During the consultation process, a project on birth registration law has been mooted. This is a very welcome proposal given that civil birth registration in England and Wales is a compulsory procedure that not only finds its roots in the early Victorian era, but also remains very similar, at least in terms of form and the information that is recorded. I first use two recent legal challenges to illustrate why the current system is coming under increasing pressure. I further use these examples to caution against a law reform agenda that is narrowly focused on the precise information recorded, without a preliminary and wider examination of what the role and purpose of birth registration is, and should be, in society. I argue that this needs to be addressed before the state can justify the parameters of the information recorded. I then use an outline of historical reforms relating to the registration of births outside of marriage to highlight the normative two-parent family model that underpins the birth registration system. I argue that legal reform must be cognizant of the tenacity of this normative family model, particularly in relation to reform proposals surrounding donor conception and the annotation of birth certificates. Finally, I draw attention to wider developments in family law that cast birth registration as a social policy tool for the facilitation of parent–child relationships, particularly unmarried fathers.The Law Commission of England and Wales is considering what its 13 During the consultation process, a project on birth registration law and certificates has been mooted. This is a very welcome proposal. Civil birth registration in England and Wales is a compulsory procedure that not only finds its roots in the early Victorian era, but also remains very similar, at least in terms of form and the information that is recorded. In this short commentary, I first use two recent legal challenges to illustrate why the current system is coming under increasing pressure. I further use these examples to caution against a law reform agenda that is narrowly focused on the precise information recorded on a birth certificate, particularly in relation to parenthood. This is not to suggest that the information recorded should not be reconsidered, but rather that the scope of a law reform project on birth registration needs to be wider given the normative family model which underpins the system.The Law Commission of England and Wales is currently considering what its 13I then draw particular attention to the wider family law and policy context within which birth registration operates, and ask what this means in relation to the information recorded. I outline reforms relating to the registration of births outside of marriage to demonstrate that, while historical changes could be interpreted as being a bit haphazard, they have, in fact, always been informed by the normative two-parent family model. I argue that legal reform cannot ignore this tenacious normative dimension, given the extent to which it shapes how the familial information on a birth certificate is understood. I also point to changes in the Adoption and Children Act 2002 and the Welfare Reform Act 2009 – relating to the joint birth registration of births outside of marriage – to show how birth registration has been conceptualized in recent times by the state as a social policy tool that facilitates a parent–child relationship. I argue that this imbues birth registration with even further significance in terms of ‘textually mediated’ statecraft , for it It has been almost a decade since the Joint Committee scrutinizing the Human Tissues and Embryos (Draft) Bill 2007) recommended that, 'as a matter of urgency', the Government give consideration to rights that may be implicated in state authorities holding personal information – namely details of gamete donors – and the information that appears on birth certificates . No government has responded to this recommendation. This is perhaps not surprising as, while donor conception is not uncommon, it affects only a relatively small proportion of the population.007 recom3In relation to the scope of a possible law reform project, I was very pleased to see the Law Commission cast this in wider terms than the Joint Committee recommendation. Any attempt to reform this one area of birth registration law is likely to prove unsatisfactory, given that the issue of whether birth certificates should indicate that a person is donor-conceived and/or include the name(s) of the gamete provider(s) continues to prove highly controversial and often polarized. In my view, this stems not only from different values being placed on genetic relationships, but also from different understandings of the purpose of birth registration.To say this is not to suggest that the issue should not be included in a law reform programme, particularly in light of the depth of feeling that it evokes. However, two recent legal challenges signal that a much wider review is warranted. The first of these cases appears, on the surface, to fit closely with the Joint Committee’s concerns. In 2014, Emma Cresswell had her birth certificate re-issued without the name of the man originally recorded as her father, who she had assumed was her biological father. Her legal action followed an argument whereby he disclosed that she and her two brothers had been conceived through sperm donation . She wasJK v Register General for England and Wales [2015] EWHC 990 (Admin)}.In a recent High Court case, a trans woman known as JK challenged the legal requirement that she be recorded as ‘father’ on her children’s birth certificates. Despite self-identifying and living her life as a woman, in the absence of a gender recognition certificate – which takes some time to acquire , and by introducing compulsory joint birth registration in all but a narrow range of exceptional cases . I discuss this normative dimension further below. For now, I want to end this historical outline by noting that the requirement to ‘re-register’ a birth following the marriage or civil partnership of the child’s parents still forms part of the current legislative framework.From my brief exploration of reforms relating to the registration of births outside of marriage, I want to make four observations. The first is that where there is political will, the law in this area can of course be reformed, despite the complexity of the task. This should remove any notion that reforming what might seem for many to be an intuitive, ingrained and straightforward procedure would be overly difficult or confusing, and somehow not worth the effort, time or costs involved. The ongoing requirement to re-register an ‘illegitimate’ birth is, by itself, a clear enough signal that reform of this 'old-age pensioner' of the statute books is needed, before even starting to think through the challenges heralded by developments in assisted and collaborative reproduction.The second observation is that historical reform of birth registration law could be interpreted as being a bit haphazard, in that different trends – such as the registration of more unmarried fathers on birth certificates and the introduction of short birth certificates – seem to occur along similar time trajectories. I mention this as I think it will be an observation that will be invoked in relation to the extent to which genetic parentage is recorded on a birth certificate. Here, there is potential for the increasing ability of unmarried (genetic) fathers to register their connection to a child to be pitched as in tension with the parenthood provisions of the Family Law Act 1987 and the Human Fertilisation and Embryology Act 1990, which made explicit provision for non-genetic parents – male or female – to be registered as legal parents, with no indication on a birth certificate that the child was conceived through donor conception. However, this seems to be only a partial telling of a story, which perhaps finds its origins in the inaccurate characterization by the Warnock Committee of the birth register 'as a true genetic record' : 4.21. WFurthermore, in terms of birth certificates not acknowledging the role of donor – or otherwise assisted – conception, comparisons are often made with adoption and parental order certificates, which record a transfer of legal parenthood in the context of adoption and surrogacy, respectively. In both cases, it is obvious that the person’s certificate is not an original birth certificate, prompting any curious individual to follow the paper trail to their original entry; this, of course, records the birth parents or sometimes the birth mother alone. However, these parents may or may not be the child’s genetic parents, so it seems odd to make this comparison. Birth parents are recorded because they, unlike mostThis leads to my third observation, which is that a normative narrative of family and kinship relations has always underpinned the birth registration system, and shaped its meaning in society. The information recorded by the state – however partial and prescriptive – is informed by the normative politics of family life. While the specifics of such may shift over time, the politics seem to remain tenaciously informed by gendered perceptions of the two-parent family model, in which children are deemed to have, at most, two ‘real’ parents . To nameEither way, it is this normative underpinning which makes it crucial that any law reform project starts by asking and attempting to clarify the very basic question of the actual purpose of birth registration; only then can we determine what information is appropriate to record. In urging the Law Commission to consider this preliminary question, I do not preclude the possibility that we might seek to change the purpose of birth registration from what it was in historical terms, or charge it with multiple purposes. However, we do need to be realistic about what we ask of an administrative procedure such as birth registration, and what legal reform can achieve in light of the wider sociolegal context in which the system operates. In terms of legal context, we cannot consider the reform of birth registration law without also considering developments in other substantive areas of law, such as citizenship and family law.In my fourth observation, I restrict my comments to developments in family law, where birth registration has become an increasingly important social policy tool in relation to parenting. Section 111 of the Adoption and Children Act 2002 reformed the law so that voluntary joint birth registration conferred automatic parental responsibility to unmarried fathers , rather th Programme,th century, despite significant developments in family life; understandings of gender in society; and the information which the state holds on individuals in other administrative, statistical, biometric and healthcare databases?In response to the Law Commission’s consultation question on whether it should review the law governing the registration of births, the answer is surely ‘yes’. Legal challenges to the current system are increasing, and while the context of each challenge varies, what we see in common across different contexts is a growing significance being placed on what individuals regard as subjectively ‘accurate’ information being recorded, and a desire to have significant life events ‘recognized’. These developments relate, in part, to people’s individual circumstances and family narratives not being countenanced in the standardized birth registration procedures and forms, but they also relate to the multiple, and sometimes competing and contradictory, understandings that people have of the purpose of birth registration. As birth certificates are increasingly required for identification, such challenges are likely to increase, particularly as different forms of parenting, family life and gender become increasingly visible and acceptable. While some may argue that legal reform in this area would not benefit a substantial enough number of people, such would only be true if the Law Commission was to cast the scope of the project in a narrow fashion. Underpinning some specific reform questions with a much wider consideration of the purpose of birth registration in the contemporary era would be an extremely useful project for wider society, with implications for everybody given the compulsory nature of birth registration. While there will undoubtedly be a huge number of proposals for the 13There is significant – and really interesting – work to be done in this area. In legal terms, the past decade has seen a growing body of academic scholarship on birth registration, but, like reform, this has been piecemeal. There is plenty of scope for more sustained considerations, particularly those of an empirical and comparative nature. Placing birth registration law on the legal reform agenda would certainly highlight registration as a serious topic for academic and other research, and would lead to greater societal understanding of both the purpose and meaning of this increasingly important procedure and ritual in contemporary society.


