Despite remarkable progress in maternal and neonatal health over past two decades, maternal and neonatal mortality in Bangladesh remain high, which is partially attributable to low use of skilled maternal and newborn health (MNH) services. Birth preparedness and complications readiness (BCPR) is recommended by the World Health Organization and by the Government of Bangladesh as a key intervention to increasing appropriate MNH services. This study aims to explore the status of BPCR in a hard-to-reach area of rural Bangladesh and to demonstrate how BPCR practices is associated with birth in the presence of a skilled birth attendant.Data was collected using multistage cluster sampling-based household survey in two sub-districts of Netrokona, Bangladesh in 2014. Interviews were conducted among women with a recent birth history in 12-months and their husbands. Univariate, bivariate, and multivariable analysis using Stata 14.0 were performed from 317 couples.Mean age of respondents was 26.1 (SD ± 5.3) years. There was a significant difference in BPCR practice between women and couples for identification of the place of birth (84% vs. 75%), identification of a birth attendant (89% vs.72%), arranging transport for birth or emergencies (20% vs. 13%), and identification of a blood donor (15% vs. 8%). In multivariable analysis, odds of giving birth in presence of a skilled birth attendant consistently increased with higher completeness of preparedness . For different levels of completeness of BPCR practice, the adjusted odds ratios were higher for couple preparedness comparatively.BPCR is associated with birth in the presence of a skilled attendant and this effect is magnified when planning is carried out by the couple. Interventions aiming to increase BPCR practices should not focus on women only, as involving the couple is most likely lead to positive care-seeking practices. Despite global progress, 303,000 women continue to die each year worldwide due to causes related to pregnancy and childbirth. Ninety-nine percent of these deaths, nearly all preventable, occur in low- and middle-income countries . BetweenWhile Bangladesh has made remarkable strides in reducing maternal and neonatal death over the past two decades, the progress was not sufficient for the country to achieve MDG-5 target  and MMR In the new era of the Sustainable Development Goals (SDGs), maternal and newborn health (MNH) has been retained as a priority. The 2030 UN Agenda aims to achieve a MMR of ≤70 deaths per 100,000 live births, and NMR of ≤12 per 1,000 live births for every country. Most countries, including Bangladesh, have declared their commitment to achieve these targets, which will require countries to maximize their efforts to ensure access to and utilization of MNH care . In addiRecognized globally as a key approach for promoting the use of skilled MNH care for women and newborns, BPCR is the process through which women and families plan actions in anticipation of birth and possible obstetric and neonatal emergencies . It has While BPCR is recommended as an integrated element of ANC contacts which are generally one-to-one interactions between women and health services providers, the benefits of BPCR practice are likely to be optimized when it is undertaken as a joint process between women and household decision-makers, and particularly male partners –18. IndeIn Bangladesh, utilization of MNH care remains low: less than half (42%) of births are attended by a skilled birth attendant . The recTo date, some evidence exists regarding the status of BPCR practice in Bangladesh , howeverhaors. Agriculture and fishing are the primary sources of income. The sub-district of Kalmakanda has a land area of 377 square kilometres and a total population of around 272,000. Barhatta covers 220 square kilometres of land with a total population of approximately 180,000.A community-based, cross-sectional household survey was conducted in hard-to-reach two sub-districts, Barhatta and Kalmakanda, of Netrokona district in Bangladesh in 2014. Netrokona is located approximately 200 kilometres north of Dhaka, the capital of Bangladesh. It is one of the 14 lowest performing districts of Bangladesh in terms of newborn and child mortality rates . NetrokoKalmakanda was included in the study as it had been selected as the implementation site of a programme focusing on health promotion and community engagement actions to improve MNH. This programme was implemented by ‘PARI Development Trust’, a local non-governmental organization (NGO), in collaboration with the Directorate General of Health Services (DGHS) and the Directorate General of Family Planning (DGFP)- branches of the Ministry of Health and Family Welfare (MOHFW). Enfants du Monde (EdM), a Geneva-based NGO provided technical support to the programme and icddr,b  conducted evaluation independently. One of the key planned interventions was the promotion of BPCR, which was initiated following the baseline study. Barhatta, an adjacent sub-district to Kalmadanda, was selected as the control site.Eligible women who gave birth within the 12-month period preceding the survey and their husbands/partners were included in the study.The sample size was calculated for evaluating the effectiveness of the health promotion and community engagement intervention package on giving birth in the presence of a skilled birth attendant. As planned, the intervention package was delivered in one of the above mentioned sub-districts  and study adopted a quasi-experimental design with a comparison sub-district (Barhatta).As baseline assumption for sample size calculation, we considered the estimates from the BMMS 2010 report  where the coverage of birth with a skilled birth attendant in Netrokona was reported to be 15.6%. We assumed a minimum of a 10-percentage point (absolute) increase in coverage of skilled birth attendance between baseline and endline. We also wanted to ensure a higher sample from the intervention site (intervention: comparison = 1.5:1). The unadjusted sample size was 404 from the intervention site and 269 from the comparison site at 80% power and 5% error probabilities. The sample size was then adjusted for design effect/cluster effect (1.25) and non-response/loss to follow up (5%). The final sample size was 425 from the intervention site and 283 from the comparison site at baseline and at endline. We present here the findings from the baseline survey. At baseline (conducted in 2014), we interviewed 725 women with a recent birth history at baseline (444 from the intervention site and 281 from the comparison site). We approached all husbands of the women and conducted 317 interviews successfully. Information from 317 wife-husband dyads is presented in this paper.This study used a multistage cluster sampling to select eligible respondents. In the first stage, four unions  were randomly selected from each of the selected sub-districts. In the second stage, four clusters  were selected from each union using the probability proportional to size (PPS) sampling technique. All eligible respondents were included from the selected clusters.In the first stage of sampling, a sketch map was drawn for each of the selected clusters representing boundaries, landmarks and bari (extended household) locations. All households and women who had a birth outcome in the 12 months preceding the survey were enumerated and listed. In the second stage, separate structured questionnaires were used for interviewing all eligible women and their husbands . The queData was analysed using Stata 14.0 . Women’s education, husbands’ education and women’s age were converted to categorical variables from continuous variables. Religion was re-categorised to Muslim and “other”, as all other religions had smaller frequencies. The household asset score was generated using the principal component analysis , 24. TheBPCR practices among women and couples were considered as the main explanatory factors. Birth in presence of a skilled birth attendant was considered to be the primary outcome of interest. Regarding BPCR practices, the following five components were included in the analysis as per the Bangladesh Maternal Health Strategy: identifying the place of birth, identifying a birth attendant, arranging transport, saving money for emergencies and identifying a potential blood donor. Couple preparedness for individual components of BPCR was considered when both the women and her husband/partner reporting to be prepared for that component. Complete BPCR was defined as having planned for 3–5 components of BPCR. We have also presented the completeness for 4–5 components and for all 5 components. Good BPCR practices were defined as the following: planning to give birth in a health facility or at home with a skilled birth attendant, discussing BPCR components with a health care provider and discussing BPCR components with the spouse. Regarding the primary outcome of interest, birth was considered to be in the presence of a skilled birth attendant if it occurred in a health facility or if a skilled birth attendant was present during a home birth .We used descriptive statistics (both univariate and bivariate) to describe BPCR practices among women and couples. Proportion test (z test) was conducted to see the statistically significant difference of BPCR practice between women and couples.The associations between individual components of BPCR practice and birth in the presence of a skilled birth attendant were assessed using multiple logistic regressions after adjusting for known confounders  when they have showed significant associations in bivariate analysis . Any sigEthical approval to conduct the study was obtained from the Institutional Review Board of icddr,b (Protocol Number: PR 14024). All participants interviewed in our survey were married and had a birth outcome in twelve months preceding the survey. As per the IRB recommendations, any married woman with a child can give consent for interviews in the Bangladeshi context (irrespective of age). Moreover, in the Bangladeshi context women move to their husbands’ residents (home) after marriage. Parents are not considered as the guardian of women after marriage irrespective of their age. In addition, husbands were informed regarding the interviews. Prior to interviews, participants were informed of the voluntary nature of their participation and their right to withdraw at any time during the study. They were also informed that refusal to participate in the study would not involve any penalty. Written and informed consent was obtained from each participant once they were fully informed. Privacy, anonymity and confidentiality of the participants were strictly maintained during data collection and analysis.The proportion of women who gave birth in health facility or with presence of a skilled birth attendant at home was 16.5%. Preparing for birth and potential complications has been identified globally and at country level as a key strategy and intervention for ensuring birth in the presence of a skilled birth attendant and improving the health of women and newborns , 14, 20.Not surprisingly, we find that BPCR practice in Netrokona is insufficient. Netrokona is among the lowest performing districts, reflected in basic development indicators , and thiAmong our study participants, we observe wide variations in planning across the five key components. Identifying a birth place and a birth attendant is the most common practice, with the majority of respondents planning for these components. However, optimal planning of a birth place and a birth attendant remains the exception among our participants, as few women and couples planned for birth in a health facility or arranged for a home birth in presence of a skilled birth attendant. This may be due to the lack of availability of skilled MNH care or to religious and cultural preferences toward giving birth at home . Such suBeyond these components, saving money for potential costs related to obstetric and neonatal emergencies was the next most common BPCR practice among our participants, followed by arranging transportation. Identification of a potential blood donor remains the most neglected component of BPCR according to our findings, with only 15% of women identifying a blood donor, and less than 10% of couples making such preparations. Our findings are generally consistent with other studies conducted in Africa and India which have found saving money to be a relatively common BPCR practice, followed by arranging transportation. Identification of a potential blood donor is consistently the rarest component taken into consideration , 34–37. Another of our key findings is that intention to deliver in a facility was highly predictive of giving birth in a facility. Though the proportion of women who planned to give birth in a facility was small, almost all who made this plan followed through on it. This finding contrasts with a study conducted in Tanzania, which found that nearly 40% of women who had planned a facility birth were not able to follow through on this plan . This maIn terms of male involvement, studies throughout Africa and Asia have demonstrated the involvement of men in birth preparedness