Background: Sudden infant death syndrome (SIDS) is one of the leading causes of infant mortality in the United States (US). The extent to which SIDS manifests with an underlying neuropathological mechanism is highly controversial. SIDS correlates with markers of poor prenatal and postnatal care, generally rooted in the lack of access and quality of healthcare endemic to select racial and ethnic groups, and thus can be viewed in the context of health disparities. However, some evidence suggests that at least a subset of SIDS cases may result from a neuropathological mechanism. To explain these issues, a triple-risk hypothesis has been proposed, whereby an underlying biological abnormality in an infant facing an extrinsic risk during a critical developmental period SIDS is hypothesized to occur. Each SIDS decedent is thus thought to have a unique combination of these risk factors leading to their death. This article reviews the neuropathological literature of SIDS and uses machine learning tools to identify distinct subtypes of SIDS decedents based on epidemiological data.Methods: We analyzed US Period Linked Birth/Infant Mortality Files from 1990 to 2017 (excluding 1992–1994). Using t-SNE, an unsupervised machine learning dimensionality reduction algorithm, we identified clusters of SIDS decedents. Following identification of these groups, we identified changes in the rates of SIDS at the state level and across three countries.Results: Through t-SNE and distance based statistical analysis, we identified three groups of SIDS decedents, each with a unique peak age of death. Within the US, SIDS is geographically heterogeneous. Following this, we found low birth weight and normal birth weight SIDS rates have not been equally impacted by implementation of clinical guidelines. We show that across countries with different levels of cultural heterogeneity, reduction in SIDS rates has also been distinct between decedents with low vs. normal birth weight.Conclusions: Different epidemiological and extrinsic risk factors exist based on the three unique SIDS groups we identified with t-SNE and distance based statistical measurements. Clinical guidelines have not equally impacted the groups, and normal birth weight infants comprise more of the cases of SIDS even though low birth weight infants have a higher SIDS rate. Few topics in forensics enwrap themselves in as much controversy as the neuropathology associated with sudden infant death syndrome (SIDS). The interaction of concurrent epidemiological risks often associated with impoverished communities adds a level of complexity to SIDS pathogenesis , 2. As SSIDS neuropathological research has primarily focused on evaluation of the brainstem, due to its critical role in the regulation of the autonomic nervous system. In 1976, Dr. Neaye identified reactive astrogliosis in the medullary reticular formation in association with SIDS . In rodeThe brainstem serotonergic (5-HT) system regulates respiration and airway patency, homeostatic functions, sleep and arousal . The medPet1-expressing neurons which regulate breathing in neonates   , 23. In Nevertheless, there are also significant indications of a health disparities component to SIDS etiology. Thirty years ago the rate of SIDS in the United States (US) was considered moderate compared to other developed countries, however the US now has among the highest SIDS and postnatal mortality rates in recent years . SIDS, aDue to these divergent perspectives, some investigators have advocated for a Triple Risk Hypothesis for SIDS. The Triple Risk Hypothesis posits that a vulnerable infant with an underlying intrinsic risk undergoes exposure to an unsurmountable exogenous stressor resulting in death . These iAlthough the Triple Risk Hypothesis has represented a useful framework to understand SIDS, the inherent variabilities and confounding factors in studying human tissue make it impossible to predict which individual infant is at clear risk of sudden death. This challenge prevents delineation of clear mechanistic pathways that could be amenable to pharmaceutical intervention. Amongst these hindrances includes an inability to objectively determine the underlying etiology and relative contribution of various extrinsic and intrinsic risks of each individual decedent. Therefore, we sought to identify unique clusters of SIDS decedents in whom different risk factors and characteristics predominate. To achieve this, we obtained data from the United States National Center of Health Statistics (NCHS) managed by the Centers for Disease Control and Prevention and applied modern unsupervised machine learning models.Neuropathology has evolved into a “big data” field with routine incorporation of machine learning and artificial intelligence informatics that spans a much larger scope than interpretation of histopathological slides. We performed an unsupervised machine learning dimensionality reduction technique known as t-distributed stochastic neighbor embedding (t-SNE). Due to the data recording methods obtained from