date, no consensus has been reached on whether either management strategy is superior or non-inferior to the other. DESIGN: Randomized controlled trial. SETTING: Academic medical centers. PATIENTS: We plan to randomize 276 persisting PUL-diagnosed women who are 18 years or older from Reproductive Medicine Network clinics and additional interested sites, all patients will be followed for 2 years for fertility and patient satisfaction outcomes. INTERVENTIONS: Randomization will be 1:1:1 ratio between expectant management, uterine evacuation and empiric use of methotrexate. After randomization to initial management plan, all patients will be followed by their clinicians until resolution of the PUL. The clinician will determine whether there is a change in management, based on clinical symptoms, and/or serial human chorionic gonadotropin (hCG) concentrations and/or additional ultrasonography. MAIN OUTCOME: The primary outcome measure in each of the 3 treatment arms is the uneventful clinical resolution of a persistent PUL without change from the initial management strategy. Secondary outcome measures include: number of ruptured ectopic pregnancies, number and type of re-interventions (additional methotrexate injections or surgical procedures), treatment complications, adverse events, number of visits, time to resolution, patient satisfaction, and future fertility. CONCLUSION: This multicenter randomized controlled trial will provide guidance for evidence-based management for women who have persisting pregnancy of unknown location.

6.
Fertil Steril ; 110(3): 452-458, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30098697

RESUMO

OBJECTIVE: To determine whether an association exists between maternal antithyroid antibodies and euploid miscarriage in women with recurrent early pregnancy loss (REPL). DESIGN: Observational cohort study. SETTING: Two academic medical centers. PATIENT(S): Women seen between 2004-2015 with a history of REPL, who were euthyroid or had subclinical hypothyroidism, had maternal antithyroid antibody testing and had at least one subsequent early pregnancy loss (<10 weeks' gestation). INTERVENTION(S): Thyroid function and antibodies were measured at consultation. Subsequent miscarriages were assessed by conventional cytogenetic analysis, and when indicated, microsatellite analysis and/or comparative genomic hybridization/single nucleotide polymorphisms were performed. MAIN OUTCOME MEASURE(S): Determine whether maternal antithyroid antibodies are associated with euploid miscarriage. RESULT(S): Cohort consisted of 74 subjects with REPL who had 130 subsequent early pregnancy losses. The prevalence of maternal antithyroid antibodies in the cohort was 17.6%. Mean TSH was significantly higher among subjects with maternal antithyroid antibodies. Otherwise, no significant differences in demographics were noted. When comparing types of early pregnancy losses between the two groups, a trend toward having more miscarriages than nonvisualized pregnancy losses was noted among subjects with maternal antithyroid antibodies (70% and 30%) compared with subjects without maternal antithyroid antibodies (55% and 43%). No significant difference was noted in the frequency of euploid miscarriage between subjects with and without maternal antithyroid antibodies (42% vs. 56%). CONCLUSION(S): Our study did not demonstrate an association between euploid miscarriage and maternal antithyroid antibodies in subjects with a history of REPL. Therefore, testing or treatment in this cohort may not be warranted.

7.
Fertil Steril ; 109(6): 1008-1009, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29935634
8.
J Nucl Med ; 59(11): 1761-1767, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29653974

RESUMO

Head motion occurring during brain PET studies leads to image blurring and to bias in measured local quantities. The objective of this work was to implement a correction method for PET data acquired with the mMR synchronous PET/MR scanner. Methods: A list-mode-based motion-correction approach has been designed. The developed rebinner chronologically reads the recorded events from the Siemens list-mode file, applies the estimated geometric transformations, and frames the detected counts into sinograms. The rigid-body motion parameters were estimated from an initial dynamic reconstruction of the PET data. We then optimized the correction for 11C-Pittsburgh compound B (11C-PIB) scans using simulated and actual data with well-controlled motion. Results: An efficient list-mode-based motion correction approach has been implemented, fully optimized, and validated using simulated and actual PET data. The average spatial resolution loss induced by inaccuracies in motion parameter estimates and by the rebinning process was estimated to correspond to a 1-mm increase in full width at half maximum with motion parameters estimated directly from the PET data with a temporal frequency of 20 s. The results show that the rebinner can be safely applied to the 11C-PIB scans, allowing almost complete removal of motion-induced artifacts. The application of the correction method to a large cohort of 11C-PIB scans led to the following observations: first, that more than 21% of the scans were affected by motion greater than 10 mm (39% for subjects with Mini-Mental State Examination scores below 20), and second, that the correction led to quantitative changes in Alzheimer-specific cortical regions of up to 30%. Conclusion: The rebinner allows accurate motion correction at a cost of minimal resolution reduction. Application of the correction to a large cohort of 11C-PIB scans confirmed the necessity of systematically correcting for motion to obtain quantitative results.

