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Despite the rising prevalence of autism spectrum disorder (ASD), there remains a significant unmet need for pharmacotherapies addressing its core and associative symptoms. While some atypical antipsychotics have been approved for managing associated irritability and aggression, their use is constrained by substantial side effects. This study aimed firstly to develop behavioral measures to explore frustration, irritability and aggression phenotypes in the rat prenatal valproic acid (VPA) model of ASD. Additionally, we investigated the potential of two novel mechanisms, 5-HT1B and TAAR1 agonism, to alleviate these behaviors. Male offspring exposed to prenatal VPA were trained to achieve stable performance on a cued operant task, followed by pharmacological assessment in an operant frustration test, bottle brush test and resident intruder test. VPA exposed rats demonstrated behaviors indicative of frustration and irritability, as well as increased aggression compared to controls. The irritability-like behavior and aggression were further exacerbated in animals previously experiencing a frustrative event during the operant test. Single administration of the 5-HT1B agonist CP-94253 or TAAR1 agonist RO5263397 attenuated the frustration-like behavior compared to vehicle. Additionally, both agonists reduced irritability-like behavior under both normal and frustrative conditions. While CP-94253 reduced aggression in the resident intruder test under both conditions, RO5263397 only produced effects in rats that previously experienced a frustrative event. Our study describes previously uncharacterized phenotypes of frustration, irritability, and aggression in the rat prenatal VPA model of ASD. Administration of selective TAAR1 or 5-HT1B receptor agonists alleviated these deficits, warranting further exploration of both targets in ASD treatment.
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OBJECTIVE: It is currently unknown whether adjunctive azithromycin prophylaxis at the time of non-elective cesarean has differential effects on neonatal outcomes in the context of prematurity. The objective of this study was to compare whether neonatal outcomes differ in term and preterm infants exposed to adjunctive azithromycin prophylaxis before non-elective cesarean delivery. STUDY DESIGN: A planned secondary analysis of a multi-center randomized controlled trial that enrolled women with singleton pregnancies ≥24 weeks gestation undergoing non-elective cesarean delivery (during labor or ≥4 h after membrane rupture). Women received standard antibiotic prophylaxis and were randomized to either adjunctive azithromycin (500 mg) or placebo. The primary composite outcome was neonatal death, suspected or confirmed neonatal sepsis, and serious neonatal morbidities (NEC, PVL, IVH, BPD). Secondary outcomes included NICU admission, neonatal readmission, culture positive infections and prevalence of resistant organisms. Odds ratios (OR) for the effect of azithromycin versus placebo were compared between gestational age strata (preterm [less than 37 weeks] versus term [37 weeks or greater]). Tests of interaction examined homogeneity of treatment effect with gestational age. RESULTS: The analysis includes 2,013 infants, 226 preterm (11.2%) and 1,787 term. Mean gestational ages were 34 and 39.5 weeks, respectively. Within term and preterm strata, maternal and delivery characteristics were similar between the azithromycin and placebo groups. There was no difference in the odds of composite neonatal outcome between those exposed to azithromycin versus placebo in preterm neonates (OR 0.82, 95% CI 0.48-1.41) and in term neonates (OR 1.06, 95% CI 0.77-1.46), with no difference between gestational age strata (p = 0.42). Analysis of secondary outcomes also revealed no differences in treatment effects within or between gestational age strata. CONCLUSION: Exposure to adjunctive azithromycin antibiotic prophylaxis for non-elective cesarean delivery does not increase neonatal morbidity or mortality in term or preterm infants. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov, NCT01235546.
