RESUMEN
Two-photon microscopy is widely used to investigate brain function across multiple spatial scales. However, measurements of neural activity are compromised by brain movement in behaving animals. Brain motion-induced artifacts are typically corrected using post hoc processing of two-dimensional images, but this approach is slow and does not correct for axial movements. Moreover, the deleterious effects of brain movement on high-speed imaging of small regions of interest and photostimulation cannot be corrected post hoc. To address this problem, we combined random-access three-dimensional (3D) laser scanning using an acousto-optic lens and rapid closed-loop field programmable gate array processing to track 3D brain movement and correct motion artifacts in real time at up to 1 kHz. Our recordings from synapses, dendrites and large neuronal populations in behaving mice and zebrafish demonstrate real-time movement-corrected 3D two-photon imaging with submicrometer precision.
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Imagenología Tridimensional/métodos , Microscopía de Fluorescencia por Excitación Multifotónica/métodos , Animales , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Movimiento , Pez CebraRESUMEN
OBJECTIVE: To determine, by expert consensus through a modified Delphi process, the role of standardized and new ultrasound signs in the prenatal evaluation of patients at high risk of placenta accreta spectrum (PAS). METHODS: A systematic review of articles providing information on ultrasound imaging signs or markers associated with PAS was performed before the development of questionnaires for the first round of the Delphi process. Only peer-reviewed original research studies in the English language describing one or more new ultrasound sign(s) for the prenatal evaluation of PAS were included. A three-round consensus-building Delphi method was then conducted under the guidance of a steering group, which included nine experts who invited an international panel of experts in obstetric ultrasound imaging in the evaluation of patients at high risk for PAS. Consensus was defined as agreement of ≥ 70% between participants. RESULTS: The systematic review identified 15 articles describing eight new ultrasound signs for the prenatal evaluation of PAS. A total of 35 external experts were approached, of whom 31 agreed and participated in the first round. Thirty external experts (97%) and seven experts from the steering group completed all three Delphi rounds. A consensus was reached that a prior history of at least one Cesarean delivery, myomectomy or PAS should be an indication for detailed PAS ultrasound assessment. The panelists also reached a consensus that seven of the 11 conventional signs of PAS should be included in the examination of high-risk patients and the routine mid-gestation scan report: (1) loss of the 'clear zone', (2) myometrial thinning, (3) bladder-wall interruption, (4) placental bulge, (5) uterovesical hypervascularity, (6) placental lacunae and (7) bridging vessels. A consensus was not reached for any of the eight new signs identified by the systematic review. With respect to other ultrasound features that are not specific to PAS but increase the probability of PAS at birth, the panelists reached a consensus for the finding of anterior placenta previa or placenta previa with cervical involvement. The experts were also asked to determine which PAS signs should be quantified and consensus was reached only for the quantification of placental lacunae using an existing score. For predicting surgical outcome in patients with a high probability of PAS at delivery, a consensus was obtained for loss of the clear zone, bladder-wall interruption, presence of placental lacunae and presence of placenta previa involving the cervix. CONCLUSIONS: We have confirmed the continued importance of seven established standardized ultrasound signs of PAS, highlighted the role of transvaginal ultrasound in evaluating the placental position and anatomy of the cervix, and identified new ultrasound signs that may become useful in the future prenatal evaluation and management of patients at high risk for PAS at birth. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.
Asunto(s)
Placenta Accreta , Placenta Previa , Recién Nacido , Embarazo , Femenino , Humanos , Placenta Accreta/diagnóstico por imagen , Placenta/diagnóstico por imagen , Técnica Delphi , Ultrasonografía , Ultrasonografía Prenatal , Estudios RetrospectivosRESUMEN
OBJECTIVE: To evaluate the association between maternal fructosamine levels at the time of delivery and stillbirth. DESIGN: Secondary analysis of a case-control study. SETTING: Multicentre study of five geographic catchment areas in the USA. POPULATION: All singleton stillbirths with known diabetes status and fructosamine measurement, and representative live birth controls. MAIN OUTCOME MEASURES: Fructosamine levels in stillbirths and live births among groups were adjusted for potential confounding factors, including diabetes. Optimal thresholds of fructosamine to discriminate stillbirth and live birth. RESULTS: A total of 529 women with a stillbirth and 1499 women with a live birth were included in the analysis. Mean fructosamine levels were significantly higher in women with a stillbirth than in women with a live birth after adjustment (177 ± 3.05 versus 165 ± 2.89 µmol/L, P < 0.001). The difference in fructosamine levels between stillbirths and live births was greater among women with diabetes (194 ± 8.54 versus 162 ± 3.21 µmol/L), compared with women without diabetes (171 ± 2.50 versus 162 ± 2.56 µmol/L). The area under the curve (AUC) for fructosamine level and stillbirth was 0.634 (0.605-0.663) overall, 0.713 (0.624-0.802) with diabetes and 0.625 (0.595-0.656) with no diabetes. CONCLUSIONS: Maternal fructosamine levels at the time of delivery were higher in women with stillbirth compared with women with live birth. Differences were substantial in women with diabetes, suggesting a potential benefit of glycaemic control in women with diabetes during pregnancy. The small differences noted in women without diabetes are not likely to justify routine screening in all cases of stillbirth. TWEETABLE ABSTRACT: Maternal serum fructosamine levels are higher in women with stillbirth than in women with live birth, especially in women with diabetes.