In many countries, birth defects are one of the leading causes of death in infants and young children (2). Infants who survive and live with these conditions are at an increased risk for long-term disabilities. For this event’s inaugural year, CDC is collaborating with 11 other organizations to implement World Birth Defects Day. The goals of this worldwide observance are to 1) increase global awareness about the occurrence of birth defects; 2) increase awareness of available treatment services; 3) expand referral and care services for all persons with birth defects; 4) increase implementation of primary prevention programs for birth defects; and 5) stimulate action among the public, members of governments, nongovernmental organizations, and health care providers to improve the care of affected children.Every year an estimated 7.9 million infants  are born with a serious birth defect (For World Birth Defects Day, CDC and its partners seek to build momentum for this initiative and together, work to increase birth defects surveillance capacity and expand prevention initiatives worldwide. CDC invites others to participate in World Birth Defects Day this year by sharing stories and information on social media using the hashtag #WorldBDDay. On March 3, all are encouraged to join the worldwide effort towards healthier women, healthier pregnancies, and healthier infants.


T1, which is a proxy for myelin content. Here, we apply the IR-DTI approach to the human brain in vivo on 7 healthy subjects for the first time. We demonstrate that the approach is able to measure differential tract properties in crossing fibre areas, reflecting the different myelination of tracts. We also show that tract-specific T1 has less inter-subject variability compared to conventional T1 in areas of crossing fibres, suggesting increased specificity to distinct fibre populations. Finally we show in simulations that changes in myelination selectively affecting one fibre bundle in crossing fibre areas can potentially be detected earlier using IR-DTI.A comprehensive tract-based characterisation of white matter should include the ability to quantify myelin and axonal attributes irrespective of the complexity of fibre organisation within the voxel. Recently, a new experimental framework that combines inversion recovery and diffusion MRI, called inversion recovery diffusion tensor imaging (IR-DTI), was introduced and applied in an animal study. IR-DTI provides the ability to assign to each unique fibre population within a voxel a specific value of the longitudinal relaxation time,  •We apply the inversion recovery DTI approach to the human brain in vivo for the first time.•We demonstrate that IR-DTI can measure tract-specific T1 in crossing fibres.•IR-DTI T1 has less inter-subject variability compared to conventional T1 in crossing fibres.•Changes in myelination affecting one fibre in crossing fibres can be detected earlier using IR-DTI. White matter (WM) is organised in bundles of axons, myelinated to a varying degree, connecting specific areas of the brain. Axons tend to group into fascicles and appear to prefer to fasciculate with axons of their own type ; as a reTractometry  to prove feasibility of IR-DTI for human applications; 2) to characterise tract profiles using tract-specific values for T1; 3) to compare IR-DTI to conventional T1 measures in their ability to discriminate multiple T1s in a voxel; and 4) to compare the sensitivity to tract specific T1changes of IR-DTI to that of conventional single T1 maps in areas of crossing fibres.Recently, a new MRI technique combining inversion recovery and diffusion, called IR-DTI, was introduced to provide fibre-specific estimates of the relaxation time n tensor . This teT1 for each voxel, according to: T1 component, it is in principle possible to perform a multi-exponential fit on the same IR data, e.g., according to: i is the number of T1 components. However, separating two or more exponential decays with similar rates may be very difficult, because of well recognised difficulties  fits a single relaxation time iculties .i populations, each characterised by a volume fraction, fi, a specific diffusion tensor Di and a specific IR-DTI instead provides the possibility of recovering multiple relaxation times within a voxel by exploiting the orientational dependence of the diffusion signal. The IR-DTI protocol comprises several inversion recovery-prepared diffusion MRI series acquired for different inversion times (TI). The combined contrast is described by the following equation : (3)S/S0T1s of 800 and 1000 ms respectively, and three crossing fibres, oriented along x-, y- and z-axis, associated with T1s of 800, 1000 and 1200 ms respectively. The fibres had identical diffusion properties , but had different volume fraction . In addition, the angle between the first two fibres was changed in the range 30°–90°. The scheme used had the following parameters: TI = 175,250,300,350,400,450,500,585,675,750,850,1100,1500 ms, 15 non-collinear gradient orientations plus 2 unweighted scans for each TI for a total of 221 measurements, b = 1000 s/mm2. 100,000 noisy repetitions were generated adding noise to generate Rician-distributed data at signal-to-noise ratio (SNR) = 20 in the unweighted scan, which is a conservative estimate of the SNR achievable in vivo , the same TI range , the same number of repetitions (i.e. 221 measurements) and the same SNR, but without diffusion weighting. IR-DTI data were fitted to Eq. T1 change, the same simulations were repeated for different values of the two T1s, simulating an increase of up to 10% in the smallest and in the largest T1, respectively. Data were then fitted to both Eqs. Simulations were used to test the capability of IR-DTI to disentangle multiple components in a crossing fibre voxel and to compare it with conventional IR. Eq. B1 inhomogeneity, dielectric pads  for the HARDI scan in order to get full brain coverage. The slice package was centred in the corpus callosum. A high-resolution quantitative T1 scan was also acquired for each participant using an MP2RAGE sequence  was 29 ± 6 years; 4 of the participants were males and 3 were females. The experimental procedures were approved by the ethics committee of the Faculty for Psychology and Neuroscience at Maastricht University, and were performed in accordance with the approved guidelines and the Declaration of Helsinki. Informed consent was obtained from each participant before conducting the experiments. To minimise the effects of ric pads  were plasequence , at two T1 value for each fibre population present in the voxel, according to Eq. Di and a Johnson noise term ; in addition, T1 maps were also computed taking the unweighted diffusion data at varying TI (IR T1) according to Eq. The SNR of the b0 image associated to the longest TI was calculated using the difference method  and retuise term . The fitty model . We havety model  that theon times , were obT1 values in areas of crossing fibres. The CC and the CING were reconstructed by manually selecting waypoints for all subjects. Fibre-specific histograms of T1 were computed by assigning the T1 were computed by assigning the T1 associated with the orientation subtending the smallest angle to the fibre trajectory. To perform statistical analysis over all subjects and over different tracts, an automated tract segmentation approach  and the genu of the corpus callosum (CC) effectively cross within a voxel, providing a good test-bed to demonstrate that the analysis can measure fibre specific approach  was chosT1 profiles were calculated for each subject and combined to find the mean profile and the associated standard deviation over all subjects.All T1s to the simulated crossing fibre data using Eq. T1s even for small crossing angles.T1 for two and three fibres crossing calculated with IR-DTI and with Eq. T1 in a two fibre crossing configuration, if the change only affects one of the two fibres. The simulations are repeated for the case in which the smallest T1 is increasing (upper panels) and for the case in which the smallest T1 is increasing (lower panels). The observed change is compared with the maximum and minimum variability found in vivo (shaded areas) and reported in T1 variability, and needs a change of 6–9% in tracts characterised by high variability. IR, which measures the weighted average of the values between the two fibres, needs much larger effect sizes (>10%). A bi-exponential fit, according to Eq. T1 (data not shown).T1 in the area of crossing of the two tracts. The two crosses represent the calculated cluster centroids. The two bundles show a clear separation on both axes, with the CING having larger T1 values than the CC. This is also shown in the histogram of T1 relaxation properties of the two tracts is consistent across subjects.T1 maps are also relatively homogeneous, with adjacent tracts showing clearly distinct values of T1 . To check consistency of the differences in T1 measured in the crossing area, in panel h the histograms of the tract-specific T1s are reported for the whole tracts CC, CST and SLF, reconstructed using tractography. CC is characterised by the smallest T1, while CST shows the largest T1. The values recovered in the crossing areas with IR-DTI are consistent with those calculated along the whole tract.f T1 see e–f. Thisf T1 see g, which T1 value in the middle of the tract) and the standard deviation across subjects along the tract is reported for IR-DTI T1 (red) and for conventional MP2RAGE T1 (green). The IR-DTI approach always results in lower standard deviations. In cases of known presence of multiple crossing tracts, the differences are particularly pronounced. For instance, the inter-subject variability in the centre of the CC is small for MP2RAGE T1, but increases to several times the variability of IR-DTI T1 in the more lateral parts of the CC where it crosses the CST and the SLF.T1 tractometry. MP2RAGE T1 shows the largest variability in all tracts, followed by IR T1, while IR-DTI T1 shows the smallest variability.T1 inside a voxel in an animal model  are highly homogeneous in their composition. Here, we demonstrate the feasibility of the approach both in simulations and in-vivo in the human brain. In addition, we demonstrate the advantages of using IR-DTI over conventional, voxel-wise approach, where most of the voxels are expected to contain contributions from different bundles . In the case where the two T1s are very close and the measures are only acquired in the TI space it is very difficult to tease apart two exponentials, unless the SNR is unrealistically high  to ensure adequate SNR, obtaining SNR values between 25 and 30 across WM. However, in our simulations we have employed a conservative value of 20 for the SNR, and demonstrated that the method is able to resolve accurately up to three fibres crossing, which suggests that there is room to improve resolution.With a double suppression of signal, both by the IR T1 (T1s, but also increases the experimental time, when TR's are increased to accommodate SAR constraints. This can be alleviated in the future, for example, by implementing state-of-the-art SAR-efficient inversion pulses (Possible limitations for translation to the clinic are the long acquisition times that result from the elevated SAR caused by both inversion and refocusing pulses, especially at 7T. 7T helps with increased signal in the doubly attenuated IR-DTI contrast and increases the differences in T1 , and thun pulses .T1s inside a voxel, with minor loss in precision when the crossing angle goes from 90 to 30°, as shown in IR-DTI can recover up to three distinct B1 inhomogeneity is challenge for 7T imaging. Using standard circularly polarized or ‘birdcage’ transmit coils yields flip angles which are up to 42% lower in the periphery of the brain compared to centrally, due to dielectric effects (B1 homogeneity ( effects . To mitiogeneity . Improveogeneity , might hT1 values. IR-DTI has great potential for application in the clinic, for instance in detecting very early tract specific alterations of myelination in crossing fibre areas that might not be detected using other MRI-based approaches.In conclusion, we demonstrate the feasibility of in-vivo IR-DTI analysis on the human brain identifying fibre-specific


