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1.
Rheumatology (Oxford) ; 63(2): 414-422, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-37184855

RESUMO

OBJECTIVE: To study whether multimodal brain MRI comprising permeability and perfusion measures coupled with machine learning can predict neurocognitive function in young patients with SLE without neuropsychiatric manifestations. METHODS: SLE patients and healthy controls (HCs) (≤40 years of age) underwent multimodal structural brain MRI that comprised voxel-based morphometry (VBM), magnetization transfer ratio (MTR) and dynamic contrast-enhanced (DCE) MRI in this cross-sectional study. Neurocognitive function assessed by Automated Neuropsychological Assessment Metrics was reported as the total throughput score (TTS). Olfactory function was assessed. A machine learning-based model (i.e. glmnet) was constructed to predict TTS. RESULTS: Thirty SLE patients and 10 HCs were studied. Both groups had comparable VBM, MTR, olfactory bulb volume (OBV), olfactory function and TTS. While after correction for multiple comparisons the uncorrected increase in the blood-brain barrier (BBB) permeability parameters compared with HCs did not remain evident in SLE patients, DCE-MRI perfusion parameters, notably an increase in right amygdala perfusion, was positively correlated with TTS in SLE patients (r = 0.636, false discovery rate P < 0.05). A machine learning-trained multimodal MRI model comprising alterations of VBM, MTR, OBV and DCE-MRI parameters mainly in the limbic system regions predicted TTS in SLE patients (r = 0.644, P < 0.0005). CONCLUSION: Multimodal brain MRI demonstrated increased right amygdala perfusion that was associated with better neurocognitive performance in young SLE patients without statistically significant BBB leakage and microstructural abnormalities. A machine learning-constructed multimodal model comprising microstructural, perfusion and permeability parameters accurately predicted neurocognitive performance in SLE patients.


Assuntos
Encéfalo , Lúpus Eritematoso Sistêmico , Humanos , Estudos Transversais , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Imageamento por Ressonância Magnética/métodos , Espectroscopia de Ressonância Magnética , Neuroimagem , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/diagnóstico por imagem , Lúpus Eritematoso Sistêmico/patologia
2.
BJOG ; 130(11): 1346-1354, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37039256

RESUMO

OBJECTIVE: To develop core outcome sets (COS) for miscarriage management and prevention. DESIGN: Modified Delphi survey combined with a consensus development meeting. SETTING: International. POPULATION: Stakeholder groups included healthcare providers, international experts, researchers, charities and couples with lived experience of miscarriage from 15 countries: 129 stakeholders for miscarriage management and 437 for miscarriage prevention. METHODS: Modified Delphi method and modified nominal group technique. RESULTS: The final COS for miscarriage management comprises six outcomes: efficacy of treatment, heavy vaginal bleeding, pelvic infection, maternal death, treatment or procedure-related complications, and patient satisfaction. The final COS for miscarriage prevention comprises 12 outcomes: pregnancy loss <24 weeks' gestation, live birth, gestation at birth, pre-term birth, congenital abnormalities, fetal growth restriction, maternal (antenatal) complications, compliance with intervention, patient satisfaction, maternal hospitalisation, neonatal or infant hospitalisation, and neonatal or infant death. Other outcomes identified as important were mental health-related outcomes, future fertility and health economic outcomes. CONCLUSIONS: This study has developed two core outcome sets, through robust methodology, that should be implemented across future randomised trials and systematic reviews in miscarriage management and prevention. This work will help to standardise outcome selection, collection and reporting, and improve the quality and safety of future studies in miscarriage.


Assuntos
Aborto Espontâneo , Morte Materna , Recém-Nascido , Gravidez , Humanos , Feminino , Aborto Espontâneo/prevenção & controle , Consenso , Retardo do Crescimento Fetal/terapia , Projetos de Pesquisa , Técnica Delphi , Avaliação de Resultados em Cuidados de Saúde , Resultado do Tratamento
3.
MAGMA ; 36(4): 553-563, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-36538248