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Antibacterianos , Antibioticoprofilaxia , Azitromicina , Cesárea , Recém-Nascido Prematuro , Humanos , Azitromicina/uso terapêutico , Azitromicina/administração & dosagem , Feminino , Antibioticoprofilaxia/métodos , Recém-Nascido , Gravidez , Cesárea/estatística & dados numéricos , Antibacterianos/uso terapêutico , Antibacterianos/administração & dosagem , Adulto , Idade Gestacional , Nascimento a Termo , Doenças do Recém-Nascido/prevenção & controle , Doenças do Recém-Nascido/epidemiologiaRESUMO
OBJECTIVE: In the antenatal late preterm steroids (ALPS) trial betamethasone significantly decreased short-term neonatal respiratory morbidity but increased the risk of neonatal hypoglycemia, diagnosed only categorically (<40 mg/dL). We sought to better characterize the nature, duration, and treatment for hypoglycemia. STUDY DESIGN: Secondary analysis of infants from ALPS, a multicenter trial randomizing women at risk for late preterm delivery to betamethasone or placebo. This study was a reabstraction of all available charts from the parent trial, all of which were requested. Unreviewed charts included those lost to follow-up or from sites not participating in the reabstraction. Duration of hypoglycemia (<40 mg/dL), lowest value and treatment, if any, were assessed by group. Measures of association and regression models were used where appropriate. RESULTS: Of 2,831 randomized, 2,609 (92.2%) were included. There were 387 (29.3%) and 223 (17.3%) with hypoglycemia in the betamethasone and placebo groups, respectively (relative risk [RR]: 1.69, 95% confidence interval [CI]: 1.46-1.96). Hypoglycemia generally occurred in the first 24 hours in both groups: 374/385 (97.1%) in the betamethasone group and 214/222 (96.4%) in the placebo group (p = 0.63). Of 387 neonates with hypoglycemia in the betamethasone group, 132 (34.1%) received treatment, while 73/223 (32.7%) received treatment in placebo group (p = 0.73). The lowest recorded blood sugar was similar between groups. Most hypoglycemia resolved by 24 hours in both (93.0 vs. 89.3% in the betamethasone and placebo groups, respectively, p = 0.18). Among infants with hypoglycemia in the first 24 hours, the time to resolution was shorter in the betamethasone group (2.80 [interquartile range: 2.03-7.03) vs. 3.74 (interquartile range: 2.15-15.08) hours; p = 0.002]. Persistence for >72 hours was rare and similar in both groups, nine (2.4%, betamethasone) and four (1.9%, placebo, p = 0.18). CONCLUSION: In this cohort, hypoglycemia was transient and most received no treatment, with a quicker resolution in the betamethasone group. Prolonged hypoglycemia was uncommon irrespective of steroid exposure. KEY POINTS: · Hypoglycemia was transient and approximately two-thirds received no treatment.. · Neonates in the ALPS trial who received betamethasone had a shorter time to resolution than those with hypoglycemia in the placebo group.. · Prolonged hypoglycemia occurred in approximately 2 out of 100 late preterm newborns, irrespective of antenatal steroid exposure..
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Hipoglicemia , Nascimento Prematuro , Síndrome do Desconforto Respiratório do Recém-Nascido , Lactente , Recém-Nascido , Feminino , Gravidez , Humanos , Nascimento Prematuro/prevenção & controle , Estudos de Coortes , Síndrome do Desconforto Respiratório do Recém-Nascido/prevenção & controle , Síndrome do Desconforto Respiratório do Recém-Nascido/tratamento farmacológico , Betametasona/efeitos adversos , Hipoglicemia/induzido quimicamenteRESUMO
BACKGROUND: The ability to diagnose preeclampsia clinically is suboptimal. Our objective was to validate a novel multianalyte assay and characterize its performance, when intended for use as an aid to rule-out preeclampsia. METHODS: Prospective, multicenter cohort study of pregnant individuals presenting between 280/7 and 366/7 weeks' with preeclampsia-associated signs and symptoms. Individuals not diagnosed with preeclampsia after baseline evaluation were enrolled in the study cohort, with those who later developed preeclampsia, classified as cases and compared with a negative control group who did not develop preeclampsia. Individuals with assay values at time of enrollment ≥0.0325, determined using a previously developed algorithm, considered at risk. The primary analysis was the time to develop preeclampsia assessed using a multivariate Cox regression model. RESULTS: One thousand thirty-six pregnant individuals were enrolled in the study cohort with an incidence of preeclampsia of 30.3% (27.6%-33.2%). The time to develop preeclampsia was shorter for those with an at-risk compared with negative assay result (log-rank P<0.0001; adjusted hazard ratio of 4.81 [3.69-6.27, P<0.0001]). The performance metrics for the assay to rule-out preeclampsia within 7 days of enrollment showed a sensitivity 76.4% (67.5%-83.5%), negative predictive value 95.0% (92.8%-96.6%), and negative likelihood ratio 0.46 (0.32-0.65). Assay performance improved if delivery occurred <37 weeks and for individuals enrolled between 28 and 35 weeks. CONCLUSIONS: We confirmed that a novel multianalyte assay was associated with the time to develop preeclampsia and has a moderate sensitivity and negative likelihood ratio but high negative predictive value when assessed as an aid to rule out preeclampsia within 7 days of enrollment. REGISTRATION: The study was registered on Clinicaltrials.gov (Identifier NCT02780414).