In the Northern Hemisphere, springtime events are frequently reported as advancing more rapidly at higher latitudes, presumably due to an acceleration of warming with latitude. However, this assumption has not been investigated in an analytical framework that simultaneously examines acceleration of warming with latitude while accounting for variation in phenological time series characteristics that might also co-vary with latitude. We analyzed 743 phenological trend estimates spanning 86 years and 42.6 degrees of latitude in the Northern Hemisphere, as well as rates of Northern Hemisphere warming over the same period and latitudinal range. We detected significant patterns of co-variation in phenological time series characteristics that may confound estimates of the magnitude of variation in trends with latitude. Notably, shorter and more recent time series tended to produce the strongest phenological trends, and these also tended to be from higher latitude studies. However, accounting for such variation only slightly modified the relationship between rates of phenological advance and latitude, which was highly significant. Furthermore, warming has increased non-linearly with latitude over the past several decades, most strongly since 1998 and northward of 59°N latitude. The acceleration of warming with latitude has likely contributed to an acceleration of phenological advance along the same gradient. Examples of earlier onset of spring events span a broad array of life history traits and taxonomic groups, including plants, invertebrates, amphibians, birds, and mammals across most of Earth’s biomes. For instance, earlier onset of spring events such as green-up and flowering in plants, migratory arrival in birds, calling and spawning in amphibians, and emergence in insects have been reported in the primary literature and several major syntheses of ecological responses to observed warming over the past two decades7, including the most recent IPCC Fifth Assessment Report8. In addition to documenting generally, though not universally, earlier onset of spring events in response to warming, one of the major insights of such work has been more rapid advancement of spring events at higher than at lower latitudes9.Advancing spring phenology constitutes one of the most well studied and oft-cited examples of ecological response to recent climatic warming5, and include, among many others, latitudinal gradients in arrival timing and nesting in birds12; nesting in sea turtles13; emergence and flight phenology in insects14; and extensively documented latitudinal variation in the timing of initiation of growth, flowering, and fruiting in plants21. This pattern ostensibly relates to the inter-related constraints of latitudinal variation in local temperature and seasonal day length on phenology22. Second, the magnitude of recent land surface warming has been generally greater at higher than at lower latitudes23. Hence, the alleviation of temperature constraints on the annual timing of expression of life history traits due to climate change has apparently contributed to or amplified latitudinal variation in phenology24.Such a latitudinal gradient in phenological trends presumably relates primarily to the convergence of two related phenomena. First, species with latitudinally broad geographical distributions tend to exhibit latitudinal gradients in the timing of expression of life history traits, with timing of events generally occurring later as latitude increases. Numerous examples of this pattern exist25 might elicit even greater phenological advances at higher than at lower latitudes, unless resulting conditions become constraining26. But this expectation has not yet been informed by an integrative, quantitative assessment of variation in rates of phenological advance and warming with latitude. To date, support for the notion that rates of phenological advance have been greater at higher than at lower latitudes, and that this difference is due to more pronounced warming at higher latitudes, has been largely piecemeal. Previous syntheses and meta-analyses have relied upon: (1) binned analyses, in which phenological trends are compared between low- and high-latitude studies or among latitudinal zones17; (2) simple correlations between rates of phenological advance and latitude that have not accounted for potentially confounding variation due to taxonomic or trait-based differences5; or (3) insights gleaned from qualitative comparisons among rates reported in the literature9.Taken together, these observations suggest that continued anthropogenic warming and resulting record temperaturesth Century and into the 21st Century. We furthermore complement our analysis with one of spatio-temporal variation in patterns of Northern Hemisphere land-surface warming over the past century to investigate the extent to which the rate of warming over this period has varied with latitude.Here we assess latitudinal variation in rates of phenological advance in an analytical framework that accounts for continuous spatial variation and potentially confounding covariates related to characteristics of the focal phenology time series. This approach departs from previous assessments that have, for instance, examined latitudinal variation in phenological trends while combining trend data derived from an array of different phenological events and taxonomic groups studied over widely disparate periods throughout the 209. In addition to these, we gathered rates of phenological change from additional primary sources, and in this case selected rates based on time series of observational data spanning at least ten years. This resulted in a pool of 743 estimates of rates of phenological change, including both significant and non-significant trends. These trends span a latitudinal gradient from 31.9°N to 74.5°N, and encompass studies beginning between 1928 and 2002 and ending between 1978 and 2013. Hence, the geographic extent of the meta-data used here includes 42.6 degrees of latitude, and the temporal extent, from earliest to latest observations upon which trend estimates are based, includes 86 years. Taxa include amphibians, birds, invertebrates, mammals, and plants. A complete list of the published rates of phenological change and their sources, as well as descriptive meta-data including taxon, latitude, and time series dates and lengths included in this analysis is provided in the online supplementary material.We compiled rates of phenological change from primary sources reviewed in three previous major syntheses and meta-analyses that included assessments of latitudinal gradients27. GAMs allow for simultaneous consideration of dependent variable responses to continuous numerical predictors and categorical predictors in the same model, and are therefore occasionally referred to as “categorical regression models”27. Our GAM included latitude and time series characteristics as continuous numerical predictors, and taxon and phenological trait as nominal categorical predictors. The meta-data pool included both significant and non-significant phenological trend estimates. Significance (two-tailed p ≤ 0.05) was determined on the basis of p-values accompanying trend estimates based on simple linear correlations or linear regression coefficients in the original sources from which the trends were obtained. Previous meta-analyses have focused on analyzing variation in significant trends only6 because, technically, non-significant trends do not differ from zero. We analyzed pooled significant and non-significant trend estimates and accounted for significance by including in our GAMs a nominal categorical predictor, “significance”. However, for comparison, we also report results of analyses focusing on significant phenological trends only.To analyze variation in rates of phenological change , in association with latitude, we first employed simple linear regression between published phenological trends expressed as days/decade and latitude of the individual study location as reported in the primary source. We then conducted additional analyses to account for potential contributions of other factors to the relationship between rate of phenological change and latitude. These included time series characteristics (the first year of observation and length of the time series upon which rate estimates were based), taxon, and phenological trait. To accomplish this, we applied a generalized additive model (GAM)Northern Hemisphere land surface temperature data were obtained from the University of Delaware (UDel) surface temperature record v301, for the period 1928–2010, and from latitudes 32.25°N through 74.25°N, to most closely overlap the temporal and spatial extent of the phenology meta-dataset described above. We used monthly mean temperatures at a spatial resolution of 1° latitude for the boreal spring months April through June to derive annual estimates of boreal spring temperature anomalies at each one-degree latitudinal band. Spring temperature anomalies were calculated as departures from the 1951–1980 mean for the April through June period at each latitudinal band.th Century and early 21st Century . Hence, this approach was intended to investigate and quantify accelerating trends in the rate of warming with latitude, and replicates, in the temporal domain, previous analyses demonstrating increasing rates of global surface warming in more recent multi-decadal periods since the mid-1800s23. We achieved this by deriving estimates of the slope of the linear regression between spring temperature anomalies and “year” for each period. Next, we analyzed variation in these trend estimates with latitude, accounting for potentially non-linear associations between rate of land surface warming and latitude by comparing linear and non-linear (quadratic) regression models. Our determination of the best-fit model is based on a balance among parsimony, F-values, and visual inspection of the fit of the model to the data. If the coefficient of determination increased by less than ten percent from the linear to the quadratic model, in the interest of parsimony we did not regard this as indicative of a better model. If non-linearity in this association was indicated, we subsequently employed piecewise non-linear (threshold) modeling to identify the threshold latitude below and above which the rate of warming differed within any given period, including the full set of temperature anomaly data (1928–2010) and each more recent decadal period up to 1998–2010. Because 1998 included a strong El Niño event, and was notable for its exceptional global land-surface temperature anomaly, we repeated our analyses using 1997–2010 and 1999–2010 as the most recent period. Results are presented using all three intervals for the most recent period. To determine whether variation in rates of warming with latitude differed significantly among more recent decadal periods, we performed an ANOVA with trends in spring warming as the dependent variable, the start year of the period of consideration as a fixed factor, and latitude as a covariate.To investigate whether the rate of spring warming in the Northern Hemisphere has increased with latitude and through time for the spatio-temporal domain considered here we employed a multi-stage approach. First, we analyzed trends in temperature anomalies for the boreal spring at 1° latitudinal increments over the entire period, from 1928 through 2010, and then for successively more recent periods in one-decade intervals . We justify this approach on the basis of the fact that, as described above, the phenological trend estimates used here derive from studies conducted over periods of various lengths and with various start years throughout the 2028. To assess potential differences between the two data products, we regressed the latitudinal mean UDel values onto CRU values for the periods 1928–2010, 1938–2010, 1948–2010, 1958–2010, 1968–2010, 1978–2010, 1988–2010, and 1998–2010. Slope estimates  of these regressions displayed no systematic departure from parity with latitude for any of the periods  gridded temperature data product for our analysis because it is one of only two temperature datasets that has sufficiently high spatial resolution for our analysis; the other is the Climatic Research Unit (CRU) TS4.01 Mean Temperature datasetAll data are available on request, and will be archived online for public access prior to publication.