9.
Magn Reson Med ; 79(1): 22-30, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28303591

RESUMO

PURPOSE: In vivo 31 P magnetic resonance spectroscopy (MRS) magnetization transfer (MT) provides a direct measure of neuronal activity at the metabolic level. This work aims to use functional 31 P MRS-MT to investigate the change in cerebral adenosine triphosphate (ATP) metabolic rates in healthy adults upon repeated visual stimuli. METHODS: A magnetization saturation transfer sequence with narrowband selective saturation of γ-ATP was developed for 31 P MT experiments at 3 T. RESULTS: Using progressive saturation of γ-ATP, the intrinsic T1 relaxation times of phosphocreatine (PCr) and inorganic phosphate (Pi) at 3 T were measured to be 5.1 ± 0.8 s and 3.0 ± 1.4 s, respectively. Using steady-state saturation of γ-ATP, a significant 24% ± 14% and 11% ± 7% increase in the forward creatine kinase (CK) pseudo-first-order reaction rate constant, k1 , was observed upon visual stimulation in the first and second cycles, respectively, of a paradigm consisting of 10-minute rest followed by 10-minute stimulation, with the measured baseline k1 being 0.35 ± 0.04 s-1 . No significant changes in forward ATP synthase reaction rate, PCr/γ-ATP, Pi/γ-ATP, and nicotinamide adenine dinucleotide/γ-ATP ratios, or intracellular pH were detected upon stimulation. CONCLUSION: This work demonstrates the potential of studying cerebral bioenergetics using functional 31 P MRS-MT to determine the change in the forward CK reaction rate at 3 T. Magn Reson Med 79:22-30, 2018. © 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.


Assuntos
Trifosfato de Adenosina/química , Mapeamento Encefálico/métodos , Espectroscopia de Ressonância Magnética , Neurônios/patologia , Isótopos de Fósforo/química , Encéfalo/diagnóstico por imagem , Creatina Quinase/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Cinética , Magnetismo , Modelos Estatísticos , Método de Monte Carlo
11.
Clin J Am Soc Nephrol ; 12(6): 940-946, 2017 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-28400421

RESUMO

BACKGROUND AND OBJECTIVES: Kidney disease is a critical concern in counseling patients with lupus considering pregnancy. This study sought to assess the risk of renal flares during pregnancy in women with previous lupus nephritis in partial or complete remission, particularly in those with antidouble-stranded DNA antibodies and low complement levels, and the risk of new-onset nephritis in patients with stable/mildly active SLE. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We assessed active nephritis (renal flares and de novo kidney disease) and associated predictors during pregnancy in patients with lupus with urine protein ≤1000 mg and serum creatinine <1.2 mg/dl at baseline; 373 patients (52% ethnic/racial minorities) enrolled between 2003 and 2012 were prospectively followed in the Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Syndrome and Systemic Lupus Erythematosus Study. Active nephritis was defined by proteinuria increase of >500 mg and/or red blood cell casts. RESULTS: Of 118 patients with previous kidney disease, 13 renal flares (11%) occurred (seven of 89 in complete remission and six of 29 in partial remission) compared with four with de novo kidney involvement (2%) in 255 patients without past kidney disease (P<0.001). Active nephritis was not associated with ethnicity, race, age, creatinine, BP, or antihypertensive and other medications. In multivariable logistic regression analyses, patients with past kidney disease in complete or partial remission more often experienced active nephritis (adjusted odds ratio, 6.88; 95% confidence interval, 1.84 to 25.71; P=0.004 and adjusted odds ratio, 20.98; 95% confidence interval, 4.69 to 93.98; P<0.001, respectively) than those without past kidney disease. Low C4 was associated with renal flares/de novo disease (adjusted odds ratio, 5.59; 95% confidence interval, 1.64 to 19.13; P<0.01) but not low C3 or positive anti-dsDNA alone. CONCLUSIONS: De novo kidney involvement in SLE, even in ethnic/racial minorities, is uncommon during pregnancy. Past kidney disease and low C4 at baseline independently associate with higher risk of developing active nephritis. Antibodies to dsDNA alone should not raise concern, even in patients with past kidney disease, if in remission.