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Pré-Eclâmpsia , Biomarcadores , Estudos de Coortes , Feminino , Humanos , Pré-Eclâmpsia/diagnóstico , Pré-Eclâmpsia/epidemiologia , Valor Preditivo dos Testes , Gravidez , Estudos ProspectivosRESUMO
OBJECTIVE: This study was aimed to evaluate the relationship between cesarean skin incision length and wound complications. STUDY DESIGN: Planned secondary analysis of a multicenter double-blind randomized trial of adjunctive azithromycin versus placebo (in addition to standard cefazolin) in women ≥24 weeks undergoing cesarean delivery during labor or ≥4 hours after membrane rupture. Skin incision length (cm) was measured just prior to skin closure. The primary outcome was a composite of wound complications (wound infection, separation, seroma, hematoma, or dehiscence) up to 6 weeks of postpartum. Individual components of the composite were examined as secondary outcomes. Outcomes were compared between groups defined by the lowest (≤25th), middle (25-75th) and highest (>75th) incision length quartiles. Logistic regression was used to adjust for potential confounding variables. RESULTS: Of the 2,013 women enrolled in the primary trial, 1,916 had recorded incision lengths and were included in this secondary analysis. The overall rate of composite wound complications was 7.8%. Median incision length was 15.0 cm (interquartile range: 14.0-16.5) with the lowest quartile defined as ≤14, middle as >14 to ≤16.5, and highest as >16.5 cm. Mean BMI, parity, use of staples, and duration of surgery differed significantly between the three incision length groups. In unadjusted analysis, the longest incision lengths were associated with an increased risk of the wound composite and wound infections (odds ratio [OR] = 2.27, 95% confidence interval [CI]: 1.43-3.60 and OR = 2.30, 95% CI: 1.27-4.15, respectively) compared with the shortest incision lengths. However, after multivariable adjustments, these associations were nullified. Additional analyses considering incision length as a continuous variable and using 10th/90th percentile cut-offs still did not suggest any associations with outcomes. CONCLUSION: Increasing skin incision length is not independently associated with an increased risk of postoperative wound complications. KEY POINTS: · After multivariable adjustments, skin incision length was not independently associated with an increased risk of postoperative wound complications.. · A reasonable incision length needed to safely perform the procedure should be used..
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Complicações Pós-Operatórias , Infecção da Ferida Cirúrgica , Cesárea/efeitos adversos , Cesárea/métodos , Feminino , Humanos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Gravidez , Seroma/epidemiologia , Seroma/etiologia , Deiscência da Ferida Operatória/epidemiologia , Deiscência da Ferida Operatória/etiologia , Infecção da Ferida Cirúrgica/epidemiologia , Infecção da Ferida Cirúrgica/etiologia , Suturas/efeitos adversosRESUMO
OBJECTIVE: To evaluate patient safety, resource utilization, and transfusion-related cost after a policy change from universal type and screen to selective type and screen on admission to labor and delivery. METHODS: Between October 2017 and September 2019, we performed a single-center implementation study focusing on risk-based type and screen instead of universal type and screen. Implementation of our policy was October 2018 and compared 1 year preimplementation with 1 year postimplementation. Patients were risk-stratified in alignment with California Maternal Quality Care Collaborative recommendations. Under the new policy, the blood bank holds a blood sample for processing (hold clot) on patients at low- and medium-risk of hemorrhage. Type and screen and crossmatch are obtained on high-risk patients or with a prior positive antibody screen. We collected patient outcomes, safety and cost data, and compliance and resource utilization metrics. Cost included direct costs of transfusion-related testing in the labor and delivery unit during the study period, from a health system perspective. RESULTS: In 1 year postimplementation, there were no differences in emergency-release transfusion events (4 vs 3, P>.99). There were fewer emergency-release red blood cell (RBC) units transfused (9 vs 24, P=.002) and O-negative RBC units transfused (8 vs 18, P=.016) postimplementation compared with preimplementation. Hysterectomies (0.05% vs 0.1%, P=.44) and intensive care unit admissions (0.45% vs 0.51%, P=.43) were not different postimplementation compared with preimplementation. Postimplementation, mean monthly type and screen-related costs (ABO typing, antibody screen, and antibody workup costs) were lower, $9,753 compared with $20,676 in the preimplementation year, P<.001. CONCLUSION: Implementation of selective type and screen policy in the labor and delivery unit was associated with projected annual savings of $181,000 in an institution with 4,000 deliveries per year, without evidence of increased maternal morbidity.
