Maternal exposure to total PM2.5 during pregnancy has been linked to decreased birth weight and other adverse outcomes, although the impact of wildfire smoke contribution has only recently been investigated. The objective of this study was to estimate associations between adverse pregnancy outcomes and ambient wildfire smoke PM2.5. Wildfire smoke PM2.5 exposures were estimated using a previously published method incorporating ground-based monitors and remote sensing data. Logistic regression models stratified by ZIP code and mixed models with random intercept by ZIP code were used to test for associations. The primary outcomes of interest were preterm birth and birth weight. Secondary outcomes included gestational hypertension, gestational diabetes, neonatal intensive care unit admission, assisted ventilation, small for gestational age, and low birth weight. Exposure to wildfire smoke PM2.5 over the full gestation and during the second trimester were positively associated with pre-term birth (OR = 1.076 (μg/m3)−1  and 1.132 (μg/m3)−1 ; p < 0.0001, respectively), while exposure during the first trimester was associated with decreased birth weight (−5.7 g/(μg/m3) ). Secondary outcomes were mixed. Colorado is regularly impacted by long-range transport of wildfire smoke from upwind regions. This smoke is a major source of ambient PM From the same meta-analysis, it was also concluded that there was a statistically significant association between PM2.5 exposure during the entire pregnancy and LBW (OR = 1.009/(μg/m3) ). The overall conclusions from the meta-analysis was that PM2.5 exposure during pregnancy was associated with low birth weight, and the late stages of the pregnancy were found to be the most critical periods ; p < 0.0001) after adjusting for co-exposures and known risk factors for preterm births. Other trimesters did not yield significant associations. However, exposure over the entire pregnancy was significantly associated with preterm birth (OR = 1.076 (μg/m3)−1 ).As shown in 3 increase in trimester-average wildfire smoke PM2.5 exposure during the first trimester was associated with −5.7 g  change in birth weight. Wildfire smoke PM2.5 was not associated with birth weight in any other trimester.Furthermore, as shown in 2.5 exposure and secondary outcomes, adjusted for confounders, are shown in 3)−1 ) as well as over the entire pregnancy (OR = 1.151 (μg/m3)−1 ). There was also a significant positive association between exposure and gestational hypertension during the first trimester (OR = 1.148 (μg/m3)−1 ), second trimester (OR = 1.124 (μg/m3)−1 ), and over the entire pregnancy (OR = 1.204 (μg/m3)−1 ). Associations between wildfire smoke PM3)−1  and 0.799 (μg/m3)−1 , respectively), while exposure over the first trimester, second trimester, and the entire pregnancy were negatively associated with assisted ventilation (OR = 0.772 (μg/m3)−1 , 0.916 (μg/m3)−1 , and 0.583 (μg/m3)−1 , respectively).Associations with NICU admission and assisted ventilation were contrary to our expectation. Exposure over the second trimester and entire pregnancy was negatively associated with NICU admission (OR = 0.927 (μg/m3)−1 ).Exposure was not associated with LBW in any trimester and associated with SGA only in the first trimester, and then only weakly (OR = 1.060 (μg/m3)−1 (50 km buffer) to 1.225 (μg/m3)−1 (5-km buffer). Furthermore, the mean association over all trimesters remained significantly positive in all sensitivity models—except when using the 5-km buffer. However, the positive association we found for the full gestation exposure was not as robust, only remaining significant at the p < 0.05 level in five of the eight models.For preterm birth , all senp < 0.05 level. However, the effect magnitude was more consistent; under seven of the eight models the point estimate fell between −7 and −3 g/(μg/m3).For continuous birth weight , the ass2.5 during the second trimester was positively associated with preterm birth. Specifically, each 1 μg/m3 increase in trimester-average wildfire smoke PM2.5 over the second trimester was associated with a 13.2% increase in the odds of preterm birth. For a woman whose second trimester corresponds to peak wildfire season  and whose exposure equals the Colorado average for the season (0.548 μg/m3), this translates to a 7.0% increased odds of pre-term birth. This result was robust to changes to the statistical model and the data processing pipeline. Positive associations with preterm birth were also found after averaging the three trimester-specific associations and when modeling exposure over the full gestational period, though the latter result was not consistently replicated in all sensitivity analyses.Exposure to wildfire smoke PM2.5, though the strongest results were found when this exposure took place in the first trimester of pregnancy. Each additional μg/m3 increase in trimester average exposure was associated with a 14.4% increase in gestational diabetes and a 14.8% increase in gestational hypertension. However, among infant outcomes, results for SGA and LBW were null or weak, while results for NICU admission and assisted ventilation were contrary to our expectation.Among secondary end points, the maternal outcomes  were positively associated with wildfire smoke PM3) in the first trimester and -9.7 g in the second trimester for the present work and Holstius et al., respectively). However, the present work used a continuous exposure variable while Holstius et al. dichotomized pregnancies into exposed/not exposed categories based on reports of fires from the California Department of Forestry and Fire Protection, making comparisons of effect magnitude problematic. Their paper also had different exclusion criteria than our study; they excluded preterm births and post-term births, while we included preterm births after 30 weeks in our analysis.Results for birth weight were similar to Holstius et al. , in whic2.5 and total PM2.5 or non-smoke PM2.5, Sun et al. [2.5 of −1.59 g/(μg/m3)  over the full gestation, which is similar to our estimate of −2.0 g/(μg/m3) for smoke PM2.5 over the same period. This similarity suggests non-differential impacts on birth weight. However, we found the strongest associations with birth weight in the first trimester while Sun et al. found the opposite, which may reflect the lack of robustness in our birth weight results.While no study has directly tested for differences in birth outcome associations between wildfire smoke PMn et al.  report a2.5 and PM10. Lamichhane et al. [3) decrease in birth weight and a 1.4% (μg/m3)−1 increase in preterm birth risk over the entire pregnancy. The former is similar in magnitude to our (non-significant) result, while the latter is lower than the 7.6% (μg/m3)−1 increase that we observed. A study in New York City [3) decrease in birth weight with PM2.5 mass, while NO2 decreased birth weight by 1.8 g/ppb. Coarse PM has also been found to negatively impact birth weight [Prior work on criteria air pollutants and birth outcomes has found increases in preterm birth risk and decreases in birth weight with total PMe et al.  found a ork City  found a h weight .Mechanical assisted ventilation provides crucial breathing support to neonates, but prolonged ventilation is a risk factor for bronchopulmonary dysplasia . While oThis study had a number of strengths. First, the study sample was relatively large and therefore there was enough power to be able to detect differences in outcome measures. Second, the study investigated a broader range of gestational outcomes than previous studies. Third, the study assessed the impact of wildfire smoke exposure using a spatially and temporally resolved multi-year wildfire exposure record. Fourth, the birth certificate dataset included many individual-specific variables for the assessment of potential confounding.2.5 may not be due to this pollutant alone but may be due in part to other, unmeasured fire-related air pollutants carried in the same plumes, such as NOx and VOCs, which differ from PM2.5 in their health effects and characteristic atmospheric lifetimes. The extent to which wildfire smoke PM2.5 tracks with these other pollutants is an active area of investigation by members of our research team.This study also has a number of limitations. First, many of birth certificate variables were self-reported by the mother, which may have led to misreporting of some confounding variables , making it difficult to control for these variables accurately. Second, ambient exposure may not accurately reflect personal exposure, either because of time spent indoors, the use of area (ZIP code) averages rather than residence-specific estimates of the exposure, or changes in residence address over the course of the pregnancy. Third, while our sample size was relatively large , few pregnant women were exposed to significant wildfire smoke for extended periods of time. That