α = 0.05 level in the primary literature from which they were derived. Hence, greater than one-third (39.6%) of published phenological trends considered in this sample constitute stasis, or a lack of significant directional change. Significant phenological trends varied from a maximum delay of 7 days/decade to a maximum advance of −36.3 days/decade, while non-significant trends varied from a maximum delay of 26.3 days/decade to a maximum advance of −51.3 days/decade. Among significant phenological trends, 415 (92.4%) were negative, indicating an overwhelming tendency toward phenological advance. The mean (±1SE) rate of advance among significant phenological trends was −6.40 (±0.34) days/decade, while the mean rate of delay among significant phenological trends was 3.12 (±0.36) days/decade, indicating that on average phenological advances, where these have occurred, have been more than twice as great as phenological delays.Of the total number of phenological trend estimates included in our analyses, 449 were reported as significant and 294 as non-significant at the P < 0.001) even after accounting for categorical significance . The slope of the relationship with latitude suggests that the decadal rate of advance in springtime events represented in this meta-data pool increases by approximately 0.4 to 0.5 days/decade with each one-degree increase in north latitude. For comparison, an analysis of statistically significant phenological trends only revealed a slightly stronger association with latitude .Pooled rate estimates, including both significant and non-significant rates, displayed substantial heteroscedasticity in association with latitude, time series length, and the first year of observation in the time series from which they were derived Fig. . In othe5. However, these relationships are not strictly comparable. Although our meta-data pool includes the phenological trend estimates used in Parmesan (2007), our analysis also included slope estimates that were published subsequent to the analysis by Parmesan (2007), including additional estimates from high latitude studies.The rate of increase in phenological advancement with latitude revealed by the simple GAM of pooled significant and non-significant trend estimates is greater than the only other such reported relationship that we are aware ofP < 0.001) and first year of observation . Among significant phenological trends only, trend estimates were strongly and non-linearly related to time series length  indicates that short-term observational studies tend to produce strongly negative estimates of rates of phenological change, i.e., phenological advance, while longer studies tend to produce more modest, and occasionally positive, trend estimates  indicates that more recent studies have also tended to produce strongly negative estimates of rates of phenological change, while earlier studies have tended to produce weaker trend estimates . More importantly in the context of the central question motivating our analyses, both time series length and the first year of observation upon which phenological trend estimates were based were significantly related to latitude. Far northern observations of phenology have been shorter than those at lower latitudes  because they have been initiated more recently   Fig. . Hence, P < 0.001) after accounting for significant associations with first year of observation  and with significance category, taxon, and trait . The GAM with time series length as a predictor revealed a stronger, significantly negative relationship between phenological trend and latitude , and a significantly positive association between phenological trend and time series length , with significance category, taxon, and trait remaining significant . However, this second GAM explained 9% more of the variation in phenological trend estimates . Hence, even after accounting for variation due to time series metrics and taxonomic- and trait-based differences among studies, which no previous study has to our knowledge attempted, the increase in rate of phenological advance with latitude remained strongly significant.Because of the correlation between the first year of observation and time series length in the phenological studies considered here, these two variables cannot be included together in a multivariate model of phenological trends. For this reason, the more complex GAMs reported above were conducted individually, each with either start year or time series length as a predictor, and both with the additional predictors: latitude, taxon, significance category, and the phenological trait upon which the trend estimate was based. In the GAM with start year as a predictor, phenological trend remained significantly negatively related to latitude  but a highly significant positive relationship at and above it . Delimiting this period as 1997–2010 or 1999–2010 also revealed strong departures from linearity in the relationship between rate of warming and latitude at a threshold of 59°N . The mean rate of warming calculated across all of these periods suggests, additionally, a generally non-linear increase in rate of warming with latitude .Hence, the relationship between rate of land surface warming and latitude in the Northern Hemisphere is highly variable, and characterized by varying degrees of non-linearity, among the successively more recent periods of the past century examined here Fig. . Indeed,ude Fig. . In supp29 and 200230, largely coincident with the onset of the rapid increase in rates of warming with latitude (Fig. 31, further acceleration of rates of warming with latitude may pose consequences for long distance migrants that track resource phenology along latitudinal gradients.Our analyses have revealed significant increases in rates of phenological advance with latitude both before and after accounting for variation in such rates attributable to taxonomic representation, life history traits, and timing and duration of observational studies from which they derive. These results have also raised a cautionary note that higher latitude studies considered here and elsewhere might produce trend estimates indicating greater rates of phenological advance than those at lower latitudes simply because they have been shorter in duration. However, our analyses also indicate that shorter studies have generally been more recent and likely have revealed greater rates of phenological advance at high latitudes because these studies coincide with the period during which warming has increased most strongly and non-linearly with latitude. Indeed, of the four arctic studies considered here, the two that reported significant rates of phenological advance commenced in 1996ude Fig. , while tSupplemental Table S1 and Supplemental Figures S1 and S2Dataset 1


BMI z-scores were obtained for subjects under the age of 20 years. Multivariable linear regression was used to evaluate the relationship between birth weight and BMI and BMI z-score, adjusted for age, sex, puberty, and fat mass percentage. Higher birth weight was associated with higher BMI and BMI z-score among CBT and controls. In conclusion, birth weight is a risk factor for higher body mass during childhood in CBT, and this may help the identification of children at risk of future obesity and cardiometabolic risk.Children with brain tumors (CBT) are at higher risk of cardiovascular disease and type 2 diabetes compared to the general population, in which birth weight is a risk factor for these diseases. However, this is not known in CBT. The primary aim of this study was to explore the association between birth weight and body mass measures in CBT, compared to non-cancer controls. This is a secondary data analysis using cross-sectional data from the CanDECIDE study (n = 78 CBT and n = 133 non-cancer controls). Age, sex, and birth weight (grams) were self-reported, and confirmed through examination of the medical records. Body mass index (BMI) was calculated from height and weight measures and reported as kg/m While brain tumors are a heterogeneous group with some fairly aggressive subtypes, advancements in imaging and therapeutic breakthroughs have increased the number of children surviving these tumors2. This important milestone has been offset by the emergence of co-morbidities and premature mortality in survivors7. While traditionally reported outcome determinants include tumor recurrence and secondary tumors, recent evidence suggests that children with brain tumors (CBT) are at higher risk of premature cardiovascular diseases including hypertension, cerebrovascular events and type 2 diabetes compared to non-cancer controls10. While the mechanisms leading to these cardiometabolic disorders are not well understood, the combined burden of the tumor and treatment with these emerging chronic disorders will increasingly contribute to adverse outcomes in CBT as these survivors live longer and get older.Brain tumors are the most common cause of cancer-related deaths in children14, and the association of obesity with future type 2 diabetes and cardiovascular diseases has been tracked to childhood15. Defining the determinants of obesity, cardiovascular disease and diabetes in CBT will permit the prioritization of children who need early intervention to improve survivors’ quality of life and lifespan.The global obesity epidemic is the main catalyst of cardiometabolic disorders in the general population17; however, it is unclear if birth weight in CBT is a risk factor for obesity during childhood. Given that CBT have excess adiposity in comparison to non-cancer controls18, it may be a potential early predictor of further adverse cardiometabolic outcomes. In addition, while CBT have similar rates of overweight/obesity when compared to non-cancer controls, this still leaves one-in-four CBT in the overweight/obese category based on body mass measures19. Body mass index (BMI) is the most used screening tool to assess obesity risk, and may still be a predictor of future cardiometabolic risk, as these children get older. Therefore, the primary aim of this paper was to explore if birth weight is a risk factor for higher body mass in CBT, compared to non-cancer controls.Over the past two decades, evidence has validated the role of birth weight as a risk factor for adult obesity and cardiometabolic disordersWe included 78 CBT  and 133 non-cancer controls  in this study. The characteristics of the study population are shown in Table Participants born at full-term comprised the largest groups . More controls were born pre-term  while both have similar distribution for early-term  and late-term .The majority of both CBT and controls were born appropriate for gestational age (AGA) . Both groups had a similar distribution for those who were born small for gestational age (SGA)  while large for gestational age (LGA) was more common