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Transfusão de Sangue/economia , Transfusão de Sangue/métodos , Trabalho de Parto , Segurança do Paciente , Adulto , Bancos de Sangue , Tipagem e Reações Cruzadas Sanguíneas/economia , Tipagem e Reações Cruzadas Sanguíneas/métodos , Custos e Análise de Custo , Feminino , Hemorragia/epidemiologia , Hospitalização/estatística & dados numéricos , Humanos , Histerectomia/estatística & dados numéricos , Unidades de Terapia Intensiva/estatística & dados numéricos , Políticas , Gravidez , Adulto JovemRESUMO
OBJECTIVE: To test associations between grades 3 or 4 (severe) intraventricular hemorrhage (IVH) and single nucleotide polymorphisms (SNPs) associated with coagulation, inflammation, angiogenesis, and organ development in an exploratory study. STUDY DESIGN: Extremely low-birthweight (ELBW) infants enrolled in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network's (NRN) Cytokines Study were included if they had cranial ultrasound (CUS) and genotyping data available in the NRN Anonymized DNA Repository and Database. Associations between SNPs and IVH severity were tested with multivariable logistic regression analysis. RESULT: One hundred thirty-nine infants with severe IVH and 687 infants with grade 1 or 0 IVH were included. One thousand two hundred seventy-nine SNPs were genotyped. Thirteen were preliminarily associated with severe IVH including five related to central nervous system (CNS) neuronal and neurovascular development. CONCLUSION: Genetic variants for CNS neuronal and neurovascular development may be associated with severe IVH in premature infants.
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Recém-Nascido de Peso Extremamente Baixo ao Nascer , Doenças do Prematuro , Peso ao Nascer , Hemorragia Cerebral/diagnóstico por imagem , Hemorragia Cerebral/genética , Criança , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro , Doenças do Prematuro/genéticaRESUMO
Preterm premature rupture of membranes (PPROM) is almost uniformly associated with preterm birth and thus sequelae of prematurity explain many of the complications associated with this condition. However, the unique inflammatory environment and oligohydramnios associated with PPROM may impart unique neonatal and childhood morbidity compared with other preterm birth pathways.
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Ruptura Prematura de Membranas Fetais/epidemiologia , Paralisia Cerebral/epidemiologia , Criança , Pré-Escolar , Corioamnionite/epidemiologia , Deficiências do Desenvolvimento/epidemiologia , Feminino , Idade Gestacional , Humanos , Lactente , Recém-Nascido , Doenças do Recém-Nascido/epidemiologia , Recém-Nascido Prematuro , Morbidade , Oligo-Hidrâmnio/epidemiologia , Gravidez , Complicações Infecciosas na Gravidez/epidemiologia , Resultado da Gravidez , Nascimento Prematuro/epidemiologiaRESUMO
Retinoic acid-related orphan receptor beta (RORß) is a transcription factor (TF) and marker of layer 4 (L4) neurons, which are distinctive both in transcriptional identity and the ability to form aggregates such as barrels in rodent somatosensory cortex. However, the relationship between transcriptional identity and L4 cytoarchitecture is largely unknown. We find RORß is required in the cortex for L4 aggregation into barrels and thalamocortical afferent (TCA) segregation. Interestingly, barrel organization also degrades with age in wildtype mice. Loss of RORß delays excitatory input and disrupts gene expression and chromatin accessibility, with down-regulation of L4 and up-regulation of L5 genes, suggesting a disruption in cellular specification. Expression and binding site accessibility change for many other TFs, including closure of neurodevelopmental TF binding sites and increased expression and binding capacity of activity-regulated TFs. Lastly, a putative target of RORß, Thsd7a, is down-regulated without RORß, and Thsd7a knock-out alone disrupts TCA organization in adult barrels.
