Normative spatiotemporal fetal brain maturation with satisfactory development at 2 years.

Maturation of the human fetal brain should follow precisely scheduled structural growth and folding of the cerebral cortex for optimal postnatal function1. We present a normative digital atlas of fetal brain maturation based on a prospective international cohort of healthy pregnant women2, selected using World Health Organization recommendations for growth standards3. Their fetuses were accurately dated in the first trimester, with satisfactory growth and neurodevelopment from early pregnancy to 2 years of age4,5. The atlas was produced using 1,059 optimal quality, three-dimensional ultrasound brain volumes from 899 of the fetuses and an automated analysis pipeline6-8. The atlas corresponds structurally to published magnetic resonance images9, but with finer anatomical details in deep grey matter. The between-study site variability represented less than 8.0% of the total variance of all brain measures, supporting pooling data from the eight study sites to produce patterns of normative maturation. We have thereby generated an average representation of each cerebral hemisphere between 14 and 31 weeks' gestation with quantification of intracranial volume variability and growth patterns. Emergent asymmetries were detectable from as early as 14 weeks, with peak asymmetries in regions associated with language development and functional lateralization between 20 and 26 weeks' gestation. These patterns were validated in 1,487 three-dimensional brain volumes from 1,295 different fetuses in the same cohort. We provide a unique spatiotemporal benchmark of fetal brain maturation from a large cohort with normative postnatal growth and neurodevelopment.

Association Between Preterm-Birth Phenotypes and Differential Morbidity, Growth, and Neurodevelopment at Age 2 Years: Results From the INTERBIO-21st Newborn Study.

Importance: The etiologic complexities of preterm birth remain inadequately understood, which may impede the development of better preventative and treatment measures. Objective: To examine the association between specific preterm-birth phenotypes and clinical, growth, and neurodevelopmental differences among preterm newborns compared with term newborns up to age 2 years. Design, Setting, and Participants: The INTERBIO-21st study included a cohort of preterm and term newborn singletons enrolled between March 2012 and June 2018 from maternity hospitals in 6 countries worldwide who were followed up from birth to age 2 years. All pregnancies were dated by ultrasonography. Data were analyzed from November 2019 to October 2020. Exposures/Interventions: Preterm-birth phenotypes. Main Outcomes and Measures: Infant size, health, nutrition, and World Health Organization motor development milestones assessed at ages 1 and 2 years; neurodevelopment evaluated at age 2 years using the INTERGROWTH-21st Neurodevelopment Assessment (INTER-NDA) tool. Results: A total of 6529 infants (3312 boys [50.7%]) were included in the analysis. Of those, 1381 were preterm births (mean [SD] gestational age at birth, 34.4 [0.1] weeks; 5148 were term births (mean [SD] gestational age at birth, 39.4 [0] weeks). Among 1381 preterm newborns, 8 phenotypes were identified: no main maternal, fetal, or placental condition detected (485 infants [35.1%]); infections (289 infants [20.9%]); preeclampsia (162 infants [11.7%]); fetal distress (131 infants [9.5%]); intrauterine growth restriction (110 infants [8.0%]); severe maternal disease (85 infants [6.2%]); bleeding (71 infants [5.1%]); and congenital anomaly (48 infants [3.5%]). For all phenotypes, a previous preterm birth was a risk factor for recurrence. Each phenotype displayed differences in neonatal morbidity and infant outcomes. For example, infants with the no main condition detected phenotype had low neonatal morbidity but increased morbidity and hospitalization incidence at age 1 year (odds ratio [OR], 2.2; 95% CI, 1.8-2.7). Compared with term newborns, the highest risk of scoring lower than the 10th centile of INTER-NDA normative values was observed in the fine motor development domain among newborns with the fetal distress (OR, 10.6; 95% CI, 5.1-22.2) phenotype. Conclusions and Relevance: Results of this study suggest that phenotypic classification may provide a better understanding of the etiologic factors and mechanisms associated with preterm birth than continuing to consider it an exclusively time-based entity.

Fetal cranial growth trajectories are associated with growth and neurodevelopment at 2 years of age: INTERBIO-21st Fetal Study.

Many observational studies and some randomized trials demonstrate how fetal growth can be influenced by environmental insults (for example, maternal infections)1 and preventive interventions (for example, multiple-micronutrient supplementation)2 that can have a long-lasting effect on health, growth, neurodevelopment and even educational attainment and income in adulthood3. In a cohort of pregnant women (n = 3,598), followed-up between 2012 and 2019 at six sites worldwide4, we studied the associations between ultrasound-derived fetal cranial growth trajectories, measured longitudinally from <14 weeks' gestation, against international standards5,6, and growth and neurodevelopment up to 2 years of age7,8. We identified five trajectories associated with specific neurodevelopmental, behavioral, visual and growth outcomes, independent of fetal abdominal growth, postnatal morbidity and anthropometric measures at birth and age 2. The trajectories, which changed within a 20-25-week gestational age window, were associated with brain development at 2 years of age according to a mirror (positive/negative) pattern, mostly focused on maturation of cognitive, language and visual skills. Further research should explore the potential for preventive interventions in pregnancy to improve infant neurodevelopmental outcomes before the critical window of opportunity that precedes the divergence of growth at 20-25 weeks' gestation.