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Fructosamina/sangre , Mortinato/epidemiología , Adulto , Estudios de Casos y Controles , Causalidad , Femenino , Humanos , Nacimiento Vivo/epidemiología , Embarazo , Curva ROC , Factores de Riesgo , Estados Unidos/epidemiologíaRESUMEN
BACKGROUND: Preterm birth remains a common cause of neonatal mortality, with a disproportionately high burden in low-income and middle-income countries. Meta-analyses of low-dose aspirin to prevent pre-eclampsia suggest that the incidence of preterm birth might also be decreased, particularly if initiated before 16 weeks of gestation. METHODS: ASPIRIN was a randomised, multicountry, double-masked, placebo-controlled trial of low-dose aspirin (81 mg daily) initiated between 6 weeks and 0 days of pregnancy, and 13 weeks and 6 days of pregnancy, in nulliparous women with an ultrasound confirming gestational age and a singleton viable pregnancy. Participants were enrolled at seven community sites in six countries (two sites in India and one site each in the Democratic Republic of the Congo, Guatemala, Kenya, Pakistan, and Zambia). Participants were randomly assigned (1:1, stratified by site) to receive aspirin or placebo tablets of identical appearance, via a sequence generated centrally by the data coordinating centre at Research Triangle Institute International (Research Triangle Park, NC, USA). Treatment was masked to research staff, health providers, and patients, and continued until 36 weeks and 7 days of gestation or delivery. The primary outcome of incidence of preterm birth, defined as the number of deliveries before 37 weeks' gestational age, was analysed in randomly assigned women with pregnancy outcomes at or after 20 weeks, according to a modified intention-to-treat (mITT) protocol. Analyses of our binary primary outcome involved a Cochran-Mantel-Haenszel test stratified by site, and generalised linear models to obtain relative risk (RR) estimates and associated confidence intervals. Serious adverse events were assessed in all women who received at least one dose of drug or placebo. This study is registered with ClinicalTrials.gov, NCT02409680, and the Clinical Trial Registry-India, CTRI/2016/05/006970. FINDINGS: From March 23, 2016 to June 30, 2018, 14â361 women were screened for inclusion and 11â976 women aged 14-40 years were randomly assigned to receive low-dose aspirin (5990 women) or placebo (5986 women). 5780 women in the aspirin group and 5764 in the placebo group were evaluable for the primary outcome. Preterm birth before 37 weeks occurred in 668 (11·6%) of the women who took aspirin and 754 (13·1%) of those who took placebo (RR 0·89 [95% CI 0·81 to 0·98], p=0·012). In women taking aspirin, we also observed significant reductions in perinatal mortality (0·86 [0·73-1·00], p=0·048), fetal loss (infant death after 16 weeks' gestation and before 7 days post partum; 0·86 [0·74-1·00], p=0·039), early preterm delivery (<34 weeks; 0·75 [0·61-0·93], p=0·039), and the incidence of women who delivered before 34 weeks with hypertensive disorders of pregnancy (0·38 [0·17-0·85], p=0·015). Other adverse maternal and neonatal events were similar between the two groups. INTERPRETATION: In populations of nulliparous women with singleton pregnancies from low-income and middle-income countries, low-dose aspirin initiated between 6 weeks and 0 days of gestation and 13 weeks and 6 days of gestation resulted in a reduced incidence of preterm delivery before 37 weeks, and reduced perinatal mortality. FUNDING: Eunice Kennedy Shriver National Institute of Child Health and Human Development.
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Aspirina/administración & dosificación , Preeclampsia/epidemiología , Nacimiento Prematuro/epidemiología , Adolescente , Adulto , Aspirina/efectos adversos , Presión Sanguínea , Parto Obstétrico/estadística & datos numéricos , Países en Desarrollo , Método Doble Ciego , Femenino , Humanos , Preeclampsia/prevención & control , Embarazo , Resultado del Embarazo/epidemiología , Nacimiento Prematuro/prevención & control , Adulto JovenRESUMEN
STUDY QUESTION: Are insufficient 25-hydroxyvitamin D (25(OH)D) concentrations, and other markers of vitamin D metabolism, associated with premenstrual symptoms in healthy women with regular menstrual cycles? SUMMARY ANSWER: 25(OH)D insufficiency was associated with specific physical premenstrual symptoms, while no associations were observed with psychological symptoms or with other markers of vitamin D metabolism. WHAT IS KNOWN ALREADY: Prior studies evaluating vitamin D and premenstrual symptoms have yielded mixed results, and it is unknown whether 25(OH)D insufficiency and other markers of vitamin D metabolism are associated with premenstrual symptoms. STUDY DESIGN, SIZE, DURATION: We used two cohorts of women with regular menstrual cycles; 1191 women aged 18-40 years in EAGeR (cross-sectional analysis of a prospective cohort within a randomized trial) and 76 women aged 18-44 years in BioCycle (prospective cohort). In EAGeR, premenstrual symptoms over the previous year were assessed at baseline, whereas in BioCycle, symptoms were assessed prospectively at multiple points over two menstrual cycles with symptoms queried over the previous week. In both cohorts, symptomatology was assessed via questionnaire regarding presence and severity of 14 physical and psychological symptoms the week before and after menses. Both studies measured 25(OH)D in serum. We also evaluated the association of additional markers of vitamin D metabolism and calcium homeostasis, including intact parathyroid hormone (iPTH), calcium (Ca), fibroblast growth factor 23 (FGF23), and 1,25 dihydroxyvitamin D (1,25(OH)2D) with premenstrual symptoms in the BioCycle cohort. PARTICIPANTS/MATERIALS, SETTING, METHODS: One cohort of women actively seeking pregnancy (Effects of Aspirin in Gestation and Reproduction (EAGeR)) and one cohort not seeking pregnancy (BioCycle) were evaluated. Log-binomial regression was used to estimate risk ratios (RR) and 95% CIs for associations between insufficient 25(OH)D (<30 ng/ml) and individual premenstrual symptoms, adjusting for age, BMI, race, smoking, income, physical activity, and season of blood draw. MAIN RESULTS AND THE ROLE OF CHANCE: 