RESUMO

OBJECTIVE: Magnetic resonance spectroscopy (MRS) provides a powerful method of measuring fat fraction. However, previous studies have shown that MRS results give lower values compared with visual estimates from biopsies in fibrotic livers. This study investigated these discrepancies and considered whether a tissue water content correction, as assessed by MRI relaxometry, could provide better agreement. MATERIALS AND METHODS: 110 patients were scanned in a 1.5 T Philips scanner and biopsies were obtained. Multiple echo MRS (30 × 30 × 30 mm volume) was used to determine Proton Density Fat Fraction (PDFF). Biopsies were assessed by visual assessment for fibrosis and steatosis grading. Digital image analysis (DIA) was also used to quantify fat fraction within tissue samples. T1 relaxation times were then used to estimate tissue water content to correct PDFF for confounding factors. RESULTS: PDFF values across the four visually assessed steatosis grades were significantly less in the higher fibrosis group (F3-F4) compared to the lower fibrosis group (F0-F2). The slope of the linear regression of PDFF vs DIA fat fraction was ~ 1 in the low fibrosis group and 0.77 in the high fibrosis group. Correcting for water content based on T1 increased the gradient but it did not reach unity. DISCUSSION: In fibrotic livers, PDFF underestimated fat fraction compared to DIA methods. Values were improved by applying a water content correction, but fat fractions were still underestimated.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Humanos , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Hepatopatia Gordurosa não Alcoólica/patologia , Prótons , Espectroscopia de Ressonância Magnética/métodos , Fibrose
4.
Lancet ; 397(10285): 1668-1674, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33915095

RESUMO

The physical and psychological effect of miscarriage is commonly underappreciated. The journey from diagnosis of miscarriage, through clinical management, to supportive aftercare can be challenging for women, their partners, and caregivers. Diagnostic challenges can lead to delayed or ineffective care and increased anxiety. Inaccurate diagnosis of a miscarriage can result in the unintended termination of a wanted pregnancy. Uncertainty about the therapeutic effects of interventions can lead to suboptimal care, with variations across facilities and countries. For this Series paper, we have developed recommendations for practice from a literature review, appraisal of guidelines, and expert group discussions. The recommendations are grouped into three categories: (1) diagnosis of miscarriage, (2) prevention of miscarriage in women with early pregnancy bleeding, and (3) management of miscarriage. We recommend that every country reports annual aggregate miscarriage data, similarly to the reporting of stillbirth. Early pregnancy services need to focus on providing an effective ultrasound service, as it is central to the diagnosis of miscarriage, and be able to provide expectant management of miscarriage, medical management with mifepristone and misoprostol, and surgical management with manual vacuum aspiration. Women with the dual risk factors of early pregnancy bleeding and a history of previous miscarriage can be recommended vaginal micronised progesterone to improve the prospects of livebirth. We urge health-care funders and providers to invest in early pregnancy care, with specific focus on training for clinical nurse specialists and doctors to provide comprehensive miscarriage care within the setting of dedicated early pregnancy units.


Assuntos
Aborto Espontâneo/diagnóstico , Aborto Espontâneo/prevenção & controle , Aborto Espontâneo/terapia , Cuidado Pré-Natal/métodos , Feminino , Humanos , Gravidez , Complicações na Gravidez/diagnóstico , Complicações na Gravidez/terapia , Ultrassonografia
5.
Lancet ; 397(10285): 1658-1667, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33915094

RESUMO

Miscarriage is generally defined as the loss of a pregnancy before viability. An estimated 23 million miscarriages occur every year worldwide, translating to 44 pregnancy losses each minute. The pooled risk of miscarriage is 15·3% (95% CI 12·5-18·7%) of all recognised pregnancies. The population prevalence of women who have had one miscarriage is 10·8% (10·3-11·4%), two miscarriages is 1·9% (1·8-2·1%), and three or more miscarriages is 0·7% (0·5-0·8%). Risk factors for miscarriage include very young or older female age (younger than 20 years and older than 35 years), older male age (older than 40 years), very low or very high body-mass index, Black ethnicity, previous miscarriages, smoking, alcohol, stress, working night shifts, air pollution, and exposure to pesticides. The consequences of miscarriage are both physical, such as bleeding or infection, and psychological. Psychological consequences include increases in the risk of anxiety, depression, post-traumatic stress disorder, and suicide. Miscarriage, and especially recurrent miscarriage, is also a sentinel risk marker for obstetric complications, including preterm birth, fetal growth restriction, placental abruption, and stillbirth in future pregnancies, and a predictor of longer-term health problems, such as cardiovascular disease and venous thromboembolism. The costs of miscarriage affect individuals, health-care systems, and society. The short-term national economic cost of miscarriage is estimated to be £471 million per year in the UK. As recurrent miscarriage is a sentinel marker for various obstetric risks in future pregnancies, women should receive care in preconception and obstetric clinics specialising in patients at high risk. As psychological morbidity is common after pregnancy loss, effective screening instruments and treatment options for mental health consequences of miscarriage need to be available. We recommend that miscarriage data are gathered and reported to facilitate comparison of rates among countries, to accelerate research, and to improve patient care and policy development.