Estimating family planning coverage from contraceptive prevalence using national household surveys.

BACKGROUND: Contraception is one of the most important health interventions currently available and yet, many women and couples still do not have reliable access to modern contraceptives. The best indicator for monitoring family planning is the proportion of women using contraception among those who need it. This indicator is frequently called demand for family planning satisfied and we argue that it should be called family planning coverage (FPC). This indicator is complex to calculate and requires a considerable number of questions to be included in a household survey. OBJECTIVES: We propose a model that can predict FPC from a much simpler indicator - contraceptive use prevalence - for situations where it cannot be derived directly. DESIGN: Using 197 Multiple Indicator Cluster Surveys and Demographic and Health Surveys from 82 countries, we explored least-squares regression models that could be used to predict FPC. Non-linearity was expected in this situation and we used a fractional polynomial approach to find the best fitting model. We also explored the effect of calendar time and of wealth on the models explored. RESULTS: Given the high correlation between the variables involved in FPC, we managed to derive a relatively simple model that depends only on contraceptive use prevalence but explains 95% of the variability of the outcome, with high precision for the estimated regression line. We also show that the relationship between the two variables has not changed with time. A concordance analysis showed agreement between observed and fitted results within a range of ±9 percentage points. CONCLUSIONS: We show that it is possible to obtain fairly good estimates of FPC using only contraceptive prevalence as a predictor, a strategy that is useful in situations where it is not possible to estimate FPC directly.

Desarrollo de un método de transcripción inversa seguida de reacción en cadena de la polimerasa para la detección del virus de la fiebre amarilla / Development of a reverse transcription polymerase chain reaction method for yellow fever virus detection

Introduction. Yellow fever is considered a re-emerging disease and is endemic in tropical regions of Africa and South America. At present, there are no standardized or commercialized kits available for yellow fever virus detection. Therefore, diagnosis must be made by time-consuming routine techniques, and sometimes, the virus or its proteins are not detected. Furthermore, co-circulation with other flaviviruses, including dengue virus, increases the difficulty of diagnosis. Objective. To develop a specific reverse transcriptase-polymerase chain reaction (RT-PCR) and nested PCR-based assay to improve the detection and diagnosis of yellow fever virus using both serum and fresh tissue samples. Materials and methods. RT-PCR primers were designed to amplify a short fragment of all yellow fever virus genotypes reported. A second set of primers was used in a nested PCR to increase sensitivity. Thirty-three clinical samples were tested with the standardized reaction. Results. The expected amplicon was obtained in 25 out of 33 samples analyzed using this approach, and 2 more samples tested positive after a subsequent nested PCR approach. Conclusion. This improved technique not only ensures the specific detection of a wide range of yellow fever virus genotypes but also may increase the sensitivity of detection by introducing a second round of amplification, allowing a rapid differential diagnosis between dengue and yellow fever infection, which is required for effective surveillance and opportune epidemiologic measures.

Introducción. La fiebre amarilla se considera una enfermedad reemergente y endémica en regiones tropicales de África y Suramérica. Actualmente, no existen estuches estandarizados o comerciales disponibles para la detección del virus de la fiebre amarilla y, por lo tanto, el diagnóstico debe hacerse mediante técnicas de rutina que consumen mucho tiempo y algunas veces no garantizan la detección del virus o de sus proteínas. Además, la cocirculación con otros flavivirus, incluyendo el del dengue, hacen el diagnóstico más complicado. Objetivo. Desarrollar un ensayo específico de amplificación basado en transcripción inversa seguida de reacción en cadena de la polimerasa, con el fin de mejorar la detección y el diagnóstico de la fiebre amarilla, tanto a partir de suero como de tejido fresco. Materiales y métodos. Se diseñaron iniciadores específicos para amplificar un fragmento conservado del virus de la fiebre amarilla. Un segundo par de iniciadores se usó en una reacción de amplificación anidada para incrementar la sensibilidad. Se probaron 33 muestras clínicas con la técnica estandarizada. Resultados. El amplímero esperado se obtuvo en 25 de las 33 muestras analizadas usando este método y 2 más resultaron positivas después de la reacción anidada. Conclusión. Esta técnica mejorada garantiza la detección de todos los genotipos virales de fiebre amarilla y puede incrementar la sensibilidad del ensayo introduciendo una segunda etapa de amplificación, lo cual permite el diagnóstico diferencial con infección por dengue y otros flavivirus, lo cual es de gran importancia para la vigilancia y la toma de medidas epidemiológicas oportunas.