and complication readiness to be context specific, with low overall involvement in some regions and high in others, with wide variation across components . In thisThe global evidence regarding the impact of BPCR practice on birth in presence of a skilled birth attendant has been mixed, with some studies finding a positive association between BPCR and skilled care, and others failing to find this relationship , 42. WhiWhile women’s planning had a predictive value of birth with a skilled birth attendant, joint planning within the couple magnified this effect across all components, BPCR completeness and BPCR good practices. This is particularly striking with regard to completeness of planning: women were significantly more likely to give birth in presence of a skilled birth attendant when the couples planned for three or four components of BPCR compared to when women undertake this planning. In addition, couples planning over independent planning by the women increased the odds of giving birth in the presence of a skilled birth attendant for the individual BPCR components and for good practices. This is consistent with a study conducted in Uganda looking at decision-making on birth preparedness planning and its influence on giving births in the presence of a skilled birth attendant among women. This study found that women who made joint decisions with spouses or other close persons  were more likely to give birth in the presence of a skilled birth attendant compared to when women undertook this planning alone .The finding that couples’ planning has an added value over woman planning is not surprising, particularly in a context such as that found in Netrokona, where women’s autonomy and decision-making remain limited . Women aOur study suggests that BPCR contributes to birth in the presence of a skilled birth attendant and that having men engaged in BPCR increases its potential benefits. The majority of studies on BPCR have been conducted in the context of Africa. Future research on BPCR should be conducting in Asian and other contexts to more fully understand the relationship between BPCR and use of skilled health services in these regions of the world. Furthermore, future research should seek to better understand how best to promote BPCR in such resource poor-setting and to include men in a way which contributes to the health and well-being of women and children.As this was a cross-sectional survey, we cannot establish causality between BPCR and the outcomes assessed. In addition, recall bias may be a limitation as respondents who had a birth in presence a skilled birth attendant may recall the practices related to BPCR more than those who did not give birth in presence a skilled birth attendant. However, we tried to minimize the recall bias by asking the questions related to BPCR before the questions related to utilization of MNH care. Moreover, some of the respondents may not have accurately remembered the details which they were asked about. However, we expect the recall error to be similar between the two outcome groups, hence will not bias the findings. There is also the possibility of social desirability bias; we believe that this limitation was mitigated to some degree by recruiting local data collectors.In addition, we know that other family members can also play an important role in the Bangladeshi context. However, we were unable to collect additional information regarding other family members in this survey. Future research should explore this additional element.Our findings suggest that BPCR is directly associated with giving birth with a skilled birth attendant, which is identified globally as a key intervention for saving the lives of women and newborns. Actions aiming to increase good BPCR practices should be prioritized, particularly in resource-poor, hard-to-reach settings such as Netrokona, where women are likely to face many challenges to accessing skilled care. Moreover, our results indicate that the benefits of the BPCR practice are maximized when it is more complete and when it is a joint process undertaken by the couple. Interventions aiming to increase BPCR practice should focus on ensuring complete preparedness. Moreover, they should move beyond focusing on women only and also target the couples as joint planning within the couple is most likely to lead to positive care-seeking practices.S1 Table(PDF)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S1 Dataset(DTA)Click here for additional data file.


Infant mortality rates are commonly used to compare the health of populations. Observed differences are often attributed to variation in child health care quality. However, any differences are at least partly explained by variation in the prevalence of risk factors at birth, such as low birth weight. This distinction is important for designing interventions to reduce infant mortality. We suggest a simple method for decomposing inter-country differences in crude infant mortality rates into two metrics representing risk factors operating before and after birth.We used data from 7 European countries participating in the EURO-PERISTAT project in 2010. We calculated crude and birth weight-standardised stillbirth and infant mortality rates using Norway as the standard population. We decomposed between-country differences in crude stillbirth and infant mortality rates into the within-country difference in crude and birth weight-standardised stillbirth and infant mortality rates (metric 1), reflecting prenatal risk factors, and the between-country difference in birth weight-standardised stillbirth and infant mortality rates (metric 2), reflecting risk factors operating after birth. We also calculated birth weight-specific mortality.Using our metrics, we showed that for England, Wales and Scotland risk factors before and after birth contributed equally to the differences in crude stillbirth and infant mortality rates relative to Norway. In Austria, Czech Republic and Switzerland the differences were driven primarily by metric 1, reflecting high rate of low birth weight. The highest values of metric 2 observed in Poland partially reflected high rates of congenital anomalies.Our suggested metrics can be used to guide policy decisions on preventing infant deaths through reducing risk factors at birth or improving the care of babies after birth. Aggregate data tabulated by birth weight/gestational age should be routinely collected and published in high-income countries where birth weight is reported on birth certificates.The online version of this article (10.1186/s12884-017-1622-z) contains supplementary material, which is available to authorized users. Infant mortality is an important indicator of the health of a nation. It reflects the quality of obstetric and neonatal care, the health and welfare of women before conception and during pregnancy, and the health of children after birth –4. InfanInternational comparisons of infant mortality are a commonly used indicator for international organisations  , 7, the Observed discrepancies in infant mortality can often be partly explained by variation in the prevalence of key risk factors at birth such as preterm birth (< 37 weeks), or low birth weight < 2500 g) [500 g 2,, 13. A kWe demonstrate a simple method for international infant mortality comparisons. We describe two intuitive metrics which can inform policy makers about the extent to which any observed differences between countries relate to disparities in the prevalence of low birth weight (or prematurity), or to the risk of death in babies born with these risk factors. This decomposition of international differences in crude mortality rates can be used to guide policy decisions on preventing infant deaths through reducing risk factors at birth or improving the care of babies after birth.We used counts of live births, stillbirths, neonatal and post-neonatal deaths from perinatal health information systems collected by the EURO-PERISTAT project for 31 European countries. EURO-PERISTAT project aimed to collect comparable data about the health and care of mothers and babies in Europe to produce reliable and unbiased indicators of perinatal health . Out of In order to minimise bias due to inter-country differences in recording of live births and deaths at borderline viability and in legal limits for terminations of pregnancy  , 18, 19.Equation 1 - Defining stillbirth and infant mortality rate and its subcomponentsWe then needed to select a standard population. Usually this would be one with a low prevalence of low birth weight, since we are interested in calculating the maximum possible reduction in early life mortality attainable by preventing low birth weight births. This needs some consideration, since directly standardised mortality rates can vary depending on the choice of standard population. The difference in the crude mortality rate between country A and the standard population was then decomposed into two metrics as follows:Equation 2 - Decomposition of the difference in crude mortality rates between country A and the standard populationMetric 1 is the within-country difference in the crude and birth weight-standardised mortality. It shows how the distribution of birth weight, particularly the prevalence of low birth weight, contributes to early life mortality in country A relative to the standard population. It indicates the number of stillbirths and infant deaths per 1000 births that could have been prevented if country A had the same proportion of low birth weight births as the standard population. Therefore, metric 1 is strongly associated with maternal health and socio-economic circumstances during pregnancy , 20, 21.Metric 2 reflects the differences in birth weight-specific mortality between country A and the standard population. High values of metric 2 can be partly attributed to variation in the quality of care after birth, from the health service or at home, and partly to variation in the prevalence of other risk factors at birth, such as congenital malformations which are not adjusted for , 22. We We demonstrate these metrics with Norway as the standard population, as Norway had the lowest proportion of low birth weight births 5.1%, Fig. %, Fig. 1Czech Republic and Austria had the lowest birth weight-standardised stillbirth and infant mortality rates , especially in the neonatal period and for babies weighing < 1000 g in post-neonatal period, reflecting differences in obstetric and neonatal intensive care for high-risk babies. These differences can partly be explained by variation in prevalence of lethal congenital anomalies, since access to terminations of pregnancy is restricted in Poland.Including stillbirths in the statistics helped to minimise impact of registration artefacts . ResultsSome of the results reflect variation in the prevalence of congenital anomalies, which we were not able to adjust for. Prevalence could vary due to differences in accessibility of antenatal screening, regulations regarding late terminations of pregnancy , and detection and recording of congenital anomalies. Repeating the analyses on counts excluding major congenital anomalies would help to account for these differences , 19.. It has been criticised, however, for introducing bias against populations with higher mean birth weight [Standardisation by birth weight or gestational age has been used in the past to quantify the contribution of low birth weight to international-differences in infant mortality , 12, 13.h weight , 26. Insh weight , 22, altOur methods are simple and intuitive and can be easily applied to counts of births and deaths tabulated by age-at-death, birth weight and/or gestation. Such data needs to be routinely collected and reported by all countries to enable international comparisons of maternal and child health. The EURO-PERISTAT project has shown that many European countries (18 out of 31) already have the capacity to report such data if required, however improving the quality of collected data is still necessary . More fuFurther research is needed to assess which interventions would be most cost-effective at reducing pre- and post-natal risk factors within each country. A comparison of cause-specific mortality can identify modifiable factors operating after birth. For example, changes to infant sleeping position are associated with lower rates of sudden infant death syndrome (SIDS) . FurtherCareful use of tabulated aggregate data on all births and infant deaths tabulated by a risk factor at birth offers a quick yet simplified way to inform the design of preventive strategies to reduce stillbirth, neonatal and post-neonatal mortality. Our suggested metrics based on birth-weight-standardised and birth weight-specific stillbirth and infant mortality rates can provide some insights into whether pre- or postnatal interventions are likely to have the largest effect on stillbirth and infant mortality rates. Countries should routinely report counts of live births, stillbirths, neonatal and infant deaths tabulated by birth weight categories  to allow these metrics to be derived, however improvements to national registration systems and standardisation of definitions are needed to ensure comparability of the data.