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Neurônios , Membro 2 do Grupo F da Subfamília 1 de Receptores Nucleares , Córtex Somatossensorial , Animais , Antígenos de Superfície/química , Antígenos de Superfície/genética , Antígenos de Superfície/metabolismo , Feminino , Masculino , Proteínas de Membrana/química , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Neurônios/química , Neurônios/citologia , Neurônios/metabolismo , Membro 2 do Grupo F da Subfamília 1 de Receptores Nucleares/química , Membro 2 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Membro 2 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Córtex Somatossensorial/química , Córtex Somatossensorial/citologia , Córtex Somatossensorial/metabolismo , Córtex Somatossensorial/fisiologia , Tálamo/química , Tálamo/metabolismo , Fatores de Transcrição/química , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transcriptoma/genéticaRESUMO
There is a pressing need to increase the rigor of research in the life and biomedical sciences. To address this issue, we propose that communities of 'rigor champions' be established to campaign for reforms of the research culture that has led to shortcomings in rigor. These communities of rigor champions would also assist in the development and adoption of a comprehensive educational platform that would teach the principles of rigorous science to researchers at all career stages.
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Pesquisa Biomédica/educação , Pesquisa Biomédica/métodos , Pesquisa Biomédica/normas , Projetos de Pesquisa/normas , HumanosRESUMO
OBJECTIVE: This study aimed to evaluate the association between clinical and examination features at admission and late preterm birth. STUDY DESIGN: The present study is a secondary analysis of a randomized trial of singleton pregnancies at 340/7 to 365/7 weeks' gestation. We included women in spontaneous preterm labor with intact membranes and compared them by gestational age at delivery (preterm vs. term). We calculated a statistical cut-point optimizing the sensitivity and specificity of initial cervical dilation and effacement at predicting preterm birth and used multivariable regression to identify factors associated with late preterm delivery. RESULTS: A total of 431 out of 732 (59%) women delivered preterm. Cervical dilation ≥ 4 cm was 60% sensitive and 68% specific for late preterm birth. Cervical effacement ≥ 75% was 59% sensitive and 65% specific for late preterm birth. Earlier gestational age at randomization, nulliparity, and fetal malpresentation were associated with late preterm birth. The final regression model including clinical and examination features significantly improved late preterm birth prediction (81% sensitivity, 48% specificity, area under the curve = 0.72, 95% confidence interval [CI]: 0.68-0.75, and p-value < 0.01). CONCLUSION: Four in 10 women in late-preterm labor subsequently delivered at term. Combination of examination and clinical features (including parity and gestational age) improved late-preterm birth prediction.
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Primeira Fase do Trabalho de Parto , Trabalho de Parto Prematuro , Nascimento Prematuro , Betametasona/administração & dosagem , Colo do Útero , Feminino , Idade Gestacional , Glucocorticoides/administração & dosagem , Humanos , Recém-Nascido , Modelos Logísticos , Paridade , Gravidez , Terceiro Trimestre da Gravidez , Prognóstico , Doenças Respiratórias/prevenção & controle , Fatores de Risco , Sensibilidade e EspecificidadeRESUMO
OBJECTIVE: To evaluate cost of outpatient (OP) versus inpatient (IP) ripening with transcervical balloons, and determine circumstances in which each strategy would be cost saving. STUDY DESIGN: We created a decision model comparing OP and IP balloon ripening in term (≥37 weeks) singleton pregnancies with unfavorable cervix. We performed a cost-minimization analysis and threshold analyses comparing two OP ripening strategies (broad and limited use) to IP ripening from a health system perspective. Base case estimates of probability, utilization, and cost were derived from the literature. The primary outcome was incremental cost of OP versus IP ripening from a hospital perspective. One- and two-way sensitivity analyses explored uncertainty in the model. RESULTS: Both OP ripening strategies were cost saving compared with IP ripening: incremental cost -$228.40/patient with broad use and -$73.48/patient with limited use. OP ripening was no longer cost saving if hours saved on labor and delivery (L&D) were <3.5, insertion visit cost >$714, or facility cost/hour on L&D <$61. Two-way sensitivity analyses showed that OP ripening was cost saving under the most plausible clinical circumstances. CONCLUSION: In patients with unfavorable cervix, OP transcervical balloon ripening was cost saving under a wide range of circumstances, particularly if OP ripening can shorten time spent on L&D by 3.5 hours.