25(OH)D insufficiency was associated with increased risk of breast fullness/tenderness (EAGeR RR 1.27, 95% CI 1.03, 1.55; BioCycle RR 1.37, 95% CI 0.56, 3.32) and generalized aches and pains (EAGeR RR 1.33, 95% CI 1.01, 1.78; BioCycle 1.36, 95% CI 0.41, 4.45), though results were imprecise in the BioCycle study. No associations were observed between insufficient 25(OH)D and psychological symptoms in either cohort. In BioCycle, iPTH, Ca, FGF23, and 1,25(OH) 2D were not associated with any premenstrual symptoms. LIMITATIONS, REASONS FOR CAUTION: Results from the EAGeR study were limited by the study design, which assessed both 25(OH)D at baseline and individual premenstrual symptoms over the past year at the baseline. As such, reverse causality is a potential concern. Though premenstrual symptoms were assessed prospectively in the BioCycle cohort, the power was limited due to small sample size. However, results were fairly consistent across both studies. WIDER IMPLICATIONS OF THE FINDINGS: Serum 25(OH)D may be associated with risk and severity of specific physical premenstrual symptoms. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland (Contract nos. HHSN267200603423, HHSN267200603424, and HHSN267200603426). JG.R. and D.L.K. have been funded by the NIH Medical Research Scholars Program, a public-private partnership jointly supported by the NIH and generous contributions to the Foundation for the NIH by the Doris Duke Charitable Foundation (Grant #2014194), the American Association for Dental Research, the Colgate Palmolive Company, Genentech, and other private donors. For a complete list, visit the foundation website at http://www.fnih.org. The authors have no conflicts of interest to disclose. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov NCT00467363.
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Ciclo Menstrual , Vitamina D , Niño , Estudios Transversales , Ejercicio Físico , Femenino , Factor-23 de Crecimiento de Fibroblastos , Humanos , Embarazo , Estudios ProspectivosRESUMEN
STUDY QUESTION: Is cannabis use assessed via urinary metabolites and self-report during preconception associated with fecundability, live birth and pregnancy loss? SUMMARY ANSWER: Preconception cannabis use was associated with reduced fecundability among women with a history of pregnancy loss attempting pregnancy despite an increased frequency of intercourse. WHAT IS KNOWN ALREADY: Cannabis use continues to rise despite limited evidence of safety during critical windows of pregnancy establishment. While existing studies suggest that self-reported cannabis use is not associated with fecundability, self-report may not be reliable. STUDY DESIGN, SIZE, DURATION: A prospective cohort study was carried out including 1228 women followed for up to six cycles while attempting pregnancy (2006 to 2012), and throughout pregnancy if they conceived. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women aged 18-40 years with a history of pregnancy loss (n = 1228) were recruited from four clinical centers. Women self-reported preconception cannabis use at baseline and urinary tetrahydrocannabinol metabolites were measured throughout preconception and early pregnancy (up to four times during the study: at baseline, after 6 months of follow-up or at the beginning of the conception cycle, and weeks 4 and 8 of pregnancy). Time to hCG-detected pregnancy, and incidence of live birth and pregnancy loss were prospectively assessed. Fecundability odds ratios (FOR) and 95% CI were estimated using discrete time Cox proportional hazards models, and risk ratios (RRs) and 95% CI using log-binomial regression adjusting for age, race, BMI, education level, baseline urine cotinine, alcohol use and antidepressant use. MAIN RESULTS AND THE ROLE OF CHANCE: Preconception cannabis use was 5% (62/1228), based on combined urinary metabolite measurements and self-report, and 1.3% (11/789) used cannabis during the first 8 weeks of gestation based on urinary metabolites only. Women with preconception cannabis use had reduced fecundability (FOR 0.59; 95% CI 0.38, 0.92). Preconception cannabis use was also associated with increased frequency of intercourse per cycle (9.4 ± 7 versus 7.5 ± 7 days; P = 0.02) and higher LH (percentage change 64%, 95% CI 3, 161) and higher LH:FSH ratio (percentage change 39%, 95% CI 7, 81). There were also suggestive, though imprecise, associations with anovulation (RR 1.92, 95% CI 0.88, 4.18), and live birth (42% (19/45) cannabis users versus 55% (578/1043) nonusers; RR 0.80, 95% CI 0.57, 1.12). No associations were observed between preconception cannabis use and pregnancy loss (RR 0.81, 95% CI 0.46, 1.42). Similar results were observed after additional adjustment for parity, income, employment status and stress. We were unable to estimate associations between cannabis use during early pregnancy and pregnancy loss due to limited sample size. LIMITATIONS, REASONS FOR CAUTION: Owing to the relatively few cannabis users in our study, we had limited ability to make conclusions regarding live birth and pregnancy loss, and were unable to account for male partner use. While results were similar after excluding smokers, alcohol use and any drug use in the past year, some residual confounding may persist due to these potential co-exposures. WIDER IMPLICATIONS OF THE FINDINGS: These findings highlight potential risks on fecundability among women attempting pregnancy with a history of pregnancy loss and the need for expanded evidence regarding the reproductive health effects of cannabis use in the current climate of increasing legalization. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland (Contract numbers: HHSN267200603423, HHSN267200603424, HHSN267200603426, HHSN275201300023I). Jeannie G. Radoc has been funded by the National Institutes of Health Medical Research Scholars Program, a public-private partnership supported jointly by the National Institutes of Health and generous contributions to the Foundation for the National Institutes of Health from the Doris Duke Charitable Foundation (DDCF Grant # 2014194), Genentech, Elsevier, and other private donors. The authors report no conflict of interest in this work and have nothing to disclose. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov NCT00467363.