being said, showing detrimental effects even at low exposures underscores the importance of potential interventions. Fourth, the birth certificate data did not contain the specific birth dates, but only month and year of birth, and therefore we could not analyze the data at a daily or weekly resolution because we could not accurately assign exposure. In addition, we were not able to conduct the analysis at a monthly resolution because we found that monthly models yielded non-robust results in sensitivity analyses, which suggested that such models were over-parameterized given the amount of data available. The date imprecision may have led to exposure misclassification as some of the exposure assigned to a particular birth or trimester may have occurred either prior to conception, after the birth occurred, or in a different trimester. However, the present work has attempted to account for such uncertainty by weighting the contributions of daily exposures to the trimester and full gestation averages. Future studies may improve the accuracy of the exposure characterization by using birth date rather than birth month, by acquiring mothers’ prior addresses during pregnancy, or by outfitting volunteers with personal or household monitoring devices. Finally, the health effects we ascribe to the effects of wildfire smoke PM2.5 exposure in the second trimester was positively associated with pre-term birth. Weaker evidence suggested a negative association between first-trimester exposure and birth weight. We also found detrimental effects of wildfire smoke on gestational diabetes and hypertension in the mother, but a seemingly protective association with assisted ventilation of the neonate. It is of great public health importance to develop interventions aimed at reducing pregnant women’s exposure to wildfire smoke. Public health agencies should consider targeting pregnant women when developing wildfire smoke exposure reduction strategies as climate change is expected to increase the frequency and intensity of wildfires in the western US over the next 50 years [This work is the first epidemiologic study to investigate the relationships between ambient wildfire smoke concentrations and pregnancy outcomes in Colorado. We found wildfire smoke PM50 years ,38,39, w


IUI has been practiced for five decades but only three unconvincing trialsattempted to demonstrate the superiority of IUI over sexual intercourse (SI). Inthe absence of evidence of its effectiveness, the National Institute forClinical Excellence (NICE) recommended IVF over IUI after 2 years of unprotectedSI. High-quality recent data in well-constructed studies suggest that biasesagainst IUI procedures and in favour of IVF are invalid. It is unethical tocontinue to misinform patients and stakeholders. The well-constructed randomisedcontrolled trials (RCT) show IUI procedure to be efficient, with minimal risk,and above all improved cost-effectiveness when compared to IVF for live birth.IUI as first-line treatment should be offered to most patients, while fundingagencies and stakeholders need to be urgently informed of the cost-benefit inoffering IUI. Fertility clinics, IVF interest groups, and regulatory bodiesshould amend their patient information and guidance to state that IUI should bethe first line treatment and that IVF should be offered only when essential.Reappraising and promoting IUI based on evidence enhances patient autonomy,choices, and trust, while allowing the fertility industry to operate within anethical and acceptable framework not seen as exploitative toward vulnerablepatients. IUI as first line treatment option is highly desirable for couples, easily accessibleand practised worldwide. The procedure is also well accepted on account of itssimplicity  from 27 countries including France, Italy, Spain, Belgium andPoland, revealed that in 24 countries the mean live birth rate (LBR) per cycle was8.6%, while twin and triplet birth rates associated with IUI were 9.5% and 0.6%,respectively. When all IVF cycles were considered, the clinical pregnancy rates (PR)per aspiration and per transfer were 29.6% and 34.5%, with a total multiple LBR of18.0%. The proportions of singleton, twin and triplet deliveries after IVF and ICSI(added together) were 82%, 17.5% and 0.5%, respectively (For the 12ectively . In contectively  despite p=0.04)and live birth rates  favouring IVF over IUI.The data appears to suggest there is a disproportionate loss of pregnancies in theIUI group compared to the IVF group. While IUI outcomes resided towards the low endof what most practitioners experience, it is difficult to comprehend how they couldjustify dismissing IUI.The Cochrane review on IUI for unexplained subfertility .Likewise, significantly positive pregnancy outcomes were seen with endometrialscratching within the follicular phase of 1,871 IUI cycles .Few studies report success rates in fertility treatments across a couple’scomplete fertility treatment history, across clinics, evaluating live birthsafter insemination, ART and natural conceptions. A study looked into the DanishART Registry and Medical Birth Registry for live births (2007-2010). Sub-fertilecouples were followed for 2 years (N=19 884), 3 years (N=14 445) and 5 years(N=5165), or until their first live birth. Cumulative live birth rates wereestimated 2, 3 and 5 years from the first treatment cycle, in all women,including dropouts. In women starting treatment with IUI (N=3028), 35% deliveredafter IUI within 5 years, 24% delivered after a shift to IVF/ICSI treatments and17% delivered after natural conception. Overall, more than 50% of the womenstarting IUI did not need demanding IVF. Within 5 years from starting treatmentswith ART (N=2137), 53% delivered after ART, 11% delivered after naturalconception, and 0.6% delivered after IUI (The overuse of IVF procedures is increasingly seen as a major risk factor inpublicly funded fertility treatments (P. 0.99) (p=0.003) or gonadotropin alone (p<0.001),but not with clomiphene alone (p=0.10)  versus CC29/323 (9.0%),relative risk (RR) 1.6  1.1-2.4)). The LBR washigher (hMG46/334 (13.8%) versus CC28/323 (8.7%), RR1.6 (95% CI 1.0-2.4), lowand comparable multiple live birth rate (hMG 3/46 (6.5%) versus CC 1/28 (3.6%),(p=0.10) . The CenThe moral concerns against selectively promoting expensive IVF over IUIparticularly highlights invalid reasoning and unproven effectiveness, whileexposing patients to risks and economic burdens . A 50% reduction in multiple LBR resulted ina significant 13% reduction in hospital care costs  for multiple births  than for singleton births ; 40% of IVF babiesare twins. The number of multiple babies has risen significantly: in 1995 justover 2600 IVF babies were born as part of a multiple birth; in 2003 more than3700 IVF babies were born as part of a multiple birth - a rise of more than 41%;126 IVF babies die each year as a consequence of having been born in a multiplebirth. Of these 51 are stillbirths, 42 died within the first week of life, and33 died later in the first year of life. These figures do not includemiscarriages or fetal reduction procedures . There iAlthough fertility clinics market themselves on league table type success rates,they are less clear about the issues derived from the multiple births producedin each clinic. More importantly, in the UK multiple births remain invisible tospecific IVF clinics. Fertility clinics remain unaccountable to multiple birthcontributions and do not have to make any financial contribution towardsimmediate care with obstetric complications. Multiple births in IVF have,therefore, been seriously overlooked in terms of the human and economic costsand one might question why financial analyses have never factored in the costeffectiveness of IVF or IUI procedures.All recent high-quality evidence suggests old conclusions should be updated.Prejudices surrounding IUI and in favour of IVF as being substandard or fraught withrisks of multiple births is completely unfounded and needs to be reappraised onevidence. Costing analyses so far have failed to capture the serious health andhuman cost of higher order births stemming from IVF procedures. It raises questionson conflict of interests, but also demands that we develop a moral and ethicalperspective when offering first line treatment options to patients in a balanced andfair manner. Only the financial interest related to offering expensive IVFprocedures stand in the way of an exciting new era of growth for IUI procedures,which can be overcome by prudent government funding policies where funding exists.Greater use of low cost IUI treatment will also increase the chance to fund IVFtreatment when needed. Public bodies and IVF interest groups have a duty of care toaccurately inform patients, the public, funding bodies and stakeholders of thebenefits, efficacy and cost-effectiveness of IUI before embarking on expensive IVFprocedures.