Assuntos
Rim/fisiopatologia , Lúpus Eritematoso Sistêmico/complicações , Nefrite Lúpica/etiologia , Complicações na Gravidez/etiologia , Adulto , Anticorpos Antinucleares/sangue , Biomarcadores/sangue , Canadá , Complemento C4/análise , Creatinina/sangue , DNA/imunologia , Progressão da Doença , Feminino , Humanos , Modelos Logísticos , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/etnologia , Nefrite Lúpica/diagnóstico , Nefrite Lúpica/etnologia , Nefrite Lúpica/fisiopatologia , Análise Multivariada , Razão de Chances , Gravidez , Complicações na Gravidez/diagnóstico , Complicações na Gravidez/etnologia , Complicações na Gravidez/fisiopatologia , Prognóstico , Estudos Prospectivos , Proteinúria/etiologia , Proteinúria/fisiopatologia , Medição de Risco , Fatores de Risco , Estados Unidos , Adulto Jovem
12.
EJNMMI Res ; 7(1): 25, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28324340

RESUMO

BACKGROUND: The use of radiolabeled choline as a positron emission tomography (PET) agent for imaging primary tumors in the prostate has been evaluated extensively over the past two decades. There are, however, conflicting reports of its sensitivity and the relationship between choline PET imaging and disease staging is not fully understood. Moreover, relatively few studies have investigated the correlation between tracer uptake and histological tumor grade. This work quantified 18F-fluorocholine in tumor and healthy prostate tissue using pharmacokinetic modeling and stratified uptake parameters by histology grade. Additionally, the effect of scan time on the estimation of the kinetic exchange rate constants was evaluated, and the tracer influx parameters from full compartmental analysis were compared to uptake values quantified by Patlak and standardized uptake value (SUV) analyses. 18F-fluorocholine was administered as a 222 MBq bolus injection to ten patients with biopsy-confirmed prostate tumors, and dynamic PET data were acquired for 60 min. Image-derived arterial input functions were scaled by discrete blood samples, and a 2-tissue, 4-parameter model accounting for blood volume (2T4k+Vb) was used to perform fully quantitative compartmental modeling on tumor, healthy prostate, and muscle tissue. Subsequently, all patients underwent radical prostatectomy, and histological analyses were performed on the prostate specimens; kinetic parameters for tumors were stratified by Gleason score. Correlations were investigated between compartmental K 1 and K i parameters and SUV and Patlak slope; the effect of scan time on parameter bias was also evaluated. RESULTS: Choline activity curves in seven tumors, eight healthy prostate regions, and nine muscle regions were analyzed. Net tracer influx was generally higher in tumor relative to healthy prostate, with the values in the highest grade tumors markedly higher than those in lower grade tumors. Influx terms from Patlak and full compartmental modeling showed good correlation within individual tissue groups. Kinetic parameters calculated from the entire 60-min scan data were accurately reproduced from the first 30 min of acquired data (R 2 ≈ 0.9). CONCLUSIONS: Strong correlations were observed between K i and Patlak slope in tumor tissue, and K 1 and SUV were also correlated but to a lesser degree. Reliable estimates of all kinetic parameters can be achieved from the first 30 min of dynamic 18F-choline data. Although SUV, K 1, K i, and Patlak slope were found to be poor differentiators of low-grade tumor compared to healthy prostate tissue, they are strong indicators of aggressive disease.

