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BACKGROUND: For some vaccine-preventable diseases, the immunologic response to vaccination is altered by a pregnant state. The effect of pregnancy on SARS-CoV-2 vaccine response remains unclear. OBJECTIVE: We sought to characterize the peak and longitudinal anti-S immunoglobulin G, immunoglobulin M, and immunoglobulin A responses to messenger RNA-based SARS-CoV-2 vaccination in pregnant persons and compare them with those in nonpregnant, reproductive-aged persons. STUDY DESIGN: We conducted 2 parallel prospective cohort studies among pregnant and nonpregnant persons who received SARS-CoV-2 messenger RNA vaccinations. Blood was collected at the time of first and second vaccine doses, 2 weeks post second dosage, and with serial longitudinal follow-up up to 41.7 weeks post vaccination initiation. Anti-S immunoglobulin M, immunoglobulin G, and immunoglobulin A were analyzed by enzyme-linked immunosorbent assay. We excluded those with previous evidence of SARS-CoV-2 infection by history or presence of antinucleocapsid antibodies. In addition, for this study, we did not include individuals who received a third or booster vaccine dosage during the study period. We also excluded pregnant persons who were not fully vaccinated (14 days post receipt of the second vaccine dosage) by time of delivery and nonpregnant persons who became pregnant through the course of the study. We studied the effect of gestational age at vaccination on the anti-S response using Spearman correlation. We compared the peak anti-S antibody responses between pregnant and nonpregnant persons using a Mann-Whitney U test. We visualized and studied the longitudinal anti-S antibody response using locally weighted scatterplot smoothing, Mann-Whitney U test, and mixed analysis of variance test. RESULTS: Data from 53 pregnant and 21 nonpregnant persons were included in this analysis. The median (interquartile range) age of the pregnant and nonpregnant participants was 35.0 (33.3-37.8) years and 36.0 (33.0-41.0) years, respectively. Six (11.3%) participants initiated vaccination in the first trimester, 23 (43.3%) in the second trimester, and 24 (45.3%) in the third trimester, with a median gestational age at delivery of 39.6 (39.0-40.0) weeks. The median (interquartile range) follow-up time from vaccine initiation to the last blood sample collected was 25.9 (11.9) weeks and 28.9 (12.9) weeks in the pregnant and nonpregnant cohort, respectively. Among pregnant persons, anti-S immunoglobulin G, immunoglobulin A, and immunoglobulin M responses were not associated with gestational age at vaccine initiation (all P>.05). The anti-S immunoglobulin G response at 2 weeks post second dosage was not statistically different between pregnant and nonpregnant persons (P>.05). However, the anti-S immunoglobulin M and immunoglobulin A responses at 2 weeks post second dosage were significantly higher in nonpregnant persons (P<.001 for both). The anti-S immunoglobulin G and immunoglobulin M levels 6 to 8 months after vaccine initiation fell to comparable proportions of the peak 2 weeks post second dosage antibody levels between pregnant and nonpregnant persons (immunoglobulin G P=.77; immunoglobulin M P=.51). In contrast, immunoglobulin A levels 6 to 8 months after vaccine initiation fell to statistically significantly higher proportions of peak 2 weeks post second dosage antibody levels in pregnant compared with nonpregnant persons (P=.002). Maternal anti-S immunoglobulin G levels were strongly correlated with umbilical cord anti-S immunoglobulin G levels (R=0.8, P<.001). CONCLUSION: The anti-S immunoglobulin A, immunoglobulin M, and immunoglobulin G response to SARS-CoV-2 vaccination in pregnancy is independent of gestational age of vaccine initiation. Maintenance of the immunoglobulin G response is comparable between pregnant and nonpregnant persons. The differential peak response of immunoglobulin M and immunoglobulin A and the differential decline of anti-S immunoglobulin A between pregnant and nonpregnant persons requires further investigation.
