However, the global annual average PM2.5 was three times than the recommended value in 1998–2014. Socio-demographic index (SDI) is a new indicator that comprehensively reflects the overall development level of a country, partly because of “the epidemiological transition”. Among other countries with higher and similar SDI levels, policy makers have the opportunity to learn from their successful experiences and avoid their mistakes by identifying whether their burdens of disease are higher or lower than the expected. However, it is unclear about the trends of the burden of PM2.5-related preterm birth in different countries and different levels of SDI regions. Additionally, the relationship between the SDI and the burden in 1990–2019 is also unclear. Methods: This was a retrospective study based on the Global Burden of Disease Study 2019 (GBD2019) database from 1990 to 2019. The burden of PM2.5-related PTB was measured by the age-standardized mortality rate (ASMR), age-standardized disability-adjusted life years rate (ASDR), mortality rate, and the disability-adjusted life years (DALYs). The annual percentage changes (APCs) and the average annual percentage changes (AAPCs) were used to reflect the trends over the past 30 years, which were calculated using a joinpoint model. The relationships between the ASMR, ASDR, and SDI were calculated using a Gaussian process regression. Findings: In 2019, the entire burden of PM2.5-related PTB was relatively high, where the ASMR and the ASDR were 0.76 and 67.71, increasing by 7.04% and 7.12%, respectively. It mainly concentrated on early neonates, boys, and on low-middle SDI regions. The increase in the burden of PM2.5-related PTB in low and low-middle SDI regions is slightly higher than the decrease in other SDI regions. In 2019, the burden varied greatly among different levels of SDI regions where ASMRs varied from 0.13 in high SDI regions to 1.19 in low-middle regions. The relationship between the expected value of the burden of PM2.5-related PTB and SDI presented an inverted U-shape, and it reached the maximum when SDI is around 0.50. The burdens in four regions  were much higher than the mean value. Boys bore more burden that girls. The sex ratio (boys:girls) of the burden showed a dramatically increasing trend in low SDI regions and a decreasing trend in middle SDI regions and high-middle SDI regions. These differences reflect the huge inequality among regions, countries, ages, and sex in the burden of PM2.5-related PTB. Conclusion: The overall burden of PM2.5-related PTB in 2019 was relatively high, mainly concentrated on early neonates, boys, and on low-middle SDI regions. It showed an increasing trend in low-middle and low SDI regions. The association between the burden and the SDI presented an inverted U-shape. It is very necessary to promulgate policies to prevent and control air pollution in countries with large and increasing exposure to PM2.5 pollution because it does not need action at an individual level. Focusing on public educational interventions, public and professional policies, and improving accessibility of prenatal care are other feasible ways for low and low-middle SDI countries. Policy makers should also appropriately allocate medical resources to boys and early newborns.Background: Preterm birth (PTB) leads to short-term and long-term adverse effects on newborns. Exposure to fine particulate matter (PM Preterm birth is defined as delivery less than 37 weeks or less than 259 days from the first day of a pregnant woman’s last menstruation to delivery . In the 2.5 was positively associated with pre-term birth in the developing and developed countries. Bekkar et al. conducted a large systematic review where 24 studies, including 318,960 births, evaluated the association between maternal exposure to PM2.5 and preterm birth [2.5 and the increased risk of preterm birth in 19 of 24 studies (79%). Based on the 11 studies evaluating whole-pregnancy exposure to PM2.5, the risk increased and its median was 11.5% (2–19%). Ottone et.al found that preterm birth was associated with PM2.5  using three-year measurements of daily concentrations of PM2.5 in northern Italy [3) increase in PM2.5 [3) increase in exposure of PM2.5 [2.5 leads to premature birth. PM2.5 could affect transplacental oxygen and nutrient transport and eventually leads to preterm birth through some complex mechanisms, such as oxidative stress, pulmonary and placental inflammation, blood coagulation, endothelial function, and hemodynamic responses [2.5 through inducing acute autonomic imbalance, and it was the explanation for vascular dysfunction [Some risk factors are related to preterm birth, including ethnic group  ,7, low srm birth . They forn Italy . Bachwenin PM2.5 . In addiof PM2.5 . There aesponses . These m2.5-related type 2 diabetes in 1990–2019.Socio-demographic index (SDI) is a new indicator that comprehensively reflects the overall development level of a country. It was first proposed by Global Burden of Disease (GBD) researchers in 2015 and it consists of key factors—a country’s income per capita, average level of educational attainment, and fertility rate—contributing to the health level of the population . The res2.5 showed different trends over time in different SDI regions. The average annual PM2.5 concentration weighted by the population in the world was twice as high as the value suggested by the World Health Organization in 1998–2014. This was mainly due to the sharp rise in PM2.5 concentrations in Asia and Africa, most of which are at the level of low and middle socio demographic index [2.5 concentrations showed negative trends in some regions with high-middle and high SDI levels, including eastern North America (−0.28 ± 0.03 μg/m3/yr) and Europe (−0.15 ± 0.03 μg/m3/yr), in 1998–2018. Remarkably, there was a negative trend in China  over 2011–2018 [PMic index . However011–2018 .2.5-associated preterm births in the world in 2010. It was estimated as 2.7 million (18%) and 3.4 million (23%) with low concentration cut-off (LCC) set at 10 μg/m3 and 4.3 μg/m3, respectively [2.5 in 2019 and its trends over the past 25 years, measured by disability-adjusted life years, years of life lost because of premature mortality, and years lived with a disability [Some previous studies have evaluated the burden of preterm birth in the world from different aspects. Chawanpaiboon et.al estimated incidence rates of preterm birth in 2014 and its changing trends in some countries . Malley ectively . Cohen esability .2.5-related preterm birth burden in regions and countries with different levels of SDI. Additionally, it is also unclear about the relationship between the burden and SDI over the past 30 years. To fill these gaps, the purposes of this study are to: (1) evaluate the burden of PM2.5-related preterm birth and its trend in the world from 1990–2019; (2) evaluate the relationship between the SDI and the burden of PM2.5-related preterm birth from 1990 to 2019; (3) evaluate the PM2.5-related preterm birth burden in different age groups and by males and females; (4) analyze the possible explanations for related trends and provide valuable advice to policy makers.However, it is unclear about the trends of PM2.5 values, causes, risk factors, different age group, sex, and SDI are also available in the data, covering 192 countries and regions in 1990–2019.We used the Global Health Data Exchange to obtain data from Global Burden of Disease Study 2019 (GBD 2019) ,36,37. Twww.who.int/data/gho/indicator-metadata-registry (accessed on 4 January 2022)). According to the International Classification of Diseases, Tenth Revision (ICD-10), neonatal preterm birth in the GBD 2017 was defined by codes P07.2–P07.39, P22–P22.9, P25–P28.9, P61.2, P77–P77.9 [ASMR is defined as a weighted average of the age-specific mortality rates per 100,000 persons, where weights are defined as the proportions of persons in the corresponding age groups of the World Health Organization (WHO) standard population. ASDR is calculated by weighting DALYs according to different age distribution in the population. DALYs is defined as the total years of life lost due to premature mortality (YLLs) and the years lived with a disability (YLDs) due to related cases of the disease or health condition in a population. The YLLs are lost years due to early death, while the YLDs are any short-term or long-term healthy life years lost as a result of disability. All the definitions mentioned above are available at the WHO website , estimation of the distribution of exposure for PM2.5, the estimation of the deaths and DALYs of neonatal preterm births attributable to PM2.5, and the estimation of the ASMR and ASDR of preterm birth attributable to PM2.5 [The calculation of ASMR and ASDR of preterm birth, attributable to PMto PM2.5 ,36.2.5 values were obtained from ground measurements and satellite retrievals. Annual average fine particle (PM2.5) was calculated by the combination of PM2.5 values and chemical transport model simulations at the resolution of 11 km × 11 km. Using these estimates, population-weighted mean concentrations can be calculated and then used to calculate the relative risk of disease mortality with the basis of integrated exposure–response functions for each cause of death [The PMof death ,40.2.5 was assumed to be a uniform distribution of 2.4–5.9 µg/m3. The lower and upper bounds were calculated from the minimum and fifth percentiles of the distribution of exposure to PM2.5 from cohort studies. The uncertainty in this low-level exposure to PM2.5 can be represented by a uniform distribution [The TMREL of PMribution ,42,43.Integrated exposure–response functions (IERs) were developed for the death attributable to neonatal preterm birth. The relative risk of mortality was calculated using risk estimates from studies of ambient air pollution ,44.2.5 were calculated using the age-specific, year-specific, sex-specific, and location-specific PAF to the numbers of deaths and DALYs [Deaths and DALYs due to PMnd DALYs ,45.PAFj2.5 were calculated by weighting the deaths and DALYs of preterm birth attributable to PM2.5 according to different age distribution in the population.ASMR and ASDR of preterm birth attributable to PMAs mentioned in the introduction, SDI is calculated by simple factors but can powerfully reflect the overall development of the society, ranging from 0.0 to 1.0. Getting the SDI with 1.0 means a country’s income per capita, average level of educational attainment, and fertility rates are at the highest level in the world . In conthttps://ghdx.healthdata.org/record/ihme-data/gbd-2019-socio-demographic-index-sdi-1950-2019 (accessed on 4 January 2022).The division of SDI was initially purposed by GBD 2015 Mortality and Causes of Death Collaborators. They divided geographies into SDI quintiles in 2015. After excluding populations less than 1 million, quintile cutoffs were selected on the basis of entire distribution of geography–years from 1980 to 2015. In 2019, they updated SDI quintiles and divided the world into five regions according to the SDI: low SDI regions (0.000–0.455), low-middle SDI regions (0.455–0.608), middle SDI regions (0.608–0.690), high-middle SDI regions (0.690–0.805), and high SDI regions (0.805–1.000). This definition can be found at the document “SDI Reference Quintiles” in the following link: 2.5 to reflect the burden of PM2.5-related PTB because of the difference of the age structure among countries and regions. We used a joinpoint model to evaluate the percentage change, annual percentage change (APCs), and average annual percentage change (AAPCs) of the burden, where each country or region was set to have 2 knots. APC and AAPC were used to evaluate the change trend of each part and the global change trend in a linear way, respectively. They are two important indicators reflecting the trend of disease burden measured by ASMR and ASDR in 1990–2019 [We used the ASMR and ASDR of preterm births attributable to PM990–2019 . The cal2.5-related PTB and SDI in two ways. First, we used Pearson correlation coefficients to measure the trend between ASMR, ASDR, and SDI at different ranges of SDI . Second, the expected value of the disease burden was measured by the Gaussian process regression [We evaluated the relationship between the burden of PMgression . It had gression ,48. The We assumed that there was a certain link between disease burden among regions with different SDI. This connection was related to the gap of