13.
Fertil Steril ; 107(3): 684-690.e2, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28081870

RESUMO

OBJECTIVE: To assess the effectiveness of luteal start vaginal micronized P in a recurrent pregnancy loss (RPL) cohort. DESIGN: Observational cohort study using prospectively collected data. SETTING: Not applicable. PATIENT(S): Women seen between 2004 and 2012 with a history of two or more unexplained pregnancy losses <10 weeks in size; endometrial biopsy (EB) performed 9-11 days after LH surge; and one or more subsequent pregnancy(ies). Women were excluded if concomitant findings, such as endometritis, maturation delay, or glandular-stromal dyssynchrony, were identified on EB. INTERVENTION(S): Vaginal micronized P was prescribed at a dose of 100-200 mg every 12 hours starting 3 days after LH surge (luteal start) if glandular epithelial nuclear cyclin E (nCyclinE) expression was elevated (>20%) in endometrial glands or empirically despite normal nCyclinE (≤20%). Women with normal nCyclinE (≤20%) who did not receive P were used as controls. MAIN OUTCOME MEASURE(S): Pregnancy success was an ongoing pregnancy >10 weeks in size. RESULT(S): One hundred sixteen women met the inclusion criteria, of whom 51% (n = 59) had elevated nCyclinE and 49% (n = 57) had normal nCyclinE. Pregnancy success in the 59 women with elevated nCyclinE significantly improved after intervention: 6% (16/255) in prior pregnancies versus 69% (57/83) in subsequent pregnancies. Pregnancy success in subsequent pregnancies was higher in women prescribed vaginal micronized P compared with controls: 68% (86/126) versus 51% (19/37); odds ratio = 2.1 (95% confidence interval, 1.0-4.4). CONCLUSION(S): In this study, we found that the use of luteal start vaginal micronized P was associated with improved pregnancy success in a strictly defined cohort of women with RPL.


Assuntos
Aborto Habitual/prevenção & controle , Endométrio/efeitos dos fármacos , Fármacos para a Fertilidade Feminina/administração & dosagem , Fase Luteal/efeitos dos fármacos , Progesterona/administração & dosagem , Aborto Habitual/diagnóstico , Aborto Habitual/fisiopatologia , Administração Intravaginal , Adulto , Ciclina E/metabolismo , Composição de Medicamentos , Endométrio/metabolismo , Endométrio/fisiopatologia , Feminino , Fármacos para a Fertilidade Feminina/efeitos adversos , Humanos , Fase Luteal/metabolismo , Gravidez , Progesterona/efeitos adversos , Estudos Prospectivos , Resultado do Tratamento
14.
Diabetes Obes Metab ; 19(1): 70-77, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27593525

RESUMO

AIM: To investigate the acute and longer-term effects of low (LGI) versus high glycaemic index (HGI) diets on hepatic fat and glycogen accumulation and related blood measures in healthy volunteers. METHODS: Eight healthy men (age 20.1 ± 0.4 years, body mass index 23.0 ± 0.9 kg/m2 ) attended a test day before and after a 7-day macronutrient- and energy-matched HGI or LGI diet, followed by a minimum 4-week wash-out period, and then returned to repeat the intervention with the alternative diet. During test days, participants consumed either an HGI or an LGI test meal corresponding to their diet week, and liver fat [ 1 H magnetic resonance spectroscopy (MRS)], glycogen ( 13 C MRS) and gastric content volume (MRI) were measured. Blood samples were obtained regularly throughout the test day to assess plasma glucose and insulin levels. RESULTS: Plasma glucose and insulin peak values and area under the curve were significantly greater after the HGI test meal compared with the LGI test meal, as expected. Hepatic glycogen concentrations increased more after the HGI test meal ( P < .05) and peak levels were significantly greater after 7 days of HGI dietary intervention compared with those at the beginning of the intervention ( P < .05). Liver fat fractions increased significantly after the HGI dietary intervention compared with the LGI dietary intervention (two-way repeated-measures analysis of variance P ≤ .05). CONCLUSIONS: Compared with an LGI diet, a 1-week HGI diet increased hepatic fat and glycogen stores. This may have important clinical relevance for dietary interventions in the prevention and management of non-alcoholic fatty liver disease.