the NCHS infant mortality files, this method was best suited for our analysis. t-SNE is a high-dimensionality reduction technique capable of modeling non-numerical data in the form of factors . Our anaInternational Classification of Diseases, Ninth Revision (ICD-9) code for deaths occurring before 1999 (code 798.0) and International Classification of Diseases, Tenth Revision (ICD-10) for deaths occurring in 1999 and after (code R95) ode R95) . These dIn addition to analyzing US SIDS rates, our study also included calculating the SIDS mortality rates in New Zealand and Argentina. Publicly available New Zealand SIDS mortality data was obtained from the Ministry of Health from 2000 to 2016, and República de Argentina data was obtained from Dirección de Estadísticas e información en salud del ministerio de salud de la nación (Argentine Government) for 1997–2015. The US and Argentina defined SIDS occurring from birth to 1 year of age and New Zealand classified it from birth to <1 year of age in their reporting statistics . All couSIDS mortality rates by birth weight were calculated using the total number of SIDS decedents in that birth weight class divided by the number of live infants born in the same birth weight class multiplied by 1,000. SIDS decedents with unknown birth weights were excluded from the rate calculation in analysis of all countries .For the US data, individual state death rate calculations were derived by dividing SIDS occurrences in a birth weight category by the number of live born infants. To avoid disclosing identifiable events, rates underwent center-scaling at zero with a standard deviation of 1 in each birth weight category. Restricted US Period Linked Birth/Death Data from 2005 to 2006 and 2014–2017 omitted state of death occurrence and were excluded from our analysis.n = 29,651; 48.51%). Infants with 39 weeks gestational age or higher did not have their age at death modified , nor did the infants who had “unknown” or “not recorded” listed as the gestational age on their birth certificate .In order to calculate the adjusted age at death, we used the gestational age recorded in the birth certificate computed using the date of birth of the infant and last menstrual period or the clinical estimate of gestation. We considered 39 weeks gestation or higher as full term as recommended by Spong et al. . GestatiMother's education was also recoded due to variations in the reporting codes between the unrevised and revised birth certificates. See Traditional methods of studying the epidemiology of SIDS typically focus on the relationship of the event and possible risk factors associated with SIDS and each other , 27. To −2 (represented as 10−2 due to being an estimate obtained using random sampled permutations)  .By far, the most extensive dataset available for the study of SIDS in the US represents the vital statistics available through the NCHS. We therefore obtained and standardized the Period Linked Birth/Infant Death data to allow for robust analysis of SIDS decedents. These data represented 61,118 instances of SIDS decedents linked to information on both the birth certificate and death certificate, including mother's marital status, education, race, and prenatal care in addition to the infant's length of gestation, birth weight, and age at death. These parameters were chosen because variables including father's education, age, and race were inconsistently reported across the various states, alcohol usage was not collected over the entire timeframe studied, and infants with multiple variables as “unknown” clustered near one another. Clusters based on unreliable reporting led us to exclude these variables. We first tested the hypothesis that unique clusters of SIDS decedents existed by performing t-SNE analysis. Following the creation of the t-SNE plot, we pseudo-colored each circle (where each circle represents one instance of a SIDS decedent). By interacting with the data in this way, we identified trends in the data as to which variable created the most segmented groups. Birth weight was the most significant driver separating the groups . InfantsUpon further data exploration, we identified a smaller, second group within the normal birth weight cluster . AlthougSD = 82.9, p < 10−2), the mean average within cluster distance was 4.23 , and the mean average between cluster distance was 4.48 . We conclude that three discrete groups of decedents were identified by machine learning-based evaluation of the NCHS epidemiological data.In these three discrete groups, we noticed age at death  did not n = 12,310), group 2  in teal , and group three  in green . Following the identification of these three groups, we next tested if the mean age of death was distinct between groups. When comparing the three groups' postnatal age at death based on the death certificate, we noticed that each group had similar peak ages at death. However, since low birth weight is highly related to prematurity, we recalculated each decedent's postconceptional age so that we could plot all decedents