Assuntos
Aborto Espontâneo/epidemiologia , Ansiedade/psicologia , Depressão/psicologia , Transtornos de Estresse Pós-Traumáticos/psicologia , Aborto Habitual/economia , Aborto Habitual/epidemiologia , Aborto Habitual/fisiopatologia , Aborto Habitual/psicologia , Aborto Espontâneo/economia , Aborto Espontâneo/fisiopatologia , Aborto Espontâneo/psicologia , Endometrite/epidemiologia , Feminino , Retardo do Crescimento Fetal/epidemiologia , Humanos , Nascimento Prematuro/epidemiologia , Prevalência , Fatores de Risco , Natimorto/epidemiologia , Suicídio/psicologia , Hemorragia Uterina/epidemiologia
6.
Lancet ; 397(10285): 1675-1682, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33915096

RESUMO

Women who have had repeated miscarriages often have uncertainties about the cause, the likelihood of recurrence, the investigations they need, and the treatments that might help. Health-care policy makers and providers have uncertainties about the optimal ways to organise and provide care. For this Series paper, we have developed recommendations for practice from literature reviews, appraisal of guidelines, and a UK-wide consensus conference that was held in December, 2019. Caregivers should individualise care according to the clinical needs and preferences of women and their partners. We define a minimum set of investigations and treatments to be offered to couples who have had recurrent miscarriages, and urge health-care policy makers and providers to make them universally available. The essential investigations include measurements of lupus anticoagulant, anticardiolipin antibodies, thyroid function, and a transvaginal pelvic ultrasound scan. The key treatments to consider are first trimester progesterone administration, levothyroxine in women with subclinical hypothyroidism, and the combination of aspirin and heparin in women with antiphospholipid antibodies. Appropriate screening and care for mental health issues and future obstetric risks, particularly preterm birth, fetal growth restriction, and stillbirth, will need to be incorporated into the care pathway for couples with a history of recurrent miscarriage. We suggest health-care services structure care using a graded model in which women are offered online health-care advice and support, care in a nurse or midwifery-led clinic, and care in a medical consultant-led clinic, according to clinical needs.


Assuntos
Aborto Habitual/diagnóstico , Aborto Habitual/prevenção & controle , Aborto Habitual/terapia , Aborto Habitual/psicologia , Feminino , Humanos , Gravidez , Complicações na Gravidez/diagnóstico , Complicações na Gravidez/prevenção & controle
7.
Eur J Neurol ; 28(5): 1479-1489, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33370497

RESUMO

BACKGROUND AND PURPOSE: Various blood biomarkers reflecting brain amyloid-ß (Aß) load have recently been proposed with promising results. However, to date, no comparative study amongst blood biomarkers has been reported. Our objective was to examine the diagnostic performance and cost effectiveness of three blood biomarkers on the same cohort. METHODS: Using the same cohort (n = 68), the performances of the single-molecule array (Simoa) Aß40, Aß42, Aß42/Aß40 and the amplified plasmonic exosome (APEX) Aß42 blood biomarkers were compared using amyloid positron emission tomography (PET) as the reference standard. The extent to which these blood tests can reduce the recruitment cost of clinical trials was also determined by identifying amyloid positive (Aß+) participants. RESULTS: Compared to Simoa biomarkers, APEX-Aß42 showed significantly higher correlations with amyloid PET retention values and excellent diagnostic performance (sensitivity 100%, specificity 93.3%, area under the curve 0.995). When utilized for clinical trial recruitment, our simulation showed that pre-screening with blood biomarkers followed by a confirmatory amyloid PET imaging would roughly half the cost (56.8% reduction for APEX-Aß42 and 48.6% for Simoa-Aß42/Aß40) compared to the situation where only PET imaging is used. Moreover, with 100% sensitivity, APEX-Aß42 pre-screening does not increase the required number of initial participants. CONCLUSIONS: With its high diagnostic performance, APEX is an ideal candidate for Aß+ subject identification, monitoring and primary care screening, and could efficiently enrich clinical trials with Aß+ participants whilst halving recruitment costs.