Assuntos
Tecido Adiposo/metabolismo , Glicemia/metabolismo , Dieta , Índice Glicêmico , Glicogênio/metabolismo , Insulina/metabolismo , Fígado/metabolismo , Área Sob a Curva , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Estudos Cross-Over , Conteúdo Gastrointestinal/diagnóstico por imagem , Voluntários Saudáveis , Humanos , Imagem por Ressonância Magnética , Masculino , Período Pós-Prandial , Espectroscopia de Prótons por Ressonância Magnética , Adulto Jovem
15.
Genet Med ; 19(1): 83-89, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27337029

RESUMO

PURPOSE: Chromosomal microarray analysis (CMA) is currently considered first-tier testing in pediatric care and prenatal diagnosis owing to its high diagnostic sensitivity for chromosomal imbalances. The aim of this study was to determine the efficacy and diagnostic power of CMA in both fresh and formalin-fixed paraffin-embedded (FFPE) samples of products of conception (POCs). METHODS: Over a 44-month period, 8,118 consecutive samples were received by our laboratory for CMA analysis. This included both fresh (76.4%) and FFPE samples (22.4%), most of which were ascertained for recurrent pregnancy loss and/or spontaneous abortion (83%). The majority of samples were evaluated by a whole-genome single-nucleotide polymorphism (SNP)-based array (81.6%); the remaining samples were evaluated by array-comparative genomic hybridization (CGH). RESULTS: A successful result was obtained in 7,396 of 8,118 (91.1%), with 92.4% of fresh tissue samples and 86.4% of FFPE samples successfully analyzed. Clinically significant abnormalities were identified in 53.7% of specimens (3,975 of 7,396), 94% of which were considered causative. CONCLUSION: Analysis of POC specimens by karyotyping fails in 20-40% of cases. SNP-based CMA is a robust platform, with successful results obtained in >90% of cases. SNP-based CMA can identify aneuploidy, polyploidy, whole-genome homozygosity, segmental genomic imbalances, and maternal cell contamination, thus maximizing sensitivity and decreasing false-negative results. Understanding the etiology of fetal loss enables clarification of recurrence risk and assists in determining appropriate management for future family planning.Genet Med 19 1, 83-89.


Assuntos
Aborto Espontâneo/genética , Hibridização Genômica Comparativa/métodos , Testes Genéticos , Diagnóstico Pré-Natal , Aborto Espontâneo/diagnóstico , Adulto , Fatores Etários , Aneuploidia , Aberrações Cromossômicas , Feminino , Humanos , Hibridização in Situ Fluorescente/métodos , Cariotipagem/métodos , Pessoa de Meia-Idade , Inclusão em Parafina , Polimorfismo de Nucleotídeo Único , Gravidez
16.
PLoS Genet ; 12(7): e1005858, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27447835

RESUMO

Fertility traits in humans are heritable, however, little is known about the genes that influence reproductive outcomes or the genetic variants that contribute to differences in these traits between individuals, particularly women. To address this gap in knowledge, we performed an unbiased genome-wide expression quantitative trait locus (eQTL) mapping study to identify common regulatory (expression) single nucleotide polymorphisms (eSNPs) in mid-secretory endometrium. We identified 423 cis-eQTLs for 132 genes that were significant at a false discovery rate (FDR) of 1%. After pruning for strong LD (r2 >0.95), we tested for associations between eSNPs and fecundability (the ability to get pregnant), measured as the length of the interval to pregnancy, in 117 women. Two eSNPs were associated with fecundability at a FDR of 5%; both were in the HLA region and were eQTLs for the TAP2 gene (P = 1.3x10-4) and the HLA-F gene (P = 4.0x10-4), respectively. The effects of these SNPs on fecundability were replicated in an independent sample. The two eSNPs reside within or near regulatory elements in decidualized human endometrial stromal cells. Our study integrating eQTL mapping in a primary tissue with association studies of a related phenotype revealed novel genes and associated alleles with independent effects on fecundability, and identified a central role for two HLA region genes in human implantation success.