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Aborto Espontáneo , Cannabis , Aborto Espontáneo/epidemiología , Aborto Espontáneo/etiología , Adolescente , Adulto , Cannabis/efectos adversos , Niño , Femenino , Fertilidad , Humanos , Nacimiento Vivo , Masculino , Embarazo , Estudios Prospectivos , Adulto JovenRESUMEN
OBJECTIVE: Parent engagement in perinatal mortality review meetings following stillbirth may benefit parents and improve patient safety. We investigated perinatal mortality review meeting practices, including the extent of parent engagement, based on self-reports from healthcare professionals from maternity care facilities in six high-income countries. DESIGN: Cross-sectional online survey. SETTING: Australia, Canada, Ireland, New Zealand, UK and USA. POPULATION: A total of 1104 healthcare professionals, comprising mainly obstetricians, gynaecologists, midwives and nurses. METHODS: Data were drawn from responses to a survey covering stillbirth-related topics. Open- and closed-items that focused on 'Data quality on causes of stillbirth' were analysed. MAIN OUTCOME MEASURES: Healthcare professionals' self-reported practices around perinatal mortality review meetings following stillbirth. RESULTS: Most clinicians (81.0%) were aware of regular audit meetings to review stillbirth at their maternity facility, although this was true for only 35.5% of US respondents. For the 854 respondents whose facility held regular meetings, less than a third (31.1%) reported some form of parent engagement, and this was usually in the form of one-way post-meeting feedback. Across all six countries, only 17.1% of respondents described an explicit approach where parents provided input, received feedback and were represented at meetings. CONCLUSIONS: We found no established practice of involving parents in the perinatal mortality review process in six high-income countries. Parent engagement may hold the key to important lessons for stillbirth prevention and care. Further understanding of approaches, barriers and enablers is warranted. TWEETABLE ABSTRACT: Parent engagement in mortality review after stillbirth is rare, based on data from six countries. We need to understand the barriers.
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Auditoría Médica/métodos , Padres , Participación del Paciente , Mortalidad Perinatal , Mortinato , Estudios Transversales , Países Desarrollados , Femenino , Encuestas de Atención de la Salud , Humanos , Recién Nacido , Masculino , Seguridad del PacienteRESUMEN
OBJECTIVE: Approximately 10% of stillbirths are attributed to fetal anomalies, but anomalies are also common in live births. We aimed to assess the relationship between anomalies, by system and stillbirth. DESIGN: Secondary analysis of a prospective, case-control study. SETTING: Multicentre, 59 hospitals in five regional catchment areas in the USA. POPULATION OR SAMPLE: All stillbirths and representative live birth controls. METHODS: Standardised postmortem examinations performed in stillbirths, medical record abstraction for stillbirths and live births. MAIN OUTCOME MEASURES: Incidence of major anomalies, by type, compared between stillbirths and live births with univariable and multivariable analyses using weighted analysis to account for study design and differential consent. RESULTS: Of 465 singleton stillbirths included, 23.4% had one or more major anomalies compared with 4.3% of 1871 live births. Having an anomaly increased the odds of stillbirth; an increasing number of anomalies was more highly associated with stillbirth. Regardless of organ system affected, the presence of an anomaly increased the odds of stillbirth. These relationships remained significant if stillbirths with known genetic abnormalities were excluded. After multivariable analyses, the adjusted odds ratio (aOR) of stillbirth for any anomaly was 4.33 (95% CI 2.80-6.70) and the systems most strongly associated with stillbirth were cystic hygroma (aOR 29.97, 95% CI 5.85-153.57), and thoracic (aOR16.18, 95% CI 4.30-60.94) and craniofacial (aOR 35.25, 95% CI 9.22-134.68) systems. CONCLUSIONS: In pregnancies affected by anomalies, the odds of stillbirth are higher with increasing numbers of anomalies. Anomalies of nearly any organ system increased the odds of stillbirth even when adjusting for gestational age and maternal race. TWEETABLE ABSTRACT: Stillbirth risk increases with anomalies of nearly any organ system and with number of anomalies seen.