TTFields) therapy is an approved treatment that has known clinical efficacy against recurrent and newly diagnosed glioblastoma. However, the distribution of the electric fields and the corresponding pattern of energy deposition in the brain are poorly understood. To evaluate the physical parameters that may influence TTFields, postacquisition MP‐RAGE, T1 and T2 MRI sequences from a responder with a right parietal glioblastoma were anatomically segmented and then solved using finite‐element method to determine the distribution of the electric fields and rate of energy deposition at the gross tumor volume (GTV) and other intracranial structures. Electric field–volume histograms (EVH) and specific absorption rate–volume histograms (SARVH) were constructed to numerically evaluate the relative and/or absolute magnitude volumetric differences between models. The electric field parameters AUCE,E V150, E95%, E50%, and E20%, as well as the SAR parameters AUCSAR,SAR V7.5, SAR95%, SAR50%, and SAR20%, facilitated comparisons between models derived from various conditions. Specifically, TTFields at the GTV were influenced by the dielectric characteristics of the adjacent tissues as well as the GTV itself, particularly the presence or absence of a necrotic core. The thickness of the cerebrospinal fluid on the convexity of the brain and the geometry of the tumor were also relevant factors. Finally, the position of the arrays also influenced the electric field distribution and rate of energy deposition in the GTV. Using EVH and SARVH, a personalized approach for TTFields treatment can be developed when various patient‐related and tumor‐related factors are incorporated into the planning procedure.Tumor Treating Fields ( Tumor treating fields (TTFields) are alternating electric fields, tuned to a frequency between 100 and 300 kHz, that have antimitotic properties against rapidly dividing cancer cells. When properly applied, these fields disrupt macromolecular protein structures thought to possess large dipole moments, such as Tubulin and Septin, which are critical for proper cytokinesis TM software that generates an array layout diagram TTFields are applied to the shaved scalp via two pairs of orthogonally positioned transducer arrays. Clinical placement of the arrays is determined by the proprietary NovoTALCritical neuroanatomical structures such as the scalp, skull, dura, cerebrospinal fluid, white matter, gray matter, brainstem, cerebellum, orbits, and bilateral ventricles were segmented based on the postacquisition MP‐RAGE image dataset from a responder with a glioblastoma in the right parietal brain. The segmentation of these masks was performed using ScanIP  where grey‐scale thresholding methods were applied to initially segmented tissues, followed by manual correction on these masks. Additionally, T1 and T2 MRI sequences were also imported into ScanIP, and then coregistered with the segmented masks for delineation of the GTV and necrotic core; the remaining unsegmented tissue was labeled as unspecified tissue and given material properties that of muscle. Structures such as orbits, brainstem, and cerebellum were segmented and their associated physical properties were included mainly for spatial reference in the model. The GTV and necrotic core were both manually segmented by the treating physician based on the visible enhancement shown on the coregistered postgadolinium T1‐ and T2‐weighted image datasets. Transducer arrays were manually placed on the surface of the scalp in the model, approximating as closely as possible to the standard display as shown in the United States Food and Drug Administration's communication on the NovoTTF‐100A system AUC) and SAR (SARAUC). The EVH was used in the comparison of electric field strength between different models and was referenced to (1) the percentage volume of a particular structure receiving at least 150 V/m (VE150), (2) the magnitude of electric field strength encompassing 95% of a particular structure's volume (E95%), (3) the magnitude of electric field strength encompassing 50% of a particular structure's volume (E50%), and (4) the magnitude of electric field strength encompassing 20% of a particular structure's volume (E20%). Similarly, the comparison of the rate of energy absorbed in different SARVH models was referenced to (1) the percentage volume of a particular structure receiving at least 7.5 W/kg (VSAR7.5), (2) the magnitude of SAR encompassing 95% of a particular structure's volume (SAR95%), (3) the magnitude of SAR encompassing 50% of a particular structure's volume (SAR50%), and (4) the magnitude of SAR encompassing 20% of a particular structure's volume (SAR20%).For the purpose of demonstrating the sensitivity of varying physical properties, such as electric conductivity and relative permittivity, tumor geometry, array disposition, the introduction or elimination of certain intracranial structures, and the expansion or contraction of cerebrospinal fluid volume, only isotropic electric conductivity values were used in order to simplify the modeling process. Data postprocessing of the solved models was performed using Microsoft Excel, including generation of volume histograms EVH and SARVH. Area under the curve was computed using Simpson's Rule integration in MATLAB 2016 for electric fields  with that of white matter, the electric field strength in terms of Emor Fig. C; proporThe influence of tumor geometry on the electric field and rate of energy deposition was also investigated. The initial GTV was kept intact as segmented in the patient's model, and was used to compare with GTVs of other standard geometric solids, while keeping the centroid of each GTV at the same location. All other parameters such as array position and electric conductivity of tissue remained the same Fig. . StandarAUC and E20%, and diminished energy absorption, as shown by SARAUC and SAR20% (Fig. AUC and E20%, as well as SARAUC and SAR20%, than that for the cube and icosahedron, and these changes are likely due to the fact that the latter ones had more angulated corners. For lesser symmetric geometric shapes, such as a cone, the orientation in three‐dimensional space of the brain was important. The EAUC and E20%, as well as SARAUC and SAR20%, had the lowest values when the cone was pointing superiorly but highest when pointing anteriorly (Figs. AUC 122.0 V/m and E20% 163.9 V/m, as well as SARAUC 6.5 W/kg and SAR20% 7.8 W/kg, were found when the conical GTV was pointing anteriorly, with the flat surface facing orthogonal to the lateral ventricle.Compared to the original tumor geometry, symmetric, less angulated geometries had a tendency to associate with a lower basal level of electric fields, as shown by lower values in E20% Fig. . In partly Figs. B and  9CAUC, VE150, E95%, E50%, and E20% for TTFields distribution as well as SARAUC, VSAR7.5, SAR95%, SAR50%, and SAR20% for rate of energy deposition. EAUC represents the aggregate electric fields as represented by the area under the curve within any segmented structures and VE150 is the volume of distribution for the electric field intensity at least 150 V/m on the histogram. Similarly, SARAUC also represents the aggregate rate of energy deposited as represented by the area under the curve within any segmented structures and VSAR7.5 is the volume of distribution for SAR at 7.5 W/kg on the histogram. In addition, E95%, E50%, and E20% are data points on the EVH curve that represent the electric field intensity that covers 95%, 50%, and 20% of the GTV, whereas SAR95%, SAR50%, and SAR20% are data points on the SARVH that represent the rate of energy deposited in 95%, 50%, and 20% of the GTV. Collectively, these parameters quantitatively represent the intrinsic characteristics of EVH and SARVH and therefore allow the comparison of TTFields among different patients.As it is being used to treat glioblastoma, TTFields at 200 kHz permeate the patient brain according to the laws of physics, including Gauss’ law, Coulomb's law, and the principles of continuity and capacitance. Our modeling of these fields using the finite‐element method reveals that the intensity of TTFields is highest at the sulci, genu of the corpus callosum, and at the medial surface of the GTV facing the lateral ventricle. To better assess quantitatively the electric field distribution and rate of energy deposition within the brain, volume histograms were constructed for the electric fields and SAR. To our knowledge, this is the first comprehensive usage of both EVH and SARVH to quantify and compare, respectively, TTFields distribution and rate of energy deposition within the patient brain and tumor in various models. Both EVH and SARVH can also facilitate the quantitative comparison of intracranial TTFields between patients, using prespecified values at the GTV and other segmented structures, such as EOur TTFields modeling is based on MP‐RAGE, T1, and T2 MRI sequences obtained from a patient with glioblastoma in the right parietal brain. Using patient‐based MRI for finite‐element modeling has several distinct advantages compared to modeling based on atlas‐based human head and/or generalized tumor model 50% changes between 3 and 6 W/kg. These results suggest that array positioning is important to maximize TTFields distribution at the GTV and to determine if the maximal electric field distribution correlates with survival in the patient population treated with TTFields.Transducer array positioning also influences TTFields distribution within the brain. In accordance to the data present by Wenger et al. Our results have limitations. First, our modeling only used isotropic values but there are local fields generated by the electrical activities of neurons and the flow of cerebrospinal fluid that influence regional electric conductivity In conclusion, we constructed volume histograms EVH and SARVH to facilitate future comparisons between glioblastoma patients undergoing treatment with TTFields. TTFields at the GTV are influenced by the dielectric characteristics of the adjacent tissues as well as the GTV itself, particularly the presence or absence of a conductive necrotic core. The amount of cerebrospinal fluid at the convexity of the brain and the geometry of the tumor are additional relevant factors. Finally, the position of the arrays also can influence the electric field distribution and rate of energy deposition within the GTV.None declared.