Assuntos
Doença de Alzheimer , Exossomos , Doença de Alzheimer/diagnóstico por imagem , Peptídeos beta-Amiloides , Biomarcadores , Humanos , Imunoensaio , Fragmentos de Peptídeos
8.
J Ultrasound Med ; 40(7): 1353-1359, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32981145

RESUMO

OBJECTIVES: To compare the use of the luteinizing hormone (LH) surge versus the last menstrual period (LMP) for the accuracy of pregnancy dating in fertile women with a diagnosis of recurrent early pregnancy loss (REPL). METHODS: This was an observational cohort study using prospectively collected data at 2 academic REPL programs between 2005 and 2018. Women with a history of REPL and at least 1 subsequent live birth after the evaluation were included. All patients conceived by intercourse timed to the LH surge. Transvaginal ultrasound was examinations were performed 2 weeks after missed menses. The gestational age (GA) was calculated by the LH surge (GALH ), LMP (GALMP ), and first crown-rump length (CRL) that measured 5 mm or greater (GACRL ). A secondary analysis compared GA based on the first measurable CRL of less than 5 mm versus GA based on the first CRL of 5 mm or greater. The GALH and GALMP were compared to determine which measure showed greater concordance with the CRL. The mean absolute difference in days between the GACRL versus GALH and GACRL versus GALMP was determined. RESULTS: A total of 115 women with 118 subsequent pregnancies resulting in live birth were included, with a mean age at delivery of 35.5 years and a mean of 3.6 prior pregnancy losses. The GALH showed a stronger correlation with the CRL (0.77) than the GALMP (0.63; P = .002). The GALH was more similar to the GACRL than the GALMP , with a mean absolute difference of 2.0 versus 3.1 days (P < .0001). CONCLUSIONS: When known, the LH surge appears to be more accurate than the LMP and should be used preferentially for dating of early pregnancy.


Assuntos
Aborto Habitual , Estatura Cabeça-Cóccix , Perda do Embrião , Feminino , Idade Gestacional , Humanos , Hormônio Luteinizante , Gravidez , Primeiro Trimestre da Gravidez , Estudos Prospectivos , Ultrassonografia Pré-Natal
9.
JAMA ; 326(5): 390-400, 2021 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-34342619

RESUMO

Importance: Women with an early nonviable pregnancy of unknown location are at high risk of ectopic pregnancy and its inherent morbidity and mortality. Successful and timely resolution of the gestation, while minimizing unscheduled interventions, are important priorities. Objective: To determine if active management is more effective in achieving pregnancy resolution than expectant management and whether the use of empirical methotrexate is noninferior to uterine evacuation followed by methotrexate if needed. Design, Setting, and Participants: This multicenter randomized clinical trial recruited 255 hemodynamically stable women with a diagnosed persisting pregnancy of unknown location between July 25, 2014, and June 4, 2019, in 12 medical centers in the United States (final follow up, August 19, 2019). Interventions: Eligible patients were randomized in a 1:1:1 ratio to expectant management (n = 86), active management with uterine evacuation followed by methotrexate if needed (n = 87), or active management with empirical methotrexate using a 2-dose protocol (n = 82). Main Outcomes and Measures: The primary outcome was successful resolution of the pregnancy without change from initial strategy. The primary hypothesis tested for superiority of the active groups combined vs expectant management, and a secondary hypothesis tested for noninferiority of empirical methotrexate compared with uterine evacuation with methotrexate as needed using a noninferiority margin of -12%. Results: Among 255 patients who were randomized (median age, 31 years; interquartile range, 27-36 years), 253 (99.2%) completed the trial. Ninety-nine patients (39%) declined their randomized allocation (26.7% declined expectant management, 48.3% declined uterine evacuation, and 41.5% declined empirical methotrexate) and crossed over to a different group. Compared with patients randomized to receive expectant management (n = 86), women randomized to receive active management (n = 169) were significantly more likely to experience successful pregnancy resolution without change in their initial management strategy (51.5% vs 36.0%; difference, 15.4% [95% CI, 2.8% to 28.1%]; rate ratio, 1.43 [95% CI, 1.04 to 1.96]). Among active management strategies, empirical methotrexate was noninferior to uterine evacuation followed by methotrexate if needed with regard to successful pregnancy resolution without change in management strategy (54.9% vs 48.3%; difference, 6.6% [1-sided 97.5% CI, -8.4% to ∞]). The most common adverse event was vaginal bleeding for all of the 3 management groups (44.2%-52.9%). Conclusions and Relevance: Among patients with a persisting pregnancy of unknown location, patients randomized to receive active management, compared with those randomized to receive expectant management, more frequently achieved successful pregnancy resolution without change from the initial management strategy. The substantial crossover between groups should be considered when interpreting the results. Trial Registration: ClinicalTrials.gov Identifier: NCT02152696.