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Anomalías Congénitas/epidemiología , Anomalías Congénitas/patología , Enfermedades Fetales/epidemiología , Enfermedades Fetales/patología , Mortinato/epidemiología , Adulto , Estudios de Casos y Controles , Femenino , Humanos , Incidencia , Nacimiento Vivo , Oportunidad Relativa , Embarazo , Estudios Prospectivos , Factores de RiesgoRESUMEN
OBJECTIVE: Stillbirths occur 10-20 times more frequently in low-income settings compared with high-income settings. We created a methodology to define the proportion of stillbirths that are potentially preventable in low-income settings and applied it to stillbirths in sites in India and Pakistan. DESIGN: Prospective observational study. SETTING: Three maternity hospitals in Davangere, India and a large public hospital in Karachi, Pakistan. POPULATION: All cases of stillbirth at ≥20 weeks of gestation occurring from July 2018 to February 2020 were screened for participation; 872 stillbirths were included in this analysis. METHODS: We prospectively defined the conditions and gestational ages that defined the stillbirth cases considered potentially preventable. Informed consent was sought from the parent(s) once the stillbirth was identified, either before or soon after delivery. All information available, including obstetric and medical history, clinical course, fetal heart sounds on admission, the presence of maceration as well as examination of the stillbirth after delivery, histology, and polymerase chain reaction for infectious pathogens of the placenta and various fetal tissues, was used to assess whether a stillbirth was potentially preventable. MAIN OUTCOME MEASURES: Whether a stillbirth was determined to be potentially preventable and the criteria for assignment to those categories. RESULTS: Of 984 enrolled, 872 stillbirths at ≥20 weeks of gestation met the inclusion criteria and were included; of these, 55.5% were deemed to be potentially preventable. Of the 649 stillbirths at ≥28 weeks of gestation and ≥1000 g birthweight, 73.5% were considered potentially preventable. The most common conditions associated with a potentially preventable stillbirth at ≥28 weeks of gestation and ≥1000 g birthweight were small for gestational age (SGA) (52.8%), maternal hypertension (50.2%), antepartum haemorrhage (31.4%) and death that occurred after hospital admission (15.7%). CONCLUSIONS: Most stillbirths in these sites were deemed preventable and were often associated with maternal hypertension, antepartum haemorrhage, SGA and intrapartum demise. TWEETABLE ABSTRACT: Most stillbirths are preventable by better care for women with hypertension, growth restriction and antepartum haemorrhage.
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Muerte Fetal/prevención & control , Atención Prenatal/estadística & datos numéricos , Calidad de la Atención de Salud/estadística & datos numéricos , Mortinato/epidemiología , Adulto , Femenino , Edad Gestacional , Humanos , India/epidemiología , Recién Nacido , Recién Nacido Pequeño para la Edad Gestacional , Complicaciones del Trabajo de Parto/epidemiología , Pakistán/epidemiología , Embarazo , Atención Prenatal/normas , Estudios ProspectivosRESUMEN
Understanding how neural circuits process information requires rapid measurements of activity from identified neurons distributed in 3D space. Here we describe an acousto-optic lens two-photon microscope that performs high-speed focusing and line scanning within a volume spanning hundreds of micrometers. We demonstrate its random-access functionality by selectively imaging cerebellar interneurons sparsely distributed in 3D space and by simultaneously recording from the soma, proximal and distal dendrites of neocortical pyramidal cells in awake behaving mice.
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Conducta Animal/fisiología , Imagenología Tridimensional/métodos , Microscopía de Fluorescencia por Excitación Multifotónica/métodos , Actividad Motora/fisiología , Neuronas/fisiología , Imagen de Colorante Sensible al Voltaje/métodos , Potenciales de Acción/fisiología , Animales , Corteza Cerebelosa/citología , Corteza Cerebelosa/fisiología , Dendritas/fisiología , Proteínas Fluorescentes Verdes/química , Proteínas Fluorescentes Verdes/genética , Interneuronas/fisiología , Ratones , Ratones Transgénicos , Técnicas de Placa-Clamp , Células Piramidales/fisiología , Corteza Visual/citología , Corteza Visual/fisiologíaRESUMEN
Neurons within cortical microcircuits are interconnected with recurrent excitatory synaptic connections that are thought to amplify signals (Douglas and Martin, 2007), form selective subnetworks (Ko et al., 2011), and aid feature discrimination. Strong inhibition (Haider et al., 2013) counterbalances excitation, enabling sensory features to be sharpened and represented by sparse codes (Willmore et al., 2011). This balance between excitation and inhibition makes it difficult to assess the strength, or gain, of recurrent excitatory connections within cortical networks, which is key to understanding their operational regime and the computations that they perform. Networks that combine an unstable high-gain excitatory population with stabilizing inhibitory feedback are known as inhibition-stabilized networks (ISNs) (Tsodyks et al., 1997). Theoretical studies using reduced network models predict that ISNs produce paradoxical responses to perturbation, but experimental perturbations failed to find evidence for ISNs in cortex (Atallah et al., 2012). Here, we reexamined this question by investigating how cortical network models consisting of many neurons behave after perturbations and found that results obtained from reduced network models fail to predict responses to perturbations in more realistic networks. Our models predict that a large proportion of the inhibitory network must be perturbed to reliably detect an ISN regime robustly in cortex. We propose that wide-field optogenetic suppression of inhibition under promoters targeting a large fraction of inhibitory neurons may provide a perturbation of sufficient strength to reveal the operating regime of cortex. Our results suggest that detailed computational models of optogenetic perturbations are necessary to interpret the results of experimental paradigms.SIGNIFICANCE STATEMENT Many useful computational mechanisms proposed for cortex require local excitatory recurrence to be very strong, such that local inhibitory feedback is necessary to avoid epileptiform runaway activity (an "inhibition-stabilized network" or "ISN" regime). However, recent experimental results suggest that this regime may not exist in cortex. We simulated activity perturbations in cortical networks of increasing realism and found that, to detect ISN-like properties in cortex, large proportions of the inhibitory population must be perturbed. Current experimental methods for inhibitory perturbation are unlikely to satisfy this requirement, implying that existing experimental observations are inconclusive about the computational regime of cortex. Our results suggest that new experimental designs targeting a majority of inhibitory neurons may be able to resolve this question.