Studies conducted mainly in high-income countries have shown that preterm births are associated with increased risk of behavioral problems and psychiatric disorders. The aim of this study was to assess the prevalence of behavioral problems from middle-childhood to early-adolescence according to gestational age at birth in a middle-income setting.n = 4231) in Pelotas, Brazil, was followed-up in several occasions from birth to 11 years. Estimated GA was based on last menstrual period or, when unknown or inconsistent, on the Dubowitz method. Behavioral problems were assessed at 4 (Child Behavior Checklist - CBCL), and at 6 and 11 years (Development and Well-Being Assessment - DAWBA) tool. Maternal socio-economic characteristics and depression at 2, 4 and 6 years post-partum, child perinatal characteristics and breastfeeding duration were used as confounders. Analyses were run by linear and logistic regression.A population-based birth cohort  and mean externalizing (18.8 ± 9.1) CBCL scores were higher among preterm girls born at <34 weeks than among full term girls . After controlling for confounders the association was no longer significant. At the age of 6 years there was no association between gestational age and behavior, neither in crude nor in adjusted analyses. Odds ratio for any psychiatric disorders at 11 years was 60%  higher among those born at 34–36 weeks than in full-term children, but the association disappeared in adjusted analyses.At this large cohort, behavioral problems from middle-childhood to early-adolescence are more related to family socio-economic characteristics and to other child perinatal conditions than to gestational age at birth. The effect of gestational age at birth, particularly the effect of prematurity  and early prematurity < 34 weeks) has been subject of several studies worldwide. –3 Althou weeks haWorldwide, the preterm birth rates range from 5% in high-income countries to 25% in low- and middle-income countries.  Since 19In Brazil, one of the top 10 countries with the highest numbers of preterm births worldwide,  the prevFrom January 1st to December 31st, 2004, all live births of mothers delivering at the maternity hospitals in Pelotas, a Southern Brazilian city, and residing at the urban area of the city were eligible to the Pelotas 2004 Birth Cohort. More than 99% of all deliveries took place in one of the five maternity hospitals available in the city. Mothers were interviewed soon after delivery regarding demographic, socio-economic, behavioral and biological characteristics, reproductive history, and health care services utilization. The non-response rate at recruitment was below 1%. A total of 4231 live births were enrolled in the cohort. Follow-ups were done at home at mean ages 3.0 ± 0.1, 11.9 ± 0.2, 23.9 ± 0.4 and 49.5 ± 1.7 months, and at a research clinic at 6.8 ± 0.3 and 10.9 ± 0.3 years, with follow-up rates between 86 and 96%. A detailed description of the methodology is given elsewhere .Estimates of gestational age were based on the last menstrual period (LMP) providing they were consistent with predicted birth weight, length, and head circumference, based on the normal curves for these parameters for each week of gestational age.  If LMP-bAdverse behavioral outcomes were assessed at four, six and 11 years of age. At the four-year follow-up children were assessed for the presence of behavioral/emotional problems by the application of the Child Behavioral Checklist (CBCL) to mothers or caregivers.  The inst(ADHD), including hyperactive, inattentive and combined sub-types and ADHD not otherwise specified. Internalizing disorders included diagnoses of anxiety and depression. For comparability, in the present analyses the ICD-10 criteria were used.At the six and 11-year follow-ups children were assessed using the Development and Well-Being Assessment (DAWBA) tool,  an instrInformation on family income in the month prior to delivery; maternal schooling, age, skin color, living with a partner, parity, smoking during pregnancy, depression ,  and typeOnly single births were included in the analyses. Due to the small number of children born at <34 weeks, the extremely, very and moderate preterm births were grouped into <34 weeks for the analyses. The CBCL scores were analyzed as continuous outcome in original score units (a higher score reflects greater problems). To assess the association between gestational age and CBCL scores ANOVA analysis was conducted. Multivariate linear regression was used to estimate the effect of gestational age at birth over total, internalizing and externalizing problems at age 4 years adjusting for potential confounding factors in separate models. Potential confounders were grouped and included in the adjusted analysis using a backward strategy selection. If the significance level was below 0.20 the variable remained in the model as a potential confounder for the next level .X2 tests were used to assess the association between gestational age and the outcomes. Crude and adjusted analyses were carried out with logistic regression. Because there was no effect modification by child sex, the adjusted linear and logistic regression analyses were carried out with the whole sample, having child sex as a confounding variable.Psychiatric disorders at six and 11 years  were analyzed as dichotomous outcomes. Pearson A total of 3204 children were followed-up from birth to 11 years of age and had full information on gestational age at birth, CBCL at four years and DAWBA at six and 11 years of age. Among them, 416 (12.9%) were preterm. Prevalence of late preterm (34–36 weeks) and preterms <34 weeks was 10.6 and 2.3%, respectively.Tables p = 0.001). Mean externalizing scores were also higher among preterm than among full-term girls. Among boys, mean internalizing problems score was higher among those born at 34–36 weeks (6.8 ± 4.7) in comparison to those born at term (6.1 ± 4.3) (p = 0.045).In Table In Table Two girls and three boys born at <34 weeks of gestation presented any psychiatric disorder at the age of 6 years Table . At 11 yNo association was observed between gestational age and psychiatric disorders neither in crude nor in adjusted analyses Table  at the aAfter controlling for a number of critical confounders, this study found no association between preterm birth and increased risk of behavioral problems at the age of four, 6 and 11 years. The lack of association of gestational age with behavioral problems and psychiatric disorders at three different ages of the same cohort participants reinforces the finding of no association between them.This finding is in line with results of other studies. , 30 In tAlso, in a large nationally representative Australian cohort of 5000 children, aged 0 to 1, 2 to 3, and 4 to 5 years of age, children born at 33–36 weeks were compared with healthy-term peers. Child mental health was measured by mother-report on the Strengths and Difficulties Questionnaire.  There weOther studies, most of them conducted in high-income countries, have reported higher risks for internalizing and externalizing problems and psychiatric morbidity among the preterm children. –3, 32 CoA higher social risk, represented by low parental educational level, younger maternal age, and low socio-economic status, is strongly associated with increased behavior problems. , 34–36 MMedical factors, such as the length of stay in a neonatal intensive care unit, a prolonged need for artificial ventilation and postnatal corticosteroid exposure may negatively affect behavioral outcome.  The accePreterm children that were included in the current analyses are a subsample of all preterm babies that belonged to the cohort. The neonatal mortality rate during the year of 2004 in Pelotas was of 12.7‰ live births   were validated for use in the Brazilian population. A number of critical co-variables, including maternal depression and family environmental characteristics, were entered in the adjusted analyses, so minimizing the likelihood of residual confounding that can spuriously lead to associations that are biased due to the lack of control for important confounders.On the other hand, a limitation is that the study relied only on the mother or the caregiver perspective for the assessment of the children behavioral functioning (the CBCL and DAWBA versions for teachers were not applied). Teachers and parents tend to notice different kinds of behavior problems.  At the aThere was no association between gestational age and behavioral problems at four, six and 11 years of age among children enrolled in the Pelotas 2004 Birth Cohort and followed-up from birth to 11 years in a middle-income setting. Behavioral problems from middle-childhood to early-adolescence were more related to family socio-economic characteristics than to GA age at birth. This study highlights the importance of targeting children from families with less favorable socio-economic conditions, a risk factor that co-occur with preterm birth in low and middle-income settings, with the aim of preventing behavioral problems in childhood and adolescence.