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Assistência Ambulatorial/economia , Maturidade Cervical , Redução de Custos , Trabalho de Parto Induzido/economia , Árvores de Decisões , Feminino , Humanos , Trabalho de Parto Induzido/métodos , Modelos Econômicos , GravidezRESUMO
BACKGROUND: Given the significant morbidity and mortality of maternal sepsis, early identification is key to improve outcomes. This study aims to evaluate the performance characteristics of the systemic inflammatory response syndrome (SIRS), quick Sequential [Sepsis-related] Organ Failure Assessment (qSOFA), and maternal early warning (MEW) criteria for identifying cases of impending sepsis in parturients. The secondary objective of this study is to identify etiologies and risk factors for maternal sepsis and to assess timing of antibiotics in patients diagnosed with sepsis. METHODS: Validated maternal sepsis cases during the delivery hospitalization from 1995 to 2012 were retrospectively identified at 7 academic medical centers in the United States and Israel. Control patients were matched by date of delivery in a 1:4 ratio. The sensitivity and specificity of SIRS, qSOFA, and MEW criteria for identifying sepsis were calculated. Data including potential risk factors, vital signs, laboratory values, and clinical management were collected for cases and controls. RESULTS: Eighty-two sepsis cases during the delivery hospitalization were identified and matched to 328 controls. The most common causes of sepsis were the following: chorioamnionitis 20 (24.4%), endometritis 19 (23.2%), and pneumonia 9 (11.0%). Escherichia coli 12 (14.6%), other Gram-negative rods 8 (9.8%), and group A Streptococcus 6 (7.3%) were the most commonly found pathogens. The sensitivities and specificities for meeting criteria for screening tools were as follows: (1) SIRS (0.93, 0.63); (2) qSOFA (0.50, 0.95); and (3) MEW criteria for identifying sepsis (0.82, 0.87). Of 82 women with sepsis, 10 (12.2%) died. The mortality rate for those who received antibiotics within 1 hour of diagnosis was 8.3%. The mortality rate was 20% for the patients who received antibiotics after >1 hour. CONCLUSIONS: Chorioamnionitis and endometritis were the most common causes of sepsis, together accounting for about half of cases. Notable differences were observed in the sensitivity and specificity of sepsis screening tools with the highest to lowest sensitivity being SIRS, MEW, and qSOFA criteria, and the highest to lowest specificity being qSOFA, MEW, and SIRS. Mortality was doubled in the cohort of patients who received antibiotics after >1 hour. Clinicians need to be vigilant to identify cases of peripartum sepsis early in its course and prioritize timely antibiotic therapy.
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Programas de Rastreamento/métodos , Complicações Infecciosas na Gravidez/diagnóstico , Complicações Infecciosas na Gravidez/etiologia , Sepse/diagnóstico , Sepse/etiologia , Adulto , Estudos de Casos e Controles , Corioamnionite/diagnóstico , Estudos de Coortes , Endometrite/diagnóstico , Feminino , Humanos , Gravidez , Estudos Retrospectivos , Fatores de Risco , Adulto JovemRESUMO
The original version of the article has been published without funding source information.
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Epidemiologic studies link increased autism spectrum disorder (ASD) risk to obstetrical conditions associated with inflammation and steroid dysregulation, referred to as prenatal metabolic syndrome (PNMS). This pilot study measured steroid-related biomarkers in early second trimester maternal serum collected during the first and second trimester evaluation of risk study. ASD case and PNMS exposure status of index offspring were determined through linkage with autism registries and birth certificate records. ASD case (N = 53) and control (N = 19) groups were enriched for PNMS exposure. Higher estradiol and lower sex hormone binding globulin (SHBG) were significantly associated with increased ASD risk. Study findings provide preliminary evidence to link greater placental estradiol activity with ASD and support future investigations of the prenatal steroid environment in ASD.