indexes. The smaller the gap, the stronger the connection. Gaussian process has a priori assumption that certain information will be transmitted between adjacent samples, that is, there is a certain correlation between them. This method assumes that the observed variables have the Gaussian distribution, and the relationship between the observed variables is reflected by the kernel matrix.2.5-related preterm birth, The observation can be expressed asThe posterior distribution can be expressed asAfter substituting This is a common choice, which is applicable the situation where the data have no prior information.We used R software  and join2.5-related preterm birth was relatively high. As shown in We studied the distribution and the trends of ASMR and ASDR in 192 countries or regions in the past 30 years. In 2019, the overall burden of PM2.5-related preterm birth occurred in South Asia (1.49 and 132.13). The second and the third countries were southern sub-Saharan Africa (1.22 and 108.68) and western sub-Saharan Africa (1.13 and 100.06), respectively, however, high-income Asia Pacific had the lowest values (0.04 and 3.74). Western sub-Saharan Africa had the largest increase rate in the ASMR and ASDR (113.21% and 110.39%), while Eastern Europe had the largest decline rate (−79.53% and −36.94%).The highest ASMR and ASDR of PMOver past thirty years, among twenty-one regions in our analysis, thirteen of them showed a decreasing trend, with the average annual percentage changes in the ASMR varying from −1.4  in Southeast Asia to −5.6  in Eastern Europe. In contrast, the AAPCs in the ASMR remained rising in other eight regions ranging from 0.3  in Central Asia to 2.7  in western sub-Saharan Africa. A similar trend can be seen in the average annual percentage changes in the ASDR . The hig2.5-related preterm birth had been increasing in the world, and its increase rates in low and low-middle SDI regions were particularly obvious , and the largest increase in it in the past 30 years, by 67.61% . Followe2.5-related preterm birth in 1990–2019, where the AAPCs were 1.7  and 1.9 , respectively. Over the past 30 years, the ASMR has maintained a downtrend in middle, high-middle, and high SDI regions, with average annual percentage changes ranging from −0.7 to −3.2. Similar trends were found in ASDR  were much higher than the expected mean value. The trends mentioned above in ASDR are similar to those in ASMR.The relationship between the burden of PM2.5-related preterm birth by different sex and age groups. The burden of PM2.5-related preterm birth is mainly concentrated on early neonates, followed by late neonates. There is almost no burden in other age groups. Boys had higher the burden of PM2.5-related preterm birth than girls in 1990, 2009, and 2019. 2.5-related preterm birth. The sex ratio of ASMR sharply increased from less than 1.20 to more than 1.35 in the low SDI regions and slightly increased in the low middle regions. It showed a decreasing trend in middle SDI regions and high-middle SDI regions, from around 1.30 to around 1.15. The sex ratio of ASMR fluctuated in high SDI regions, but it was generally high, ranging from about 1.25 to 1.3. Similar trends were seen in the sex ratio of ASDR.2.5-related preterm birth varied greatly from country to country. In 2019, the gap between countries with the lowest burden and countries with the highest burden exceeded 90 times. Six countries  had the lowest ASMR (0.02) in PM2.5-related preterm birth, while Sudan had the highest ASMR (1.96). The ASMRs in eight countries  were more than 1.5, however, they were below 0.5 in 139 countries. As shown in 2.5-related preterm birth. Conversely, seven regions  had relatively low burden.2.5-related preterm birth decreased the most in twenty-four countries, by more than 80%. In contrast, eight countries  had the highest growth rates, more than 150%  were much higher than the expected mean value. These four regions should pay more attention on the burden of PM2.5-related preterm birth. Boys bore more burden that girls and the sex ratio (boys:girls) of the burden showed a dramatically increasing trend in low SDI regions and showed a decreasing trend in middle SDI regions and high-middle SDI regions. These differences reflect the huge inequality among regions, countries, ages, and sex in the burden of PM2.5-related preterm birth.We evaluated the burden of PM2.5-related preterm birth increased moderately in the world by around 7%. However, it is not because each of the SDI regions increased slightly, instead, the increase in the burden of PM2.5-related preterm birth in low-middle and low SDI regions is slightly higher than the decrease in high, high-middle, and middle SDI regions. Some reasons may explain that the burden continued to increase in the low and low-middle SDI regions and continued to decrease in the middle, high-middle, and high SDI regions. First, air quality was mainly improving in high-middle and high SDI countries. For example, the annual change of PM2.5 concentrations showed negative trends in some regions at high-middle and high SDI levels, including eastern North America (−0.28 ± 0.03 μg/m3/yr) and Europe (−0.15 ± 0.03 μg/m3/yr) in 1998–2018 [2.5 concentrations, more than 1 μg/m3/yr, and Middle East, central and southern Africa also had positive trends with 0.25–0.50 μg/m3/yr [Over the past 30 years, the burden of PM998–2018 . These i998–2018 ,56. In cμg/m3/yr . Second,μg/m3/yr ,58.2.5-related preterm birth and the SDI presented an inverted U-shape. With the increase in SDI, the burden increased gradually, reaching the maximum when the SDI is around 0.50, and then it decreased gradually. Some possible reasons may explain that higher SDI regions had a higher burden of PM2.5-related preterm birth than lower SDI regions. First, countries with higher SDI levels paid more attention to the improvement of health level and environment protection level [2.5 pollution levels were reduced [2.5 exposure level in lower SDI regions is still higher than that in higher SDI regions, especially household air pollution exposure [2.5-related preterm birth. It may be explained by the fact that the negative impact of environmental pollution on residents is higher than that of economic development, facility-based delivery, and health care in middle and low-middle SDI regions.We found that the relationship between the expected value of the burden of PMon level , and thu reduced . Howeverexposure . Second,exposure . There wexposure . Similarexposure . The thiexposure . Howeverexposure . For exaexposure . Fourth,exposure . HoweverSDI is a new indicator that comprehensively reflects the overall development level of a country. Rather than comparing the difference of disease burden between developing countries and developed countries, it is better to compare them among different SDI countries, which can more deeply reveal the relationship between core social-demographic factors and disease burden, as well as the trend of the distribution of risk factors with the social-demographic index. Policymakers in low, low-middle, and middle SDI countries can learn from the experience in two ways. First, learn from the successful ways of high-middle and high SDI countries to deal with risk factors and disease burden. Second, among countries with similar SDI to theirs, identify countries with higher and lower disease burden than the expected, and then learn from their successful experiences and avoid their mistakes. Specifically, policymakers can learn from the experience of high-middle and high SDI countries in the following aspects: public educational interventions, public and professional policies, and prenatal care. First, the public has an inaccurate understanding that improving the level of care for newborns has solved the problems caused by premature birth . In fact2.5-related preterm birth in China decreased from 0.31 to 0.21, by 33.23% (not shown in results). Such burden remained at a fairly low level, which was at the same level as that in high SDI regions. Improving air quality, encouraging hospital-based birth strategy, and improving neonatal care were China’s three ways to reduce the burden of PM2.5-related preterm birth. First, in the last several years, the Chinese government has taken many measures to improve air quality. For example, it promulgated the air pollution prevention and control action plan, resulting in the improved air quality [2.5 highlights the huge impact of the lack of policy actions [2.5, and it does not need action in individual level [Policymakers in low, low-middle, and middle SDI regions can learn from the experience of countries with similar levels of SDI to their own. Among low, low-middle, and middle SDI countries having a decreasing trend of the burden, some of China’s practices are worth learning from. Over the past 30 years, the ASMR in PM quality . Since 1 quality . In cont actions . The impal level ,76.Thus,al level ,78,79,80al level . Third, al level . It is dal level . Althougal level .2.5-related preterm birth than girls. PM2.5 leads to premature birth through complex effects. PM2.5 could affect transplacental oxygen and nutrient transport and eventually leads to preterm birth through some complex mechanisms, such as oxidative stress, pulmonary and placental inflammation, blood coagulation, endothelial function, and hemodynamic responses [2.5 exposure was associated with the neural development of fetus [We also noticed that boys bore higher burdens of PMesponses . These mesponses . In the esponses ,86. One esponses ,88. Secoof fetus . It had of fetus . Male neof fetus ,92,93. Oof fetus . It was of fetus ,96.2.5 is a particulate mixed pollutant. Different countries with different economic and social levels have different composition and main effect components of PM2.5. Second, due to the lack of other important risk factors, such as occupation, ethnicity, etc., the secondary analysis of GBD data cannot adjust the bias of PM2.5-induced preterm birth. Third, the level of exposure to PM2.5 is based on the average level of the outdoor environment. It did not deal with indoor pollution because of the lack of the data. Fourth, there is the potential of an ecological fallacy because we studied people at the group level, and PM2.5 levels at individual levels may not be closely related to premature births.There are some limitations in this study. First of all, PM2.5-related PTB in 2019 was relatively high, mainly concentrated on early neonates, boys, and on low-middle SDI regions. It showed an increasing trend in low-middle and low SDI regions. The association between the burden and the SDI presented an inverted U-shape. It is very necessary to promulgate policies to prevent and control air pollution in countries with large and increasing exposure to PM2.5 pollution because it does not need action at an individual level. Focusing on public educational interventions, public and professional policies, and improving the accessibility of prenatal care are other feasible ways for low and low-middle SDI countries. Policy makers should also appropriately allocate medical resources to boys and early newborns.The overall burden of PM