Our objectives were to define the microstructural developmental trajectory of six corpus callosum subregions and identify perinatal clinical factors that influence early development of these subregions in very preterm infants. We performed a longitudinal cohort study of very preterm infants  (N = 36) who underwent structural MRI and diffusion tensor imaging serially at four time points - before 32, 32, 38, and 52 weeks postmenstrual age. We divided the corpus callosum into six subregions, performed probabilistic tractography, and used linear mixed effects models to evaluate the influence of antecedent clinical factors on its microstructural growth trajectory. The genu and splenium demonstrated the most rapid developmental maturation, exhibited by a steep increase in fractional anisotropy. We identified several factors that favored greater corpus callosum microstructural development, including advancing postmenstrual age, higher birth weight, and college level or higher maternal education. Bronchopulmonary dysplasia, low 5-minute Apgar scores, caffeine therapy/apnea of prematurity and male sex were associated with reduced corpus callosum microstructural integrity/development over the first six months after very preterm birth. We identified a unique postnatal microstructural growth trajectory and associated clinical factor profile for each of the six corpus callosum subregions that is consistent with the heterogeneous functional role of these white matter subregions. The CC is also one of the most adversely affected brain structures by premature birth, thereby contributing to a variety of neurodevelopmental impairments (NDI) that are frequently observed in very preterm infants3. Because CC fibers extend throughout different regions of the brain, its large structure can be subdivided into subregions that are structurally and functionally unique4. Most anatomists segment the CC into six to seven regions of interest (ROI) - splenium, isthmus, posterior midbody (PMB), anterior midbody (AMB), rostral body (RB), genu, and rostrum. Although the basic CC structure is complete by 18–20 weeks’ gestation, there is rapid growth during the third trimester, as well as up to two years postnatally. Weeks 23 to 33 of gestation form an especially critical window of development when various processes in the cytoarchitectural formation of the brain are active5. During this time, neuronal migration, formation of structural and functional connections, as well as active myelination are occurring throughout the brain5. Very preterm birth before 33 weeks’ gestation abruptly interrupts these processes, resulting in a considerably diminished rate of CC growth postnatally as compared to in utero. Aberrant microstructural development and/or direct injury to the CC results in weaker interhemispheric connections, which likely translates to poorer motor and cognitive function and neurodevelopmental disorders, such as cerebral palsy, later in life13. With the increasing prevalence of subtle brain injuries15 and continued high risk of NDI in very preterm infants, utilization of advanced imaging techniques, such as diffusion tensor imaging (DTI), is needed to understand the pathogenesis and facilitate sensitive detection of white matter abnormalities19.The corpus callosum (CC), consisting of millions of fibers, is the largest white matter structure of the brain. It is essential for integrating higher level  functions between the cerebral hemispheresin vivo based on the orientation and degree of water molecule diffusion that occurs through tissue fibers20. Well-established measures such as fractional anisotropy (FA) and mean diffusivity (MD) can be used as proxies of microstructural integrity of white matter fibers and serve as valuable diagnostic and prognostic biomarkers for detection of white matter injury/delayed brain maturation and prediction of NDI22. There are a limited number of studies that have used advanced MRI to examine the sub-segmental growth and development of the CC antenatally or soon after preterm birth28. Moreover, there are no studies that have examined sub-segmental CC microstructural development between 40 and 52 weeks postmenstrual age (PMA) and its relationship with perinatal risk factors in preterm infants during these first few months after birth. Assessment of CC microstructure is important in order to characterize its trajectory of myelination and axonal development during the most vulnerable period of brain development for preterm infants, as well as identify the impact of clinically modifiable extra-uterine factors30. Serial DTI studies that have examined the growth rate of the CC within the first few weeks after birth have also reported a positive association between reduced growth rate and delayed psychomotor development evaluated at 1 or 2 years of age27.Diffusion tensor imaging allows brain development to be studied 36. While other clinical antecedents, including bronchopulmonary dysplasia (BPD)39, caffeine therapy40 and breast milk, have been identified as factors that affect white matter development as a whole, the effect of these variables specifically on the early developmental trajectory of each CC subregion has not been studied in depth using advanced MRI techniques. To further our understanding of the clinical factors that influence the early longitudinal growth of each functionally distinct CC subregion, we performed up to 4 serial DTI exams in very preterm infants immediately after birth and extending up to six months after birth. Our objective was to perform probabilistic tractography and determine the early developmental trajectory of six CC subregions and the associated clinical factors that are protective or predispose this important white matter structure to injury or abnormal development in very preterm infants.Previous studies have examined factors such as sex, birth weight, and degree of prematurity, and their effects on the growth and development of the CC either as a whole structure or at a single time pointOf the 40 enrolled subjects, we excluded 4 because of poor image quality  or severe white matter injury (N = 2), parental request to withdraw infant from the study N = 1) after the first MRI, or early death of the infant (N = 1) after the first MRI. For the 36 study infants, the mean (SD) gestational age was 26.9 (2.3) weeks, and birth weight was 983 (326) grams. Maternal demographics, as well as demographic and clinical characteristics of the infants, are summarized in Table  after th41, was not present in 11, mild in 19, and moderate in 6 on one or more structural brain MRI exams up to 52 weeks PMA. None of the infants exhibited injury to the CC. Of the 6 cases read as having moderate degree of injury/delayed development, 4 infants had sequelae of prior intraventricular hemorrhage with secondary ventriculomegaly and mild to moderate degree of brain volume loss/delay. One infant had more than a four weeks delay in gray and white matter maturation with brain volume loss/delay and one infant exhibited diffuse excessive high signal intensity in multiple white matter regions with mild brain volume loss/delay.Of the 36 infants in the final cohort, brain injury or delayed development, as evaluated using our standardized previously published MRI scoring system42.The ICC values for the PMB and isthmus ranged from 0.87 to 0.95 for the FA and MD measurements. Because evaluating ICC alone can be misleading, Table The microstructural growth trajectory of the CC subregions differed considerably based on the four DTI scalars. In general, FA increased while MD, AD, and RD decreased or remained stable over the first six months after birth Figs –4. The tWe identified multiple clinical antecedents of the four DTI scalars for each subregion of the CC. Increasing FA was significantly and directly correlated with increasing PMA and higher birth weight for each of the six CC subregions (p < 0.05 to p < 0.001); Fig. in vivo surrogate measures.We employed serial DTI studies, commencing soon after birth, to examine the developmental trajectory of six structurally/functionally unique subregions of the CC over the first six months following very preterm birth. We used DTI parameters, including FA, MD, AD, and RD, to serve as important surrogate measures for white matter microstructural integrity. We performed serial DTI scans over the critical window of the third trimester, when very preterm babies are most vulnerable while receiving care in the neonatal intensive care unit, and over the first few months after discharge, when plasticity and recovery from earlier insults are feasible. Additionally, we identified several important antenatal and neonatal clinical factors that significantly impact CC bundle development, as evidenced by 44. These seminal studies identified that myelination of each brain structure varies in chronology and tempo. Yakovlev and Lecours’ work suggested that the commissural zones of the forebrain display the longest processes of myelination and begin to show evidence of myelination (identified with Weigart’s hematoxylin preparations) at 16 weeks postnatal43. Furthermore, Brody et al. reported myelination of the CC occurs most rapidly in the first 2 years45. Following a comprehensive review, Dubois et al. hypothesized that early white matter development progresses through three stages – fiber organization, “pre-myelination”, and “true” myelination – that are characterized by a unique set of changes in DTI parameters. It is now well-established that overall, FA measures the anisotropy of water within white matter bundles, while the diffusivity metrics indicate brain water content and membrane density46. However, it is likely that compaction and fiber diameter also contribute to these microstructural measures.Yakovlev and Lecours as well as Gilles studied myelination in infancy using detailed histological methods of white matter staining47. This last stage occurs in the CC mid-body first at round 40 weeks PMA, followed by myelination of the splenium and finally the genu within the first few postnatal months, making it a particularly crucial time period for proper maturation of the largest white matter bundle44. This is consistent with Gilles’ overall summary that the first signs of corpus callosum  myelination occurs during weeks 36 to 40 of gestation44. Additionally, the sequence of myelination identified by Yakovlev and Lecours also suggested that myelination of the corpus callosum begins with the splenium at 16 weeks postnatal and gradually progresses in the rostral direction. However, both Gilles’ and Yakovlev and Lecours’ groups suggest that the majority of corpus collosum myelination occurs in the early postnatal months, extending into the first decade of life45. Our data revealed a steep increase of FA values with time in the splenium and genu, which may suggest this third stage of white matter maturation. FA in all six subregions of the CC showed a statistically significant increase over time. Furthermore, the first stage involves more directionally organized axonal fibers, which can be expressed by increased anisotropy and decreased mean and radial diffusivity but is distinguished by an increase in axial/parallel diffusivity19. We observed greater change in RD than AD over time, consistent with prior evidence in other white matter tracks48. Overall, RD in all subregions of the CC showed a statistically significant decrease with time. This is consistent with the assumption of a cylindrically