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Transtorno do Espectro Autista/sangue , Estradiol/sangue , Segundo Trimestre da Gravidez/sangue , Globulina de Ligação a Hormônio Sexual/metabolismo , Adulto , Biomarcadores , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Projetos Piloto , Gravidez , Sistema de Registros , Adulto JovemRESUMO
KDM1A-mediated H3K4 demethylation is a well-established mechanism underlying transcriptional gene repression, but its role in gene activation is less clear. Here, we report a critical function and mechanism of action of KDM1A in glucocorticoid receptor (GR)-mediated gene transcription. Biochemical purification of the nuclear GR complex revealed KDM1A as an integral component. In cell-free assays, GR modulates KDM1A-catalyzed H3K4 progressive demethylation by limiting the loss of H3K4me1. Similarly, in cells, KDM1A binds to most GR binding sites in the genome, where it removes preprogrammed H3K4me2 but leaves H3K4me1 untouched. Blocking KDM1A catalytic activity prevents H3K4me2 removal, severely impairs GR binding to chromatin, and dysregulates GR-targeted genes. Taken together, these data suggest KDM1A-mediated H3K4me2 demethylation at GRBSs promotes GR binding and plays an important role in glucocorticoid-induced gene transcription, broadening the mechanisms that contribute to nuclear receptor-mediated gene activation.
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Cromatina/metabolismo , Elementos Facilitadores Genéticos , Regulação da Expressão Gênica , Histona Desmetilases/metabolismo , Histonas/metabolismo , Receptores de Glucocorticoides/metabolismo , Ativação Transcricional , Células A549 , Cromatina/genética , Desmetilação , Células HeLa , Histona Desmetilases/genética , Histonas/genética , Humanos , Regiões Promotoras Genéticas , Receptores de Glucocorticoides/genéticaRESUMO
OBJECTIVE: Drug-induced deaths, defined as intentional or unintentional consumption of illicit substances or diverted medications leading to death, are the leading cause of death for reproductive-age women in the United States. Our objective was to describe pregnancy-associated deaths attributed to drug-induced causes to identify opportunities for intervention. METHODS: Using the Utah Perinatal Morality Review Committee database, we performed a retrospective cohort study of all pregnancy-associated deaths-death of a woman during pregnancy or within 1 year from the end of pregnancy-from 2005 to 2014. We performed a detailed descriptive analysis of women with drug-induced deaths. We compared characteristics of women with drug-induced and other pregnancy-associated deaths. RESULTS: From 2005 to 2014, 136 pregnancy-associated deaths were identified. Drug-induced death was the leading cause of pregnancy-associated death (n=35, 26%) and 89% occurred in the postpartum period. More specifically, those with a drug-induced death were more likely to die in the late postpartum period, defined as death occurring within 43 days to 1 year of the end of the pregnancy, (n=28/35, 80%) compared with women whose deaths were from other pregnancy-associated causes (n=34/101, 34%) (P<.001). The majority of drug-induced deaths were attributed to opioids (n=27/35, 77%), prescription opioids (n=21/35, 60%), and polysubstance use (n=29/35, 83%). From 2005 to 2014, the pregnancy-associated mortality ratio increased 76%, from 23.3 in 2005 to 41.0 in 2014. During this same time period, the drug-induced pregnancy-associated mortality ratio increased 200%, from 3.9 in 2005 to 11.7 in 2014. CONCLUSION: Drug-induced death is the leading cause of pregnancy-associated death in Utah and occurs primarily in the late postpartum period. Interventional studies focused on identifying and treating women at risk of drug-induced death are urgently needed.
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Analgésicos Opioides/efeitos adversos , Mortalidade Materna , Transtornos Relacionados ao Uso de Opioides/mortalidade , Gravidez/estatística & dados numéricos , Adolescente , Adulto , Bases de Dados Factuais , Feminino , Humanos , Vigilância da População/métodos , Complicações na Gravidez/mortalidade , Resultado da Gravidez , Estudos Retrospectivos , Utah/epidemiologia , Adulto JovemRESUMO
OBJECTIVE: Hospital readmissions are increasingly tracked and assessed for value-based compensation. Our objective was to determine the incidence and risk factors associated with post-cesarean delivery (CD) readmissions or unexpected visits, defined as unexpected office or emergency room visits. STUDY DESIGN: This is a secondary analysis of a multicenter randomized controlled trial of adjunctive azithromycin prophylaxis for CD performed in laboring patients with viable pregnancies. Patients were followed up to 6 weeks postpartum. Our primary outcome was a composite of hospital readmission or unexpected visit, defined as unscheduled clinic or emergency department visits. Data of hospital readmissions, unexpected visits, and their reasons were collected. Demographics, antepartum, intrapartum, and postpartum risk factors were evaluated in bivariate analyses and multivariable logistic regression modeling. RESULTS: A total of 1,019 women were randomized to azithromycin and 994 to placebo. The prevalence of readmission or unexpected visit was 10.2% (95% confidence interval [CI]: 8.9-11.6), with rates of 3.8% (95% CI: 3.0-4.7%) hospital readmissions, 6.9% (95% CI: 5.8-8.0%) emergency room visits, and 4.2% (95% CI: 3.4-5.2%) unexpected clinic visits. The most common causes were infectious disease and hypertensive disorder. Women with readmissions or unexpected visits were more likely to be obese and diabetic, as well as experience longer length of ruptured membranes, intrauterine pressure catheter placement, and postpartum fevers. On multivariable analysis, diabetes (adjusted odds ratio [aOR]: 1.6, 95% CI: 1.1-2.4), prolonged ruptured membranes (aOR: 1.9, 95% CI: 1.3-2.8), and postpartum fevers (aOR: 4.6, 95% CI: 3.0-7.0) were significantly positively associated with readmission or unscheduled visit, while azithromycin was a protective (aOR: 0.6, 95% CI: 0.5-0.9). CONCLUSION: Women who had postpartum fever were at especially high risk for readmission or unexpected visits. Diabetes, prolonged ruptured membranes, and postpartum fevers were significantly associated with the adverse outcome, and azithromycin was associated with lower rates of readmission and unexpected visits.