Mean DTI metrics were measured in each tissue region using a previously developed DTI processing pipeline and compared between tissues using multivariate analysis of covariance. Associations between FA in NAWM and several CVD risk factors were also examined. DTI metrics in vascular lesions differed significantly from healthy tissue. Specifically, all tissue types had significantly different MD values, while FA was also found to be different in most tissue types. FA in NAWM was inversely related to hypertension and modified Rankin scale (mRS). This study demonstrated the differences between conventional DTI metrics, FA, MD, AD, and RD, in cerebral vascular lesions and healthy tissue types. Therefore, incorporating DTI to characterize the integrity of the tissue microstructure could help to define the extent and severity of various brain vascular anomalies. The association between FA within NAWM and clinical evaluation of hypertension and disability provides further evidence that white matter microstructural integrity is impacted by cerebrovascular function.Alterations in tissue microstructure in normal-appearing white matter (NAWM), specifically measured by diffusion tensor imaging (DTI) fractional anisotropy (FA), have been associated with cognitive outcomes following stroke. The purpose of this study was to comprehensively compare conventional DTI measures of tissue microstructure in NAWM to diverse vascular brain lesions in people with cerebrovascular disease (CVD) and to examine associations between FA in NAWM and cerebrovascular risk factors. DTI metrics including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were measured in cerebral tissues and cerebrovascular anomalies from 152 people with CVD participating in the Ontario Neurodegenerative Disease Research Initiative (ONDRI). Ten cerebral tissue types were segmented including NAWM, and vascular lesions including stroke, periventricular and deep white matter hyperintensities, periventricular and deep lacunar infarcts, and perivascular spaces (PVS) using T Cerebrovascular disease (CVD) contributes to several neurological disorders including vascular cognitive impairment no dementia (VCIND), vascular dementia (VaD), and mixed vascular/neurodegenerative dementia. Vascular cognitive impairment (VCI) remains the second leading cause of dementia after Alzheimer's disease (AD) accounting for 20% of dementia cases , 2. More1- and T2-weighted images can typically detect large hemorrhages as well as large chronic stroke lesions [2∗-weighted images can identify microhemorrhages [VCI pathogenesis is associated with cerebrovascular anomalies in both white matter (WM) and grey matter (GM) including stroke and ischemic lesions, lacunar infarcts, and microhemorrhages . Clinica lesions , and T2∗orrhages . Fluid-aorrhages . Furtherorrhages , 8. Howeorrhages , 6.Diffusion tensor imaging (DTI) measures of fractional anisotropy (FA) and mean diffusivity (MD) provide a high level of sensitivity to tissue microstructure in comparison with other MRI techniques. Interestingly, FA in normal-appearing WM (NAWM) has been shown to be sensitive to microstructural abnormalities in several conditions –11 incluAlthough conventional DTI metrics , and radial diffusivity (RD)) are sensitive to many vascular pathologies, these measures may not be ideal indicators of tissue microstructure in brain regions where the single compartment diffusion tensor model does not adequately represent tissue microcompartments and their arrangements –30. ConsOne hundred and fifty-two participants from the Ontario Neurodegenerative Disease Research Initiative (ONDRI) with CVD and complete imaging datasets were included. ONDRI is a provincial collaborative longitudinal research program in Ontario to study diverse neurodegenerative diseases such as Alzheimer's, Parkinson's, and CVD –33. The Five major CVD risk factors were documented for the study participants: (1) diabetes, (2) hypertension (HTN), (3) high cholesterol or hypercholesterolemia (HCL), (4) coronary artery disease (CAD), and (5) other cardiovascular conditions . These clinical conditions were identified through medical histories and conditions at screening. The global cognition was also assessed in the studied subjects by the Montreal Cognitive Assessment (MoCA) (ranging from 0 to 30) . The par1-, T2-, and T2∗-weighted, FLAIR, resting state functional MRI (fMRI), and diffusion MRI (dMRI) images were available and incorporated from 10 different 3.0 T MRI scanners across Ontario. The DTI processing pipelines utilized T1-weighted (voxel dimensions of 1.0 × 1.0 × 1.0 mm3), T2-weighted images (0.9375 × 0.9375 × 3.0 mm3), and DTI data. All the ONDRI DTI data were acquired with 30 different gradient directions (with b = 1000 s/mm and flip angle 90°) plus at least one b0 volume with voxel dimensions of 2.0 × 2.0 × 2.0 mm3.The acquisition of neuroimaging data for ONDRI participants has been previously described and was consistent with the Canadian Dementia Imaging Protocol (CDIP) . Briefly2-weighted images and FLAIR images were coregistered to the T1-weighted image, and a PD-T2-based mask was automatically generated and manually edited. Using this mask, the T1-weighted image was segmented using a multifeature histogram method [The procedures used to segment regions of interest have been detailed previously (Semiautomatic Brain Region Extraction (SABRE) , Lesion m method  to generm method , 37. Eacm method –38. Lesim method  and cort3 (corresponding to at least three DTI voxels) were not considered to reduce partial volume errors. The careful segmentation of these normal and pathological tissues provided a unique opportunity to characterize the associated water diffusion metrics obtained by DTI.In this study, the variation of DTI metrics in these 10 different tissue/lesion classes was examined and compared. Lesion volumes < 24 mm1-weighted structural image, and tensor fitting to produce maps of FA, MD, AD, and RD in each subject.DTI data were analyzed using an automated pipeline previously described and validated , 43 consThe DTI scalar metric maps for FA, MD, AD, and RD, along with the cerebral tissue/lesion masks, were used to calculate the mean of the DTI metrics in the 10 cerebral tissue types and lesions previously described. The mean values of the DTI metrics were compared between brain lesions and healthy tissues to determine whether DTI metrics could be used for lesion classification and to develop complex DTI-based biomarkers for diagnostic and therapeutic purposes despite the substantial variability in the location and size of the various lesions identified in the brain.The mean and coefficient of variation (CV) were measured for the four major DTI metrics  in each of the 10 different cerebral tissue types/lesions to compare DTI metric variations between these tissue types/lesions. All the region of interest (ROI) statistical analyses described below were implemented in MATLAB  and IBM SPSS .p values < 0.05 were considered significant.A flowchart of the statistical tests conducted is provided in p values < 0.0071 (significance level was defined as α = 0.05 divided by 7 tests) after the Bonferroni correction for multiple comparisons.FA is the DTI metric most sensitive to pathology-related microstructural alterations within NAWM –22; hencp values < 0.01 (significance level is defined as α = 0.05 divided by 5 tests) after the Bonferroni correction for multiple comparisons.FA in NAWM was also evaluated in association with five major CVD risk factors , using ANCOVA. For each CVD risk factor, ANCOVA was conducted to compare FA in NAWM in subjects with the specific CVD risk factor to that in subjects without the specific CVD risk factor. These comparisons were also repeated when weighting the FA measurements in NAWM by the WMH volumes normalized to the TIV to increase the influence of subjects with greater WMH volume. All ANCOVAs were adjusted for age, sex, education level, BMI, ethnicity, smoking history, and alcohol consumption. In our analyses, significant difference between the groups were identified by p values < 0.05.Similarly, FA in NAWM was evaluated in association with mRS as well as NIH stroke scale (NIHSS). The mRS is a measure of the level of disability or dependence in stroke patients or people with other neurological disorders . The NIH2) BMI, with 14.6 ± 2.9 (mean ± SD) education level, 54% with a smoking history of at least three months, 67% with alcohol consumption, and 83.6% White, while the remaining subjects were from Black (5.3%), Jewish (2.0%), Hispanic (0.6%), West Asian (1.3%), South Asian (2.0%), Chinese (3.2%), Japanese (0.6%), Filipino (0.6%), and multiple ethnicities (0.6%). Prevalence of diabetes was 22%, HTN was 74%, HCL was 79%, CAD was 17%, and other cardiovascular conditions were 35%. The concentrations of blood components such as glucose, triglyceride, cholesterol, HDL cholesterol, and LDL cholesterol along with systolic blood pressure (SBP) and diastolic blood pressure (DBP) which might impact brain WM tissue integrity [3) to very large , 76% were identified as having PVSs, 37% with dLACN, and 56% with pLACN visible in their scans )  to very large . The locations of the stroke lesions were also variable with strokes located in different brain regions across the cohort. All other vascular lesions displayed a similar heterogeneity. The mean FA is provided in descending order for each tissue type ). Follow-up ANCOVA showed that each DTI metric (FA and MD) varied significantly between tissue types . Linear regressions adjusted by age, sex, and education level showed significant correlation between MD and AD  in FA and MD values between all tissue types, with 45 paired comparisons out of a possible 45 showing significant difference in their FA and/or MD values .There were significant differences between the DTI measures of the different tissues  between FA in NAWM and blood analytes as well as blood pressure were as follows: glucose , triglyceride , cholesterol , HDL cholesterol , LDL cholesterol , SBP , and DBP . After the Bonferroni correction, no significant correlations were identified. When linear regression was weighted by normalized WMH volumes, correlations  between FA in NAWM and blood analytes as well as blood pressure were as follows: glucose , triglyceride , cholesterol , HDL cholesterol , LDL cholesterol , SBP , and DBP . After the Bonferroni correction, no significant correlations were identified.There were no significant correlations identified between FA in NAWM and blood analytes or blood pressure. Linear regression results  showed that FA in NAWM was lower in people with HTN  and remained significant after the Bonferroni correction. Specifically, CVD subjects with HTN had significantly lower FA in NAWM  compared to those without HTN . However, when the FA measurements in NAWM were weighted by normalized WMH volumes, ANCOVA showed a significant group effect . Pairwise comparisons of the adjusted mean FA in NAWM between subjects with different mRS scores showed that CVD subjects with an mRS of 2 (N = 38) had significantly lower FA in NAWM in comparison with the CVD subjects with an mRS of both 0  and 1 . The FA differences in NAWM between CVD subjects with an mRS of 0 and 2 were 3.2% and 5.1% when the FA measurements were weighted by normalized WMH volumes, while the FA differences between CVD subjects with an mRS of 1 and 2 were 1.6% and 2.4% when the FA measurements were weighted by normalized WMH volumes  and only one subject with an mRS of 4 (moderately severe disability), which may explain why no difference was detected between NAWM FA in people with higher levels of disability compared to those with lower levels of disability.There was also a significant difference in the weighted mean FA in NAWM  when comparing between CVD subjects with various degrees of disability as evaluated by the mRS score. However, after post hoc pairwise comparisons, only subjects with an mRS of 2 (slight disability) had lower FA in NAWM than subjects with an mRS of both 0 (no symptoms) and 1  . This reSeveral limitations must be considered in the current study. First, the conventional DTI metrics FA and MD were utilized derived based on the single compartment diffusion tensor model . AlthougFuture work should determine an ideal complement of quantitative diffusion biomarkers to identify vascular lesions and to predict tissue damage and consequent cognitive or functional decline.This study characterized conventional DTI metrics FA, MD, AD, and RD in a cohort of 152 individuals with vascular lesions and found that FA and MD not only differed between vascular lesions and healthy tissue but also differed between vascular lesion subtypes. The variation in diffusion metrics observed within stroke regions and white matter hyperintensities provided unique contrast when compared to T1-weighted, T2-weighted, and FLAIR images. Consequently, the diffusion measures could improve the accuracy of tissue and vascular lesion classification using sophisticated multifeature image segmentation approaches and aid in the interpretation of imaging findings in people with CVD-related brain pathologies. This study also demonstrated an association between fractional anisotropy in normal-appearing white matter and hypertension in CVD subjects which highlights the key role of cerebrovascular disruption in promoting various neurodegenerative and neurological disorders. The association between normal-appearing white matter microstructure deterioration inferred by decreased fractional anisotropy and modified Rankin scale, a measure of degree of disability in stroke patients, also suggests that subtle global changes in normal-appearing white matter microstructure may impact the global disability outcome measure beyond the direct effects of vascular anomalies in people with CVD.