symmetric decrease in diffusion due to myelination48.An increase in FA during the third stage indicates “true” axonal myelination and decreased membrane permeability49. This would also explain the transient rise in RD during the same time period and within the same CC subregions. One study also found that because crossing fibers can sometimes cause such fictitious changes in AD and RD based on the degree of pathology of the underlying tissue, white matter development is more holistically characterized by changes in FA and MD values49. The above changes would suggest that by 26 to 28 weeks gestational age, “pre-myelination” of the CC is already underway. During this second stage, there is a decrease in overall water diffusivity as glial cells and oligodendrocyte lineage precursors multiply46. Considering this chronology and its reflection in DTI measures allowed us to take a more objective look at the impact of prematurity on each specific region of the CC when measuring the developmental growth trajectory51.We only observed an increase in AD in the RB and AMB between approximately 28 and 40 weeks PMA, after which AD began to decrease. Axial diffusivity in the remaining four CC subregions remained stable or decreased slightly over time suggesting this transient increase in the mid-body of the CC likely reflected the presence of crossing fibers (e.g. projection fibers) rather than fiber organization1. This study found that the anterior CC is active during taste stimuli, the central portion is responsible for motor tasks, and the central and posterior subregions play a role in tactile stimulation. More specifically, the splenium is responsible for integrating and communicating auditory and visual information. Using DTI tracking, the researchers were also able to show crossing fibers through the different CC subregions. The genu is also known to be involved in working memory, and this is associated with higher FA and lower RD values within the tract22. These studies extend what is already known about infants and children with injury or developmental abnormality of the CC. Functionally, these typically manifest as delays in walking, talking, or reading, and clumsiness and poor motor coordination, particularly on skills that require coordinated use of both hands or legs. Data analysis in our study revealed trends linking each clinical factor exclusively to a specific segment or group of segments within the corpus callosum, further supporting the notion that each subregion of the CC has both structural and functional heterogeneity4.A recent functional topography study utilized fMRI and DTI to map the functional/structural differences between these specific subregions of the CC in healthy adults and patients with callosotomy38. Our results also suggest that the genu and splenium are strongly influenced by age and birth weight, and the splenium is additionally associated with illness severity/need for resuscitation at birth, as reflected by low 5-minute Apgar scores. The process of white matter maturation, notably in the anterior- and posterior-most regions of the CC, is especially vulnerable to delay if the infant prematurely enters the extra-uterine environment38.Between 26 and 54 weeks PMA, FA values for all six CC subregions, especially in the splenium and genu, increased as gestational age increased, suggesting rapidly increasing white matter microstructural integrity and maturation. Not surprisingly, this same relationship, albeit not as strong, was evident between birth weight and FA as well. A significant relationship was also found between PMA and AD for the AMB, RB, and genu subregions and RD for all six CC subregions. These relationships may have been influenced by crossing fibers through these subregions of the CC, thereby falsely lowering AD and RD values. Decreasing diffusivity values over time denotes growth in white matter cyto-architecture. Our results, overall, are consistent with previous studies that have identified a similar positive relationship between gestational age and white matter growth in terms of fractional anisotropy and diffusivity53. Larger studies examining whole brain connectivity are warranted to further elucidate the structural basis for poor academic outcomes of infants born to mothers with lower educational status.The relationship between maternal education level and white matter development has not been extensively studied. We found that a below-college degree maternal education level was significantly associated with increased diffusivity values of the AMB and RB, suggesting delays in maturation for these CC subregions. Delayed maturation of these CC subregions may in part explain the well-known association between maternal socioeconomic status, especially lower maternal education, and poorer cognitive and behavioral outcomes in preterm infants54. These studies found that a longer duration of human milk, as well as caffeine therapy, were strongly associated with greater CC maturation40. This difference in findings might be explained by our smaller sample size or because all subjects in our cohort were administered both caffeine therapy and breast milk to some extent, and this lack of heterogeneity may have obscured the true relationship between these factors and CC maturation. Caffeine therapy may also be serving as a proxy for infants with more severe apnea of prematurity, a condition associated with worse neurodevelopment.We found a significant direct correlation between increasing exposure to caffeine therapy for apnea of prematurity and axial and radial diffusivity of the AMB. No significant correlation was found between the duration of breast milk and CC development (FA and diffusivity measures). Our group and others have examined the effects of caffeine therapy and breast milk on neonatal brain development56. One study examined whole brain white matter using an automated observer independent method called tract-based spatial statistics and found that preterm infants given mechanical ventilation for more than 2 days in the perinatal period exhibited decreased FA values in the genu of the CC55. Another group found that chronic lung disease and postnatal infection in preterm infants correlated with decreased FA in the CC as a whole, as well as the posterior limb of internal capsule56. Additionally, 15 very preterm infants in our cohort were born with an Apgar scores ≤5 at 5 minutes. These infants exhibited greater diffusivity values in the splenium, AMB, and RB, implying lesser overall CC development as compared to infants with higher 5 minute Apgar scores. While an association between low Apgar scores and microstructure in six brain regions  has been reported34, no prior study has reported an association between low Apgar scores and CC subsegmental development during the first few months of life.Infants that survived without BPD had lower diffusivity in the RB, signifying greater fiber integrity when compared to subjects diagnosed with BPD. This finding supported our hypothesis, which was based on previous studies that identified an association between chronic neonatal respiratory disease and white matter abnormalities58. When compared to female infants, males had greater axial and radial diffusivity in the PMB. Previously, Rose et al. identified delayed splenium development (lower FA and higher MD) on DTI at term-equivalent age in males as compared to females (PMB and other parts of the CC body were not examined)10. Fractional anisotropy in the splenium also correlated with abnormal neurodevelopment at 18 to 22 months corrected age. Other groups have also found that the growth of the CC in the first 2 weeks after birth was poorer among males compared to females2, and male sex was correlated with a smaller PMB3. These findings suggest that sex differences in the maturation of the posterior subregion of the CC may partially explain the vulnerability of very preterm boys to higher rates of NDI.It is now well established that preterm females exhibit lower rates of NDI than their male counterparts, though the reasons for this are not yet well characterized59. Recent advances in acquisition of higher order diffusion model data as well as multi b-value/multi-shell diffusion MRI in neonates will facilitate more robust studies to sensitively assess brain cellular compartment models in the developing very preterm brain60.Our study had a few limitations. Although we performed between two to four MRI scans per infant and a total of over 100 MRI scans, we studied a relatively small number of infants. In addition to imaging infants using a higher resolution 3 T MRI scanner, we employed probabilistic tractography methods to improve our ability to generate accurate CC segmental tracts, which tend to reside in regions of multiple crossing fibers, and to quantify developmental changes in the white matter tracts61. A more accurate mapping of the structural and functional division of the CC will lay the foundation for early prediction of developmental disabilities in populations at high risk for brain injury and delayed brain development. We are currently following this cohort to 2 years corrected age to measure these functional outcomes and determine if detailed tractography measures of CC subregions can serve as important prognostic biomarkers of NDI.Overall, we identified several factors that favored greater CC microstructural development, including advancing age, higher birth weight, and college level or higher maternal education. Bronchopulmonary dysplasia, low 5 minute Apgar scores, and male gender were associated with reduced CC microstructural integrity/development over the first six months after very preterm birth. Because the CC is involved with important psychomotor functions and hemispheric communication, damage or persistently delayed development is likely an important contributor to adverse motor, cognitive and behavioral long-term outcomesIn this longitudinal cohort study, 40 very preterm infants born at less than or equal to 32 weeks of gestation were enrolled. All very preterm infants from the Neonatal Intensive Care Unit at Nationwide Children’s Hospital, Columbus, Ohio from 8/2012 to 6/2014 were eligible for recruitment. We excluded subjects with any known congenital anomalies of the central nervous system or cyanotic heart disease. Additionally, infants on very high mechanical ventilator support (e.g. peak inspiratory pressure >30 and/or Fraction of inspired oxygen >50%) within the first 28 days after birth were considered ineligible for the study due to increased risk associated with moving them to MRI. We performed three advanced MRI scans  at 32 weeks, 38 weeks, and 52 weeks PMA. We also performed a fourth MRI for infants <30 weeks gestational age, between 2 and 4 weeks after birth. For all inpatient scans – typically the first three MRI time points – we used a 3 Tesla-MRI compatible transport incubator  to minimize handling and enhance safety. Two neonatal research nurses and a neonatologist accompanied each study infant to MRI. One neonatal research nurse was present for outpatient scans. Before each MRI, infants were fed (if not NPO) and swaddled to induce natural sleep; sedation was not used under any circumstance. To protect the infants from MRI noise, the subjects’ ears were protected with Insta-Putty Silicone Ear Plugs  and Natus Mini Muffs . We continuously monitored all infants during scanning for desaturations, bradycardias, or any movements. The same MR technologist/physicist