Assuntos
Abortivos não Esteroides/administração & dosagem , Metotrexato/administração & dosagem , Gravidez Ectópica/tratamento farmacológico , Gravidez Ectópica/cirurgia , Conduta Expectante , Aborto Espontâneo , Adulto , Gonadotropina Coriônica/sangue , Terapia Combinada , Dilatação e Curetagem , Feminino , Humanos , Satisfação do Paciente , Gravidez , Ultrassonografia Pré-Natal , Hemorragia Uterina
10.
Hum Brain Mapp ; 41(8): 2037-2047, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31944479

RESUMO

Hippocampal atrophy and abnormal ß-Amyloid (Aß) deposition are established markers of Alzheimer's disease (AD). Nonetheless, longitudinal trajectory of Aß-associated hippocampal subfield atrophy prior to dementia remains unclear. We hypothesized that elevated Aß correlated with longitudinal subfield atrophy selectively in no cognitive impairment (NCI), spreading to other subfields in mild cognitive impairment (MCI). We analyzed data from two independent longitudinal cohorts of nondemented elderly, including global PET-Aß in AD-vulnerable cortical regions and longitudinal subfield volumes quantified with a novel auto-segmentation method (FreeSurfer v.6.0). Moreover, we investigated associations of Aß-related progressive subfield atrophy with memory decline. Across both datasets, we found a converging pattern that higher Aß correlated with faster CA1 volume decline in NCI. This pattern spread to other hippocampal subfields in MCI group, correlating with memory decline. Our results for the first time suggest a longitudinal focal-to-widespread trajectory of Aß-associated hippocampal subfield atrophy over disease progression in nondemented elderly.


Assuntos
Envelhecimento , Peptídeos beta-Amiloides/metabolismo , Disfunção Cognitiva , Hipocampo/patologia , Transtornos da Memória , Idoso , Envelhecimento/metabolismo , Envelhecimento/patologia , Atrofia/patologia , Região CA1 Hipocampal/diagnóstico por imagem , Região CA1 Hipocampal/patologia , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Feminino , Hipocampo/diagnóstico por imagem , Humanos , Interpretação de Imagem Assistida por Computador , Processamento de Imagem Assistida por Computador , Estudos Longitudinais , Masculino , Transtornos da Memória/diagnóstico por imagem , Transtornos da Memória/metabolismo , Transtornos da Memória/patologia , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons
11.
Eur J Nucl Med Mol Imaging ; 47(2): 319-331, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31863136

RESUMO

PURPOSE: The analysis of the [11C]PiB-PET amyloid images of a unique Asian cohort of 186 participants featuring overlapping vascular diseases raised the question about the validity of current standards for amyloid quantification under abnormal conditions. In this work, we implemented a novel pipeline for improved amyloid PET quantification of this atypical cohort. METHODS: The investigated data correction and amyloid quantification methods included motion correction, standardized uptake value ratio (SUVr) quantification using the parcellated MRI (standard method) and SUVr quantification without MRI. We introduced a novel amyloid analysis method yielding 2 biomarkers: AßL which quantifies the global Aß burden and ns that characterizes the non-specific uptake. Cut-off points were first determined using visual assessment as ground truth and then using unsupervised classification techniques. RESULTS: Subject's motion impacts the accuracy of the measurement outcome but has however a limited effect on the visual rating and cut-off point determination. SUVr computation can be reliably performed for all the subjects without MRI parcellation while, when required, the parcellation failed or was of mediocre quality in 10% of the cases. The novel biomarker AßL showed an association increase of 29.5% with the cognitive tests and increased effect size between positive and negative scans compared with SUVr. ns was found sensitive to cerebral microbleeds, white matter hyperintensity, volume, and age. The cut-off points for SUVr using parcellated MRI, SUVr without parcellation, and AßL were 1.56, 1.39, and 25.5. Finally, k-means produced valid cut-off points without the requirement of visual assessment. CONCLUSION: The optimal processing for the amyloid quantification of this atypical cohort allows the quantification of all the subjects, producing SUVr values and two novel biomarkers: AßL, showing important increased in their association with various cognitive tests, and ns, a parameter sensitive to non-specific retention variations caused by age and cerebrovascular diseases.