To determine if preterm birth is associated with adaptation of the hypothalamic–pituitary–adrenal (HPA) axis and whether HPA axis programming relates to the degree of prematurity (defined as extremely preterm birth at <28 weeks or very preterm birth at 28–32 weeks gestation).This study reports findings from a prospective birth cohort. Saliva cortisol concentrations were measured prevaccination and postvaccination, and in the morning and evening, at 4 months chronological age.Infants born at a single Scottish hospital.45 term-born, 42 very preterm and 16 extremely preterm infants.Cortisol stress response to vaccination (postvaccination minus prevaccination cortisol concentrations), diurnal slope  and mean log-transformed daily cortisol.Compared with infants born at term, infants born extremely preterm had a blunted cortisol response to vaccination  and a flattened diurnal slope . In contrast, the cortisol response to vaccination  and diurnal slope at 4 months  did not differ significantly in infants born very preterm compared with infants born at term.Infants born extremely preterm have blunted cortisol reactivity and a flattened diurnal slope. These patterns of HPA axis regulation are commonly seen after childhood adversity and could contribute to later metabolic and neurodevelopmental phenotypes observed in this population. Results from salivary cortisol concentrations of infants at 4 months of age suggests that extremely preterm birth disrupts the normative development of the HPA axis in infancy, with patterns of cortisol secretion resembling those seen after childhood adversity. Preterm birth is associated with adverse metabolic and neurodevelopmental phenotypes across the life course.Hypothalamic–pituitary–adrenal axis (HPA) dysregulation has been observed following multiple types of prenatal and childhood adversity and is a potential biological mediator of later pathology.At 4 months postnatal age extremely preterm birth is associated with a blunted cortisol response to vaccination and a flattened diurnal rhythm.Future studies investigating whether HPA axis adaptations after preterm birth continue across the life course and relate to adverse neurodevelopmental and metabolic phenotypes appear warranted.Preterm birth (<37 weeks gestation) is associated with an increased risk of adverse health across the life course, including neurodevelopmental impairment,The hypothalamic–pituitary–adrenal (HPA) axis, the primary regulator of human endogenous cortisol secretion, is a potential biological mediator between early life adversity and later adverse neurodevelopmental and cardiometabolic phenotypes. Its candidacy is supported by a growing body of preclinical and human observation research that demonstrates a complex interplay between early life adversity, adaptations in cortisol regulation and health across the life course.Previous studies of infant HPA axis regulation after preterm birth have typically focused on stress reactivity. There is emerging evidence that infants born preterm may have a blunted cortisol response to physiological and psychological stressorsTo date, only one study has assessed basal cortisol of term and preterm infants across infancy. Infants born between 28 and 32 weeks (very preterm) and <28 weeks (extremely preterm) had lower cortisol concentrations than term infants at 3 months corrected age, with extremely preterm infants having higher levels at 8 months.This study presents data from a prospective birth cohort conducted with the primary aim of investigating whether preterm birth predisposes infants to differences in stress-induced and diurnal cortisol release in infancy. We hypothesised preterm birth would predispose infants to a blunted stress response to vaccination and flatter decline in cortisol across the day.The ‘Stress Response Systems in Mothers and Preterm Infants’ study recruited infants born at the Royal Infirmary of Edinburgh, UK, between March 2018 and August 2019. All parents gave written informed consent. Exclusion criteria were regular maternal steroid use in pregnancy and congenital chromosomal or structural abnormalities in infants.At 4 months chronological age infants had four saliva samples collected at the time of routine scheduled vaccinations against diphtheria, tetanus, pertussis, polio, haemophilus influenzae type b and hepatitis B (DTaP/IPV/Hib/HepB), meningitis B and pneumococcus (13 serotypes). Vaccinations were administered as three intramuscular injections at participants’ general practitioner surgeries, as per routine clinical care. Appointments were attended by a member of the research team, who collected samples immediately before and 20 min after vaccinations, assessing cortisol reactivity. Morning (07:30–09:30) and evening (19:30–21:30) samples were collected by participants’ parents in their own homes, assessing diurnal cortisol regulation. Parents were asked to collect these samples on a single day in the week preceding the vaccination and to refrigerate samples before transferring them to the research team at the vaccination appointment. Saliva was collected using Salimetrics SalivaBio Infant Swabs, stored at −80°C and analysed by liquid chromatography tandem mass spectrometry (LC-MS/MS) at Edinburgh University Clinical Research Facility Mass Spectrometry Core .10.1136/fetalneonatal-2021-321593.supp1Supplementary data10-transformed for further analysis. Prevaccine cortisol concentrations were positively skewed. However, vaccine cortisol concentrations were not transformed in the presented analysis as postvaccine cortisol concentrations and subsequent regression model residuals showed only slight asymmetry. Cortisol distributions across all timepoints are presented through violin plots in Analyses were performed using IBM SPSS Statistics V.25. Continuous data are summarised as mean±SD if normally distributed and median (IQR) if skewed. One participant concurrently using topical steroids was excluded from analysis. One morning cortisol sample was also excluded . Distributions of cortisol concentrations were assessed for normality using histograms. Cortisol concentrations for the assessment of diurnal cortisol regulation were positively skewed and logComparisons of HPA axis regulation between term and preterm infants (defined as a single group) and preterm subgroups (defined as extremely preterm birth at <28 weeks or very preterm birth at 28–32 weeks gestation) were conducted using linear mixed models. Cortisol reactivity in response to vaccination and diurnal cortisol patterns  were tested separately. In each model, time  was specified as a repeated measure. Preterm birth’s influence on cortisol reactivity and diurnal cortisol decline across the day was tested by the time*preterm/term group interaction. To test if HPA axis programming is limited, or differs by degree of prematurity, the time*extremely preterm/very preterm/term interaction was assessed. To assess if associations between preterm birth and HPA axis regulation differed by sex, the time*sex*preterm/term interaction was tested. This process was also undertaken for assessment of mean diurnal cortisol levels, using morning and evening cortisol concentrations in models that did not include an interaction with time.All analyses were conducted with models specifying a diagonal covariance structure . This is because the variance of cortisol concentrations at the different timepoints differed, and models incorporating a correlation in cortisol concentrations between participant samples did not improve the model fit assessed through comparison of −2 log likelihood ratios.Sensitivity analyses were conducted assessing the potential effect of comparing infants at chronological compared with corrected ages. In this study, where saliva was collected at 4 months chronological age, the corrected age of saliva samples collected in the morning and evening  and around the vaccination (r=0.876) was strongly correlated with birth gestation. As corrected age at saliva sampling could not directly be adjusted for in models without introducing multicollinearity, the potential influence of corrected age at sampling on cortisol concentration was assessed through univariate analysis in term and preterm groups separately.Effect sizes are reported as mean differences in cortisol concentrations for normally distributed data and percentage differences of geometric means for skewed data, with 95% CI. P<0.05 was considered statistically significant.Infant and sampling demographics are presented in Salivary cortisol increased in response to vaccination in all groups (p<0.001) . CompareAt 4 months chronological age, cortisol concentrations reduced across the day, with higher cortisol in the morning than evening (p<0.001) . CompareMean diurnal cortisol concentrations were negatively associated with corrected age at sampling in term (p=0.02) but not in preterm (p=0.73) infants. Cortisol diurnal slope and reactivity to vaccination were not associated with corrected age at sampling in either the term or preterm group .This study has two main findings. First, extremely preterm birth is associated with altered HPA axis regulation, including both blunted stress response and flattened diurnal slope in infancy. Second, infant sex was related to HPA axis programming of cortisol reactivity but not diurnal cortisol concentrations.The ‘developmental origins of health and disease’ (DOHaD) hypothesis postulates that environmental exposures in early life, during periods critical for development, can influence health across the life course.At 4 months chronological age extremely preterm infants had a reduced cortisol response to vaccination and a reduced decline in cortisol across the day. While our primary hypothesis was that infants born ≤32 weeks gestation would show adaptation of the HPA axis, an increased propensity for HPA axis programming in infants born extremely preterm appears physiologically plausible, when viewed through a DOHaD lens, as this group face an earlier disruption to environment and greater morbidity in the newborn period. Additionally, evidence from previous studies provides precedent that HPA axis programming may be gestation-specific.This study adds to evidence that early exposure to an ex utero environment contributes to blunted cortisol reactivity across life.This study is the first to address whether preterm birth influences diurnal slope in infancy. However, available data from studies in childhood are indicative of a flattening of the HPA axis after preterm birth, including two reports of reduced morning cortisolThe altered patterns of saliva cortisol observed in this study are of clinical interest as HPA axis dysregulation is potentially causative of cardiometabolicMultiple perinatal exposures hold the potential to contribute to programming of the HPA axis in a preterm population. These include intrauterine and extrauterine nutritional deficiencies and growth restriction,Additionally, perinatal hormonal exposures could change the way that cortisol secretion is regulated at the level of the hypothalamus or pituitary glands across infancy, or alter the development of the adrenal cortex. Preterm infants are commonly exposed to exogenous steroids and higher endogenous cortisol concentrations than would be expected at a comparative gestation in utero,Preterm infants also have reduced exposure to hormones typically secreted during the third trimester by the placenta, such as reduced corticotropin-releasing hormone, oestrogen and kisspeptin exposure. Reduced exposure to these hormones likely changes the developmental trajectory of the adrenal gland,This study’s primary strength is that it combines assessment of both cortisol stress response and diurnal rhythm, providing an indepth characterisation of the preterm HPA axis in infancy. Additionally cortisol concentrations were quantified using LC-MS/MS using a long 16 min chromatographic analysis, such that temporal separation confidently excludes contribution by cortisone and corticosterone and its 11-dehydrocorticosterone, while distinct mass differences of cortisol (~362 Da) and androgens (~290 Da) allow quantification without interference by other adrenal steroids.A potential limitation is that sampling was scheduled according to chronological age and so the corrected ages of participants in the extremely preterm group were younger than those at sampling of term group. There has been disagreement around whether adrenal function relates to postmenstrual age or time after birth, particularly around the involution of the fetal zone and continued production of fetal zone steroids.Another limitation is that cortisol concentrations before the vaccination were higher than morning cortisol concentrations in the preterm groups. This suggests that attending the vaccination appointment may itself be a mild stressor. Additionally, the sample sizes of the extremely preterm group and female infants born preterm were relatively small, reducing the precision of effect size estimates for these groups.Preterm birth has also been associated with adaptations in adrenal androgen secretion from the postnatal period into young adulthood,Extremely preterm birth disrupts the normative development of the HPA axis in infancy, with patterns of cortisol secretion resembling those seen after childhood adversity. Future research needs include testing how HPA axis adaptation relates to adverse neurodevelopmental and metabolic phenotypes seen after preterm birth and assessing whether psychosocial interventions can ‘reprogramme’ the preterm HPA axis.