conducted all imaging. We obtained approval for this study from the Institutional Review Board of Nationwide Children’s Hospital and all research was performed in accordance with relevant guidelines and regulations. Informed consent was obtained from all participants’ parents and/or their legal guardians.2; time = 5 min, 12 sec. We also acquired an axial T2-weighted fast spin echo: TE/TR = 142/10000 ms; FOV 160 mm, matrix 320 × 256; slice thickness 2 mm; time = 4 min, 30 sec. A pediatric neuroradiologist examined all structural MRI scans using a standardized scoring system41.A 3 T GE HDX Scanner was used for all scans. We used an 8-channel infant head coil that was installed within the Nomag transport incubator . Single shot echo planar DTI was acquired in 30 non-collinear directions using the following parameters: TE/TR 86/6000 ms, field of view 160 mm, matrix 256 × 256; slice thickness 2.4 mm, and b = 1000 s/mmInfants with isolated germinal matrix or intraventricular hemorrhage without ventricular dilation, mild diffuse excessive high signal intensity (restricted to anterior caps or posterior crossroads) or with focal (<5 mm) signal abnormalities/cystic changes were coded as having mild abnormalities on their term-equivalent age MRI. Infants with intraventricular hemorrhage with ventricular dilation, moderate ventriculomegaly without hemorrhage, extensive (>5 mm) signal abnormalities/cystic changes, moderate-severe diffuse excessive high signal intensity , or a 2 to 4 weeks’ delay in gyral maturation were defined as having moderate abnormalities. Infants were defined as having severe abnormalities if they exhibited parenchymal hemorrhage/periventricular venous infract, bilateral cystic periventricular leukomalacia, severe hydrocephalus/ventriculomegaly, or a greater than 4-week delay in gyral maturation on their term-equivalent age MRI.59. This software permits inclusion of datasets with up to 60 diffusion directions.DTI data were transferred to an offline workstation for further image processing and analysis. We pre-processed all images using FSL 5.0 software of FMRIB Software Library  and DTIStudio 3.0.2 of MRI Studio . Briefly, we converted raw DTI DICOM data into analyze format using DTI Studio and imported this into FSL to perform eddy current correction. To further minimize the effects of motion and artifacts, we performed Automatic Image Registration (AIR) and automatic outlier slice rejection in DTI Studio. Next, we performed, tensor estimation and generated scalar maps . Figure et al.25. Of the 30 segments, proceeding in an anterior to posterior direction, the first 5 segments were labeled as the genu (5/30), the next 5 as the rostral body (RB) (5/30), followed by anterior midbody (AMB) (5/30), posterior midbody (PMB) (5/30), isthmus (4/30), and splenium (6/30)  tool to perform probabilistic tractography , the CC bundle was segmented on the most clearly delineated midbrain slice in the sagittal orientation. The “Auto-Trace” tool was selected to trace out the CC and divide it into 30 vertical segments of the same width Fig. . This al30) Fig. . The ros30) Fig.  was typiphy Figs  and 7. W62. Each variable was defined as previously described38 and correlated with our four DTI scalars.Clinical variables were chosen based on a systematic search in PubMed/Medline of previous literature using Medical Subject Headings, including “Corpus Callosum/growth and development”, “Infant, Premature”, “magnetic resonance imaging”, “risk factors”, “Diffusion Magnetic Resonance Imaging”, and “Neural Pathways/pathology”. Based on this search, we found the following perinatal risk factors were significantly associated with CC and/or NDI: maternal age, maternal education, gestational age/PMA, birth weight, sex, low Apgar score at 5 minutes, total days of breast milk received in first 28 days after birth, BPD, and duration of caffeine therapy63.We measured four DTI parameters  for the six different regions of the CC. Linear mixed effect models with random intercept and random slope were used to determine the effects of covariates on the trajectory of each parameter, controlling for PMA at MRI scan. PMA at MRI scan was retained in all models, even when insignificant, to control for the effects of age at MRI scan. The fitted mean values and their 95% confidence intervals based on linear mixed effect models were plotted. A quadratic term for PMA at MRI was evaluated in each model to permit fitting for non-linear data, if present; it was removed from the model when insignificant. The values for “Mean FA/RD/AD Difference” in Table 64. Repeatability is defined as 2.77 times the within-subject SD and is the 95% interval for change between two or more repeat measurements.To assess inter-rater reliability, we calculated the inter-class correlation coefficient (ICC) for the PMB and isthmus in the R statistical program using a two-way, consistency-based model. Results were analyzed to determine the consistency and reliability of segmentation methods as performed by two raters on a randomly selected subset of 15 cases. Within-subject standard deviation (SD) and repeatability were also determined as additional more robust measures of reliability. The within-subject SD is defined as the common SD of repeated measurements and calculated by obtaining the square root of the mean within-subject varianceAll of the data generated or analyzed during this study are included in this published article. They are also available from the corresponding author on reasonable request.


Significant grain refinement in cast metals can be achieved through the application of electric currents during the solidification process. The present paper investigates the distribution of electric currents on the grain size of solidified Al-7wt.%Si alloy under the application of electric current with constant parameters flowing through two parallel electrodes into the melt within a cylindrical mould. The distribution of electric current was controlled by applying an electrical insulation material coating, boron nitride (NB), to the sidewall of the electrodes. Experimental results showed that the employment of these insulated electrodes can reduce grain size in comparison with the reference case of electrodes without BN coating. Flow measurements were performed in Ga-20wt.%In-12wt.%Sn liquid metal. Higher intensity forced flow occurred when the sidewall of the electrodes was insulated. In order to understand the underlying mechanism behind the stronger forced flow, corresponding numerical simulations were performed to reveal the distributions of the electric current, magnetic field, Lorentz force, and the resultant forced flow. The results achieved indicate that the mechanism of grain refinement driven by electric current is dendrite fragmentation induced by forced flow. In addition, a novel approach to enhance the grain refinement without additional input of current energy was developed. A large number of investigations have revealed that the grain structure can be refined effectively through the application of external energy fields in forms such as electric currents10. In particular, even lower electric consumption and more significant grain refinement can been realised through the implementation of electric current pulse (ECP), in which current is discharged in very short time periods from a capacitor bank with extremely high voltage of up to 103 volts and conducted into melt through two electrodes11. Under ECP, the solidified structure can be modified from dendritic to globular grains accompanied by a distinct reduction in grain size, ascribed to the dendrite fracture caused by the electric-current-induced strong shear stresses. Significant grain refinement has been achieved with ECP in a broad range of metals and their alloys including Zn-12, Al-14, Mg-15, Fe-16 based alloys, indicating its excellent applicability to different metals and their alloying systems.It has been discovered that the passage of an electric current through a solidifying metal can lead to grain refinement owing to induced electromagnetic fields and their related effects. Solidification under the application of a current field has been attracting considerable interest both from academic researchers and industry for over 4 decades due to its high effectiveness at improving the metal microstructure, and independency to the alloy chemistry18, crystal rain13 and dendrite fragmentation2. It has been reported that the heterogeneous nucleation under the application of electric current can be effectively stimulated, owing to the free energy minimisation provoked by the application of electric current18. More recently, the electric-current-induced free energy minimization for crystal nucleation has been considered as a driving force for the finer microstructure generated19, rotation of disk-like particles20 and motion of micro-particles by pulsed electric current21. Through an experimental study involving commercial pure aluminium solidifying under the configuration of a pair of vertically arranged parallel electrodes immersed into the melt through free surface, Li et al. have proposed a crystal rain mechanism to explain the grain refinement occurring13. It is believed that a thin layer of melt will solidify in the early stage of the melt solidification at the top free surface of the melt, which is exposed directly to the air, and a large number of nuclei from the top surface can be detached, resulting in the crystal rain being influenced by the electromagnetic force.Numerous hypotheses regarding the grain refinement mechanisms with consideration of electric currents have been proposed, including heterogeneous nucleation22. Through an experimental study, Räbiger et al.2 have demonstrated that a strong global forced flow was induced by applying electric currents in the melt under the configuration of two parallel electrodes immersed from the free surface into the electrically conducting melt. Furthermore, the corresponding numerical simulations showed the forced convection was attributed to the induced electromagnetic force, which was confined to a narrow region beneath two electrodes. When higher intensity flow was generated, finer grains were observed in the Al-7wt.%Si alloy. In addition, the experimental results indicated that almost identical equiaxed structures were observed under the same flow intensity caused by ECP and travelling magnetic field (TMF). It is widely accepted that the TMF-induced forced flow plays a key role in the grain refinement of solidified alloys24. It is therefore convincing to conclude that the forced flow would be the key driving force behind the grain refinement of alloys driven by ECP. It is most likely that dendrite fragmentation is one of the main mechanisms for grain refinement resulting from the application of electric current during metal solidification, due to the fact that forced flow induced temperature and solute fluctuations trigger remelting of dendrite arms to produce dendrite fragmentation.The electric-current-induced forced convection flow and its effect on the solidification of metals was recently investigatedIn order to clarify the effect of these three potential mechanisms, current study investigates the influence of the electric current distribution on the forced flow as well as the resulting grain refinement under the application of the same electric current parameter. The configuration of two parallel electrodes immersed from the free surface into the melt was employed to conduct electric current in two ways. The reference is the electric current flowing through the lateral surface of electrodes into the free surface of melt, whereas the other is only the electric current flowing through the bottom of electrodes into the bulk melt by coating of an electrical insulation material, boron nitride (BN), on the lateral surface of the electrodes.IDC = 152 A conducting through the two kinds of electrodes. In both of the two solidified samples, it was found that a large quantity of refined equiaxed grains were produced in comparison with the solidified macrostructure of sample without electric current achieved in our previous study2. As shown in Fig. Figure IDC = 152 A flowing through the sidewall and bottom surface of the electrodes respectively. The same flow pattern can be observed under both of these two different electric current distributions. The flow direction at the cylinder axis was downward in the upper part and upward in the bottom part, as shown in Fig. Flow measurements were performed in a Ga-20wt.