Development of a reverse transcription polymerase chain reaction method for yellow fever virus detection.

INTRODUCTION: Yellow fever is considered a re-emerging disease and is endemic in tropical regions of Africa and South America. At present, there are no standardized or commercialized kits available for yellow fever virus detection. Therefore, diagnosis must be made by time-consuming routine techniques, and sometimes, the virus or its proteins are not detected. Furthermore, co-circulation with other flaviviruses, including dengue virus, increases the difficulty of diagnosis. OBJECTIVE: To develop a specific reverse transcriptase-polymerase chain reaction (RT-PCR) and nested PCR-based assay to improve the detection and diagnosis of yellow fever virus using both serum and fresh tissue samples. MATERIALS AND METHODS: RT-PCR primers were designed to amplify a short fragment of all yellow fever virus genotypes reported. A second set of primers was used in a nested PCR to increase sensitivity. Thirty-three clinical samples were tested with the standardized reaction. RESULTS: The expected amplicon was obtained in 25 out of 33 samples analyzed using this approach, and 2 more samples tested positive after a subsequent nested PCR approach. CONCLUSION: This improved technique not only ensures the specific detection of a wide range of yellow fever virus genotypes but also may increase the sensitivity of detection by introducing a second round of amplification, allowing a rapid differential diagnosis between dengue and yellow fever infection, which is required for effective surveillance and opportune epidemiologic measures.

Childbearing during adolescence and offspring mortality: findings from three population-based cohorts in southern Brazil.

BACKGROUND: The role of young maternal age as a determinant of adverse child health outcomes is controversial, with existing studies providing conflicting results. This work assessed the association between adolescent childbearing and early offspring mortality in three birth cohort studies from the city of Pelotas in Southern Brazil. METHODS: All hospital births from 1982 (6,011), 1993 (5,304), and 2004 (4,287) were identified and these infants were followed up. Deaths were monitored through vital registration, visits to hospitals and cemeteries. The analyses were restricted to women younger than 30 years who delivered singletons (72%, 70% and 67% of the original cohorts, respectively). Maternal age was categorized into three groups (< 16, 16-19, and 20-29 years). Further analyses compared mothers aged 12-19 and 20-29 years. The outcome variables included fetal, perinatal, neonatal, postneonatal and infant mortality. Crude and adjusted odds ratios (ORs) were estimated with logistic regression models. RESULTS: There were no interactions between maternal age and cohort year. After adjustment for confounding, pooled ORs for mothers aged 12-19 years were 0.6 (95% CI = 0.4; 1.0) for fetal death, 0.9 (0.6; 1.3) for perinatal death, 1.0 (0.7; 1.6) for early neonatal death, 1.6 (0.7; 3.4) for late neonatal death, 1.8 (1.1; 2.9) for postneonatal death, and 1.6 (1.2; 2.1) for infant death, when compared to mothers aged 20-29 years. Further adjustment for mediating variables led to the disappearance of the excess of postneonatal mortality. The number of mothers younger than 16 years was not sufficient for most analyses. CONCLUSION: The slightly increased odds of postneonatal mortality among children of adolescent mothers suggest that social and environmental factors may be more important than maternal biologic immaturity.

Axonal degeneration in sheep caused by the ingestion of Halimium brasiliense.

Nervous system disease is reported in sheep from 2 farms in southern Brazil and in 33 farms in Uruguay. The illness was seasonal, occurring from May to November, during the growing season of Halimium brasiliense, and primarily affected sheep older than 3 years of age. Clinical signs included transient seizures that occurred mainly when sheep were disturbed or frightened. Most affected sheep recovered when removed to other pastures. Feeding trials produced clinical signs in 1 sheep after the ingestion of 2,117 g/kg of body weight of H. brasiliense over 142 days. Two sheep that had previously recovered from spontaneous toxicosis developed clinical signs after the ingestion of 263 g and 565 g of H. brasiliense per kg body weight given over 36 and 31 days, respectively. The main histologic lesion was vacuolation of the brain and spinal cord, with rare axonal spheroid formation. Transmission electron microscopy revealed segmental axonal swelling with degeneration and disappearance of the axonal organelles and vacuolation of the axoplasm. A pigment identified as ceroid was also present in neurons, astrocytes, and macrophages. These lesions suggested a novel morphologic manifestation of a toxic axonopathy.

Conjunctival pigmentation in Stevens-Johnson syndrome.