Antenatal corticosteroids (ACS) administration is a standardized prenatal care for accelerating fetal maturation before anticipated preterm delivery, however, its effect on nutrition and growth is yet uncertain. This study aimed to examine if ACS application is associated with improvement in postnatal growth and nutrition in very preterm infants (VPIs).P < 0.05 (2-sided) indicated statistical significance.This was a secondary analysis of a multicenter prospective survey included infants born before 32 weeks gestation and admitted to 28 tertiary neonatal intensive care units throughout China from September 2019 to December 2020. Infants were divided into no ACS, partial ACS and complete ACS groups according to the steroids exposure. For infants exposed to antenatal corticosteroids, complete ACS was defined as receiving all doses of steroids 24 h-7 days before delivery, otherwise it was referred to partial ACS. The primary outcomes of postnatal growth were compared among the 3 groups. The multivariable regression analyses were applied to evaluate the association of different steroids coverage with postnatal growth and nutritional outcomes while adjusting for potential confounders. For each outcome, no ACS coverage was defined as the reference group. Data were presented as unstandardized coefficients or adjusted odds ratios with 95% confidence intervals, P < 0.001). In multivariable analyses, both complete and partial ACS coverage were associated with shorter cumulative fasting time, faster weight growth velocity, less dramatic decline in Z-score of weight, and lower incidence of extrauterine growth restriction  when compared with no ACS. Moreover, the faster length growth velocity and earlier enteral feeding start time were observed only in infants with complete ACS coverage.Among 2,514 infants included, complete ACS, partial ACS and no ACS group accounted for 48.7% , 29.2%  and 22.1% , respectively. The median weight growth velocity was 14.6 g/kg/d, 14.1 g/kg/d and 13.5 g/kg/d in complete, partial and no ACS group respectively with significant difference (Both complete and partial ACS are associated with better postnatal growth outcomes in very preterm infants. This efficacy appeared to be more obvious in infants exposed to complete ACS. The bNearly 200,000 very preterm infants (VPIs), defined as gestational age (GA) less than 32 weeks, are born in China every year , 6, and Given the lack of data concerning the association between ACS and nutrition of VPIs, we aimed to determine the hypothesis that ACS may improve postnatal growth and nutrition and reduce the incidence of EUGR among VPIs through a national, multi-center retrospective study.2.This was a secondary analysis of the data from a multicenter prospective survey  aiming t2.1.Infants born at GA <32 weeks, hospitalized for >14 days, and admitted to the participating neonatal intensive care units (NICUs) within 24 h after birth were eligible for this study. Every participating unit uniformly followed the clinical guidelines such as: European Consensus Guidelines on the Management of Respiratory Distress Syndrome - 2019 Update ; postnatal growth and nutritional outcomes during hospitalization; and major morbidities and treatments during hospitalization. Demographic characteristics included GA at birth, birth weight, birth length, birth head circumference (HC), gender, mode of delivery, multiple birth, 1-minute and 5-minute Apgar score, small for gestational age (SGA) and ACS coverage.The personnel in charge of data entry of each unit were uniformly trained. The EpiData database was established strictly according to the unified questionnaire, data of the case report form were recorded in double pairs, all participating units collected and uploaded the clinical data of preterm infants in time, and the database was locked after verification. The team leader maintained close contact with all participating units at any time point, checked the case records, and solved the possible problems in time.2.2.2.During hospitalization, the body weight of VPIs was routinely measured by the attending nurses, using scales incorporated in incubators or external automatic scales. Beside body weight, anthropometric measures include length and HC, which were performed weekly until discharge. Length and HC were measured by an infantometer and a non-stretchable tape respectively. Postnatal growth indicators included body weight, length, and HC; greatest weight loss; days to regain birth weight and the incidence of EUGR.The primary outcome of growth compared among the 3 groups included: growth velocity of weight, length and HC; change in Z-score of weight, length and HC from birth to discharge; and the incidence of EUGR. Weight growth velocity after regain of birth weight(g/kg/d) was calculated using an exponential model . Length 2.2.3.The secondary outcome of nutritional status was evaluated among the 3 groups, including enteral feeding start time, days to full enteral feeding, cumulative fasting days, breastfeeding, accumulated energy intake for the first week, accumulative doses of amino acid and fat emulsions during the first week of hospitalization, and duration of parenteral nutrition. The time to reach full enteral feeding was the time required for oral feeding up to 150 ml/kg/d . Breastf2.2.4.Major morbidities included: NRDS grade III–IV, moderate-to-severe BPD, hemodynamically significant patent ductus arteriosus (hsPDA), early- and late-onset sepsis, retinopathy of prematurity (ROP) requiring intervention, NEC (Bell stage ≥2) and IVH grade III–IV. The main treatments included: invasive mechanical ventilation (IMV) use; duration of IMV, non-invasive ventilation (NIV) and overall oxygen support; postpartum corticosteroid exposure; and duration of hospital stay. The diagnoses of these major morbidities were established by referring to Practical Neonatology (5th edition) .2.3.U test or Kruskal-Wallis H test were used for between-group comparisons. Pairwise comparisons between multiple groups were performed by Bonferroni test. Univariate analyses were performed for the comparisons of perinatal characteristics and nutritional outcomes among the cohorts.All data were analyzed using SPSS 23.0 for Windows . Categorical variables are shown as number of cases and percentages, and chi-square test was used for between-group comparisons unless the cell frequency was <5, in which case the Fisher's exact test was used. Distribution of continuous variables was assessed using the Shapiro–Wilk test. Non-normally distributed continuous variables are shown as median and interquartile range [M (IQR)], and the Mann–Whitney Multivariable linear regression analyses were performed to assess the association of different ACS coverage with nutritional outcomes controlling potential confounders such as GA at birth, birth weight, gender, mode of delivery, multiple birth, 1-min and 5-min Apgar score, SGA, gestational hypertension, diabetes, breastfeeding, NRDS grade III-IV, moderate to severe BPD and IMV use. Linear relationship between continuous independent variables and dependent variables was verified by producing partial regression scatter plots. Durbin-Watson test was performed to assess the independence of residuals. The approximately normal distribution of standardized residuals was verified by histogram plots. The scatter plots composed by studentized residuals and unstandardized predicted values were produced to test the homoscedasticity of residuals. Tolerance and variance inflation factor were calculated to examine the multicollinearity of independent variables. Studentized deleted residuals, leverage values and cook's distances were calculated to investigate the significant outliers.Multivariable logistic regression models were used to determine independent factors associated with EUGR adjusting for confounding factors as follows: GA at birth, birth weight, duration of hospital stay, gender, mode of delivery, multiple birth, 1-min and 5-min Apgar score, SGA, gestational hypertension, diabetes, breastfeeding, NRDS grade III-IV, moderate to severe BPD and IMV use. The Box-Tidwell method was used to check the linearity between the continuous independent variables and the logit conversion value of EUGR (yes or no). The Hosmer–Lemeshow test was conducted to determine the model's goodness of fit. Collinearity diagnostics was also conducted through tolerance and variance inflation factor calculation. Casewise diagnostics was used to identify the outliers outside the 2 standard deviations.P-values <0.05 were considered statistically significant.Considering ACS grouping are probably unequal spaced, we set dummy variable for ACS in all of the multivariable linear and logistic regression models, which made no-ACS group as reference, the other two groups were compared with it. Additionally, in subgroup analyses, the comparison between any ACS and no ACS was stratified by GA . All statistical tests were two-tailed, and 3.A total of 2,800 preterm infants with GA < 32 weeks were admitted during the study period. 6 infants aged <24 weeks at birth, 84 died during hospitalization or discharge against medical advice, 40 with severe congenital developmental abnormalities , inherited metabolic diseases or chromosomal abnormalities were excluded. A total of 47 infants were excluded because of missing data on weight, height, or HC. Finally, 2,514 VPIs were enrolled in the study. The flow chart of the included infants is shown in 3.1.n = 1,959) infants received at least 1 dose of ACS. Of these population, complete ACS group accounted for 48.7%  and partial ACS group 29.2% (n = 735). The incidences of cesarean section, multiple pregnancy, hypertension during pregnancy were significantly higher in the complete ACS and any ACS group than those in the no ACS group. Complete ACS was associated with lower median birth weight and lower male prevalence when compared to no ACS. There were no significant differences in GA, length, HC at birth; 1-min and 5-min Apgar score; SGA; and gestational diabetes among the 3 groups  and shorter median cumulative fasting days  than no ACS coverage. Partial ACS coverage was also associated with significantly reduced median cumulative fasting days  when compared with no ACS coverage : −5.808 ] can be seen only with complete ACS coverage. Reduced cumulative fasting time was observed both in infants exposed to complete and partial ACS .3.3.P < 0.001 and P < 0.001, respectively). Partial ACS coverage also demonstrated a significantly promoted weight growth velocity compared to no ACS coverage. Growth velocity of HC and decrements in Z-score of length and HC did not differ among the 3 groups : 0.640 and 0.500, respectively] and less dramatic decrease in Z-score of weight. While improved length growth velocity[coefficient(95%CI): 0.050] was observed only in infants exposed to complete ACS with statistical significance .3.4.P = 0.022), especially for those born at GA 24–27weeks or with birth weight between 1,000 and 1,499 g  : 0.603 and 0.636, respectively] than no ACS . Subgrou = 0.05) .4.Few studies have investigated the impacts of ACS on the postnatal nutrition of VPIs. In our study, both univariate and multivariable analysis showed that only complete ACS promoted earlier establishment of enteral feeding. Costalos et al.  studied P < 0.007) and reduces the incidence of EUGR   . ConsequOn the other hand, we found that ACS exposed VPIs were less likely to develop severe RDS and the reductions in the prevalence and duration of IMV may also contribute to the observed decrease in BPD in this population. Of note, our findings also showed that the most frequent need for NIV was observed in partial ACS