Electrically switchable magnetization is considered a milestone in the development of ultralow power spintronic devices, and it has been a long sought-after goal for electric-field control of magnetoresistance in magnetic tunnel junctions with ultralow power consumption. Here, through integrating spintronics and multiferroics, we investigate MgO-based magnetic tunnel junctions on ferroelectric substrate with a high tunnel magnetoresistance ratio of 235%. A giant, reversible and nonvolatile electric-field manipulation of magnetoresistance to about 55% is realized at room temperature without the assistance of a magnetic field. Through strain-mediated magnetoelectric coupling, the electric field modifies the magnetic anisotropy of the free layer leading to its magnetization rotation so that the relative magnetization configuration of the magnetic tunnel junction can be efficiently modulated. Our findings offer significant fundamental insight into information storage using electric writing and magnetic reading and represent a crucial step towards low-power spintronic devices. Electric field controlled magnetism provides an energy efficient way for the operations in the spintronic devices. Here the authors show strain induced, reversible, nonvolatile electric field control of magnetization and magnetoresistance in a magnetic tunnel junction on a ferroelectric substrate at room temperature and zero magnetic field. Magnetoresistive random access memory (MRAM), whose key attributes are non-volatility, infinite endurance and fast random access4, is currently the most promising contender for next-generation memory and universal memory7. A magnetic tunnel junction (MTJ) with large tunnel magnetoresistance (TMR)9, which has two ferromagnetic (FM) layers sandwiching a thin insulating barrier, has been chosen as the MRAM storage element because of its large signal for the read operation7. In pursuit of lower power consumption, a tremendous flurry of research activities has focused on controlling MTJs with electric fields14 instead of traditional magnetic fields or spin transfer torque effect with high electric current density15. Utilizing electric-field-induced change of coercivity or magnetization precession, both Wang et al.12 and Shiota et al.13 realized voltage control of magnetoresistance (MR) in MTJs. However, in their work, a bias magnetic field is indispensable to ensure the asymmetric potential wells or fix the precessional axis16 and, more importantly, the high voltage (nearly 1 V) directly applied on the junctions is close to the breakdown voltage17.Developing high-density, high-speed, and low-power memory is becoming imperative due to the ever-growing demands for data storage and the increasing gap between processor and off-chip memory speeds21, whose technological appeal is the ability to control magnetism with electric fields, have revived the magnetoelectric research22. Integrating spintronics and multiferroics is emerging as a leading candidate for memory and logic23, and opens a new avenue for exploring energy-efficient electric-field-controlled MTJs. Efforts have been made toward employing an ultrathin ferroelectric (FE) or multiferroic layer as the tunnel barrier to modify the MR of MTJs based on FE-polarization-reversal-induced variation of interfacial spin polarization26. However, an ultrathin barrier layer with only a few nanometers thick is very difficult to keep ferroelectric27. Moreover, operation at cryogenic temperature is detrimental for practical applications. To overcome these drawbacks, a scheme of MTJ stacks grown on FE substrate was proposed theoretically29, which relied on the recent progress in the room temperature electric-field control of magnetism in FM/FE multiferroic heterostructures40. Through strain-mediated magnetoelectric coupling, MR of MTJs can be electrically controlled by rotating magnetization of the free layer. Based on this scheme, an ultrahigh storage capacity, ultralow power dissipation and high-speed MRAM device has been proposed11. The three-terminal design of this scheme separates the write and read cells41, and the voltage is not exerted on the MTJ to avoid damaging it. However, this geometry complicates the fabrication process14 in comparison with the more common two-terminal MTJs. To date, only a few experimental trials with small and volatile manipulation of MR in MTJs by electric fields have been reported43. Non-volatile electrically controlled magnetism47 was demonstrated in multiferroic heterostructures, however, it has not been used in spintronic devices. Therefore, room temperature, giant, and non-volatile electrical manipulation of MR in MTJs without a bias magnetic field is highly desirable, while still elusive, though it would be a crucial step towards practical devices such as MRAM.Recently, multiferroic materials1/3Nb2/3)0.7Ti0.3O3 (PMN-PT) and a giant non-volatile electric-field-controlled MR in MTJs with a relative change of about 55% was achieved at zero magnetic field, which can be ascribed to the electric-field-induced magnetization rotation of the free layer via strain-mediated magnetoelectric coupling. This non-volatile electric-field manipulation of MR in MTJs is significant for developing future spintronic devices with ultralow energy consumption and realizing information storage with electric writing and magnetic reading.Here, we report room temperature, giant, and non-volatile manipulation of MR in the MgO-based MTJs solely by electric fields without the assistance of a magnetic field using MTJs/FE configuration. Through integrating spintronics and multiferroics, high quality MTJs based on MgO tunnel barriers were deposited on Pb single crystal  and −1.6 kV cm−1 (referred as −0 kV cm−1) respectively, suggesting that the electric modulation is giant and non-volatile. The reason to select 8 kV cm−1 and −1.6 kV cm−1 will be mentioned later in the study of ferroelectric property and the strain property of the PMN-PT (011) single crystal. Around H = 0 Oe, there were two high and low resistance states for E = +0 kV cm−1, which correspond to the nearly antiparallel and parallel magnetization configurations of the two CoFeB layers  of PMN-PT, implying its close relationship with the FE polarization switching as discussed later. As expected, at E = 0 kV cm−1, two distinctive resistance states with a large difference indicate clearly that the giant, non-volatile and reversible electrical manipulation of MR in the MTJ has been achieved. To re-confirm the reversible and non-volatile switching of the two resistance states, we performed the switching experiments using 8 kV cm−1 and –1.6 kV cm−1 electric-field pulses as shown in Fig. 43 and may originate from the release process of the charges induced by ferroelectric polarization.To explore the electric effects on the MTJs, the MR curves were measured at room temperature with different electric fields and a striking effect of the electric field on MR was observed . However, the hysteresis loop measured at E = −0 kV cm−1 shows a different behavior in the same magnetic field range. The smaller squareness of the M-H loop and the smoother magnetization change at E = −0 kV cm−1 than those at E = +0 kV cm−1 are ascribed to the electrical modulation of magnetic anisotropy in both the FM layers. Around zero magnetic field, the magnetization of the pinned layer is fixed in the [100] direction by the exchange bias, which is not affected by electric fields50, while only the magnetization of the free layer can be rotated by electric fields leading to the non-collinear magnetization configuration  were investigated  and turns back instead, leading to a loop-like non-volatile strain. Due to the converse piezoelectric effect, an electric field induces tensile and compressive strain along the  crystal axis of PMN-PT. The cross-section of the annealed sample was characterized by HRTEM  equipped with a spherical aberration corrector. In order to simplify the magnetic measurements, the MTJ stack sequence in Fig. 70Fe30, Co40Fe40B20, and Ir20Mn80 alloy with nominal target compositions, respectively. All the stack structures in this study were deposited by a multisource high-vacuum magnetron sputtering system with a base vacuum of 1 × 10−6 Pa. An Au layer with a thickness of 300 nm was sputtered on the bottom of PMN-PT as an electrode.The MTJ multilayer films for magnetotransport measurements consisted of, from the substrate side, Ta(5)/Ru(5)/IrMn(8)/CoFe2.3)/Ru(0.85)CoFeB(2.6)/MgO(2.3)/CoFeB(2.6)/Ta(5)/Ru(7)  and were deposited on PMN-PT (011) single crystals with a size of 10 × 10 × 0.5 mm.3/Ru(0.8−1 is larger than that at −0 kV cm−1 and the relative resistance change is [R(+0) − R(−0)]/R(−0). For case II, the resistance at +0 kV cm−1 is smaller than that at −0 kV cm−1 and the relative resistance change is [R(−0) − R(+0)]/R(+0). R(+0) and R(−0) denote the resistance for E = +0 kV cm−1 and E = −0 kV cm−1 at a certain magnetic field, respectively. The relative resistance change shows the modulation of magnetoresistance in MTJs by electric fields.The relative resistance change in Fig. 11) using FE films, which needs to be explored in future experiments. All the measurements were carried out at room temperature.Electric-field control of magnetism was performed using a Quantum Design magnetic property measurement system (MPMS) with in situ electric fields. The resistance of MTJs was acquired via a homemade electromagnet system using the four-probe method with a Keithley 6221 current source and a Keithley 2182 nanovolt meter. The voltage applied to the PMN-PT was generated by a Keithley 6517 electrometer. The duration of the used voltage pulses in our present work is about 5 s and the width of voltage pulses in theory can be less than 20 ns for our devices .The P-E loops of PMN-PT were measured using a Radiant Technologies Precision Premier II system. The strain properties were measured using a strain gauge glued on the PMN-PTSupplementary informationPeer Review File