Assuntos
Membro 3 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/genética , Fertilidade/genética , Antígenos de Histocompatibilidade Classe I/genética , Locos de Características Quantitativas/genética , Membro 3 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/biossíntese , Adulto , Mapeamento Cromossômico , Endométrio/metabolismo , Endométrio/patologia , Feminino , Fertilidade/fisiologia , Regulação da Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Antígenos de Histocompatibilidade Classe I/biossíntese , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único , Gravidez , Sequências Reguladoras de Ácido Nucleico
17.
Arthritis Rheumatol ; 68(8): 1964-9, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26990620

RESUMO

OBJECTIVE: To measure variance in antiphospholipid antibody (aPL) levels during pregnancy and to determine if variation affects pregnancy outcomes. METHODS: We used data from the PROMISSE (Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Antibody Syndrome and Systemic Lupus Erythematosus) study, a multicenter prospective study of pregnant women with aPL and/or systemic lupus erythematosus (SLE). Antiphospholipid antibodies were considered present if any of the following were positive: anticardiolipin (aCL), anti-ß2 -glycoprotein I (anti-ß2 GPI) titers ≥40 IgG phospholipid (GPL) or IgM phospholipid (MPL) units, and/or lupus anticoagulant (LAC). Antiphospholipid antibodies were measured every trimester and postpartum. Adverse pregnancy outcomes were defined as fetal/neonatal death, preterm delivery (<36 weeks) due to preeclampsia or placental insufficiency, or growth restriction. RESULTS: One hundred fifty-two aPL-positive patients were studied. Fifty-seven percent had clinical antiphospholipid syndrome (APS) and 36% had SLE. IgG aPL levels were significantly lower during the second and third trimesters compared to initial screening, but IgG aCL and anti-ß2 GPI remained high-positive through pregnancy in 93% of patients during the second trimester, and in 85% of patients during the third trimester. IgM aPL titers were negative in the majority of patients and decreased modestly during pregnancy among patients who were positive. LAC frequency also decreased, but 75% of patients remained positive through the second trimester. Only 4% of patients with aPL at baseline did not have aPL in either the second or third trimesters. Changes in aPL levels or aPL status were not associated with adverse pregnancy outcomes. LAC was the only aPL associated with adverse pregnancy outcomes. CONCLUSION: The aPL in the cohort decreased marginally during pregnancy, and changes were not associated with pregnancy outcomes. Our results suggest that, among women with aPL and/or SLE, measuring aPL early in pregnancy is sufficient to assess risk. Repeat aPL testing through pregnancy is unnecessary.


Assuntos
Anticorpos Antifosfolipídeos/sangue , Síndrome Antifosfolipídica/sangue , Lúpus Eritematoso Sistêmico/sangue , Complicações na Gravidez/sangue , Adulto , Feminino , Humanos , Gravidez , Resultado da Gravidez , Estudos Prospectivos , Medição de Risco
18.
Mol Hum Reprod ; 22(5): 364-72, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26826164