group. Since RDS in partial ACS group was milder than no ACS group but severer than complete ACS group, the IMV duration in partial ACS group was shorter than no ACS group while more infants may have the chance to receive NIV support. Consequently, the prevalence of Moderate-to-severe BPD in partial ACS group was slightly lower than no ACS group, but the difference did not reach statistical significance in pairwise comparison.post hoc analysis of various ACS coverage, infants with complete ACS exposure had the fastest weight growth velocity, while no ACS exposure was associated with the slowest weight growth velocity, suggesting that the beneficial effect of ACS on weight growth appeared to be dose-dependent. Despite the higher incidences of cesarean section, multiple pregnancy and hypertension during pregnancy in ACS group, our multivariable analysis with adjustment of these perinatal baseline characteristics identified that complete and partial ACS coverage both accelerated weight growth. Moreover, this effect appeared to be more evident in infants exposed to complete ACS.Growth velocity during NICU hospitalization for preterm infants exerts a significant, and possibly independent, effect on neurodevelopmental and anthropometric outcomes . A retroThe change in Z score of weight indicates the change in weight percentile for GA, reflecting the real situation of weight change. We always observe a dramatic decline in Z score of weight, length and HC from birth to discharge, which reflects a nutritional gap between intrauterine and extrauterine stages. Complete course of ACS appeared to alleviate the decline in Z-score of weight significantly and partial course was also observed to have a slight but significant protective effect, implying a truly beneficial effect of ACS on postnatal growth.Monitoring of body length is an excellent means of assessing linear growth, which is also the most accurate indicator of lean body mass compared with weight or HC . We founOur findings demonstrated that both complete and partial ACS coverage were independent protective factors against EUGR, which is consistent with a previous multi-center, retrospective analysis reported by Clark et al.  confirmiIn subgroup analysis stratified by GA, the significant reduction in EUGR was observed in GA 24–27 weeks and GA 30–31 weeks, and even almost in GA 28–29 weeks. The previous literature  found thOur findings showed that the ACS exposure rate among infants born at GA < 28 weeks was 78.3%, which reflects substantial progress over previously reported rates in China, including 39% in 2008–2012 , 35.8% iWe addressed a significant and understudied topic about the association between ACS and postnatal growth of VPIs. Our results were derived from a large and recent multicenter cohort of VPIs who were cared for at 28 tertiary NICUs in 7 administrative regions throughout China, which makes our findings more generalizable. The data were prospectively collected and consistently defined with rigorous quality control. To our knowledge, this study provided one of the largest sample national-level assessment of the effectiveness of ACS on nutrition of VPIs in China, aiming to provide an evidence-based medical reference to optimize the nutrition for these patients.The present study has several limitations. Firstly, this was a secondary analysis of prospectively collected data, although multivariable regression analyses were conducted, some potential confounders could not be eliminated. Secondly, this study excluded infants who were hospitalized for <2 weeks, those who died during hospitalization, potentially leading to bias in the investigation of the incidence of ACS use and its impact on clinical morbidities during hospitalization. Additionally, data on ACS coverage were recorded as ordinal categorical variable, the specific regimens such as timing, dose and dexamethasone or betamethasone were not available, which makes it impossible to comprehensively evaluate the efficacy of ACS. Future studies with larger population are needed to reassess the association between ACS and postnatal growth stratified by GA and birth weight. We hope to identify the specific population who will acquire the greatest growth benefit from ACS exposure. Whether certain subgroups of fetal growth restriction or multiple pregnancy would benefit likewise from ACS needs to be investigated. Furthermore, the long-term impacts of ACS on growth outcomes in childhood call for further research.5.ACS promoted enteral nutrition in VPIs, accelerated their weight growth, alleviated their decline in Z-score of weight, and it was an independent protective factor against EUGR. This efficacy appeared to be more obvious in infants exposed to complete ACS. The ACS management in China still has substantial room for improvement. These implications indicate the importance of increasing the ACS administration rate and implementing standardized nutrition guidelines for VPIs in improving postnatal growth for this special population.


Under field conditions, Tempranillo Blanco yields less than Tempranillo Tinto, the lower weight of their bunches being related to a lower pollen viability and berry and seed setting.Tempranillo Blanco is a somatic variant of Tempranillo Tinto that appeared as a natural, spontaneous mutation in 1988 in a single shoot of a single plant in an old vineyard. It was vegetatively propagated, and currently wines from Tempranillo Blanco are commercially available. The mutation that originated Tempranillo Blanco comprised single-nucleotide variations, chromosomal deletions, and reorganizations, losing hundreds of genes and putatively affecting the functioning and regulation of many others. The most evident, visual change in Tempranillo Blanco is the anthocyanin lost, producing this grapevine variety bunches of colorless grapes. This review aims to summarize from the available literature differences found between Tempranillo Blanco and Tinto in addition to the color of the grapes, in a climate change context and using fruit-bearing cuttings grown in temperature-gradient greenhouses as research-oriented greenhouses. The differences found include changes in growth, water use, bunch mass, grape quality , and some aspects of their photosynthetic response when grown in an atmosphere of elevated CO Tempranillo Blanco is a new green-yellow variety of Tempranillo Tinto that was discovered in a centenary vineyard in 1988 [From a genetic point of view, Tempranillo Blanco is the result of a spontaneous, catastrophic genome alteration that resulted in 313 hemizygous genes because of right arm deletions of linkage groups 2 and 5 [From an ampelographic point of view, differences between Tempranillo Blanco and Tinto are scarce, except the color of the berries, green-yellow, and blue-black, respectively. Tempranillo Blanco leaves are smaller than those of Tempranillo Tinto, similar in form, with greater swelling of the adaxial side and greater density of trichomes on abaxial veins. In Tempranillo Blanco, the cluster is medium-sized and loose (large in size in Tempranillo Tinto), and the berry has a slightly flattened shape . There are also differences in the number of seeds per berry and in seed length and width, with Tempranillo Blanco having a lower number of seeds but being larger in size (higher length and width) ,4.Lower bunch size in Tempranillo Blanco than in Tempranillo Tinto was related to an impaired pollen viability and berry and seed setting ,5. AdditGrapes from Tempranillo Blanco, as above mentioned, are green-yellow. Grapes mature early, and so wines can reach a high alcohol content (≥13.3% in volume). The total acidity content of both grapes and wines is also high. In terms of acid concentration, tartaric acid has medium-high values, however, their contribution to wine acidity is low and limited by the potassium levels present, which are usually high. Acidity is therefore determined by the high concentration of malic acid, which strengthens wine freshness, a characteristic considered positive at sensory level. Sensory analysis of Tempranillo Blanco wines shows high-quality organoleptic characteristics. In Tempranillo Blanco wines, the concentration of fruity aromas of a fermentative character is high, highlighting some alcohol acetates, such as isoamyl acetate (banana aroma), with a high incidence in the aroma, and hexil acetate (pear aroma). Likewise, ethyl esters of fatty acids are also abundant in wines, mainly ethyl-3-hydroxybutyrate and ethyl butyrate  .Different methods have been used to evaluate differences between Tempranillo Tinto and Tempranillo Blanco. This review includes genetic approaches, agronomic characterization and evaluation of the resulting wines under field conditions, response to climatic variables both in the field and under fully controlled conditions in greenhouses, and response to simulations of future, foreseen conditions related to climate change. Fruit-bearing cutting is an experimental approach that allows growing a grapevine plant in a pot, which facilitates its management and where abiotic stress factors can be applied either individually or in combination in a fully controlled way.Vitis vinifera L. cv. Tempranillo Tinto (RJ-43 clone) and Tempranillo Blanco (CI-101 clone) dormant cuttings were obtained from an experimental vineyard of the ICVV . We used clone RJ-43 as one of the most widely grown Tempranillo Tinto clones. In fact, genetic comparisons between Tempranillo Tinto and Blanco were made using clone RJ-51 as a reference, representative, and widely cultivated clone in La Rioja [In this review, data from Tempranillo Blanco and Tinto fruit-bearing cuttings were used. La Rioja ,3. In thLa Rioja  and Tell−1) was used to root the cuttings. Cuttings were placed in a rock-wool heat-bed (27 °C) inside a cool room (4 °C). The rooted-cuttings, one month later, were planted in 0.8 L plastic pots ) and placed in the pre-culture greenhouse. On each plant, we allowed only a single flowering stem to develop, which resulted in one cluster per plant. Vegetative growth was controlled until fruit set by manual pruning, maintaining four leaves per plant. When plants reached fruit-set stage, they were transplanted to 13 L plastic pots ). Pre-culture greenhouse conditions were as follows: 26/15 °C and 60/80% relative humidity (RH) (day/night) and 15 h photoperiod. Natural sunlight was supplemented with 500 µmol m−2 s−1 PPFD (photosynthetic photon flux density) at inflorescence level with high-pressure metal halide lamps . Lamps were triggered when sunlight dropped below 900 µmol m−2 s−1. Nutrient solution was that described by Ollat et al. [Fruit-bearing cuttings were obtained according to Mullins , as desc2 concentration, etc.) comparing current and foreseen conditions and to assign a physiological response to one specific factor [2 from CO2 cylinders and water stress control.Under field conditions, sometimes is difficult to identify which factor is causing a specific response. In addition, in a context of climate change, simulating future climatic conditions in the field is not easily affordable and economically expensive. This trouble can be solved using the approach of growing plants under fully controlled conditions. Today, climate change can be simulated using greenhouses . In the c factor . TGG arec factor . Brieflyc factor  for deta2 mol−1 (ppm) versus 700 ppm. Additionally, substrate water content was monitored by placing sensors into the pots . Ten cuttings (10 cuttings × 2 cultivars × 2 CO2 concentrations × 2 temperatures × 2 water availabilities) were used per combination. We used 4 TGG, two at elevated CO2 and two at current one. On each TGG, one module of elevated