A growing body of evidence is beginning to highlight how mass incarceration shapes inequalities in population health. Non-Hispanic blacks are disproportionately affected by incarceration and criminal law enforcement, an enduring legacy of a racially-biased criminal justice system with broad health implications for black families and communities. Louisiana has consistently maintained one of the highest rates of black incarceration in the nation. Concurrently, large racial disparities in population health persist.N = 23,954). We fit a log-Poisson model with generalized estimating equations to approximate the relative risk of preterm birth and low birth weight associated with an interquartile range increase in incarceration, controlling for confounders. In sensitivity analyses, we additionally adjusted for the parish-level index crime prevalence and analyzed regression models wherein white incarceration was used to predict the risk of adverse birth outcomes in order to quantify the degree to which mass incarceration may harm health above and beyond living in a high crime area.We conducted a cross-sectional analysis of all births among non-Hispanic black women in Louisiana in 2014 to identify associations between parish-level  prevalence of jail incarceration within the black population and adverse birth outcomes (There was a significant 3% higher risk of preterm birth among black women associated with an interquartile range increase in the parish-level incarceration prevalence of black individuals, independent of other factors. Adjusting for the prevalence of index crimes did not substantively change the results of the models.Due to the positive significant associations between the prevalence of black individuals incarcerated in Louisiana jails and estimated risk of preterm birth, mass incarceration may be an underlying cause of the persistent inequities in reproductive health outcomes experienced by black women in Louisiana. Not only are there economic and social impacts stemming from mass incarceration, but there may also be implications for population health and health inequities, including the persistence of racial disparities in preterm birth and low birth weight. Preterm and low birth weight infants experience greater incidence of morbidities and mortality in their developmental stages as well as in adulthood. According to the Infant Mortality Statistics 2013 Period Linked Death dataset, 36.1% of infant deaths in the U.S. were related to preterm birth, and preterm infants had mortality rates that were 63% higher than for full term infants [There are substantial and alarming racial disparities in reproductive health outcomes experienced by black women in the U.S. While the overall rate of preterm birth (< 37 weeks’ gestation) has steadily declined with improvements in healthcare access and quality, non-Hispanic black women continue to experience a 1.5 fold greater risk for preterm birth and double the risk of delivering a low birth weight infant (< 2500 g) compared to women who are non-Hispanic white, inequities that appear to be increasing . EmerginMass incarceration is a markedly racialized experience in the U.S. and an issue of growing concern for researchers interested in identifying the root causes of population health inequities. On an individual level, incarceration has been associated with greater prevalence of HIV/AIDS, diabetes, hypertension, pulmonary disorders, and mental illness when compared to those who have not experienced incarceration , 7. At tIn the U.S., jails are municipal or county-level detention facilities that are administered by local law enforcement agencies for the purposes of confining individuals who have been accused of or convicted for minor criminal offenses . While sThe purpose of this analysis was to determine whether mass incarceration of black individuals in Louisiana is associated with adverse birth outcomes among black women. Recent studies have shown that indicators of structural racism – such as residential segregation and differential access to education, employment, income, and political power – share in the overall influence on racial health inequities as affected communities are denied equal access to the resources and opportunities needed to achieve health and well-being , 16. We N = 23,954), data accessed through the National Center for Health Statistics. We identified preterm births (those occurring < 37 weeks’ gestation) and low birth weight births (those < 2500 g) as our primary outcomes of interest. Birth records included a geographic identifier for maternal parish of residence for linkage to data on incarceration and other parish-level contextual factors. As all data were deidentified, this study was deemed exempt by Tulane University Institutional Review Board.This analysis includes all birth records issued to non-Hispanic black women  in Louisiana in 2014 . Jail data were isolated from prison data for this analysis in order to specifically estimate parish-level effects. Data were provided by the Vera Institute of Justice based on analysis of incarceration trend data from the Bureau of Justice Statistics, the Census of Jails, and the Annual Survey of Jails . Since s> 30), parity , and the Kotelchuck Index of Prenatal Care Adequacy based on the ratio of observed prenatal visits to the number that would be expected given dates of care initiation and delivery  [Other measures included in the analysis were individual-level covariates available on the birth record and known to be associated with adverse birth outcomes, including insurance type , maternal age  , 20. In We identified the distribution of maternal and parish-level characteristics within the total study population and stratified by outcome status. We mapped parish-level incidence of preterm birth, low birth weight, and jail incarceration across Louisiana in ArcGIS in order to visualize patterns and variation. Next, we fit modified Poisson regression models with generalized estimating equations to account for women clustered within parishes. The first model (Model A), estimated the relative risk (RR) and 95% confidence interval (CI) for preterm birth associated with an IQR increase in the prevalence of incarcerated black persons, adjusted for maternal and parish-level characteristics. Model B included the same covariates with low birth weight as the outcome.Lastly, we conducted sensitivity analyses to test the robustness of our findings. Given the growing body of literature highlighting the association between area violence and adverse reproductive health outcomes –23, we sA total of 23,954 births to black women were recorded in Louisiana in 2014. These births occurred across 63 of Louisiana’s 64 parishes; Cameron parish (which recorded no births to non-Hispanic black women that year) was not included in the analysis. Data on jail incarcerated populations by race were not available for Tensas and Plaquemines Parishes in 2014 and therefore births in these parishes were excluded. The final analytic sample with data on all covariates included 23,762 births in 61 parishes . Of these births, 15.34% were preterm   and low birth weight (Model D) were essentially unchanged after the addition of the parish-level crime prevalence Table . When adThis cross-sectional analysis of births among black women in Louisiana demonstrated that higher parish-level incarceration prevalence for black individuals were associated with significantly greater risks for preterm birth among parish residents. These results suggest that mass incarceration may – at least in part – contribute to the racial disparity in adverse birth outcomes in Louisiana. Moreover, this association was not explained by greater prevalence of crime in areas with high incarceration, as demonstrated in the sensitivity analysis, implying that prevalence of incarcerated black persons may be an important marker of structural inequality and a determinant of adverse birth outcomes among black women. Additional sensitivity analyses also demonstrated that white incarceration prevalence was not predictive of preterm birth or low birth weight among black women, suggesting that high incarceration overall may not be a proxy for a social condition impacting both blacks and whites, and is instead an indicator of the racism experienced by blacks.N = 414), Wildeman concluded that with each 1 per 1000 increase in incarceration, there was a .25 per 1000 increase in the U.S. infant mortality rate [While prior research has provided evidence of associations between mass incarceration and other public health outcomes , few stuity rate . WildemaChronic and psychosocial stress is another important risk factor for adverse birth outcomes, as demonstrated by a study in which preconception stress increased the odds for preterm birth by 19% and the odds of small-for-gestational-age birth by 14%, and consequentially increased the odds of infant mortality . Mass inWith the increasing need for comprehensive interventions on the persistent gaps in perinatal outcomes for black women in the U.S., attention must be paid to factors that systematically disadvantage black communities, such as discriminatory arrest practices, unfair sentencing laws, and overuse of the bail system. For example, little is known about how disproportionally high contact with the criminal justice system among black individuals impacts population health and well-being. However, the findings of this study suggest that such a connection exists and that there are specific effects on black perinatal health. Inequities may also persist because race and gender are closely tied to resources like money, power, prestige, and social connectedness, and access to them is so integral to avoiding and minimizing disease that they should be considered potential fundamental causes of disease as well . Tyan PaThis study has several limitations. Firstly, the cross-sectional nature of the data does not allow for conclusions to be drawn about causal pathways in the association between mass incarceration and adverse birth outcomes. Complete data on incarceration trends in Louisiana were only available up to 2014, so we were unable to analyze data that have become available following the 2017 adoption of comprehensive criminal justice reform in Louisiana which has resulted in a 2.9% decrease in state prison admissions of any type, and a 7.6% decrease in the total prison population . SimilarWhile scant research considers the indirect health consequences of mass incarceration, there is growing acceptance that it is a critical determinant of public health. Our findings support the notion that mass incarceration is a “social-structural” determinant of public health outcomes. Furthermore, given the disproportionate number of black people incarcerated in the U.S., mass incarceration is a critical indicator of structural inequity and must be acknowledged as a way that structural racism causes fundamental health inequity in our society , making