Assuntos
Antibacterianos/uso terapêutico , Azitromicina/uso terapêutico , Cesárea , Readmissão do Paciente/estatística & dados numéricos , Adulto , Antibioticoprofilaxia , Serviço Hospitalar de Emergência/estatística & dados numéricos , Feminino , Febre/epidemiologia , Febre/prevenção & controle , Humanos , Incidência , Gravidez , Infecção Puerperal/epidemiologia , Infecção Puerperal/prevenção & controle , Fatores de RiscoRESUMO
Importance: Administration of corticosteroids to women at high risk for delivery in the late preterm period (34-36 weeks' gestation) improves short-term neonatal outcomes. The cost implications of this intervention are not known. Objective: To compare the cost-effectiveness of treatment with antenatal corticosteroids with no treatment for women at risk for late preterm delivery. Design, Setting, and Participants: This secondary analysis of the Antenatal Late Preterm Steroids trial, a multicenter randomized clinical trial of antenatal corticosteroids vs placebo in women at risk for late preterm delivery conducted from October 30, 2010, to February 27, 2015. took a third-party payer perspective. Maternal costs were based on Medicaid rates and included those of betamethasone, as well as the outpatient visits or inpatient stay required to administer betamethasone. All direct medical costs for newborn care were included. For infants admitted to the neonatal intensive care unit, comprehensive daily costs were stratified by the acuity of respiratory illness. For infants admitted to the regular newborn nursery, nationally representative cost estimates from the literature were used. Effectiveness was measured as the proportion of infants without the primary outcome of the study: a composite of treatment in the first 72 hours of continuous positive airway pressure or high-flow nasal cannula for 2 hours or more, supplemental oxygen with a fraction of inspired oxygen of 30% or more for 4 hours or more, and extracorporeal membrane oxygenation or mechanical ventilation. This secondary analysis was initially started in June 2016 and revision of the analysis began in May 2017. Exposures: Betamethasone treatment. Main Outcomes and Measures: Incremental cost-effectiveness ratio. Results: Costs were determined for 1426 mother-infant pairs in the betamethasone group (mean [SD] maternal age, 28.6 [6.3] years; 827 [58.0%] white) and 1395 mother-infant pairs in the placebo group (mean [SD] maternal age, 27.9 [6.2] years; 794 [56.9%] white). Treatment with betamethasone was associated with a total mean (SD) woman-infant-pair cost of $4681 ($5798), which was significantly less than the mean (SD) amount of $5379 ($8422) for women and infants in the placebo group (difference, $698; 95% CI, $186-$1257; P = .02). The Antenatal Late Preterm Steroids trial determined that betamethasone use is effective: respiratory morbidity decreased by 2.9% (95% CI, -0.5% to -5.4%). Thus, the cost-effectiveness ratio was -$23 986 per case of respiratory morbidity averted. Inspection of the bootstrap replications confirmed that treatment was the dominant strategy in 5000 samples (98.8%). Sensitivity analyses showed that these results held under most assumptions. Conclusions and Relevance: The findings suggest that antenatal betamethasone treatment is associated with a statistically significant decrease in health care costs and with improved outcomes; thus, this treatment may be an economically desirable strategy.