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Potenciales de Acción/fisiología , Neocórtex/fisiología , Red Nerviosa/fisiología , Inhibición Neural/fisiología , Animales , HumanosRESUMEN
Objectives To prospectively estimate the association of preconception antiphospholipid antibodies (aPL) with subsequent pregnancy loss using a cohort design. aPL have been associated with recurrent early pregnancy loss (EPL) prior to 10 weeks in previous case-control studies. Prospective ascertainment of pregnancy loss is challenging, as most women do not seek care prior to EPL. Methods Secondary analysis of the Effects of Aspirin in Gestation and Reproduction trial of preconception low-dose aspirin. Preconception anticardiolipin (aCL) and anti-ß2-glycoprotein-I (a-ß2-I) were assessed in 1208 women with one or two prior pregnancy losses and no more than two prior live births. Comparison cohorts were defined by positive aPL (+aPL) or negative aPL (-aPL) status. All women were followed for six menstrual cycles while trying to conceive; if successful, they underwent an ultrasound at 6-7 weeks' gestation. EPL was defined as loss prior to 10 weeks' gestation; embryonic loss was loss after visualization of an embryo but prior to 10 weeks; clinical loss was any loss after visualization of an embryo (with or without fetal cardiac activity detected). Results In total, 14/1208 (1%) tested positive for +aPL. 786/1208 (65%) women had positive human chorionic gonadotropin during the study period, of which 9/786 (1%) had +aPL. Of the 786 pregnant women, 589 (75%) had live births and 24% had pregnancy losses. Women with +aPL experienced EPL at similar rates as women with -aPL, 44% vs 21% (aRR 2.4, 95% confidence interval (CI) 0.5-10.9). Embryonic loss was more common in women with +aCL IgM (aRR 4.8, 95% CI 1.0-23.0) and in women with two positive aPL. Clinical pregnancy loss was more common in women with positive a-ß2-I IgM (50% vs 16.5%, aRR 3.7, 95% CI 1.3-10.8). Conclusion Positive levels of aPL are rare in women with one or two prior pregnancy losses and are not clearly associated with an increased rate of subsequent loss. Clinical trial registration The original source study was registered at ClinicalTrials.gov (#NCT00467363).
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Aborto Espontáneo/inmunología , Anticuerpos Antifosfolípidos/aislamiento & purificación , Adulto , Femenino , Humanos , Embarazo , Estudios Prospectivos , Adulto JovenRESUMEN
OBJECTIVES: Systemic sclerosis (SSc) is heterogenous. The objectives of this study were to evaluate the purpose, strengths and limitations of existing SSc subset criteria, and identify ideas among experts about subsets. METHODS: We conducted semi-structured interviews with randomly sampled international SSc experts. The interview transcripts underwent an iterative process with text deconstructed to single thought units until a saturated conceptual framework with coding was achieved and respondent occurrence tabulated. Serial cross-referential analyses of clusters were developed. RESULTS: Thirty experts from 13 countries were included; 67% were male, 63% were from Europe and 37% from North America; median experience of 22.5 years, with a median of 55 new SSc patients annually. Three thematic clusters regarding subsetting were identified: research and communication; management; and prognosis (prediction of internal organ involvement, survival). The strength of the limited/diffuse system was its ease of use, however 10% stated this system had marginal value. Shortcomings of the diffuse/limited classification were the risk of misclassification, predictions/generalizations did not always hold true, and that the elbow or knee threshold was arbitrary. Eighty-seven percent use more than 2 subsets including: SSc sine scleroderma, overlap conditions, antibody-determined subsets, speed of progression, and age of onset (juvenile, elderly). CONCLUSIONS: We have synthesized an international view of the construct of SSc subsets in the modern era. We found a number of factors underlying the construct of SSc subsets. Considerations for the next phase include rate of change and hierarchal clustering (e.g. limited/diffuse, then by antibodies).
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Medición de Riesgo/métodos , Esclerodermia Sistémica/diagnóstico , Adulto , Estudios Transversales , Progresión de la Enfermedad , Femenino , Humanos , Masculino , PronósticoRESUMEN
OBJECTIVE: To assess weight change and attempted weight loss during the 12-18 months before spontaneous conception in relation to the risk of pregnancy loss. DESIGN: Prospective cohort study. SETTING: United States, 2007-2011. METHODS: Women (n = 629) who were attempting pregnancy reported at baseline any weight loss attempts over the past 12 months, and their minimum and maximum weights during that time. Follow up lasted one to six menstrual cycles and throughout pregnancy. Using bodyweight measured at 4 weeks' gestation, participants were categorised as having weight loss ≥5%, weight gain ≥5%, both, or neither, over the previous 12-18 months. Log-binomial models adjusted for potential confounders. MAIN OUTCOME MEASURES: Risk ratio (RR) and 95% confidence interval (CI) of pregnancy loss. RESULTS: Attempted weight loss was reported by 44% of women and actual weight loss by 11%, but neither was consistently associated with pregnancy loss. The RR for recent weight gain ≥5% was 1.65 (CI 1.09, 2.49). CONCLUSIONS: Weight gain over the period spanning 12-18 months pre-conception to 4 weeks' gestation may increase the risk of pregnancy loss among fertile women with prior pregnancy losses. Attempted and actual weight loss were not associated with pregnancy loss; however, replication is needed from larger studies with data on particular weight-loss methods. TWEETABLE ABSTRACT: Recent weight gain before and around the time of conception may increase the risk of pregnancy loss.