%In-12wt.%Sn liquid metal to investigate the influence of electric current distribution on the forced flow. Figure Although the same flow pattern was generated, the flow intensity inside the melt is obviously stronger at all positions when the sidewall of the electrodes was coated by BN to confine the electric current to flow only through the bottom surface of the electrodes. Particularly, at the measurement location beneath the electrodes, the largest vertical velocity was only about 40 mm/s in the reference case of the electrodes without BN in Fig. 7A/m2 was achieved and dramatically reduced by a factor of 10 to 1 × 106 A/m2 during the spreading process. A significant concentration of electric current can be obtained at the location where the electric current runs into the melt from the electrodes in both cases. In the reference case of the electrodes sidewall without BN, the electric current is concentrated in the region of the electrodes sidewall, adjacent the free surface. In comparison, the highest electric current intensity is generated within the narrow region beneath the electrode’s bottom surface for the case of electrodes with the electrically insulated sidewall.In order to understand the electric current induced melt flow in a cavity of a cylindrical mould, corresponding numerical simulations were performed to reveal the distribution of the electric current, the self-induced magnetic field and the resulting Lorenz force inside the bulk melt. The numerical results showed that the parallel electric currents flowing through the electrodes immediately spread into the melt as shown in Fig. As shown in Fig. Since both the magnetic field and Lorenz force are induced by the electric current, it should be noticed that the concentrated region of magnetic field and Lorenz force can be influenced by coating the electrical insulation materials on the lateral surface of electrodes, as shown in Fig. 2.The metallographic images of the as-cast grain structure have shown that a smaller grain size can be achieved by confining the electric current such that it only flows through the bottom of the electrodes into the melt, even though the same parameters are employed for the electric currents. The numerical results further prove that a forced melt flow with higher intensity is generated under the situation when the electric current flows through the bottom surface of the electrodes rather than the sidewall, which is confirmed by the corresponding flow measurements. The results convincingly demonstrate that the grain refinement of solidified alloys is driven by the intensity of the electric-current-induced forced flow. The most likely grain refinement mechanism is the dendrite fragmentation. The induced forced flow causes localized fluctuations of both temperature and solute concentration in order to provoke the occurrence of dendrite fragmentation. The stronger forced flow significantly promotes higher dendrite fragmentation rates as well as finer grains. This is the reason why the finer grains are produced in the current experimental condition, since the stronger forced flow is generated by controlling the distribution of electric current. Moreover, it has been recognized that the solidified shell with dendrite structure is firstly formed on the wall of mould during the initial solidification period. The concentrated Joule heating and Lorentz force as shown in Fig. EC* is given by17:K is the constant of material, J is the electric current density, Vn is the volume of nucleus, ζ is calculated by17:However, the other two mechanisms, heterogeneous nucleation promoted by electric-current-induced free energy minimization and crystal rain mechanisms, should be clarified. According to the proposed free energy minimization mechanism, the change in the free energy under the application of electric current ΔGσ0 is the electric conductivity of the melt, and σn is the electric conductivity of the nucleus. Since the electric conductivity of the melt is less than that of the nuclei (solid phase) in Al-7wt.%Si alloy, the ΔGEC* has a negative value, which means the free energy ΔGEC* decreases under the application of electric current, reducing the nucleation energy barrier. According to equation J inside the melt. In this study, the maximum electric current density in the concertation region is 1.4 × 107A/m2 in the case of electrodes without BN, whereas a little lower maximum electric current density with value of 1 × 107A/m2 was generated when the sidewall of electrodes was electrically insulated as shown in Fig. 21, the crystal rain mechanism is proposed in which a solidified shell is formed at the free surface, and crystal rain from the shell can then be promoted by the concentrated electric current at the free surface  was prepared using commercially pure Al (99.99 wt.%) and pure Si (99.999 wt.%) in a clay graphite crucible using a resistance furnace. After melting, the alloy was pouring into a stainless mould with a diameter of 50 mm. The cast alloys were then cut to the same weight of 310 g for casting experiments. Alloyed samples were remelted in the double walled mould, heated to 750 °C holding for 45 mins, and subsequently cooled to 720 °C in the resistance furnace. After holding for 30 mins at 720 °C, the molten alloy with the mould was removed from the furnace and then assembled with thermocouples and electrodes, eventually transferred to the cooling platform to solidify the sample.13. Such an electrode means that the electric current can flow through the sidewall of the electrode. The electrical insulation material, BN, was applied to control this electric current distribution. As the schematic view demonstrates, shown in Fig. Electrodes without the insulation material were employed as the reference, a consideration which was adopted in previous research3, 5 mL HF, and 5 mL H2O, and then directly photographed via a digital camera (Konica Minolta) for the macrostructure analysis. Selected regions in the other section were ground and polished from 6 μm to 1 μm, electro-etched in Barker’s etching reagent at 25 V, 15HZ for 120 s, and then examined under an optical microscope Axio Imager A2m  using the polarized light for the quantitative analysis of grain size by the linear intercept method.The solidified samples were longitudinally sectioned for metallographic analysis. One section was ground using SiC paper, etched in a solution composed of 60 mL HCl, 30 mL HNO2. Hence, the similar flow structure and intensity can be assumed in these two alloy melts for the same employed configuration and electric current parameter. An 8 MHz transducer  from the DOP2000 velocimeter  was located at the three positions of the bottom along the vertical direction  technique was performed to monitor the melt velocity under the application of the electric current. Since the temperature of the Al-Si melt was higher than temperature limitation of the sensor, a ternary eutectic alloy (Ga-20wt.%In-12wt.%Sn), which undergoes melting at room temperature, was used in a vessel made from perspex with the same inner size as the solidification experiment. The similar dimensionless parameter S is achieved in both Al-7wt%Si and Ga-20wt.%In-12wt.%Sn alloy meltCommercial software CFX (ANSYS) was employed to numerically simulate the distributions of electric current, induced magnetic field, Lorentz force and forced flow inside the GaInSn liquid. The material properties used for this simulation are shown in Table The following three boundary condition types have been assigned:Current Inlet (top face on one of electrodes): fixed value for electric current density.Current Outlet (top face on another electrode): electric potential equal to zero.Current insulation : zero gradient of electric current density normal to the wall.Electric field:Magnetic field:Magnetic insulation : magnetic flux density equal to zero.Slip wall (free surface of the fluid next to the air): slip condition was set where velocity normal to the wall equal to zero.No slip wall : velocity  equal to zero.Fluid field:J gives by:According to Ohm’s law, the electric current density B is calculated by Biot-Savart’s law:0, V and r are the permeability of a vacuum, the volume and the vector of displacement, respectively.The magnetic field strength F is determined from the interaction between electric current and induced magnetic field, which is defined as:Lorenz force According to the magneto-hydrodynamic theory, the governing equations of fluid flow are based on the continuity equationThe current paper investigates the influence of electric current distribution on the forced flow and the resulting solidified structures of Al-7wt.%Si alloy. The experimental results showed that although the same electric current parameter of direct current is applied, finer grain size is achieved when the electric current is limited by boron nitride (BN) such that it flows only through the bottom of electrodes in comparison with the reference case without the limitation of BN. This phenomenon is due to the stronger forced flow caused in the case of electrodes with their sidewall coated with BN, as the flow measurement results clearly demonstrated. The numerical results show that the electric current is significantly concentrated at the narrow region beneath the bottom of the electrodes for the case with the electrodes sidewall coated by BN, whereas in the case without the BN coating, the electric current rapidly spreads from the lateral surface of the electrodes, adjacent the free surface, into the melt. Since the interaction of electric current and self-induced magnetic field results in Lorentz force, the corresponding simulated distribution of Lorentz force shows that concentration of the electric current underneath the bottom surface generates higher downward Lorentz force, causing a stronger downward jet to force the global flow in the bulk melt more as well as achieve a finer gain size.Three proposed mechanisms of electric-current induced grain refinement have been clarified by the knowledge gained in this study. The most likely mechanism is the dendrite fragmentation initiated by the electric-current induced forced flow. The present research not only provides more insights into understanding the grain refinement mechanism under the application of electric current, but also presents a potential approach to achieving a reduction in grain size without an additional input of energy.