Objective: Respiratory support for stabilizing very preterm infants at birth varies between centers. We retrospectively compared two strategies that involved either increasing continuous positive airway pressures (CPAP), or increasing oxygen supplementation.Methods: Matched-pairs of infants (<28 weeks of gestation) were born either at the Leiden University Medical Center , or at the University Hospital of Cologne . Respiratory support was initiated non-invasively via facemask at both units. Infants (n = 54) were matched between centers for gestational age and birth weight, to compare physiological and short-term clinical outcomes.Results: In the low-pressure group, 20/27 (74%) infants received 1–2 sustained inflations  and 22/27 (81%) received PPV (1:19–3:01 min) using pressures of 25–27 cm H2O. Within 3 min of birth [median (IQR)], mean airway pressures  and FiO2  were different in low- vs. high-pressure groups, respectively. SpO2 and heart rates were similar. After 3 min, higher FiO2 levels  produced higher SpO2 levels  in the low-pressure group, but SpO2/FiO2 and heart rates were similar. While intubation rates during admission were significantly different , pneumothorax rates  and the occurrence of spontaneous intestinal perforations  were similar between groups.Conclusion: Infants (<28 weeks) can be supported non-invasively at birth with either higher or lower pressures and while higher-pressure support may require less oxygen, it does not eliminate the need for oxygen supplementation. Future studies need to examine the effect of high pressures and pressure titration in the delivery room. Most very preterm infants require respiratory support in the delivery room, as they are unable to adequately aerate their lungs –5. Histo2O are currently recommended in the delivery room  content of 0.3, blended with air. The FiO2 can then be increased to achieve oxygen saturation (SpO2) values within the ranges depicted by the Dawson's nomogram , CPAP pressures of 5–8 cm HWe performed a retrospective matched-pairs study and included infants born between 24 0/7 and 27 6/7 weeks of gestation. Infants born between the introduction of the New Life Box respiratory function monitor  and August 2017 were included. The monitor was introduced at the University Hospital of Cologne in August 2014 and at the LUMC in March 2014. Infants with congenital abnormalities were excluded, as well as infants who's recording could not be identified or infants with incomplete files. Infants born at the University Hospital of Cologne were matched 1:1 with infants born at the LUMC. Matching criteria were gestational age (+/– 4 days) and birth weight (+/– 25% grams). The database was scanned in chronological order and in case of multiple potential matches, the first potential match was included. Infants could not be matched in a 1:2 ratio due to an unequal distribution of gestation and birth weight.2O CPAP is given initially and can be increased to 8 cm H2O. If the infant is apneic or bradycardic, sustained inflations  and PPV  are given. The fraction of inspired oxygen (FiO2) is initially set at 0.3 and can be adjusted step-wise up to 1.0 based on the 25th percentile of the Dawson criteria. Respiratory support was provided by the Neopuff™ T-Piece resuscitator  via facemask .At the LUMC (low-pressure group), 5 cm H2O CPAP, delivered by the Benveniste Valve™  via facemask . If infants are apneic or bradycardic, the flow is increased by 2L/min subsequently increasing the pressure to a maximum of 32 cm H2O. Sustained inflations and positive pressure ventilation are not included in the local protocol. The FiO2 is initiated at 0.3 and can be increased to 0.4. The delivery room management is essentially as described by Mehler et al.  infants are initially supported with 12 cm Hr et al. , however2 in the first 7 min after birth. The 7 min timeframe was chosen to minimize the effect of other medical interventions. An overview of the data showed that FiO2 in the lower CPAP group was increased above 0.40 in median (IQR) 2.55 (2.48–3.22) min. To compare the effect of different pressure support strategies only, we analyzed the data in Phase I and II, represented before and after FiO2 increase.The primary study outcome was SpO2, mean airway pressure and the SpO2/FiO2 ratio. The SpO2/FiO2 ratio represents the gas exchange efficiency of the lungs as the surface area and the oxygen gradient mainly drive gas exchange. Apgar score at 5 min after birth, pneumothorax rate <72 h, the incidence of intubation <72 h, intraventricular hemorrhages (> grade 2) and spontaneous intestinal perforations, reflected the short-term clinical outcome. The occurrence of spontaneous intestinal perforations could be a potential effect of high pressures on gas entering the intestinal tract. Gestational age, birth weight, gender, mode of delivery and Apgar score at 1 min after birth were collected from the medical records to describe baseline characteristics.Secondary delivery room study outcomes were heart rate, FiO2 and heart rate, a Masimo SET pulse oximeter probe  was placed around the right wrist of the infant. FiO2 was measured using a portable oxygen analyzer AX300-I , and the airway pressures were registered by a variable orifice flow sensor  connected to the facemask, measuring the flow in and out the infant. The signals were digitized at 200 Hz using the NewLifeBox-R physiological recording system  and all signals were recorded by the NewLifeBox Neo-RSD computer system  supported by Polybench physiological software . Pulmochart software  was used to calculate the mean airway pressure averaging the airway pressure between two inspiratory onsets.To record SpORecordings started 1 min after birth, with the exception of infants who were delivered on the resuscitation table within the amniotic sac, as previously described by Mehler et al.  Opening The local institutional Research Ethics Committee of the LUMC and the University Hospital of Cologne and the LUMC approved the study protocol and issued a statement of no objection for performing this research.2O of CPAP according to the LUMC local protocol. The mean ± sd oxygen saturation in the first 7 min after birth was 68 ± 13%. To detect an absolute increase of 10% in SpO2 when using higher pressure levels, using a power of 80% and α = 0.05, 54 infants (28 in each group) where calculated to be required. Infants included in the clinical trial . Numerical data were assessed for normality by visual inspection of histograms. The data were analyzed by the Related-Samples Wilcoxon Signed Rank test and presented as median (IQR).Data were analyzed using IBM SPSS Statistics version 23.0 . Categorical data were analyzed using Related-Samples McNemar tests and are presented as *time interaction were included as fixed factors in the model. The model corrected for Apgar score ‘1 minute after birth. As all infants born at the University Hospital of Cologne were born by cesarean section, we were unable to correct for mode of delivery. Therefore, a sensitivity analysis was also performed including infants born by cesarean section only. The SpO2 and FiO2 variables were transformed using logit transformations: Ln(X/(1–X)) for SpO2 and Ln(79/100*(X−0.21)/(1–79/100*(X−0.21))) for FiO2, to ensure that the estimated values of both parameters remained between 0–100% and 21–100%, respectively, in the statistical model. Raw data is presented as median (IQR). P-values <0.05 were considered statistically significant and reported p-values are two sided.Physiological parameters were compared between groups over time using a linear mixed-effect regression model, accounting for the relation between multiple measurements of the same infant with a heterogeneous first-order autoregressive covariance structure on the residuals. Group, time and groupp < 0.001) and Apgar score ‘1 min after birth (5 (3–7) vs. 6 (5–7), p = 0.048) were significantly different between groups. Nine infants of the high-pressure group were delivered within the amniotic sac, and for two infants it is unknown if they were delivered within the amniotic sac.In total, 54 infants were included in this study. The University Hospital of Cologne and the LUMC stored 87 and 527 recordings of neonatal resuscitations. Twelve infants could not be identified and 429 infants were excluded based on gestation. One hundred and twenty five infants were excluded due to congenital abnormalities, incomplete files or because they could not be matched . The gro2O, p < 0.001] (2  were different between groups (2  (p = 0.576] (2/FiO2 ratio   vs. 19 (16–23) cm H< 0.001]  and FiO2n groups . SpO2 [4= 0.759] , heart r= 0.576] , and SpO= 0.348]  were sim2O, p < 0.001] and FiO2  became more pronounced between groups. In the low-pressure group, caffeine was administrated to six infants at 4:45 (4:19–6:36) min. SpO2  was significantly higher in the low-pressure group, whereas heart rate  and SpO2/FiO2 ratio were not different between groups   vs. 28 (24–31) cm H= 0.483] .2O due to contributions of sustained inflations and PPV  infants received PPV for 2:08 (1:19–3:01) min using positive inspiratory pressures of 26 (25–27) cm H2O.The mean airway pressure of the low-pressure group exceeded the CPAP limit of 8 cm H and PPV . 20/27 (p = 0.013). The pneumothorax incidence  and occurrence of spontaneous intestinal  perforations during admission were not significantly higher in the high-pressure group  increasing the gas exchange surface area by using higher CPAP levels and (ii) increasing the gradient for oxygen diffusion by increasing the FiOTM performed the literature search, data collection, interpretation and analysis, and wrote the manuscript. AtP designed the structure of the article, helped with data interpretation, and writing and editing of the report. AO, JD, and SH were involved with the data interpretation. NvG was involved in data analysis and revised the content of the statistics paragraph. All authors contributed to the final draft by reviewing the manuscript. All authors approved the final version to be published and agree on the accountability for all aspects of the work.