Assuntos
Formação de Anticorpos , COVID-19 , Feminino , Gravidez , Humanos , Adulto , Lactente , Vacinas contra COVID-19 , SARS-CoV-2/genética , Estudos Prospectivos , COVID-19/diagnóstico , COVID-19/epidemiologia , COVID-19/prevenção & controle , Vacinação , Imunoglobulina G , Imunoglobulina M , Imunoglobulina ARESUMO
Spondylocarpotarsal syndrome (SCT) is a rare musculoskeletal disorder characterized by short stature and vertebral, carpal, and tarsal fusions resulting from biallelic nonsense mutations in the gene encoding filamin B (FLNB). Utilizing a FLNB knockout mouse, we showed that the vertebral fusions in SCT evolved from intervertebral disc (IVD) degeneration and ossification of the annulus fibrosus (AF), eventually leading to full trabecular bone formation. This resulted from alterations in the TGFß/BMP signaling pathway that included increased canonical TGFß and noncanonical BMP signaling. In this study, the role of FLNB in the TGFß/BMP pathway was elucidated using in vitro, in vivo, and ex vivo treatment methodologies. The data demonstrated that FLNB interacts with inhibitory Smads 6 and 7 (i-Smads) to regulate TGFß/BMP signaling and that loss of FLNB produces increased TGFß receptor activity and decreased Smad 1 ubiquitination. Through the use of small molecule inhibitors in an ex vivo spine model, TGFß/BMP signaling was modulated to design a targeted treatment for SCT and disc degeneration. Inhibition of canonical and noncanonical TGFß/BMP pathway activity restored Flnb-/- IVD morphology. These most effective improvements resulted from specific inhibition of TGFß and p38 signaling activation. FLNB acts as a bridge for TGFß/BMP signaling crosstalk through i-Smads and is key for the critical balance in TGFß/BMP signaling that maintains the IVD. These findings further our understanding of IVD biology and reveal new molecular targets for disc degeneration as well as congenital vertebral fusion disorders.
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BACKGROUND: Fetal fraction from noninvasive prenatal screening has been used as a predictive marker for hypertensive disorders of pregnancy in spontaneous pregnancies. OBJECTIVE: We aimed to determine whether fetal fraction from noninvasive prenatal screening predicts hypertensive disorders of pregnancy in pregnancies conceived by assisted reproductive technology, stratified by fresh and frozen embryo transfer. STUDY DESIGN: Retrospective cohort study of women with singleton pregnancies who underwent fresh or frozen embryo transfer, had noninvasive prenatal screening, and had a live birth >20 weeks at a single institution from 2013 to 2019. Women with major anomalies, nonreportable noninvasive prenatal screening, or chronic hypertension were excluded. Fetal fraction was corrected for gestational age, noninvasive prenatal screening platform, and defined as low if it is less than fifth percentile for the study population. The primary outcome was hypertensive disorders of pregnancy during delivery hospitalization, stratified by fresh vs frozen embryo transfer. We performed multivariable logistic regression analyses to determine whether low fetal fraction predicts hypertensive disorders of pregnancy for fresh and frozen embryo transfer, controlling for age, prepregnancy body mass index, heparin use, low-dose aspirin use, estradiol level if fresh embryo transfer, and trophectoderm biopsy and cycle type if frozen embryo transfer. RESULTS: We included 81 women with low fetal fraction and 847 women with normal fetal fraction. The adjusted prevalence of hypertensive disorders of pregnancy in women with low fetal fraction was 24.9% in fresh embryo transfer and 34.5% in frozen embryo transfer. In fresh embryo transfer pregnancies, the odds of hypertensive disorders of pregnancy were higher among women with low fetal fraction (adjusted odds ratio, 2.46; 95% confidence interval, 1.07-5.30; P=.026). In frozen embryo transfer pregnancies, there was no association between low fetal fraction and hypertensive disorders of pregnancy (adjusted odds ratio, 1.43; 95% confidence interval, 0.69-2.88; P=.321). CONCLUSION: Low fetal fraction is associated with hypertensive disorders of pregnancy in women who conceive by fresh embryo transfer. Fetal fraction may represent a clinically useful marker for screening for hypertension and allow clinicians to target risk reduction strategies, such as low-dose aspirin, in pregnancies conceived by fresh embryo transfer.