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Aborto Espontáneo/etiología , Aumento de Peso , Pérdida de Peso , Adulto , Femenino , Humanos , Embarazo , Estudios Prospectivos , Riesgo , Estados UnidosRESUMEN
OBJECTIVE: To assess the frequency of additional care, and parents' perceptions of quality, respectful care, in pregnancies subsequent to stillbirth. DESIGN: Multi-language web-based survey. SETTING: International. POPULATION: A total of 2716 parents, from 40 high- and middle-income countries. METHODS: Data were obtained from a broader survey of parents' experiences following stillbirth. Data were analysed using descriptive statistics and stratified by geographic region. Subgroup analyses explored variation in additional care by gestational age at index stillbirth. MAIN OUTCOME MEASURES: Frequency of additional care, and perceptions of quality, respectful care. RESULTS: The majority (66%) of parents conceived their subsequent pregnancy within 1 year of stillbirth. Additional antenatal care visits and ultrasound scans were provided for 67% and 70% of all parents, respectively, although there was wide variation across geographic regions. Care addressing psychosocial needs was less frequently provided, such as additional visits to a bereavement counsellor (10%) and access to named care provider's phone number (27%). Compared with parents whose stillbirth occurred at ≤ 29 weeks of gestation, parents whose stillbirth occurred at ≥ 30 weeks of gestation were more likely to receive various forms of additional care, particularly the option for early delivery after 37 weeks. Around half (47-63%) of all parents felt that elements of quality, respectful care were consistently applied, such as spending enough time with parents and involving parents in decision-making. CONCLUSIONS: Greater attention is required to providing thoughtful, empathic and collaborative care in all pregnancies following stillbirth. Specific education and training for health professionals is needed. TWEETABLE ABSTRACT: More support for providing quality care in pregnancies after stillbirth is needed. PLAIN LANGUAGE SUMMARY: Study rationale and design More than two million babies are stillborn every year. Most parents will conceive again soon after having a stillborn baby. These parents are more likely to have another stillborn baby in the next pregnancy than parents who have not had a stillborn baby before. The next pregnancy after stillbirth is often an extremely anxious time for parents, as they worry about whether their baby will survive. In this study we asked 2716 parents from 40 countries about the care they received during their first pregnancy after stillbirth. Parents were recruited mainly through the International Stillbirth Alliance and completed on online survey that was available in six languages. Findings Parents often had extra antenatal visits and extra ultrasound scans in the next pregnancy, but they rarely had extra emotional support. Also, many parents felt their care providers did not always listen to them and spend enough time with them, involve them in decisions, and take their concerns seriously. Parents were more likely to receive various forms of extra care in the next pregnancy if their baby had died later in pregnancy compared to earlier in pregnancy. Limitations In this study we only have information from parents who were able and willing to complete an online survey. Most of the parents were involved in charity and support groups and most parents lived in developed countries. We do not know how well the findings relate to other parents. Finally, our study does not include parents who may have tried for another pregnancy but were not able to conceive. Potential impact This study can help to improve care through the development of best practice guidelines for pregnancies following stillbirth. The results suggest that parents need better emotional support in these pregnancies, and more opportunities to participate actively in decisions about care. Extra support should be available no matter how far along in pregnancy the previous stillborn baby died.
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Padres/psicología , Atención Prenatal/normas , Mortinato/psicología , Adulto , Países Desarrollados , Países en Desarrollo , Femenino , Humanos , Internet , Masculino , Persona de Mediana Edad , Calidad de la Atención de Salud , Encuestas y Cuestionarios , Adulto JovenRESUMEN
BACKGROUND: Stillbirth is a global health problem. The World Health Organization (WHO) application of the International Classification of Diseases for perinatal mortality (ICD-PM) aims to improve data on stillbirth to enable prevention. OBJECTIVES: To identify globally reported causes of stillbirth, classification systems, and alignment with the ICD-PM. SEARCH STRATEGY: We searched CINAHL, EMBASE, Medline, Global Health, and Pubmed from 2009 to 2016. SELECTION CRITERIA: Reports of stillbirth causes in unselective cohorts. DATA COLLECTION AND ANALYSIS: Pooled estimates of causes were derived for country representative reports. Systems and causes were assessed for alignment with the ICD-PM. Data are presented by income setting (low, middle, and high income countries; LIC, MIC, HIC). MAIN RESULTS: Eighty-five reports from 50 countries (489 089 stillbirths) were included. The most frequent categories were Unexplained, Antepartum haemorrhage, and Other (all settings); Infection and Hypoxic peripartum (LIC), and Placental (MIC, HIC). Overall report quality was low. Only one classification system fully aligned with ICD-PM. All stillbirth causes mapped to ICD-PM. In a subset from HIC, mapping obscured major causes. CONCLUSIONS: There is a paucity of quality information on causes of stillbirth globally. Improving investigation of stillbirths and standardisation of audit and classification is urgently needed and should be achievable in all well-resourced settings. Implementation of the WHO Perinatal Mortality