in controls . Maternal gestational diabetes was reported in two CBT (2.60%) and in one control (0.80%), while preeclampsia was reported in five CBT (6.40%) and 10 controls (7.50%).The majority of the subjects had normal birth weight . Six CBT (7.70%) and six controls (4.50%) were born with a low birth weight (<2500 grams). High birth weight (>4000 grams) was reported in ten CBT (12.80%) and 23 controls (17.30%).Brain tumor characteristics and therapeutic modalities are reported in Table To explore the association of birth weight with body mass, we performed multivariable regression analyses in CBT, adjusted for age, sex, puberty, and %FM. For every unit increase in birth weight, BMI increased by 0.18 units  in CBT and by 0.17 units  in controls. Similarly, for every unit increase in birth weight, BMI z-score also increased by 3.69 units  in CBT and by 2.15 units  in controls.To determine if the association between birth weight and body mass differs between CBT and controls, an interaction term (birth weight*brain tumor status) was introduced Table . Birth wThe emergence of cardiovascular diseases and type 2 diabetes in survivors of childhood brain tumors are likely to contribute to adverse prognoses, and there is an urgent need to identify the drivers of these outcomes to mitigate their effects on the life span and quality of life. In this study, we demonstrate that birth weight is a risk factor for higher body mass in CBT during childhood, and this relationship was similar to that noted in non-cancer controls.22. One of the potential early and feasible measures that forecast these outcomes is birth weight.The influence of the in- and ex-utero environments on the risk of obesity and cardiometabolic risk is an important determinant of health outcomes, based on evidence from studies in the general population23. It is estimated that 10–40% of birth weight is driven by genetic factors, with several loci identified to suggest genetic links with body weight and mass24. In addition, fetal metabolic programing in utero in response to the intrauterine environment contributes to cardiometabolic health postnatally through epigenetic and other mechanisms25.Birth weight is driven by several factors, including genes that determine body size and growth, and the intrauterine environment26. Clinically, this manifests with infants being born small or large for gestational age27. However, it is likely that at intermediate stages of metabolic stress, some babies may have a birth weight within the normal range, but have been exposed to an environment that can alter their metabolic trajectory28.The exposure of an embryo to an adverse intrauterine environment and excess metabolic stress leads to the re-programming of the metabolic pathways, to adapt to in-utero scarcity or excess of nutrients34.The evidence for the association of certain categories of birth weight with adult BMI and cardiometabolic disorders was highlighted in studies from David Barker and the Dutch famine cohort and others, and showed that birth weight and maternal-fetal undernutrition was linked to low birth weight that was associated with adult obesity and adverse cardiometabolic outcomes22. However, recent studies report that in those with a birth weight that is sometimes within the normal range, or who have high birth weight (>4000 grams), are at risk of adult obesity36. Contrary to previous evidence39, some studies did not show linear, J-shaped or U-shaped associations of birth weight with adult obesity36.In addition, the link between birth weight and obesity was highlighted in previous reports showing that those born SGA or LGA to be at risk of adult obesity41. Birth weight may help identify those CBT who are at risk of adult obesity. Detailed study of growth paths and longer follow-up period are needed to determine if birth weight is a risk factor for obesity in CBT as they reach adulthood.Our data show a positive relationship between birth weight and body mass measures in CBT and controls in childhood. This is congruent with recent large-scale studies that have provided further evidence of similar results in the general pediatric population44, the association between birth weight, childhood BMI and future cardiometabolic risk is more complex45. It has been reported that birth weight below 3.4 kg, which is still considered appropriate for gestational age, and high BMI during childhood were independently associated with increased risk of coronary heart disease20. The association between low birth weight and type 2 diabetes was also reported47. The evidence indicates that both birth weight and BMI need to be scrutinized in CBT and controls to identify subjects who are at an increased risk of cardiometabolic disorders, as they appear to be independently linked to these outcomes.While available evidence suggest that obese children are at risk of becoming obese adults35, it is less clear how a normal birth weight affect this trajectory of adult obesity and cardiometabolic outcomes in CBT. Our data suggest that as weight trends higher while still within the normal range, this represents a risk factor for higher body mass. However, more prospective data sets are required to validate this observation and its association with cardiometabolic outcomes in CBT.While the majority of evidence has focused on high (>4000 g) and low (<2500 g) birth weight and its association with obesity riskOne of the strengths of our study is the inclusion of non-cancer controls to provide a comparison group. It is a strength to have this control group because when all is equal for birth weight between cases and controls, we can test the effect of having cancer and therapy on the association between birth weight and BMI.48. CBT can have disproportionate effects of their tumor and its treatment on cardiometabolic outcomes at a similar obesity rate, and birth weight may be a potential risk factor for these outcomes50.It has been shown that CBT have increased adiposity early in life post completion of therapy, and are at higher risk of cardiovascular diseases and diabetes compared to the general population, despite having similar BMI to controls51. This will require further clarification in future studies.There are several limitations in this study. We did not have sufficient power to determine the association of birth weight with young adult BMI, as the number of young adult subjects in our study was small. While we demonstrate that birth weight is positively associated with body mass measures in adolescence, our data does not distinguish whether this is a result of the expansion of lean body mass or fat mass, as BMI is a measure of total body mass. A recent study showed that birth weight was associated with fat-free mass, but not with fat mass among children and adolescents52, and this paper is not related to the primary study question. Therefore, the study was not designed to answer this question specifically. Prospective collection of data from diagnosis onwards and correlating growth data with those from earlier time points may help define growth patterns of those survivors at risk of obesity.This analysis is cross-sectional and therefore it is not clear if subjects were overweight or obese before their brain tumor diagnoses. In addition, the data used in the study were collected as a part of the Canadian Study of Determinants of Endometabolic Health in Children (CanDECIDE study)48. Our results suggest that birth weight is a risk factor for higher body mass in CBT in the early years post treatment. Future studies need to focus on determining the early origins of obesity and cardiometabolic risk in survivors. This will help identify survivors who are at particular risk of these complications, and birth weight may be one of the risk markers used to stratify cardiometabolic risk in CBT.In conclusion, cardiometabolic disorders are occurring at a relatively young age in CBT, and are emerging as significant morbidities and as potential determinants of longevity53.This secondary data analysis used data that were collected as a part of the CanDECIDE Study. This is a cohort study conducted at McMaster Children’s Hospital in Hamilton, Ontario, CanadaBriefly, we recruited participants who were 5 years and older, with no history of autoimmune diseases or infection, and have not received immunosuppressive therapy for at least 15 days prior to enrollment. Participants were consecutively recruited and the study recruitment took place between November 2012-March 2017. The Hamilton Integrated Research Ethics Board approved the study, and participants provided written informed consent. The study procedures were carried out in accordance with relevant guidelines and legal regulations.53. While reported birth weight correlates with measured birth weight54, the reported birth weight was verified from the medical records. In CBT, we also collected data regarding tumor type, location, sidedness and treatment modalities.The collected data included age, sex, ethnicity, puberty, pregnancy gestation, maternal gestational diabetes and preeclampsia, and reported birth weight using standardized questionnaires55. Normal birth weight was defined to be between 2500–4000 grams56. Infants born SGA were defined as those with a birth weight below the10th percentile, AGA as 10th-90th percentile, and LGA as above 90th percentile using Canadian reference ranges57.Gestation was defined for those born at less than 37 weeks as preterm, between 37–38 + 6/40 weeks as early term, 39–40 + 6/40 weeks as full term, and 41–41 + 6/40 weeks as late term gestations2 for all subjects. For those under 20 years of age , BMI percentile and BMI z-scores were also obtained based on the Children’s BMI Tool for Schools58 and the Centers for Disease Control and Prevention (CDC) growth chart59, respectively. Subjects with BMI ≥ 85th –<95th percentile were classified as overweight, and those above 95th percentile were classified as obese60.Anthropometric measurements performed included height measured to 0.1 cm using a stadiometer, and weight measured using an electronic weighing scale  and measured to the closest 0.1 kg. BMI was calculated in kg/m18.Adiposity was determined by measuring fat mass percentage (%FM) using the Tanita body fat monitor  for those under 18 years of age, and with the InBody520 body composition analyzer  for those 18 years and older as previously reported61. Kolmogorov-Smirnov test was used to assess the normality of data distribution, and data were log-transformed if they were non-normally distributed. Outliers were examined with box plot and visual inspection of extreme values. Multiple imputations was done for missing data62. Mean and standard deviation (SD) were reported for continuous variables, while the categorical variables were reported as counts with percentages. Independent sample t-tests were used to compare continuous variables between CBT and non-cancer controls while chi-square tests were performed to compare categorical variables.All analyses were performed using PASW version 18 statistical packageTo explore the association between birth weight and body mass measures in CBT, multivariable linear regression analysis was performed in this group. The dependent variables included BMI and BMI z-scores in separate models. The independent variables included birth weight, age, sex, puberty, and %FM.The relationship between birth weight and body mass in CBT and non-cancer controls was explored by adding an interaction term (birth weight*brain tumor status). Both CBT and non-cancer controls were included in the regression analysis.Results were presented as estimated β coefficients, 95% confidence intervals (CI), and associated p-value. The criterion for statistical significance was set at alpha = 0.05.The dataset used for statistical analysis for the current study is available from the corresponding author.