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Hipertensão Induzida pela Gravidez , Transferência Embrionária , Feminino , Fertilização in vitro , Humanos , Hipertensão Induzida pela Gravidez/diagnóstico , Gravidez , Gravidez Múltipla , Estudos RetrospectivosRESUMO
Central vascular access device (CVAD) placement is a common procedure in children. When selecting a CVAD, available evidence and specified indications should be used to choose the device that best supports the patient's treatment and carries the lowest risks. A multidisciplinary team developed a care algorithm to standardize preoperative screening before pediatric CVAD placement, with 3 major parts: CVAD selection, patient risk stratification, and preoperative evaluation. Using a stepwise approach of provider education and incorporation into the electronic health record, the team achieved 82% stratification among inpatients. The team's algorithm integrates the existing literature and recommendations for safe and effective CVAD placement.
Assuntos
Algoritmos , Cateteres Venosos Centrais , Segurança do Paciente , Pediatria , Melhoria de Qualidade , Dispositivos de Acesso Vascular/normas , Criança , Humanos , Programas de Rastreamento , Equipe de Assistência ao Paciente , Fatores de RiscoRESUMO
Defects in the biosynthesis and/or function of primary cilia cause a spectrum of disorders collectively referred to as ciliopathies. A subset of these disorders is distinguished by profound abnormalities of the skeleton that include a long narrow chest with markedly short ribs, extremely short limbs, and polydactyly. These include the perinatal lethal short-rib polydactyly syndromes (SRPS) and the less severe asphyxiating thoracic dystrophy (ATD), Ellis-van Creveld (EVC) syndrome, and cranioectodermal dysplasia (CED) phenotypes. To identify new genes and define the spectrum of mutations in the skeletal ciliopathies, we analyzed 152 unrelated families with SRPS, ATD, and EVC. Causal variants were discovered in 14 genes in 120 families, including one newly associated gene and two genes previously associated with other ciliopathies. These three genes encode components of three different ciliary complexes; FUZ, which encodes a planar cell polarity complex molecule; TRAF3IP1, which encodes an anterograde ciliary transport protein; and LBR, which encodes a nuclear membrane protein with sterol reductase activity. The results established the molecular basis of SRPS type IV, in which mutations were identified in four different ciliary genes. The data provide systematic insight regarding the genotypes associated with a large cohort of these genetically heterogeneous phenotypes and identified new ciliary components required for normal skeletal development.
Assuntos
Ciliopatias/diagnóstico , Ciliopatias/genética , Estudos de Associação Genética , Variação Genética , Fenótipo , Esqueleto/anormalidades , Dineínas do Citoplasma/genética , Marcadores Genéticos , Genótipo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Mutação , Proteínas/genética , Radiografia , Sequenciamento do ExomaRESUMO
Spondylocarpotarsal synostosis (SCT) is a skeletal disorder characterized by progressive vertebral, carpal and tarsal fusions, and mild short stature. The majority of affected individuals have an autosomal recessive form of SCT and are homozygous or compound heterozygous for nonsense mutations in the gene that encodes the cytoskeletal protein filamin B (FLNB), but a subset do not have FLNB mutations. Exome sequence analysis of three SCT patients negative for FLNB mutations identified an autosomal dominant form of the disease due to heterozygosity for missense or nonsense mutations in MYH3, which encodes embryonic myosin. Cells transfected with the MYH3 missense mutations had reduced TGFß signaling, revealing a regulatory role for embryonic myosin in the TGFß signaling pathway. In wild-type mice, there was persistent postnatal expression of embryonic myosin in the small muscles joining the neural arches of the spine suggesting that loss of myosin function in these muscles contribute to the disease. Our findings demonstrate that dominant mutations in MYH3 underlie autosomal dominant SCT, identify a postnatal role for embryonic myosin and suggest that altered regulation of signal transduction in the muscles within the spine may lead to the development of vertebral fusions.