Audit and Review guide is needed, particularly across high burden settings. FUNDING: HR, SH, SHL, and AW were supported by an NHMRC-CRE grant (APP1116640). VF was funded by an NHMRC-CDF (APP1123611). TWEETABLE ABSTRACT: Urgent need to improve data on causes of stillbirths across all settings to meet global targets. PLAIN LANGUAGE SUMMARY: Background and methods Nearly three million babies are stillborn every year. These deaths have deep and long-lasting effects on parents, healthcare providers, and the society. One of the major challenges to preventing stillbirths is the lack of information about why they happen. In this study, we collected reports on the causes of stillbirth from high-, middle-, and low-income countries to: (1) Understand the causes of stillbirth, and (2) Understand how to improve reporting of stillbirths. Findings We found 85 reports from 50 different countries. The information available from the reports was inconsistent and often of poor quality, so it was hard to get a clear picture about what are the causes of stillbirth across the world. Many different definitions of stillbirth were used. There was also wide variation in what investigations of the mother and baby were undertaken to identify the cause of stillbirth. Stillbirths in all income settings (low-, middle-, and high-income countries) were most frequently reported as Unexplained, Other, and Haemorrhage (bleeding). Unexplained and Other are not helpful in understanding why a baby was stillborn. In low-income countries, stillbirths were often attributed to Infection and Complications during labour and birth. In middle- and high-income countries, stillbirths were often reported as Placental complications. Limitations We may have missed some reports as searches were carried out in English only. The available reports were of poor quality. Implications Many countries, particularly those where the majority of stillbirths occur, do not report any information about these deaths. Where there are reports, the quality is often poor. It is important to improve the investigation and reporting of stillbirth using a standardised system so that policy makers and healthcare workers can develop effective stillbirth prevention programs. All stillbirths should be investigated and reported in line with the World Health Organization standards.
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Mortinato , Causas de Muerte , Femenino , Salud Global , Humanos , Servicios de Salud Materna , Embarazo , Complicaciones del Embarazo/prevención & controlAsunto(s)
Placenta Accreta , Cesárea , Femenino , Humanos , Histerectomía , Placenta Accreta/cirugía , EmbarazoRESUMEN
Chronic lung disease of prematurity (CLD) is a frequent sequela of premature birth and oxygen toxicity is a major associated risk factor. Impaired alveolarization, scarring, and inflammation are hallmarks of CLD. Mast cell hyperplasia is a feature of CLD but the role of mast cells in its pathogenesis is unknown. We hypothesized that mast cell hyperplasia is a consequence of neonatal hyperoxia and contributes to CLD. Additionally, mast cell products may have diagnostic and prognostic value in preterm infants predisposed to CLD. To model CLD, neonatal wild-type and mast cell-deficient mice were placed in an O2 chamber delivering hyperoxic gas mixture [inspired O2 fraction (FiO2 ) of 0.8] (HO) for 2 wk and then returned to room air (RA) for an additional 3 wk. Age-matched controls were kept in RA (FiO2 of 0.21). Lungs from HO mice had increased numbers of mast cells, alveolar simplification and enlargement, and increased lung compliance. Mast cell deficiency proved protective by preserving air space integrity and lung compliance. The mast cell mediators ß-hexosaminidase (ß-hex), histamine, and elastase increased in the bronchoalveolar lavage fluid of HO wild-type mice. Tracheal aspirate fluids (TAs) from oxygenated and mechanically ventilated preterm infants were analyzed for mast cell products. In TAs from infants with confirmed cases of CLD, ß-hex was elevated over time and correlated with FiO2 Mast cell exosomes were also present in the TAs. Collectively, these data show that mast cells play a significant role in hyperoxia-induced lung injury and their products could serve as potential biomarkers in evolving CLD.
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Displasia Broncopulmonar/patología , Exosomas/metabolismo , Hiperoxia/patología , Mastocitos/metabolismo , Animales , Animales Recién Nacidos , Displasia Broncopulmonar/inmunología , Displasia Broncopulmonar/metabolismo , Células Cultivadas , Humanos , Hiperoxia/inmunología , Hiperoxia/metabolismo , Recién Nacido , Pulmón/inmunología , Pulmón/patología , Ratones , Proteoma/metabolismo , Tráquea/metabolismoRESUMEN
Acousto-optic deflectors (AODs) arranged in series and driven with linearly chirped frequencies can rapidly focus and tilt optical wavefronts, enabling high-speed 3D random access microscopy. Non-linearly chirped acoustic drive frequencies can also be used to shape the optical wavefront allowing a range of higher-order aberrations to be generated. However, to date, wavefront shaping with AODs has been achieved by using single laser pulses for strobed illumination to 'freeze' the moving acoustic wavefront, limiting voxel acquisition rates. Here we show that dynamic wavefront shaping can be achieved by applying non-linear drive frequencies to a pair of AODs with counter-propagating acoustic waves, which comprise a cylindrical acousto-optic lens (AOL). Using a cylindrical AOL we demonstrate high-speed continuous axial line scanning and the first experimental AOL-based correction of a cylindrical lens aberration at 30 kHz, accurate to 1/35th of a wave at 800 nm. Furthermore, we develop a model to show how spherical aberration, which is the major aberration in AOL-based remote-focusing systems, can be partially or fully corrected with AOLs consisting of four or six AODs, respectively.