Studies have suggested a potential role for endothelial progenitor cells in the pathophysiology of prematurity‐related complications involving blood vessels; however, this knowledge has never been synthesized. We conducted a systematic review of the published data to examine the characteristics of endothelial progenitor cells in relation to preterm birth in humans. Preterm infants compared with term controls displayed similar or increased circulating/cord blood endothelial progenitor cell counts. However, the preterm endothelial progenitor cells were more vulnerable to exogenous factors such as oxidative stress. A reduced number, in particular of endothelial colony‐forming cells, was associated with bronchopulmonary dysplasia. No studies have examined endothelial progenitor cells beyond the neonatal period. These findings could prove useful in the identification of biomarkers for prognostication or therapeutic strategies for vascular‐related diseases in preterm‐born individuals. S Endothelial progenitor cells (EPCs) are central for maintaining healthy blood vessels. A way in which EPCs can be altered right from birth, especially after preterm delivery, is now being discovered. Preterm neonates are at risk of diseases marked by abnormal blood vessel development such as bronchopulmonary dysplasia. In adulthood, these individuals are vulnerable to chronic health problems, including hypertension and emphysema, also characterized by impaired blood vessels. Synthesizing the knowledge about the relationship between EPCs and preterm birth will help clarify whether EPCs can be used for the prediction of diseases occurring after prematurity and whether restoring EPC function can be a target for future treatment.Worldwide, approximately 10% of infants are born prematurely (<37 weeks of gestation). Advances in perinatology have markedly improved the survival of premature infants but many experience significant morbidities. The first generation of extremely preterm survivors <28 weeks), who are now entering adulthood, manifest cardiovascular disease risk conditions early in life, such as elevated blood pressure, altered myocardial shape and function, and signs of pulmonary obstruction 8 weeks, Recently, endothelial progenitor cells (EPCs) have emerged as a potential biomarker and therapeutic target that could be used to detect and treat medical complications of preterm birth. EPCs play a critical role during vascular repair and regeneration by homing to sites of tissue injury to restore vascular integrity and ensure normal endothelial function We searched PubMed, MEDLINE, Embase, CINAHL COMPLETE, and EBM reviews for articles published in English from January 1997 (first study on EPCs) to January 21, 2015, using the medical subject terms “preterm birth” OR “low birth weight” AND “endothelial progenitor cells” . The reference lists of relevant reports were manually reviewed for additional citations. The first selection of studies based on title and abstract, assessment of full‐text articles for inclusion, and data extraction and quality assessment without blinding to journal or authorship using an adapted version of the Newcastle‐Ottawa Quality Assessment Scale  Our systematic review included 18 articles summarized in Tables Given the lack of clear consensus regarding EPC definition in the included studies, several methods to characterize these cells were used and included cell enumeration by flow cytometry, number of colony formations in vitro, cell functional assays (in vitro growth and tubular formation), and in vivo vasculogenesis. Most studies searched for a combination of stem cell markers CD34+, CD133+) and endothelial markers  3+ and enTen studies examined the effect of preterm birth on EPC count and function Table . Two stuSafranow et al. Three studies n = 5) versus term (n = 30) after normotensive pregnancies.Baker et al. 2 dependence at 28 days). Moreover, those born at <28 weeks of gestational age had lower ECFC counts than those of the remaining preterm infants born at older gestational ages. Furthermore, infants with retinopathy of prematurity (ROP) displayed reduced numbers of ECFCs, although the difference was no longer statistically significant after adjusting for the degree of prematurity. Other morbidities, including sepsis, patent ductus arteriosus (PDA), brain injury, maternal hypertension, and chorioamnionitis, were not associated with the ECFC counts. In contrast to ECFCs, the same investigators did not observe any correlation between the EPC (CD34+/CD45−/VEGFR2+/CD133+) counts at birth or at 7 or 28 days and any of the studied antenatal or postnatal conditions Eleven studies examined the link between EPC counts and maternal conditions and neonatal complications associated with preterm birth Table . Borghes2 dependence at 28 days displaying similar numbers of EPC soon after birth. Infants who developed BPD had lower CD34+/CD133+/KDR+ cell counts at 7 and 21 days, but the levels were again comparable at 28 days and 36 weeks.Likewise, Paviotti et al. Baker et al. assembled a cohort of 48 preterm infants for whom cord blood was cultured for ECFC colonies and enumeration was further performed through flow cytometry Bui et al. provided pilot data to show trends toward lower counts of CD34+/CD45−/VEGFR2+ in peripheral blood over a 3‐week period in infants who were later diagnosed with BPD Although Baker et al. Finally, a few studies reported higher EPC counts in preterm infants with specific postnatal complications. Safranow et al. 2 40%) was shown to significantly inhibit the growth potential of preterm ECFCs, with minimal effect on term cells A series of studies have delved further into mechanistic pathways that could explain differences between preterm and term EPCs by investigating in vitro ECFC function in response to prematurity‐related environmental stressors (hyperoxia) and proangiogenic factors. All studies assessing ECFC cells were defined as cobblestone‐shape colonies formed within a range of 5–28 days and kept using similar media conditions. A summary of findings is described in Table Overall, EPCs and, in particular, ECFCs were either similar or increased in preterm infants compared with term controls. After a preterm birth, infants are still rapidly growing and developing. This stage corresponds to the third trimester of gestation, a period of substantial microvasculature development and mobilization of stem cells, which are systemically increased in the fetus compared with postnatal levels BPD, the most common complication of prematurity, was frequently associated with reduced EPC counts and impaired cell function. Preterm birth occurs at the saccular stage of lung development when the airways and pulmonary vessels come together. Lung angiogenesis, through secretion of VEGF and NO, among others, participates in the subsequent alveolarization process ROP is another complication characterized by uncontrolled vascular growth into the vitreous mediated by hypoxia, inflammation, and oxidative stress, which induce angiogenic factors  At birth, circulating EPCs, including the ECFC subtype, are present, most often at similar or sometimes increased numbers, in preterm‐born neonates compared with term controls. However, in vitro cell analysis indicated increased vulnerability of preterm ECFCs to hyperoxia‐induced oxidative stress with resulting dysfunction. Finally, convincing evidence supports the relationship between reduced numbers of the EPC subtype ECFC and the development of BPD but not with other relevant perinatal complications for now.Given the burden of preterm birth complications at the individual and societal level, unraveling the mechanisms underlying alterations in preterm EPCs could pave the way for new treatment options that restore EPC function. However, careful cell characterization that also includes functional assays to define EPC is of upmost importance.M.B.: conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; A.M.N.: financial support, manuscript writing, final approval of manuscript; B.T.: manuscript writing, final approval of manuscript; T.M.L. conception and design, financial support, collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript.T.M.L. has received research funding from the Merck, Sharpe, and Dohme grant program–University of Montreal Faculty of Medicine. The other authors indicated no potential conflicts of interest.Supporting InformationClick here for additional data file.