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Panicle architecture is one of the main important agronomical traits that determine branch number and grain number in rice. Although a large number of genes involved in panicle development have been identified in recent years, the complex processes of inflorescence patterning need to be further characterized in rice. Brassinosteroids (BRs) are a class of steroid phytohormones. A great understanding of how BRs contribute to plant height and leaf erectness have been reported, however, the molecular and genetic mechanisms of panicle architecture influenced by BRs remain unclear.PMM1, encoding a cytochrome P450 protein involved in BRs biosynthesis, and characterized its role in panicle architecture in rice. Three alleles of pmm1 were identified from our T-DNA insertional mutant library. Map-based cloning revealed that a large fragment deletion from the 2nd to 9th exons of PMM1 was responsible for the clustered primary branch morphology in pmm1–1. PMM1 is a new allele of DWARF11 (D11) PMM1 transcripts are preferentially expressed in young panicles, particularly expressed in the primordia of branches and spikelets during inflorescence development. Furthermore, overexpression of OsDWARF4 (D4), another gene encoding cytochrome P450, completely rescued the abnormal panicle phenotype of pmm1–1. Overall, it can be concluded that PMM1 is an important gene involved in BRs biosynthesis and affecting the differentiation of spikelet primordia and patterns of panicle branches in rice.Here, we identified PMM1 is a new allele of D11, which encodes a cytochrome P450 protein involved in BRs biosynthesis pathway. Overexpression of D4 could successfully rescue the abnormal panicle architecture of pmm1 plants, indicating that PMM1/D11 and D4 function redundantly in BRs biosynthesis. Thus, our results demonstrated that PMM1 determines the inflorescence architecture by controlling brassinosteroid biosynthesis in rice.The online version of this article (10.1186/s12870-018-1577-x) contains supplementary material, which is available to authorized users. Inflorescence architecture and spikelet formation are unique features of grasses such as rice, maize and wheat. In rice, inflorescence  architecture can be categorized into nine successive stages according to the morphological dynamic changes . During SMALL PANICLE (SPA), REDUCED CULM NUMBER1 (RCN1), LAX PANICLE1 (LAX1), and LAX2 are involved in the initiation of BM and SM [ABERRANT PANICLE ORGANIZATION1 (APO1), APO2/RFL and TAWAW1 (TWA1) are responsible for the identity of BM by preventing precocious conversion of BM to SM [FRIZZLE PANICLE (FZP) is required for floral organ initiation and identity through preventing formation of axillary meristems of rice spikelets [TILLERS ABSENT1 (TAB1) has been shown to be involved in the activity of axillary meristems in rice [GRAIN NUMBER1 (Gn1a), DENSE AND ERECT PANICLE1 (DEP1), DEP2 and DEP3, showed effects on the number of branches or spikelets in rice [SHORT PANICLE1 (SP1), ABERRANT SPIKELET AND PANICLE1 (ASP1), PANICLE APICAL ABORTION1 (PAAB1), TUTOU1 (TUT1) and SQUAMOSA PROMOTERBINDING PROTEIN-LIKE 6 (SPL6) have been identified to be involved in the elongation of inflorescence branches and degeneration of panicles in rice [OsLG1/SPR3 encodes a SBP-domain transcription factor and regulates a closed panicle trait, a selected trait during rice domestication [CL and CL-DZ have been described as genes that lead to typical clustered spikelets and are necessary for the formation of bract primordia in the primary and secondary branch meristems [panicle morphology mutant 1 (pmm1), which also causes a clustered primary branches in panicle [CLUSTERED PRIMARY BRANCH1 (CPB1) was identified to influence the development of panicle architecture, leaf angle and seed size [In recent years, multiple genes have been identified to determine inflorescence development processes and finally form the morphology of panicle. M and SM –9. ABERRBM to SM –16. FRIZpikelets –19. TILL in rice , 21. Som in rice –27. SHOR in rice –32. Besitication –35. In aeristems , 37. Our panicle . CLUSTEReed size . DespiteOsBRI1/DWARF61, DWARF1, OsBZR1, 14–3-3, OsBAK1, OsBRL, SG1, XIAO, DWARF62, and OsGRAS19 [s dwarf2 (d2), dwarf4 (d4), dwarf11 (d11), brd1 and brd2, showed defects in BR biosynthesis, but the defects could be rescued by exogenous application of BRs [DWARF4 (D4) and DWARF11 (D11) encode a cytochrome P450, which involved in BRs biosynthesis and have been characterized to control the plant architecture [D4 encodes CYP90B and catalyzes C-22 hydroxylation, which is a rate-limiting step of BRs biosynthesis [D4 caused defects in rice plant morphology, such as a slight dwarfed stature and more erect leaves, indicating that D4 may mainly function during vegetative organs in rice [D11, which encodes CYP724B1, is essential to maintain the levels of bioactive BRs synthesis [d11 mutant showed the pleiotropic defective morphologies including erect leaves, shortened internodes and small seeds [D11 and D4 and their roles in panicle architecture need to further elucidate.Brassinosteroids (BRs) are a class of steroid phytohormones, which influence both plant height and leaf erectness in rice . So far,OsGRAS19 –50. BR-dn of BRs –57. Bothitecture , 54. D4 ynthesis , 59. Mutynthesis . d11 mutll seeds . Howeverpmm1, which exhibited a clustered primary branches phenotype during panicle development. Our genetic mapping results revealed that PMM1 is a new allele of D11, which encodes a cytochrome P450 protein involved in BRs biosynthesis pathway. Transgenic analysis indicated that PMM1/D11 and D4 function redundantly in BRs biosynthesis, indicating that BRs biosynthesis is required for the panicle architecture in rice.In this study, we identified two additional alleles of panicle morphology mutant 1 (pmm1) [pmm1–1. The panicle morphology of pmm1–1 was dramatically altered compared with that of wild type (WT), such as clustered primary branching, opposite grains, and small grains  , which spmm1 compared with WT. In the paddy field, all the pmm1 plants  appeared slightly dwarf and produced erected leaves . No remarkable morphological differences in apices were observed between pmm1–1 and WT   has been shown to function redundantly with D11 in BRs biosynthesis [D4 in the panicle architecture in rice, we firstly conducted the sequences comparison between D4 and D11. Sequence alignment showed that the amino acid sequence of D11 shared more than 40% identity with D4 , respectively. qRT-PCR analysis confirmed the positive transgenic lines  had overexpression of D4 in young panicles compared with the negative transgenic lines  exhibited larger leaf angles, a typical phenotypic characteristic of excess BRs , plant height and the abnormal panicle morphology could be completely recovered by overexpression of D4 expression in pmm1–1  displayed large leaf angles  and seven BR signal transduction genes  in the young panicles of pmm1–1 by qRT-PCR. Compared to that of WT, the expression levels of BR-signaling genes did not altered significantly in pmm1–1 except for MDP1, which was significantly reduced in pmm1–1  showed dramatically increased compared to the WT  in young panicles of pmm1–1 and WT. The expression of both MCM2 and MCM3 significantly increased in pmm1–1 compared with that in WT, but that of the other cell cycle-related genes  were not significantly changed  caused an obvious clustered primary branches in panicle. Previous literature have reported that CPB1 gene, an allele of DWRAF11, also controls panicle architecture and seed size in rice [DWRAF11 resulted in remarkable clustered branches in panicles, indicating that BR biosynthesis in panicle is essential for normal inflorescence architecture in rice.In this study, we identified 3 independent lines with mutations in dia Fig. b. We spe in rice . MutatioPMM1 also resulted in a typical phenotype of BR biosynthesis deficiency, such as compact plant type with reduced leaf angle, small and round grains , insertion (d11–2) or substitution  [cpb1 showed clustered primary branches but no obvious clustered spikelets [Oryza sativa cytochrome P450 family member CYP724B1 affects plant architecture, especially inflorescence architecture, might be in a transcript dosage-dependent manner, or depending on rice varieties.Besides the typical characteristic phenotypes of BR deficiency, the nd cpb1) , 55. Nevpikelets . These rBRD1, BRD2 and XIAO [XIAO was reported to be involved in the control of organ size by cell cycling. We have observed the small and round grains in three pmm1 mutants  variety Zhonghua 11 (ZH11). Three pmm1 mutants were obtained by screening the enhancer trap mutant library [All rice plants used in this study were  library . Rice plEcoRI and XbaI, and a 6.2-kb genomic DNA fragment containing the entire PMM1 coding region and the 1600-bp upstream and 800-bp downstream sequences was inserted into pCAMBIA2301. The empty vector pCAMBIA2301 (http://www.cambia.org/daisy/cambia/585) was used as a negative control. For overexpression of PMM1/D11 or OsDWARF4, full-length cDNA of PMM1/D11 or DWARF4 was cloned into the pU1301 vector, which was then electroporated into the Agrobacterium tumefaciens strain EHA105, and finally transformed into rice callus to generate transgenic plants.To prepare the complementation vector, we digested ZH11 BAC clone OSJNBa0020J04 (kindly provided by Luo Meizhong) with pmm1–1 mutants were dissected, subsequently fixed with a blade, and immediately placed in 70% ethanol, 5% acetic acid, and 3.7% formaldehyde for 24 h at 4 °C overnight. Tissues were dehydrated through an ethanol series of 25 to 100% and dried. Following ethanol dehydration, the samples were critical point dried, sputter coated with gold in an E-100 ion sputter, and then observed under a scanning electron microscope .For scanning electron microscopy, young panicles at different developmental stages from WT and 15 as the primer, using a reverse transcription kit (Invitrogen). qRT-PCR was carried out using ABI7500 real-time PCR system with the SYBR Premix Ex Taq (TaKaRa) following the manufacturer’s instructions. The rice UBIQUITIN5 gene was used as an internal control. Gene expression level was determined from three independent replicates, each consisting of three plants, and three technical replicates per tissue sample were analyzed. The primers for real-time PCR are listed in Additional file Total RNA was extracted from frozen samples using TRIZOL reagent (Invitrogen). After RNase-free DNase I treatment, the first-strand cDNA was synthesized from 4 μg of total RNA with oligo (dT)pmm1–1 mutant were used for BR induction experiments. Rice seeds were sterilized with 0.1% HgCl2 and then grown on 1% agar medium containing half-strength MS medium in complete darkness at 28 °C for 10 days. For BL (Wuhan DingGuo Biotech. Co. Ltd) induction of shoot elongation, rice seeds were grown on 1% agar medium containing half-strength MS medium and various concentrations (10− 7 M and 10− 6 M) of BL and incubated at 28 °C under continuous light. After 2 weeks, the length of coleoptile and the appearance of hypocotyl were measured. A total of 45 plants were used for each treatment.The WT and RNA in situ hybridization was performed as described previously . The proAdditional file 1:Table S1. Primers of SSR markers for mapping PMM1. (DOCX 16 kb)Additional file 2:Table S2. Predicted genes in the region containing PMM1. (DOCX 17 kb)Additional file 3:Figure S1. Sequence alignment of amino acids of OsDWARF4 and PMM1/OsDWARF11. (a) Sequence alignment of OsDWARF4 (CYP90B2) and OsDWARF11 (CYP724B1) from rice using the MEGA5.2 analysis tool. Identical and similar amino acid residues are shaded in black and gay, respectively. (b) Relative expression of OsDWARF4 in the root, stem, leaf and sheath and in developing panicles with 1, 2, 3.5, 4.5, 6.5, 8, 10 and 16.5-cm lengths before heading. Rice UBIQIUTIN5 was used as an internal control. Data are presented as means ± SE (n = 3). Significant at **P < 0.01. (DOCX 3903 kb)Additional file 4:Figure S2. Phenotype comparison of lamina joint inclination and plant height between the wild type (WT) and pmm1–1 plants. (a) A close-up view of flag leaf angles of the WT and pmm1–1 plants. (b) A close-up view of the secondary leaf angles the WT and pmm1–1 plants. (c) Measurements of flag leaf angles of the WT and pmm1–1 plants. (d) Measurements of the secondary leaf angles of WT and pmm1–1 plants. (e) The panicle and culm of the WT (left) and pmm1–1 (right). (f) The internodes and panicle of the WT (left) and pmm1–1 (right). (g) Measurements of the length between the WT and pmm1–1 plants. (h) The expression levels of genes associated with lamina joint inclination. (i) The expression levels of BR-related genes associated with internode elongation. Rice UBIQIUTIN5 was used as an internal control. Data are presented as means ± SE (n = 3). Significant at **P < 0.01. (DOCX 5072 kb)Additional file 5:Table S3. Primers for qRT-PCR, genotyping, and plasmid construction. (DOCX 18 kb)