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Anormalidades Múltiplas/genética , Anormalidades Múltiplas/metabolismo , Proteínas do Citoesqueleto/genética , Genes Dominantes , Vértebras Lombares/anormalidades , Doenças Musculoesqueléticas/genética , Doenças Musculoesqueléticas/metabolismo , Mutação , Miosinas/genética , Miosinas/metabolismo , Escoliose/congênito , Transdução de Sinais , Sinostose/genética , Sinostose/metabolismo , Vértebras Torácicas/anormalidades , Fator de Crescimento Transformador beta/metabolismo , Anormalidades Múltiplas/diagnóstico , Alelos , Proteínas Morfogenéticas Ósseas/metabolismo , Feminino , Genótipo , Humanos , Vértebras Lombares/metabolismo , Masculino , Doenças Musculoesqueléticas/diagnóstico , Fenótipo , Radiografia , Escoliose/diagnóstico , Escoliose/genética , Escoliose/metabolismo , Sinostose/diagnóstico , Vértebras Torácicas/metabolismo , Sequenciamento do ExomaRESUMO
Short-rib polydactyly syndromes (SRPS) and Asphyxiating thoracic dystrophy (ATD) or Jeune Syndrome are recessively inherited skeletal ciliopathies characterized by profound skeletal abnormalities and are frequently associated with polydactyly and multiorgan system involvement. SRPS are produced by mutations in genes that participate in the formation and function of primary cilia and usually result from disruption of retrograde intraflagellar (IFT) transport of the cilium. Herein we describe a new spectrum of SRPS caused by mutations in the gene IFT81, a key component of the IFT-B complex essential for anterograde transport. In mutant chondrocytes, the mutations led to low levels of IFT81 and mutant cells produced elongated cilia, had altered hedgehog signaling, had increased post-translation modification of tubulin, and showed evidence of destabilization of additional anterograde transport complex components. These findings demonstrate the importance of IFT81 in the skeleton, its role in the anterograde transport complex, and expand the number of loci associated with SRPS.
RESUMO
The short rib polydactyly syndromes (SRPS) are a group of recessively inherited, perinatal-lethal skeletal disorders primarily characterized by short ribs, shortened long bones, varying types of polydactyly and concomitant visceral abnormalities. Mutations in several genes affecting cilia function cause SRPS, revealing a role for cilia function in skeletal development. To identify additional SRPS genes and discover novel ciliary molecules required for normal skeletogenesis, we performed exome sequencing in a cohort of patients and identified homozygosity for a missense mutation, p.E80K, in Intestinal Cell Kinase, ICK, in one SRPS family. The p.E80K mutation abolished serine/threonine kinase activity, resulting in altered ICK subcellular and ciliary localization, increased cilia length, aberrant cartilage growth plate structure, defective Hedgehog and altered ERK signalling. These data identify ICK as an SRPS-associated gene and reveal that abnormalities in signalling pathways contribute to defective skeletogenesis.
Assuntos
Anormalidades Múltiplas/genética , Proteínas Hedgehog/genética , Proteínas Serina-Treonina Quinases/genética , Síndrome de Costela Curta e Polidactilia/genética , Esqueleto/crescimento & desenvolvimento , Anormalidades Múltiplas/fisiopatologia , Cílios/genética , Cílios/patologia , Exoma/genética , Feminino , Humanos , Lactente , Sistema de Sinalização das MAP Quinases , Linhagem , Gravidez , Análise de Sequência de DNA , Síndrome de Costela Curta e Polidactilia/patologia , Transdução de Sinais , Esqueleto/anormalidadesRESUMO
Spondylocarpotarsal synostosis (SCT) is an autosomal recessive disorder characterized by progressive vertebral fusions and caused by loss of function mutations in Filamin B (FLNB). FLNB acts as a signaling scaffold by linking the actin cytoskleteon to signal transduction systems, yet the disease mechanisms for SCT remain unclear. Employing a Flnb knockout mouse, we found morphologic and molecular evidence that the intervertebral discs (IVDs) of Flnb-/-mice undergo rapid and progressive degeneration during postnatal development as a result of abnormal cell fate changes in the IVD, particularly the annulus fibrosus (AF). In Flnb-/-mice, the AF cells lose their typical fibroblast-like characteristics and acquire the molecular and phenotypic signature of hypertrophic chondrocytes. This change is characterized by hallmarks of endochondral-like ossification including alterations in collagen matrix, expression of Collagen X, increased apoptosis, and inappropriate ossification of the disc tissue. We show that conversion of the AF cells into chondrocytes is coincident with upregulated TGFß signaling via Smad2/3 and BMP induced p38 signaling as well as sustained activation of canonical and noncanonical target genes p21 and Ctgf. These findings indicate that FLNB is involved in attenuation of TGFß/BMP signaling and influences AF cell fate. Furthermore, we demonstrate that the IVD disruptions in Flnb-/-mice resemble aging degenerative discs and reveal new insights into the molecular causes of vertebral fusions and disc degeneration.