Peptide based nano-assemblies with their self-organizing ability has shown lot of promise due to their high degree of thermal and chemical stability, for biomaterial fabrication. Developing an effective way to control the organization of these structures is important for fabricating application-oriented materials at the molecular level. The present study reports the impact of electric and magnetic field-mediated perturbation of the self-assembly phenomenon, upon the chemical and structural properties of diphenylalanine assembly. Our studies show that, electric field effectively arrests aggregation and self-assembly formation, while the molecule is allowed to anneal in the presence of applied electric fields of varying magnitudes, both AC and DC. The electric field exposure also modulated the morphology of the self-assembled structures without affecting the overall chemical constitution of the material. Our results on the modulatory effect of the electric field are in good agreement with theoretical studies based on molecular dynamics reported earlier on amyloid forming molecular systems. Furthermore, we demonstrate that the self-assemblies formed post electric-field exposure, showed difference in their crystal habit. Modulation of nano-level architecture of peptide based model systems with external stimulus, points to a potentially rewarding strategy to re-work proven nano-materials to expand their application spectrum. Ability to design, control morphology, and tune up physical and chemical properties at nanoscale characterize the heart of nanotechnology. Generation of nano-level architecture should ideally have a design phase at molecular scale. Morphology of such systems can be better controlled, if they assemble further-on to micro dimensions. Nanotechnology research mostly focuses on the latter half by way of their imminent utility while fabricating materials at larger dimensions. Application of physical agents for tailoring the nanostructure morphology can be very useful for nanostructure fabrication.1. It can self-assemble into a variety of structures like microtubes, nanotubes2, microcrystals, nanofibers3, nanorods5 and nanowires6.In last decade, there has been an increased focus on organic and bio-organic nano-assemblies. Peptide nanotubes, their physical properties, and assembly morphologies are extensively studied due to their excellent biocompatibility as well as functional and structural diversity. Many ordered supramolecular structures have been constructed using peptides as the building blocks. The most extensively utilized peptide-based building block is diphenylalanine (Phe-Phe or FF), which is the shortest bio-molecule known to self-assemble into ordered nanostructures. FF incidentally is also the core recognition motif of the β-amyloid polypeptide, a peptide associated with Alzheimer’s disease7, bio-sensing8, energy storage devices, and hydrogels for tissue engineering10. The crystal structure of FF exhibits a non-centrosymmetric hexagonal space group (P61)11, which allows it to possess properties like piezoelectricity13, optical activity15 and ferroelectricity16. Due to its low dimensional highly ordered structure it also exhibits quantum confinement17, forming quantum dots18. Self-assembled structures formed by analogues of FF such as Ac-Phe-Phe-NH2, NH2-Phe-Phe- NH2, NH2-(p-nitro-Phe)-(p-nitro-Phe)-COOH, NH2(4-phenyl-Phe)-(4-phenyl-Phe)-COOH, PEGylated tetra-phenylalanine (L6-F4), β-AspFF etc. have also resulted in tubular, fibrillar and squared plate structures respectively20.The potential of these supramolecular structures have been utilized in diverse fields including nanofabrication, drug delivery vehicles22, solvent mediated control23, covalent modifications24, vapour deposition26, temperature27, surface29, relative humidity30, symmetry31 and magnetite coating on the surface of nanotubes32 have been employed to regulate the architecture of diphenylalanine self-assemblies. But studies with fairly high magnetic fields have not yielded the level of response as expected, though a response was forced, at a magnetic field range of 12 T or more33. Recent theoretical investigations, predict measurable response to applied electric field but practical demonstration has not been reported so far, with the best of our knowledge. The present study aims to investigate the impact of electric and magnetic field mediated perturbation, upon the chemical and physical properties of peptide nano assemblies, with diphenylalanine as the model molecular system. Electric field studies on biomolecules (like DNA and proteins) have shown permanent or induced dipole formation along the direction of applied field, indicating that electric field interaction could modulate their dipole moments35. Molecular dynamics studies in the presence of external electric fields on Aβ amyloid peptides and insulin have conclusively predicted the effect of an external field in modulating structure formation36. Martin Garcia and Ojeda May have predicted that an external constant electric field can even modify the secondary structure of a protein, by inducing a transition from β-sheet to α-helical like conformation37. Andrij Baumketner in a recent study, explored the feasibility of using external electric field to disaggregate amyloid fibrils, by inducing folding into an α-helical state reducing their β sheet conformation38. This is especially important because FF is the core recognition motif of β-amyloid segment. Here in this study, we attempt to confirm the effect of AC (Alternating Current) and DC (Direct Current) electric field on diphenylalanine self-assembly using experimental approach.One of the key challenges in the field of supramolecular chemistry has been controlling the self-assembly of molecules into ordered functional units. Previously, a number of strategies including pH mediated control39. These aromatic side chains play an important role in directing the amyloid fibril self-assembly through π-π stacking interactions40. Magnetic field has been previously employed to align β-amyloid fibrils for X-ray fiber diffraction studies44. So far various groups have reported studies involving magnetic field exposure of self-assembled diphenylalanine assemblies post formation33. We, however use electric or magnetic field, concurrently while formation of nano-assemblies. This is achieved by starting the experiment at a temperature (95 °C) that do not support assembly. The system is then cooled to facilitate assembly under electric or magnetic field of chosen strength at desired optimum concentrations for assembly. Our results indicate that field induced perturbation approach can be a promising tool for controlling nano-assembly, thus generating novel architectures.Protein crystals have been reported to show alignment in the presence of strong magnetic field. This alignment was believed to be the result of diamagnetic anisotropy of the peptide bonds and aromatic amino acids in protein molecules−1/50 Hz, 300 Vcm−1/50 Hz AC electric field, and 150 Vcm−1, 300 Vcm−1 DC) fields, magnetic field and ambient conditions continuously for 5 hours till the system cools and gets equilibrated at room temperature (25 °C) completely  T33, perThe right angled static light scatter of the samples exposed to AC and DC electric field showed an increase in scattering intensity with time, indicating spontaneous initiation of peptide self-assembly Fig. . In cont−1) formed an exclusive tube-like morphology and were randomly oriented in comparison to the field samples. The results indicate the possibility that electric field exposure modulates the formation of the peptide self-assemblies, though the magnitude of this influence may vary with sample molecular systems.The samples were analyzed using FE-SEM to gain an insight into the effect of electric field on the peptide self-assemblies, Fig. . MorpholTo investigate the effect of electric field exposure upon the physical properties of peptide self-assemblies, melting points of each sample were measured. The samples showed the difference in their melting points, further confirming a modulation in the assembly architecture of FF nanostructures Table .Table 1MHigh-resolution micro-Raman spectroscopy is a non-invasive technique that can be employed to examine the functional group composition of the material. This technique was performed on dried diphenylalanine self-assemblies, from each of the experimental conditions to probe the impact of field exposure on the chemical composition of the peptide. The Raman spectra of the self-assemblies formed in control and field exposed samples are shown in Fig. −1, 1034 cm−1, 1590 cm−1, 1429 cm−1 and 1608 cm−1 46 Peak at 1688 cm−1 band can be attributed to C=O stretching while small peaks detected between 1154 to 1300 cm−1 can be assigned to the acyclic C-C stretching46. Supplementary Table The Raman bands correspond to aromatic rings of FF are at 1004 cm47.To confirm the phase purity and examine any possible difference in crystal structure on the self-assemblies formed with and without electric field exposure, powder X-ray diffraction (PXRD) measurements were performed with Cu-Kα radiation (λ = 1.54 Å). Le-Bail profile fitting has been performed by assuming hexagonal crystal structure symmetry with P61 space group48. P-V is an approximation of Voigt function, which is a linear combination of the Gaussian profile and Lorentzian profile49, 50. This function allows to accommodate asymmetries in the X-ray diffraction peaks. The scattered points in Fig. 1. No spurious peaks were observed in the X-ray diffraction pattern which confirms the formation of pure diphenylalanine.A pseudo-Voigt (P-V) function was used to fit the profile by using Full Prof Suite51. In order to estimate the individual contribution of ‘P’ and ‘η’ on peak broadening, the Williamson Hall (W-H) analysis was employed  of the particles gives a rough estimation of the domain size which diffract coherently. It is mostly not the same as particle size due to the formation of polycrystalline aggregatesLattice strain on the other hand quantifies the distribution of lattice constants originating from imperfections in the crystals, such as dislocations inside the lattice. Figure We demonstrated that electric field could arrest the hierarchical self-assembly of diphenylalanine, and self-assembly was initiated only after (at least 10 minutes) the withdrawal of external electric field whereas magnetic field at the experimental (0.6 T) range has no significant effect on assembly formation. FF is the core recognition motif of amyloid β polypeptide. Electric field effect is in agreement with the earlier observation made by Andrij Baumketner, that external electric field can disaggregate amyloid fibrils by inducing folding. Self-assembly of diphenylalanine peptide after annealing in the presence of electric field showed the distinct morphological difference. Hill and co-workers earlier studied the little effect of magnetic field, and the results are in full agreement with our observation. The electric field exposure also modulated the stability of the self-assembled structures without affecting the overall chemical constitution of the material. Furthermore, we demonstrated that the self-assemblies formed post electric-field exposure showed the difference in their crystal habit. W-H analysis of the X-ray diffraction patterns revealed the differences in the peptide self-assemblies formed post electric field exposure of varying magnitudes, with respect to their lattice parameters as well as crystallite size. The microstrain associated with self-assembled structures also varied with changes in the magnitude of the electric field. We infer that our strategy in employing electric field mediated perturbation of electrostatic interactions directing the peptide self-assembly can be used to generate nanostructures with distinct morphologies from the same material. Further, in line with the theoretical investigations discussed in the earlier sections, this experiment suggests that electric field can modulate the physical properties of nanostructures and therefore has the potential to be deployed as a fabrication tool for a myriad of application-oriented materials without any chemical additives.The FF peptide was purchased from Sigma-Aldrich. Deionized water was used for all the experiments.27. The vial containing the sample was kept in a water bath (Grant sub aqua 26 plus) set at 95 °C, allowing peptide to dissolve completely. Fresh stock was prepared for each experiment to avoid any pre-aggregation. Peptide nano/micro tubes were formed while cooling to room temperature (25 °C).Fresh solution of diphenylalanine peptide was prepared by dissolving the lyophilized