We report a 29-year-old white female with conjunctival pigmentation after a Stevens-Johnson syndrome (SJS) episode triggered by sulfasalazine. The patient developed bilateral tarsal and forniceal conjunctiva and black pigmentation. Diagnostic biopsy showed stromal monocyte infiltration consistent with chronic phase SJS and conjunctival pigment of melanic origin and not due to drug deposition. Treatment with topical steroids and unpreserved artificial tears resulted in improvement of clinical symptoms; however, pigmentation was unchanged after 2 years.

Conjunctival pigmentation in Stevens-Johnson syndrome.

We report a 29-year-old white woman with conjunctival pigmentation after a Stevens-Johnson syndrome (SJS) episode triggered by sulfasalazine. The patient developed bilateral tarsal and forniceal conjunctiva and black pigmentation. Diagnostic biopsy showed stromal monocyte infiltration consistent with chronic phase SJS and conjunctival pigment of melanic origin that was not due to drug deposition. Treatment with topical steroids and unpreserved artificial tears resulted in improvement of clinical symptoms; however, pigmentation was unchanged after 2 years.

Histopathology of epi-LASIK in eyes with virgin corneas and eyes with previously altered corneas.

PURPOSE: To perform a histological analysis of free epithelial flaps that were intentionally created with an Epi-K epikeratome (Moria S.A.) during epi-LASIK in eyes with virgin corneas and eyes with previous corneal surgery or keratoconus. SETTING: Vissum-Instituto Oftalmológico de Alicante, Alicante, Spain. METHODS: This prospective and consecutive case series comprised 18 free flaps obtained from 18 patients. Twelve patients had virgin corneas, and 6 had altered corneas from previous surgery, trauma, or keratoconus. The flaps were fixed in 4% buffered formaldehyde (pH 7) for posterior histopathological analysis. Serial cuts of each flap were performed, and the sheets were stained with hematoxylin-eosin and periodic acid-Schiff. The main outcome measure was the histopathology of the corneal flaps. RESULTS: All flaps from virgin corneas consisted entirely of epithelium without residual stromal tissue or Bowman's layer. Histopathological analysis of the flaps after epi-LASIK in patients with previously altered corneas showed varying levels of stroma in all cases. CONCLUSION: Epi-LASIK with the Epi-K epikeratome effectively cleaved the epithelium from Bowman's layer in healthy corneas; however, when the integrity of Bowman's layer is compromised, epi-LASIK should be avoided as stromal invasion will likely occur.

Cavitary choroidal melanoma.

CASE REPORT: We report an unusual case of cavitary choroidal melanoma. The results of ultrasonography, magnetic resonance imaging, computed tomography, and immunohistochemical studies are presented for a 38-year-old woman who developed an amelanotic tumor in the posterior choroid. B-scan ultrasonography disclosed intratumoral cavitations. Systemic and extraocular extension studies were negative. Enucleation was performed and histopathologic examination showed a choroidal melanoma of spindle cell type, with intratumoral cavitations lined by flattened tumor cells. COMMENTS: The majority of previous reports of intraocular cavitary tumors describe cavitary ciliary body tumors. Uveal melanoma should be included in the differential diagnosis of choroidal cavitary lesions. As far as we know, this is the second documented clinicopathologic correlation of a cavitary choroidal melanoma.

Cetose em vacas de corte em gestaçäo / Ketosis in pregnant beef cows

Descreveram-se 6 surtos de cetose em bovinos de corte que ocorreram durante o inverno, em vacas gordas ou em bom estado nos últimos 3 meses de gestaçäo, submetidas a períodos variáveis de carência alimentar. Os animais apresentaram constipaçäo, incoordenaçäo, tremores musculares e hiperexcitabilidade, com posterior decúbito e morte após uma evoluçäo de 3 a 7 dias. Nas necrópsias a única alteraçäo significativa foi a degeneraçäo graxa do fígado. Os surtos foram controlados mediante uma alimentaçäo adequada

Intoxicaçäo crônica por cobre em ovinos no Rio Grande do Sul / Chronic copper poisoning in sheep in Rio Grande do Sul, southern Brazil

Descreve-se intoxicaçäo crônica por cobre (Cu) em ovinos estabulados em 4 estabelecimentos no Rio Grande do Sul. Os sinais clínicos e as lesöes macroscópicas e histológicas foram características da intoxicaçäo. Os níveis de Cu em fígado e rins de 5 ovinos afetados variaram de 489 a 1760 ppm e 60 a 470 ppm na matéria seca, respectivamente. Os níveis de Cu em 28 raçöes, provenientes de 8 diferentes fabricantes, foram de 23,2 ñ 6,73 (X ñ S). Conclui-se que a intoxicaçäo ocorre devido aos altos níveis de Cu das raçöes para ovinos utilizadas no Rio Grande do Sul. Recomenda-se näo adicionar cobre na formulaçäo de raçöes para essa espécie