RESUMO

STUDY HYPOTHESIS: Exome sequencing can identify genetic causes of idiopathic recurrent pregnancy loss (RPL). STUDY FINDING: We identified compound heterozygous deleterious mutations affecting DYNC2H1 and ALOX15 in two out of four families with RPL. Both genes have a role in early development. Bioinformatics analysis of all genes with rare and putatively pathogenic mutations in miscarriages and couples showed enrichment in pathways relevant to pregnancy loss, including the complement and coagulation cascades pathways. WHAT IS KNOWN ALREADY: Next generation sequencing (NGS) is increasingly being used to identify known and novel gene mutations in children with developmental delay and in fetuses with ultrasound-detected anomalies. In contrast, NGS is rarely used to study pregnancy loss. Chromosome microarray analysis detects putatively causative DNA copy number variants (CNVs) in ∼2% of miscarriages and CNVs of unknown significance (predominantly parental in origin) in up to 40% of miscarriages. Therefore, a large number of miscarriages still have an unknown cause. STUDY DESIGN, SAMPLES/MATERIALS, METHODS: Whole exome sequencing (WES) was performed using Illumina HiSeq 2000 platform on seven euploid miscarriages from four families with RPL. Golden Helix SVS v8.1.5 was used for data assessment and inheritance analysis for deleterious DNA variants predicted to severely disrupt protein-coding genes by introducing a frameshift, loss of the stop codon, gain of the stop codon, changes in splicing or the initial codon. Webgestalt (http://bioinfo.vanderbilt.edu/webgestalt/) was used for pathway and disease association enrichment analysis of a gene pool containing putatively pathogenic variants in miscarriages and couples in comparison to control gene pools. MAIN RESULTS AND THE ROLE OF CHANCE: Compound heterozygous mutations in DYNC2H1 and ALOX15 were identified in miscarriages from two families with RPL. DYNC2H1 is involved in cilia biogenesis and has been associated with fetal lethality in humans. ALOX15 is expressed in placenta and its dysregulation has been associated with inflammation, placental, dysfunction, abnormal oxidative stress response and angiogenesis. The pool of putatively pathogenic single nucleotide variants (SNVs) and small insertions and deletions (indels) detected in the miscarriages showed enrichment in 'complement and coagulation cascades pathway', and 'ciliary motility disorders'. We conclude that CNVs, individual SNVs and pool of deleterious gene mutations identified by exome sequencing could contribute to RPL. LIMITATIONS, REASONS FOR CAUTION: The size of our sample cohort is small. The functional effect of candidate mutations should be evaluated to determine whether the mutations are causative. WIDER IMPLICATIONS OF THE FINDINGS: This is the first study to assess whether SNVs may contribute to the pathogenesis of miscarriage. Furthermore, our findings suggest that collective effect of mutations in relevant biological pathways could be implicated in RPL. STUDY FUNDING AND COMPETING INTERESTS: The study was funded by Canadian Institutes of Health Research (grant MOP 106467) and Michael Smith Foundation of Health Research Career Scholar salary award to ERS.


Assuntos
Aborto Habitual/genética , Sequenciamento Completo do Exoma/métodos , Araquidonato 15-Lipoxigenase/genética , Biologia Computacional , Dineínas do Citoplasma/genética , Variações do Número de Cópias de DNA/genética , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação/genética , Gravidez
19.
Am J Obstet Gynecol ; 214(1): 108.e1-108.e14, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26432463

RESUMO

BACKGROUND: Over 20% of pregnancies in patients with systemic lupus erythematosus (SLE) and/or antiphospholipid antibodies (APL) result in an adverse pregnancy outcome (APO) related to abnormal placentation. The ability to identify, early in pregnancy, patients who are destined for poor outcomes would significantly impact care of this high-risk population. In nonautoimmune patients, circulating angiogenic factors are dysregulated in disorders of placentation, such as preeclampsia (PE) and fetal growth restriction. OBJECTIVE: We sought to determine whether early dysregulation of circulating angiogenic factors can predict APO in high-risk SLE and/or APL pregnancies. STUDY DESIGN: We used data and samples from the Predictors of Pregnancy Outcome: Biomarkers in APL Syndrome and SLE (PROMISSE), a multicenter prospective study that enrolled 492 pregnant women with SLE and/or APL from September 2003 through August 2013. Patients were followed through pregnancy from <12 weeks gestation. Circulating levels of soluble fms-like tyrosine kinase-1 (sFlt1), placental growth factor (PlGF), and soluble endoglin were measured monthly and subjects followed up for APO, classified as severe (PE <34 weeks, fetal/neonatal death, indicated preterm delivery <30 weeks) or moderate (PE ≥34 weeks, indicated preterm delivery 30-36 weeks, growth restriction without PE). RESULTS: Severe APOs occurred in 12% and moderate APOs in 10% of patients. By 12-15 weeks, sFlt1, PlGF, and soluble endoglin levels were markedly altered in women who developed severe APO. After adjusting for clinical risk factors, sFlt1 was the strongest predictor of severe APO among 12-15 week measures (odds ratio, 17.3 comparing highest and lowest quartiles; 95% confidence interval [CI], 3.5-84.8; positive predictive value [PPV], 61%; negative predictive value [NPV], 93%). At 16-19 weeks, the combination of sFlt1 and PlGF was most predictive of severe APO, with risk greatest for subjects with both PlGF in lowest quartile (<70.3 pg/mL) and sFlt1 in highest quartile (>1872 pg/mL; odds ratio, 31.1; 95% CI, 8.0-121.9; PPV, 58%; NPV, 95%). Severe APO rate in this high-risk subgroup was 94% (95% CI, 70-99.8%), if lupus anticoagulant or history of high blood pressure was additionally present. In contrast, among patients with both sFlt1 <1872 pg/mL and PlGF >70.3 pg/mL, rate of severe APO was only 4.6% (95% CI, 2.1-8.6%). CONCLUSION: Circulating angiogenic factors measured during early gestation have a high NPV in ruling out the development of severe adverse outcomes among patients with SLE and/or APL syndrome. Timely risk stratification of patients is important for effective clinical care and optimal allocation of health care resources.