Assuntos
Doença de Alzheimer , Transtornos Cerebrovasculares , Amiloide , Peptídeos beta-Amiloides , Compostos de Anilina , Biomarcadores , Transtornos Cerebrovasculares/diagnóstico por imagem , Humanos , Tomografia por Emissão de Pósitrons
12.
Am J Obstet Gynecol ; 223(2): 167-176, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32008730

RESUMO

Progesterone is essential for the maintenance of pregnancy. Several small trials have suggested that progesterone supplementation may reduce the risk of miscarriage in women with recurrent or threatened miscarriage. Cochrane Reviews summarized the evidence and found that the trials were small with substantial methodologic weaknesses. Since then, the effects of first-trimester use of vaginal micronized progesterone have been evaluated in 2 large, high-quality, multicenter placebo-controlled trials, one targeting women with unexplained recurrent miscarriages (the PROMISE [PROgesterone in recurrent MIScarriagE] trial) and the other targeting women with early pregnancy bleeding (the PRISM [PRogesterone In Spontaneous Miscarriage] trial). The PROMISE trial studied 836 women from 45 hospitals in the United Kingdom and the Netherlands and found a 3% greater live birth rate with progesterone but with substantial statistical uncertainty. The PRISM trial studied 4153 women from 48 hospitals in the United Kingdom and found a 3% greater live birth rate with progesterone, but with a P value of .08. A key finding, first observed in the PROMISE trial, and then replicated in the PRISM trial, was that treatment with vaginal micronized progesterone 400 mg twice daily was associated with increasing live birth rates according to the number of previous miscarriages. Prespecified PRISM trial subgroup analysis in women with the dual risk factors of previous miscarriage(s) and current pregnancy bleeding fulfilled all 11 conditions for credible subgroup analysis. For the subgroup of women with a history of 1 or more miscarriage(s) and current pregnancy bleeding, the live birth rate was 75% (689/914) with progesterone vs 70% (619/886) with placebo (rate difference 5%; risk ratio, 1.09, 95% confidence interval, 1.03-1.15; P=.003). The benefit was greater for the subgroup of women with 3 or more previous miscarriages and current pregnancy bleeding; live birth rate was 72% (98/137) with progesterone vs 57% (85/148) with placebo (rate difference 15%; risk ratio, 1.28, 95% confidence interval, 1.08-1.51; P=.004). No short-term safety concerns were identified from the PROMISE and PRISM trials. Therefore, women with a history of miscarriage who present with bleeding in early pregnancy may benefit from the use of vaginal micronized progesterone 400 mg twice daily. Women and their care providers should use the findings for shared decision-making.


Assuntos
Aborto Habitual/prevenção & controle , Ameaça de Aborto/tratamento farmacológico , Progesterona/uso terapêutico , Progestinas/uso terapêutico , Administração Intravaginal , Feminino , Humanos , Gravidez , Primeiro Trimestre da Gravidez , Progesterona/administração & dosagem , Progestinas/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
13.
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
14.
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
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.
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 , Imageamento por Ressonância Magnética , Masculino , Período Pós-Prandial , Espectroscopia de Prótons por Ressonância Magnética , Adulto Jovem
17.
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 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
18.
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
19.
Ann Intern Med ; 163(3): 153-63, 2015 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-26098843