Prematurity and low birth weight are significant predictors of perinatal morbidity and mortality and are influenced by the overall health and socioeconomic status of the pregnant mother. Although Cyprus is characterized by the highest prematurity rate in Europe (13.1% in 2014), the relationship between maternal health and socioeconomic characteristics with prematurity and low birth weight has never been investigated. We aimed to investigate the association of maternal demographic, clinical and socioeconomic characteristics with premature delivery and low neonatal birth weight in Cyprus.In a case-control design, questionnaire data were collected from 348 women who gave birth prematurely (cases) and 349 women who gave birth at term (controls). Information was obtained on gestation duration and birth weight as well as maternal demographic, socioeconomic and clinical profiles, including parameters such as smoking, body mass index, alcohol consumption, presence of gestational diabetes and mental health factors.Premature delivery was associated with greater maternal age , absence of gestational diabetes , long working hours  and emotional stress . Within the cases group, emotional stress was also associated with lower birth-weight .The findings of this study demonstrate the positive association of maternal psychological factors, working conditions as well as maternal age with prematurity and low birth weight in Cyprus. Additional, prospective, studies are needed in the country to further investigate these associations and inform public health intervention measures.The online version of this article (10.1186/s12978-018-0603-7) contains supplementary material, which is available to authorized users. Prematurity and low birth weight are important determinants of neonatal health and are influenced by the overall health and socioeconomic conditions of the pregnant mother. While prematurity rates vary significantly across the world, Cyprus is characterized by the highest prematurity rate in Europe. However, the factors that are associated with prematurity and low birth weight in Cyprus have never been studied.This study was designed to understand the influence of demographic, mental health and socioeconomic factors on premature delivery and low birth weight in Cyprus. We identified 348 mothers with premature deliveries at the island’s largest maternity unit during a one year period and we also enrolled 349 mothers with term pregnancies as controls. Through the use of a specifically designed questionnaire we obtained data on socioeconomic characteristics from both groups of mothers. Basic information about clinical and demographic characteristics was available from medical charts.Comparison between mothers with preterm pregnancies and mothers with term pregnancies demonstrated that maternal age at birth, long working hours and emotional stress were associated with a higher risk for prematurity while emotional stress was also associated with lower birth weight among premature neonates. Combinations of two or more factors were associated with a sharp increase of prematurity risk, demonstrating a cumulative effect.Healthcare professionals should take into account the overall socioeconomic status of pregnant women during observation, towards identifying high risk pregnancies for prematurity and implementation of appropriate clinical management. Furthermore, healthcare policy makers should aim for the development of public health intervention measures targeting high risk pregnant women.Optimal fetal development is widely recognized  as an important factor of infant’s survival and subsequent social development. In particular, birth weight, neonatal viability and gestational age, are considered as important health determinants throughout lifetime . FurtherPreterm labor is the leading cause of perinatal morbidity and mortality in developed countries, where the majority of deaths occur in neonates with a gestational age of less than 32 weeks . In receFurthermore, low birth weight (LBW) is associated with increased mortality as well as acute and long-term health problems –15. In ESeveral risk factors have been found to be associated with premature birth and LBW, including maternal age, ethnicity, lifestyle maternal characteristics such as smoking and alcohol consumption, education level, working conditions, access to obstetric observation, diabetes mellitus, mental stress and depression, body mass index (BMI) before pregnancy and additional weight-gain during pregnancy . DespiteThe source population were all mothers that gave birth between March 2015 and April 2016 at “Archbishop Makarios III” hospital in Nicosia, Cyprus. “Archibishop Makarios III” hospital is the main tertiary maternal and pediatric hospital in Cyprus which hosts the only tertiary NICU on the island. Mothers who gave birth to premature neonates (gestation < 37 weeks) were included in the study as cases and mothers that gave birth to term neonates (gestation > 37 weeks) were included in the study as controls. Data collection commenced in March 2015 and was completed in April 2016. Mothers with multiple pregnancies or mothers that underwent infertility treatment as well as mothers of stillborn neonates and mothers of neonates with chromosomal abnormalities were excluded from the study. Sample size calculation was performed using OpenEpi  assumingInformation on duration of gestation period and birth weight was obtained from hospital records while all other information was collected through a structured self-administered questionnaire. The questionnaire  in the unadjusted analysis was used in order to calculate the OR and 95% Confidence Intervals (95% CI) for pre-term birth.All variables used in the analysis were checked for normality with the use of histograms. Summary statistics for participant characteristics were calculated separately for cases and controls and categorical variables are reported as absolute and relative (%) frequencies, while continuous variables are reported as mean estimates and standard deviation. In unadjusted analyses, differences in participant characteristics between cases and controls were investigated using chi square test in the case of categorical variables and independent pvalue < 0.10).Among cases, the relationship between different characteristics and gestational age as well as birth weight were examined using the Pearson correlation coefficient and adjusted analyses were performed using a multivariate linear regression model. The linear regression models included all variables that were significantly correlated with birth weight  of each significant risk factor. Lastly, to demonstrate the extent to which different significant risk factors overlap, a Venn diagram was produced using Venny software . The OR p-value < 0.05 was applied to demonstrate statistical significance. All statistical analyses were performed using STATA .For the multivariate logistic, binary logistic and linear regressions a two tailed pvalue < 0.001) and more frequently reported practicing a manual labour profession  or working > 8 h per day . Birth weight was significantly lower in cases . The distribution of birth weight in the two groups according to the WHO categorisation is displayed in Fig. A total of 697 mothers were included in the study (348 cases and 349 controls). Only one mother did not complete the questionnaire resulting in a final response rate of 99.8% for cases and 100% for controls. Cases were older than controls , gestational diabetes , stress  and long working hours . The results of multivariate analysis for prematurity are summarized in Table Table pvalue < 0.001), the OR for the presence of any two risk factors was 6.13  and the OR for the presence for any three risk factors was 25.70 . Trend test calculation was statistically significant . Figure pvalue < 0.001) followed by the combination of advanced maternal age and stress .Among the significant maternal risk factors for prematurity, clustering of two or more factors was associated with a sharp increase of prematurity risk as displayed in Table β: -323.68, 95% CI: -570.36, − 77.00, pvalue = 0.010). The remaining parameters were not found to significant predictors of birth weight among preterm infants. Table Multivariate analysis within the group of preterm infants, demonstrated that stress was the only parameter that was significantly associated with birth weight


We report a process to identify and prioritise research questions in preterm birth that are most important to people affected by preterm birth and healthcare practitioners in the United Kingdom and Republic of Ireland.Using consensus development methods established by the James Lind Alliance, unanswered research questions were identified using an online survey, a paper survey distributed in NHS preterm birth clinics and neonatal units, and through searching published systematic reviews and guidelines. Prioritisation of these questions was by online voting, with paper copies at the same NHS clinics and units, followed by a decision-making workshop of people affected by preterm birth and healthcare professionals.Overall 26 organisations participated. Three hundred and eighty six people responded to the survey, and 636 systematic reviews and 12 clinical guidelines were inspected for research recommendations. From this, a list of 122 uncertainties about the effects of treatment was collated: 70 from the survey, 28 from systematic reviews, and 24 from guidelines. After removing 18 duplicates, the 104 remaining questions went to a public online vote on the top 10. Five hundred and seven people voted; 231 (45%) people affected by preterm birth, 216 (43%) health professionals, and 55 (11%) affected by preterm birth who were also a health professional. Although the top priority was the same for all types of voter, there was variation in how other questions were ranked.Following review by the Steering Group, the top 30 questions were then taken to the prioritisation workshop. A list of top 15 questions was agreed, but with some clear differences in priorities between people affected by preterm birth and healthcare professionals.These research questions prioritised by a partnership process between service users and healthcare professionals should inform the decisions of those who plan to fund research. Priorities of people affected by preterm birth