temperature and one at ambient temperature were used. On each module, 20 plants were grown (10 of Tempranillo Blanco and 10 of Tempranillo Tinto), of which half of them were fully irrigated and the other half were water stressed. Therefore, 160 cuttings in total were used per experiment.Treatments started one week after fruit set and ended at maturity (berries with 22°Brix) and were as follows: ambient temperature versus ambient +4 °C; 400 μmol CO2O L−1 substrate) [2O L−1 substrate [Under full irrigation, plants were maintained at 300–400 g Hbstrate) . Pot watbstrate) , possiblbstrate)  for furtubstrate . At thisubstrate ,14. Reprubstrate ,14. Wateubstrate .Sampling was made at five phenological stages: (I) one week before veraison (around 60 days after flowering), (II) mid-veraison, (III) one week after mid-veraison, (IV) two weeks after mid-veraison, and (V) maturity (around 22°Brix). Roots, shoots, petioles, leaves, and whole clusters (berries and rachises) were sampled. Plants were maintained without pruning from fruit set to maturity allowing vegetation to grow freely.2 , vegetative growth  was more stimulated than reproductive growth (fresh weight (FW) of berries and rachises) by elevated CO2 [2 increased leaf DW by 22% and when combined with elevated temperature it reached 29%. Grapevine berry diameter is a trait that shows high variability [2 was 8% larger than in those grown at ambient CO2. A new varietal difference could also be observed in terms of vegetative biomass. Whereas in Tempranillo Blanco elevated CO2 produced larger increases in leaf mass (30%), CO2 specially stimulated root biomass in Tempranillo Tinto (48%) [2-mediated leaf DW increases were larger in droughted (45%) than in full irrigated (24%) plants. Final leaf DW values of droughted plants grown in presence of elevated CO2, however, did not reach those of control, full-irrigated plants. The enhanced growth observed in grapevine grown at elevated CO2 is likely a consequence of its high photosynthetic rates [2 exposure, increasing water use efficiency [Whether water and nutrients are not limiting factors, grapevine growth  and yielultivars . In lineultivars ,18,19, tated CO2 . For insiability . In agreiability , berry dto (48%) . Moreoveic rates ,24,25,26ic rates ,28 as weeaf mass %, CO2 spficiency .According to our results, differences in reproductive performance between Tempranillo Blanco and Tinto are not so strong. We made a 3-year experiment growing Tempranillo Blanco and Tinto fruit-bearing cuttings in TGGs simulating future climate change conditions. As a whole and taking into account all the years and treatments, bunch FW of Tempranillo Blanco was 8% higher than that of Tempranillo Tinto . No diff2 modify berry characteristics [Grape quality is affected by many features . Experieristics ,34,35,36eristics . Compareeristics . In addieristics . The coneristics . Resultseristics  for comp2 concentration, and a reduction in water for irrigation as three of the major factors related to climate change. Upon exposure to elevated CO2, within the first days, stomata close, transpiration decreases, but photosynthesis increases [2 may last [2, a phenomenon that decreases the plant photosynthetic capacity) [2 concentration (either current or elevated) and comparing photosynthesis in plants grown at ambient and elevated CO2 [2 in Tempranillo Blanco and Tinto plants that were grown at current and elevated CO2 concentration [2. Tempranillo Blanco had slightly higher photosynthetic rates than Tempranillo Tinto, but only at the phenological stages of one and two weeks after mid-veraison [In this review, we have analyzed elevated temperature, elevated COncreases ,40,41,42may last ,44. Howeapacity) ,48,49,50ated CO2  measuredntration . Decreasveraison .2 show increases in the C/N ratio [2 increased leaf C/N ratio values in both Tempranillo Blanco and Tinto [2, which indicates that the phenomenon of acclimation to elevated CO2 in Tempranillo grapevine is not altered by the interaction with other stress factors. This means that this phenomenon would probably occur in the future due to the increased atmospheric CO2 concentration, independently of whether changes in temperature and precipitation are more or less intense. Photosynthetic acclimation was more intense one week before veraison and at maturity [Another line of evidence comes from C/N data. Despite decreases in photosynthesis, plants that are acclimated to an excess of CO/N ratio ,50. Unde/N ratio ,51. Elevnd Tinto , as a cond Tinto ,52. Thusnd Tinto  for Tempnd Tinto ,52,53. Imaturity . The posmaturity .2 concentration (Ci), (ii) impaired Rubisco activity and/or (iii) reduced amount of Rubisco [2 closed stomata [2 concentration (Ci) values at maturity were much less affected by growing the plants at different CO2 concentration  stomatal closure and its associated decrease in sub-stomatal CO Rubisco ,54,55,56 stomata , confirm stomata ,58, Tempntration .2 decreased Ci when compared to ambient CO2  under elevated CO2, decreases of such magnitude in green, healthy leaves do not affect either leaf absorptance or photosynthesis [2 conductance), photosynthetic electron transport, biochemical (different enzymes including Rubisco), and/or end-product limitations. Regarding diffusional limitations, on one hand, stomatal conductance (see above) did not limit photosynthesis. On the other hand, mesophyll conductance was reported to decrease in Tempranillo Tinto when grown under elevated CO2 [2-acclimated Tempranillo Blanco and Tinto was reported to be negatively correlated to photosynthetic rates [Finally, in line with reports working with alfalfa , Rubisco changes . Leaf wa changes  and photynthesis ,63. Otheated CO2 . Interesated CO2 ,65, leafic rates . It was ic rates .2-mediated C/N ratio increase was very similar between varieties, 24% in Tempranillo Blanco and 29% in Tempranillo Tinto. All these findings led us to conclude that the extent of the photosynthetic acclimation does not change with the variety [In the same work, the possible relationship between C/N ratios and starch in leaves was investigated , giving  variety . On the 2 concentration. Tempranillo Tinto consumed more water than the Tempranillo Blanco variety, and its larger consumption was associated with a larger leaf area per plant, a higher density of roots, and a higher number of stomata per unit leaf area. Elevated CO2 stimulated growth, but a varietal difference could be observed. When grown under elevated CO2, CO2 stimulated preferentially root (Tempranillo Tinto) and leaf (Tempranillo Blanco) growth. Differences in both technological and phenolic maturity were also observed. Within the former, sugars and pH increased. The low acidity of Tempranillo Blanco was ascribed to lower malic and tartaric acid concentrations than in Tempranillo Tinto. Within the latter, total polyphenol index was lower in Tempranillo Blanco than in Tempranillo Tinto. Causes are found in the absence of anthocyanins (resulting in green-yellow grapes) and the lower concentration of flavonols. Additionally, bunch FW and water content in berries were higher in Tempranillo Blanco when compared to Tempranillo Tinto. Photosynthetic acclimation is a phenomenon of photosynthetic down-regulation that usually occurs when plants are grown during at least some weeks at elevated CO2 concentration. The extent of the photosynthetic acclimation in response to elevated CO2 concentration was similar in Tempranillo Blanco and Tinto. Specific single-nucleotide variations affecting amino acid metabolism might be the origin of the lower levels of leaf N concentration in Tempranillo Blanco, although the functional implications of this specific mutation deserve further investigation. These findings may be used as clues for carrying out further research on the genetic differences between Tempranillo Tinto and its mutated variety Tempranillo Blanco.This review summarizes from the available literature differences found between Tempranillo Blanco and Tinto, in a climate change context and using fruit-bearing cuttings grown in temperature gradient greenhouses. Differences found include changes in growth, water use, grape mass, grape quality , and in some aspects of their photosynthetic response when grown in an atmosphere of elevated CO2, water availability, etc. can be set as desired. Once clear differences are identified, results should be confirmed in the field. With the exception of Tello et al. [Some questions, however, arise from the results summarized in this review. How different are the new features indicated in this work between Tempranillo Tinto RJ-43 clone and Tempranillo Blanco to those observed between two random Tempranillo Tinto clones? The answer is not easy. Tempranillo Tinto is an old cultivar with many available clones, many of them with strong phenotypic differences ,67. It i


The study included 267 preterm neonates, and 23.59% (95% CI 18.9–29.1) were develop hypoglycemia. Moreover, 49 (18.35%) preterm neonates died during the study period. In this study, preterm neonates with hypothermia [Adjusted Odds Ratio ], birth asphyxia , seizure , and also preterm neonates born from diabetic mothers  were significantly associated with the occurrence of hypoglycemia in the neonatal intensive care. The proportion of hypoglycemia and associated factors among preterm neonates admitted to the neonatal intensive care unit at Debre Tabor Comprehensive Specialized Hospital was found to be high. The associated factors for the occurrence of hypoglycemia were discovered to be neonates with hypothermia, birth asphyxia, seizure, and neonates born with a diabetes mother. Thus, recognizing and treating the above associated factors is essential to preventing, and controlling hypoglycemia.The burden of hypoglycemia is high in resource limited countries, such as Ethiopia. However, there are no sufficient studies conducted in Ethiopia in general and in the study setting in particular in the previous era. Hence, this study aims to assess the proportion of hypoglycemia and associated factors among preterm neonates admitted to the neonatal intensive care unit at Debre Tabor Comprehensive Specialized Hospital, Ethiopia, in 2021. A hospital-based cross-sectional study was conducted from October 1 to December 30, 2021, at Debre Tabor Comprehensive Specialized Hospital in the neonatal intensive care unit ward. The data was entered in Epi-info 7 and exported to STATA version 14. A binary and multivariable logistic regression was computed at 95% confidence interval (CI). During bivariable analysis, variables having a  Prematurity, small for gestational age, prenatal hypoxia, and neonates delivered to diabetic moms are all at risk for neonatal hypoglycemia4.Neonatal hypoglycemia is characterized by a lower-than-normal blood glucose level6.Preterm neonates are particularly susceptible to developing hypoglycemia and its associated complications because of their low glycogen and fat reserves, inability to produce new glucose through gluconeogenesis pathways, higher metabolic demands brought on by their relatively larger brains, and inability to mount a counter-regulatory response to hypoglycemia7. However, hypoglycemia is the most prevalent metabolic abnormality in the newborn period8, which is linked to increased neonatal morbidity and mortality3.In many circumstances, preventing hypoglycemia is the most critical event during the prenatal to neonatal transition period10. Moreover, chronic hypoglycemia causes long-term neurodevelopmental problems, cerebral palsy, and mortality in the neonatal era11. Hence, early detection of recurrent or chronic hypoglycemia is crucial to improving the survival of neonates14.If left