RESUMO

BACKGROUND: Because systemic lupus erythematosus (SLE) affects women of reproductive age, pregnancy is a major concern. OBJECTIVE: To identify predictors of adverse pregnancy outcomes (APOs) in patients with inactive or stable active SLE. DESIGN: Prospective cohort. SETTING: Multicenter. PATIENTS: 385 patients (49% non-Hispanic white; 31% with prior nephritis) with SLE in the PROMISSE (Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Antibody Syndrome and Systemic Lupus Erythematosus) study. Exclusion criteria were urinary protein-creatinine ratio greater than 1000 mg/g, creatinine level greater than 1.2 mg/dL, prednisone use greater than 20 mg/d, and multifetal pregnancy. MEASUREMENTS: APOs included fetal or neonatal death; birth before 36 weeks due to placental insufficiency, hypertension, or preeclampsia; and small-for-gestational-age (SGA) neonate (birthweight below the fifth percentile). Disease activity was assessed with the Systemic Lupus Erythematosus Pregnancy Disease Activity Index and the Physician's Global Assessment (PGA). RESULTS: APOs occurred in 19.0% (95% CI, 15.2% to 23.2%) of pregnancies; fetal death occurred in 4%, neonatal death occurred in 1%, preterm delivery occurred in 9%, and SGA neonate occurred in 10%. Severe flares in the second and third trimesters occurred in 2.5% and 3.0%, respectively. Baseline predictors of APOs included presence of lupus anticoagulant (LAC) (odds ratio [OR], 8.32 [CI, 3.59 to 19.26]), antihypertensive use (OR, 7.05 [CI, 3.05 to 16.31]), PGA score greater than 1 (OR, 4.02 [CI, 1.84 to 8.82]), and low platelet count (OR, 1.33 [CI, 1.09 to 1.63] per decrease of 50 × 109 cells/L). Non-Hispanic white race was protective (OR, 0.45 [CI, 0.24 to 0.84]). Maternal flares, higher disease activity, and smaller increases in C3 level later in pregnancy also predicted APOs. Among women without baseline risk factors, the APO rate was 7.8%. For those who either were LAC-positive or were LAC-negative but nonwhite or Hispanic and using antihypertensives, the APO rate was 58.0% and fetal or neonatal mortality was 22.0%. LIMITATION: Patients with high disease activity were excluded. CONCLUSION: In pregnant patients with inactive or stable mild/moderate SLE, severe flares are infrequent and, absent specific risk factors, outcomes are favorable. PRIMARY FUNDING SOURCE: National Institutes of Health.


Assuntos
Lúpus Eritematoso Sistêmico/complicações , Complicações na Gravidez , Resultado da Gravidez , Adolescente , Adulto , Feminino , Morte Fetal , Seguimentos , Humanos , Lactente , Mortalidade Infantil , Recém-Nascido Prematuro , Pessoa de Meia-Idade , Complicações do Trabalho de Parto , Gravidez , Estudos Prospectivos , Fatores de Risco , Adulto Jovem
20.
Mol Hum Reprod ; 21(8): 655-61, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26071097

RESUMO

Studies of copy number variants (CNVs) in miscarriages are rare in comparison to post-natal cases with developmental abnormalities. The overall characteristics of miscarriage CNVs (size, gene content and function) are therefore largely unexplored. Our goal was to assess and compare the characteristics of CNVs identified in 101 euploid miscarriages from four high-resolution array studies that documented both common miscarriage CNVs (i.e. CNVs found in controls from the Database of Genomic Variants, DGV) and rare miscarriage CNVs (not reported in DGV). Our miscarriage analysis included 24 rare CNVs with 93 genes, and 372 common CNVs (merged into 119 common CNV regions; CNVRs) with 354 genes. The rare and common CNVs were comparable in size (median size of ∼ 0.16 and 0.14 Mb, respectively); however, rare CNVs showed a significantly higher gene density, with 56 genes/Mb in rare and 24 genes/Mb in common CNVs (P = 0.03). Rare CNVs also had two times more genes with mouse knock-out models which were reported for 42% of rare and 19% of common CNV genes. No specific pathway enrichment was noted for 24 rare CNV genes, but common CNV genes showed significant enrichment in genes from immune-response related pathways and pregnancy/reproduction-related biological processes. Our analysis of CNVs from euploid miscarriages suggests that both rare and common CNVs could have a role in miscarriage by impacting pregnancy-related genes or pathways. Cataloguing of all CNVs and detailed description of their characteristics (e.g. gene content, genomic breakpoints) is desirable in the future for better understanding of their relevance to pregnancy loss.


Assuntos
Aborto Espontâneo/genética , Variações do Número de Cópias de DNA/genética , Genoma Humano/genética , Feminino , Genômica , Humanos , Análise em Microsséries
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