form of the peptide in deionized water (at 95 °C) to a concentration of 2 mg/ml53.To ensure the absence of any pre-aggregation in peptide stock solution a right angle scatter was recorded using a spectrofluorometer (Jasco FP 8500) at 450 nm. The slit width was set at 2.5 nm−1 (control), 150 Vcm−1 and 300 Vcm−1  for a duration of 5 hours, at three different DC and AC electric fields: 0 Vcmm−1 Fig. . Two parm−1 Fig. . These pSimilar to electric field experiment, a magnetic field experiment was also performed with 2 mg/ml FF solution at room temperature for a duration of 5 hours. Peptide solution (95 °C) was taken in a microcentrifuge tube and allowed to cool in the presence of magnetic field measuring 0.6 T Fig. .53. Post electric annealing, field-exposed peptide solution was taken in a fluorescence cuvette  of 1 cm path length, and its static light scattering was recorded immediately for 12000 seconds. For control as well as magnetic field sample which already comprised dense FF aggregates, static light scattering was recorded only for 1000 seconds. The term “post incubation/annealing” refers to the time period after 5 hours, when both electric as well as magnetic field were switched off.Static light scattering was recorded for each of the sample to quantify the aggregation in FF annealed under an electric and magnetic field in comparison to the control sample immediately after an incubation of 5 hours, using a spectrofluorometer (Jasco FP 8500) at 450 nm. The slit width was set at 2.5 nmFE-SEM analyses were performed using a Zeiss Sigma FE-SEM at 2–3 kV. Field exposed peptide samples were loaded on a glass slide for analyses and air dried. Samples were coated with gold for enhancing conductivity.Melting points for the diphenylalanine self-assemblies formed under different experimental conditions were recorded using Optics Technology Digital Melting Point Apparatus. The solid samples (FF self-assemblies) were packed in thin glass capillaries and loaded in the apparatus. For each sample, the temperature at which the first drop of liquid appears was recorded as the melting point of that sample.Raman measurements of dried FF self- assemblies were performed using a high-resolution micro-Raman spectrometer ; 514 nm laser was used for all the experiments.X-Ray diffraction (XRD) patterns were obtained from a Rigaku X-ray diffractometer (Model: TRAX III) powder diffractometer operating at 50 kV and 100 mA using Ni-filtered Cu-Kα radiation (λ = 1.54 Å). The diffractograms were recorded in the 2θ range of 0–30°.Supporting information


Low birth weight (LBW) remains a leading global cause of childhood morbidity and mortality. This study leverages a large national survey to determine current prevalence and socioeconomic, demographic and heath related factors associated with LBW in Bangladesh.Data from the Multiple Indicator Cluster Survey (MICS) 2012–13 of Bangladesh were analyzed. A total of 2319 women for whom contemporaneous birth weight data was available and who had a live birth in the two years preceding the survey were sampled for this study. However, this analysis only was able to take advantage of 29% of the total sample with 71% missing birth weight for newborns. The indicator, LBW (< 2500 g) of infants, was examined as the outcome variable in association with different socioeconomic, demographic and health-related covariates. Mixed-effects logistic regression was performed to identify possible factors related to LBW.In the selected sub-sample, about 20% of infants were born with LBW, with lowest rates observed in Rajshahi (11%) and highest rates in Rangpur (28%). Education of mothers  and poor antenatal care (ANC)  were associated with LBW after adjusting for mother’s age, parity and cluster effects. Mothers from wealthier families were less likely to give birth to an LBW infant. Further indicators that wealth continues to play a role in LBW were that place of delivery, ANC and delivery assistance by quality health workers were significantly associated with LBW. However there has been a notable fall in LBW prevalence in Bangladesh since the last comparable survey , and an evidence of possible elimination of rural/urban disparities.Low birth weight remains associated with key indicators not just of maternal poverty  but also markers of structural poverty in health care . Results based on this sub-sample indicate LBW is still a public health concern in Bangladesh and an integrated effort from all stakeholders should be continued and interventions based on the study findings should be devised to further reduce the risk of LBW. Low birth weight (LBW) remains a leading public health problem especially in developing countries, but in both the developed and developing world LBW remains associated with cardio-metabolic , 2 psychThe vast majority 95.6%) of LBW births occur in low and middle income countries .6% of LB, 8. Cons1Substantial research effort has been expended to assess and identify the determinants of LBW. Findings suggest low birth weight is closely associated in with gestational age, and the two terms are often mistakenly used interchangeably; however, preterm infants (below 37 completed weeks) have a higher mortality weight than full-term infants who are low weight for their gestational age . PretermIn this study, we aim to explore the prevalence statistics on LBW and analyze socioeconomic, demographic and health factors related to LBW in the population of Bangladesh based on a sub-sample from a nationally representative data. Additionally we aim to assess the nation’s progress towards SDGs from this sub-study. This study provides a measure of the success of public health policy and interventions, and at a broad level aims to help shape future approaches to reducing the prevalence of LBW.The data were taken from Bangladesh Multiple Indicator Cluster Survey (MICS) 2012–2013 which was conducted from December 2012 to April 2013 by the Bangladesh Bureau of Statistics (BBS) under the Ministry of Planning . This UnThe survey samples were selected using a two-stage stratified cluster sampling procedure. Administrative districts were considered as strata and classified as United Nations Development Assistance Framework (UNDAF) priority districts and non-UNDAF districts. Allocating 20 sample households per cluster, 50 sample clusters were selected from each of 20 UNDAF districts and 40 sample clusters were selected from each of 44 non-UNDAF districts. These sample clusters were selected using the probability-proportional-to-size (PPS) method, based on total number of households in each cluster. The sample households in each cluster were selected from a list of households using a systematic random selection procedure. A total 55,200 sample households in 2760 sample clusters were selected for inclusion. In our study, a sample of 7866 women (15–49 years) who had a live birth in last two years preceding the survey were included. Our analysis focused only on the sub-sample of 2319 mothers, who were able to provide birth weight information.low birth weight (birth weight < 2500 g) and normal (birth weight ≥ 2500 g). Drawing on a range of studies carried out to assess the magnitude of LBW and to identify its determinants [Outcome variable birth weight was measured in grams categorized as binary variable: rminants , 25, 26,p-values. The analysis was conducted with R (version 3.2.0).We calculated summary statistics of variables, including the prevalence of low birth weight across the socioeconomic, demographic and health related variables. Chi-square tests were performed to find the association between low birth weight and different predictors. We used a mixed effect modelling approach, specifically mixed effects logistic regression, to adjust cluster level variation. Models additionally adjusted for mother’s age, parity. For presentation, we report the adjusted odds ratios (AOR) estimates with 95% confidence intervals (CI) and A large number of newborns are delivered at home with no formal record of weight preserved presenting a major challenge in collecting accurate information on weight at birth in developing countries, including Bangladesh. In our dataset, 71% of newborns show no birth weight information. Among the complete cases, there are two sources of information . We explored the possibility of systematic difference in these two groups, splitting into two sources such as mother’s recall  and health card  to identify any significant change in the estimates and the association of potential factors related to low birth weight. Most importantly, results based on this sub-sample are not generalizable for overall Bangladesh.A total 2319 cases were identified for whom birth weight values were available. Table Table Table The separate analyses for card and recall birth weight data are presented in Table Low birth weight remains one of the major public health challenges in Bangladesh. Our findings based on sub-sample reveal that about 20% of the children are born as low birth weight babies, which is consistent with the reported prevalence of low birth weight (22 %) in Bangladesh . HoweverThe key finding of an association between maternal and household head secondary education and low birth weight is in accord with previous research, but may be as much an indicator of an association between wealth and associated access to adequate nutrition, as it is between education and access to information about proper family planning and maternal feeding practices –31.quality of ANC received by women was also found to be critical [This sub-sample based study found a significant association between ANC and low birth weight, with mothers who had access to ANC during pregnancy having significantly lower risk of bearing a LBW child. This is consistent with different studies done in Ethiopia and Nepal , 33, butcritical , 36. TheThe proportion of LBW newborns was significantly higher for mothers who delivered at home, a finding is in accordance with studies conducted in India , 38. OurOne finding clearly at variance with international trends is the finding that children delivered by caesarean were less likely to be of low birth weight. This may be due to the fact that relatively advanced interventions are more accessible to wealthier households. Certainly, our study also showed that children from wealthy households were less likely to be low birth weight, in line with international studies , 39, 40.Contrary to previous epidemiological studies of Bangladesh, our study finds a possible evidence that previously stark differences in birth weights between children born in rural and urban areas has been eliminated, with a particularly dramatic fall in LBW prevalence in rural areas largely explaining this change. The most recent National Low Birth Weight Survey of Bangladesh (2003–2004) estimated that about 36% of total infants were born with LBW, with 29% prevalence in urban areas and 37% in rural areas. Our figures based on sub-sample suggest that both figures have now dropped to around 20%, perhaps indicating that rural-urban disparities in LBW prevalence have been improved in the Bangladesh MICS 2012–13. Although given that the frequency of children being weighed at birth varies significantly between urban and rural areas , and thaTo reduce the prevalence of LBW and to improve the conditions of the discussed risk factors, interventions need to be accelerated at multiple levels such as country/region . Community-level interventions  supplements for women of reproductive age and adolescent girls due to the high prevalence of anaemia etc.) are also suggested. Interventions relating to planning prior to pregnancy , and antenatal care  are also recommended . RegularA number of limitations suggest that the findings need to be treated with caution. First of all, some selection bias is likely to have arisen because of the large number of cases with missing data relating to birth weight of infants, with almost 71% of infants were not weighed at birth. Due to this, it is probable that the overall prevalence of LBW is underestimated or over estimated. Moreover, children who were not weighed at birth were more likely to be born of older , comparatively less-educated mothers (about 80% to non-educated mothers) and belong to households with low level of wealth  and rural region (about 69%) than children who were weighed at birth . ExclusiWhile there was significant erosion in sample size because of large number of missing data, the conclusion that there has been a significant drop in prevalence of LBW births is supported by a later study on birth weights, done at a large single medical college hospital in Dhaka in 2003–2005. Being an urban study, our data  would suggest this study  would be