untreated, persistent or recurrent hypoglycemia can have serious neurologic and developmental consequences17, which cause common neonatal complications, such as severe malaria, bacterial sepsis, severe malnutrition, and newborn sickness19. Hence, healthcare providers must be on the lookout for all possible indicators of neonatal hypoglycemia with risk factors to maximize detection and treatment of neonates with hypoglycemia20.The challenges to diagnosis and preventing neonatal hypoglycemia are due to their numerous and unclear symptoms10. The overall incidence of hypoglycemia in neonates ranges from 1.3 to 3 per 1000 live births10, with risk groups ranging from 30 to 60%11.Although the prevalence of neonatal hypoglycemia varies depending on the definition, demographic, feeding method, timing, and type of glucose test used10, and it is also interlinked with numerous neonatal complications and mortality9. In this regard, screening and managing neonatal hypoglycemia is a challenge for healthcare providers in the neonatal intensive care unit19. Thus, data is essential to recognizing and managing hypoglycemia in preterm neonates. However, there are no sufficient studies conducted in Ethiopia in general and in the study setting in particular in the previous era. Hence, this study aims to assess the rate of hypoglycemia and associated factors among preterm neonates admitted to the Neonatal Intensive Care Unit at Debre Tabor Comprehensive Specialized Hospital, Northcentral, Ethiopia, in 2021.In Ethiopia, the burden of neonatal hypoglycemia is very high21.A hospital-based cross-sectional study was conducted from October 1 to December 30, 2021, at Debre Tabor Comprehensive Specialized Hospital in the Neonatal Intensive Care Unit ward. The hospital is located 670 km from Addis Ababa, the capital city of EthiopiaAll preterm neonates admitted to the neonatal intensive care unit from October 1 to December 30, 2021, at Debre Tabor Comprehensive Specialized Hospital were eligible for the study. Preterm neonates admitted without mothers or caregivers were excluded in the study. Sampling size and.8.The sample size was determined using the single population proportion formula by considering the following assumptions: 95% confidence interval, 5% margin of error (d), and taking the p value from the previous study conducted in St. Paul’s Hospital Millennium Medical College Neonatal Intensive Care Unit, EthiopiaTherefore, the final sample size after adding 5% was 304. However, there were 279 preterm neonates admitted and meeting the inclusion criteria at Debre Tabor Comprehensive Specialized Hospital between October 1 and December 30, 2021.Hence, we included all preterm neonates admitted to the neonatal intensive care unit at Debre Tabor Comprehensive Specialized Hospital during the study period.The data was collected by interviewing mothers and caregivers. Besides, the clinically relevant information was obtained from the medical records of the neonate. The abstraction tool contained socio-demographic, obstetrics, and preterm neonate-related characteristics that enabled the evaluation of the outcome variable. At first, the abstraction tool was developed in English and translated into the local language, Amharic, and then back to English to keep consistency.22.Hypoglycemia is defined as a plasma glucose level of less than 47 mg/dL during the study period23.Hypothermia is defined as an abnormal thermal state in which the newborn's body temperature drops below 36.5 °C24.Preterm refers to a baby born before 37 weeks of pregnancy have been completed25.Birth asphyxia is defined as a profound metabolic or mixed acidemia, the persistence of an Apgar score of 0–3 for longer than 5 min25.Neonatal sepsis is defined as a clinical sign with the presence of risk factors, lab tests, or confirmed by blood culturep- value of less than 0.25 were chosen for multivariable logistic regression analysis, and variables having a p-value of less than 0.05 in multivariable analysis had significant associations with the dependent variable.The data was entered in Epi-info 7 and exported to STATA version 14. Descriptive statistics such as frequencies, proportions, and cross tabulation were employed. The crude odds ratio (COR) and adjusted odds ratio (AOR) were calculated at 95 percent confidence intervals (CI) for binary and multivariable logistic regression to examine the strength of association between the outcome variable and independent factors. During bivariable analysis, variables having a Ethical clearance was obtained from the Ethics Review Committee of Debre Tabor University, Ethiopia with Ref NO/HP/713/01/2021 G.C. And then, the official letter was obtained from Debre Tabor Comprehensive Specialized Hospital for permission. All methods were carried out in accordance with relevant guidelines and regulations. The informed consent was obtained from all subjects and/or their legal guardian(s). The names and medical record identification numbers were not collected to keep the study participants' privacy.Out of 279 study participants, 267 were included in the study, with a completion rate of 95.7%. The mean age with standard deviation (SD) of the mother was 28.7 (6.9) years old. Nearly half (50.19%) of mothers were in the age group of 20–34 years. The majority (74.16% and 85.0%) of mothers were from urban areas and had spontaneous vaginal delivery.From the total of mothers, 58.80%, 13.48%, and 15.73% of mothers had RH (Rhesus) + ve, Antepartum Hemorrhage (APH), and Premature rupture of membranes (PROM) respectively. Moreover, 13.48% and 18.35% of mothers had diabetes mellitus (DM), respectively. Of the total mothers included in the study, 83.15% of them had ante-natal care (ANC). Of these, 74.91% of mothers had had at least four ANC follow-ups.From the total of preterm neonates included in the study, 52.43% and 76.78% were male and had a birth weight of >  = 1500 g, respectively, during the study period. The majority of preterm neonates, 85.02%, were initiated by breastfeeding for one hour, and 83.52% had a 5th minute Appearance, Pulse, Grimace, Activity, and Respiration (APGAR) score of greater than 7. During the study period, 26.97%, 17.60%, 10.86%, and 10.11% of preterm neonates had hypothermia, sepsis, birth asphyxia, and seizures, respectively . Moreover, 49 (18.35%) of preterm neonates died during the study period.p- value of less than 0.25 at 95% CI with hypoglycemia. Whereas, in multivariable analysis, variable including maternal diabetes, hypothermia, birth asphyxia, and seizure were having a p-value of less than 0.05 at 95% CI, which had statistically significant associations with hypoglycemia.Both bi-variable and multivariable logistic regression was computed. In binary logistic regression, variable including PROM, maternal diabetes, preeclampsia, sex of neonates, birth weight, initiation of breastfeeding, 5th min APGAR score, hypothermia, sepsis, birth asphyxia, and seizure were having a In this study, preterm neonates with hypothermia were 4.5 times more likely to develop hypoglycemia than preterm neonates without hypothermia . Likewise, preterm neonates with birth asphyxia were 5.1 times more likely to develop hypoglycemia than preterm neonates without birth asphyxia . Preterm neonates who had seizure were 4.7 times more likely to develop hypoglycemia than preterm neonates who had no seizure . Preterm neonates born of diabetic mothers were 6.7 times more likely to develop hypoglycemia than preterm neonates born without a diabetic mother  . Furthermore, hypothermia, birth asphyxia, seizure, and neonates born to diabetic mothers were discovered to be risk factors for hypoglycemia.26, and Ethiopia, 25%8. However, the finding is higher than the study conducted in Israel22, in Kenyatta National Hospital 14.7%27, in Tehran hospital 15.15%28, in India 21.2%29, and Uganda 2.2%3.This finding is consistent with another study conducted in Nigeria, which found that 28.3%31. In this regard, the study was conducted in a level II neonatal intensive care unit with limited equipment or materials to support sick neonates and also limited opportunities for updated and advanced training to improve quality, which may increase the rate of neonatal hypoglycemia in the study area as compared with another study setting.These differences may have been due to variations in the sampling size, study period, setting, and study design. Moreover, the level of the healthcare system regarding the detection and treatment of hypoglycemia is often different between developed and resource-limited countries or continents33. As a result, preventing and managing hypothermia through warm chains and skin-to-skin care is critical to avoid hypoglycemia and its associated complications34.The odds of hypoglycemia among preterm neonates with hypothermia were 4.5 times higher as compared to preterm neonates without hypothermia. When a baby gets cold, he or she uses up more glycogen to keep warm, and then they must use their glucose stores to keep warm, which causes blood sugar to drop and the baby to become hypothermic, as well as hypoglycemic36. Prevention and treatment of birth asphyxia by trained and skilled healthcare providers is critical for every birth neonate, regardless of the cause, in order to avoid hypoglycemia and improve survival rates38.The odds of hypoglycemia among preterm neonates with birth asphyxia were 5.1 times higher as compared to a preterm with no birth asphyxia. Because anaerobic metabolism is used to maintain blood glucose concentrations in the neonatal period, birth asphyxia increases the risk of hyperinsulinism39. Thus, diagnosing and managing neonatal seizures is essential to improving the survival of neonates. The odds of hypoglycemia among preterm neonates born to diabetes mothers were 6.7 times higher as compared to preterm neonates born to non-diabetic mothers. Maternal diabetes is one of the major problems in neonates following a pregnancy complicated by diabetes. Another is hypoglycemia. Because glucose freely crosses the placenta, maternal hyperglycemia associated with GDM causes elevated glucose levels in the fetus, resulting in hyperinsulinism41. Thus, frequent monitoring and evaluation of glucose levels among delivered mothers is crucial worldwide in general and in the study area in particular to reduce the burden of hypoglycemia in neonates43.The odds of hypoglycemia in preterm neonates with seizures were 4.7 times higher than in preterm neonates without seizures. This can result in altered glucose metabolism, the reduction of intracellular energy metabolites and phosphocreatine, and the accumulation of metabolic intermediates, such as lactate and adenosine, which result in neonatal hypoglycemiaAlthough this study attempted to explore hypoglycemia and its associated factors for the first time in the study, it has some limitations. Firstly, it was a cross-sectional study; it’s a snapshot, which is fronting for a chicken-egg dilemma, and secondly, the study was conducted in a single setting, Hence, risk validation and development model, randomized control trials, and/or cohort studies are recommended to better realize the detection rate of hypoglycemia and associated factors among neonates.The proportion of hypoglycemia and associated factors among preterm neonates admitted to the neonatal intensive care unit at Debre Tabor Comprehensive Specialized Hospital was found to be high. The associated factors for the occurrence of hypoglycemia were discovered to be neonates with hypothermia, birth asphyxia, seizure, and neonates born with a diabetes mother. Thus, recognizing and treating the above associated factors is essential to preventing, and controlling hypoglycemia.