Assuntos
Antígenos CD/sangue , Síndrome Antifosfolipídica/sangue , Retardo do Crescimento Fetal/sangue , Lúpus Eritematoso Sistêmico/sangue , Pré-Eclâmpsia/sangue , Proteínas da Gravidez/sangue , Receptores de Superfície Celular/sangue , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/sangue , Adulto , Anti-Inflamatórios não Esteroides/uso terapêutico , Anticorpos Antifosfolipídeos/sangue , Anticoagulantes/uso terapêutico , Síndrome Antifosfolipídica/tratamento farmacológico , Aspirina/uso terapêutico , Biomarcadores/sangue , Endoglina , Feminino , Idade Gestacional , Heparina/uso terapêutico , Humanos , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Fator de Crescimento Placentário , Valor Preditivo dos Testes , Gravidez , Resultado da Gravidez , Primeiro Trimestre da Gravidez/sangue , Segundo Trimestre da Gravidez/sangue , Gravidez de Alto Risco , Estudos Prospectivos , Índice de Gravidade de Doença , Adulto Jovem
20.
J Vet Diagn Invest ; 27(4): 476-88, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26179094

RESUMO

Fitness for purpose and validation are increasingly becoming a benchmark in the development of test methods for the diagnosis of infectious diseases in aquatic animals. The design of the evaluation and the analysis of data are critical to demonstrate test method performance characteristics and fitness for purpose, as stated in the World Organization for Animal Health pathway for test validation. Three test methods for the detection of the oyster parasite Haplosporidium nelsoni were selected for the validation study described herein: histology, end-point polymerase chain reaction (PCR), and real-time PCR (qPCR). Preliminary work evaluated the analytical sensitivity and specificity of the PCR and qPCR assay in development. The following stage used test results on 100 oysters in 3 different laboratories to assess diagnostic sensitivity (DSe), diagnostic specificity (DSp), repeatability, and reproducibility. Repeatability and reproducibility were within 68-95%. The final part of the project evaluated DSe and DSp using test results on 400 oysters and results from the first 100 oysters tested. In the absence of a 100% gold standard test, latent class modeling methods were explored to characterize the tests (i.e., Bayesian analyses). For both PCR methods, DSe was >90%, and in the 60% range for histology, whereas DSp was >90% for all methods. Based on the results of this validation, a threshold cycle value of 30 for qPCR corresponds to the limit of sensitivity for histology where unreliable detection becomes more frequent, thus providing a threshold helpful in diagnostic settings where both histology and qPCR are used.


Assuntos
Crassostrea/parasitologia , Haplosporídios/isolamento & purificação , Infecções por Protozoários/parasitologia , Animais , Teorema de Bayes , Canadá , Haplosporídios/genética , Reação em Cadeia da Polimerase em Tempo Real/veterinária , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
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