were sometimes different from those of healthcare professionals, and future priority setting partnerships should consider reporting these separately, as well as in total. Preterm birth has major impacts on survival, quality of life, psychosocial and emotional stress on the family, and costs for health services . ImproviTraditionally the research agenda has been determined primarily by researchers, either in academia or industry, who have used processes for priority setting that lack transparency , 5. ThisWe report the outcomes of a process to identify and prioritise research questions in preterm birth that are most important to people affected by preterm birth and healthcare practitioners in the United Kingdom and Ireland using methods established by the James Lind Alliance . This paThe Preterm Birth Priority Setting Partnership was convened in November 2011, following an introductory meeting in July 2011. The partnership followed the four stages of the James Lind Alliance process .At the introductory workshop it was clear that many participants felt the scope of the partnership should be wider than was initially envisaged. Additional topics proposed for inclusion in the scope were uncertainties about the causes of preterm birth, about the prognosis following being born preterm, and about treatments long before birth. As widening the scope too far would risk leaving the prioritisation unachievable within a reasonable time frame and the existing resources, the Steering Group decided the scope would be restricted to uncertainties about treatments, to interventions during pregnancy and around the time of birth or shortly afterwards .Research questions were gathered from people affected by preterm birth, clinicians and researchers, using methods developed by the James Lind Alliance . First, At an interim review of demographic data about home ownership and ethnicity from this survey there was concern that the respondents were not representative of the population at risk of preterm birth. To try and access a more high risk group, paper copies of the survey , after an introductory session participants were assigned to one of four small groups, each with a facilitator, to discuss ranking for each uncertainty. Groups were pre-specified in advance to include a mix of parents, people born preterm, clinicians and other health professionals. The groups were provided with a set of 30 large cards, each printed with one shortlisted research question. On the reverse were examples of wording from the original submissions, and a breakdown of how people affected by preterm birth and healthcare professionals had scored that question in their voting. Following discussion, these cards were placed in ranked order. Over the lunchtime break, rankings from the four groups were aggregated into a single ranking order. These aggregate rankings were presented at a plenary session, to demonstrate where there was existing consensus between groups, and where there were differences. Participants were then reconvened into three small groups, again pre-planned so each had a new mix of participants and retained a balance of backgrounds, to discuss the aggregate ranking. Similar processes were used as in the earlier small groups, with the aim of agreeing the top ten research questions and ranking all 30 questions. Aggregated ranking from the three small groups was taken to a final plenary session, with the 30 cards laid out on the floor in ranked order. Participants then debated and agreed the final ranking.Forty two organisations were approached and invited to participate in the priority setting partnership  said that they were affected by preterm birth, 107 (28%) that they were health professionals, 43 (11%) that they were both affected by preterm birth and a health care professional, and 32 (8%) did not answer this question ; 231 (45%) said they had been affected by preterm birth, 216 (43%) that they were a health professional, and 55 (11%) that they were affected by preterm birth and also a health professional  are most effective to predict or prevent preterm birth?) was the same for all three types of respondent Table , but theThe workshop to prioritise these 30 questions was attended by 34 participants; 13 parents or adults who had been born preterm and 21 health professions . Several of the health professionals also had personal experience of preterm birth. In addition, there were four facilitators (two from the James Lind Alliance and two non-voting members of the Steering Group), five observers .During the prioritisation workshop, two questions were merged as it was agreed they overlapped, and the wording of a few others was modified for clarification. Following the first round of small group discussion, there was considerable variation in the top priorities between the four groups. Following the second round of small group discussion there was agreement about the top few priorities. During the final plenary discussion about the aggregated ranking there was consensus about the top seven questions, less consensus about the next three, and disagreement about those ranked as between 10 and 20. As it was not possible to achieve consensus about the top 10 questions within the timeframe, a proposal to expand this to a top 15 was agreed. Consensus about the top 15 was then achieved Table . This toThe unanswered research questions relevant to preterm birth identified during this process were prioritised in the United Kingdom and Republic of Ireland by people affected by preterm birth , by a range of health professionals, and by people who were both personally affected by preterm birth and a health professional. To our knowledge this is the first such process in preterm birth. People affected by preterm birth and health professionals had many shared priorities, but our process demonstrates that on some questions they have different perspectives. Priorities may also change over time and in different settings, Hence, although the top research priorities from this process should be considered by those who plan and fund research in this area, the full list of 104 unanswered questions is also relevant to decision-making about research funding. This is particularly true if we wish to make research more relevant to those whose lives have been affected by preterm birth, and the healthcare workers who care for them.While several of the top priorities for research are broad topics already well recognised as important, such as what is the optimum milk feeding regimen for preterm infants and prevention of infection, others are indicative of areas previously underrepresented in research; for example packages of care to support families after discharge, and what is the role of stress, trauma and physical workload in the risk of preterm birth, and are there effective ways to reduce this risk and does this influence outcome. This is in keeping with findings from previous James Lind Alliance partnerships, which suggests and highlights the value of partnership and shared decision making with an inclusive stakeholder group with balanced representation of service users and clinicians .In line with the literature on consensus development , the strPreterm birth is associated with factors such as lower socio-economic status, ethnicity (such as African origin), and maternal age (being lower than 18 years or above 35 years) . DespiteMaintaining balanced representation between people affected by preterm birth and the different groups of health professionals for the final prioritisation workshop was challenging. This may have had implications for the final decisions, as happens in guideline development, where consensus development research concludes that differences in how groups are constituted  leads to different decisions . At our Large changes in ranking following the public vote and the final prioritisation appeared to be related to difficulty in the perspective of people affected by preterm birth being heard in the large group session, and an imbalance between the different priorities of two key types of health professional (neonatologists and obstetricians). This was further complicated by fewer obstetricians than expected attending the workshop, and by some of the healthcare professionals also being researchers. Another element of our work, reported in detail elsewhere, was a nested observational study of how service users and healthcare professionals interact when making collective decisions about research priorities . This suReporting of the process for prioritisation is therefore important for transparency, and to identify ways to improve it. Future prioritisation processes, particularly those with a similar wide range of healthcare professionals, should endeavour to anticipate potential different perspectives and mitigate any imbalance where possible, and should report voting separately by ‘service users’ and healthcare professionals. Similarly, whilst it may be appropriate to include healthcare professionals who are also researchers in prioritisation, this potential conflict of interest should be declared and taken into account.This priority setting was limited to the United Kingdom and Ireland, and is therefore most readily generalisable to settings with a similar population and health system. Previous research prioritisation processes for preterm birth , 25 did http://www.jla.nihr.ac.uk/about-the-james-lind-alliance/about-psps.htm) which can then shape the health research agenda [Failure to take account of the views of users of research (i.e. clinicians and the patients who look to them for help) contributes to research waste . James Lh agenda –14. The We present the top 30 unanswered research questions identified and prioritised by the priority setting partnership, along with the full list of 104 questions. These include treatment and prevention as well as how care should be organised and staff training. They should be publicised to the public, to research funders and commissioners, and to those who support and conduct research.People affected by preterm birth and health professionals sometimes had different priorities. Future priority setting partnerships should consider reporting the priorities of service users and healthcare professionals separately, as well as in total. Those with a wide range of healthcare professionals involved should anticipate potential different perspectives and mitigate any imbalance where possible. Healthcare professionals who are also researchers should declare this potential conflict before participating in prioritisation, so that it can be taken into account.Additional file 1. Survey form.Additional file 2. Mapping systematic reviews.Additional file 3. Long list of questions sent for voting.Additional file 4. Organisations invited to participate.Additional file 5. Submissions formatted as research questions.Additional file 6. Reasons for excluding submissions.