along the same timeline. When plotting the three distinct groups based on their postnatal age corrected for gestation, we discovered differences in the distribution and arithmetic mean of age at death between the three groups. In group 1, the mean age at death was 67.89 days (SD = 61.95); group 2's mean age at death was 96.80 days (SD = 60.71); and group 3's mean age at death was 88.22 days (SD = 62.82). Evaluation of statistical significance by ANOVA/TukeyHSD test demonstrated a significance of p < 2e−16 and an adjusted p-value of 2e−16, 2e−16, and 3e−14, for groups 2-1, groups 3-1, and groups 3-2, respectively. These data indicate that the mean peak incidence of SIDS within these three groups occurs at distinct neurodevelopmental ages. In addition to the groups having significantly different postconceptional ages at death, it is important to note that many infants (~10%) born prematurely in group 1 died of SIDS before they reached full-term gestation with a calculated p-value <2e−16 using a chi-square test. This larger percentage of infants dying before reaching full term gestation in the low birth weight group could suggest that in this group of SIDS decedents, neurodevelopmental pathologies may play more important roles in SIDS pathogenesis relative to the other groups.Having identified these three groups using an unsupervised learning approach, we next sought to identify potential differences between these groups that might provide insight into the etiology of SIDS. In p < 0.001), indicating that a strong geographical heterogeneity in SIDS incidence across the US. We also note that regions of SIDS hotspots mirror the geographic distributions of African American and Native American populations as well as regions with lowest GDP per capita. This correlation was determined in two separate linear regression models analyzing the 2013 SIDS rate based on race  in each state compared to the GDP . State GDP shows a significant linear relationship with the rate of white infants dying of SIDS but no correlation with Black infants. The linear regression data are reported in After determining there were three discrete groups based on maternal and infantile characteristics, we wanted to see how each state performed over time in regards to reducing the rate of SIDS in these groups. Due to limited data availability, we were only able to perform this analysis with group 1  and a second group based on infants born weighing 2,500 g or greater. Data were center-scaled within birth weight categories including geographical information on SIDS death from 1995 to 2013 (excluding 2005–2006). We found over time, states have generally reduced the rate of SIDS for these two groups, however, disparities are still present. In the low birth weight group, states that had higher rates of SIDS include West Virginia, Arkansas, Wyoming, Mississippi, North and South Dakota, Montana, Louisiana, and the District of Columbia . In the To evaluate the progress of SIDS reduction over time, we plotted the rate of SIDS within the two distinct clusters based on birth weight from 1995 to 2017. Clinical guidelines, such as the Back to Sleep campaign, had a momentous effect on declining the SIDS rates in the US beginning in 1994, but the SIDS rate plateaued in the early 2000s . HoweverWe broadened our analysis to see if the two distinct groups we identified had similar trends in other countries with different levels of cultural heterogeneity than the US  , 43. In Phox2b. Severe impairment in autonomic nervous system breathing control without cardiorespiratory disease is characteristic of CCHS  , 45, Rap of CCHS , 52. Lac finding , 54. Mouenerator . AlthougPet1-derived neurons, which generate a large population of 5HT neurons, undergo silencing . The LCR is characterized by a preceding period of hypoxia with bradycardia, swallowing, and a cough to clear the airway of obstructive fluids. Discovered in piglets, the swallowing and coughing response during the LCR exhibits low complexity values, signifying it is induced by a homogenous group of neurons . PigletsIn addition to the rapid development of the neurons controlling the LCR postnatally, the majority of postnatal proliferating cells in the pons are oligodendrocytes , 62. PreIn the US, sudden infant death cases fall under the jurisdiction of the local medicolegal investigation systems, which are currently a mixture of coroner, medical examiner, and hybrid systems. This heterogeneity of systems and investigative practices combined with funding limitations and a national shortage of forensic pathologists has led to inconsistencies in the certification of sudden, unexpected deaths in infants , 65. In In 2019, the National Association of Medical Examiners' (NAME) Panel on Sudden Unexpected Death in Pediatrics, an expert panel composed of medical examiners, pediatricians, and federal agency representatives, released “Unexpected Pediatric Deaths: Investigation, Certification, and Family Needs” which recognized this issue and the need for consensus guidelines for the investigation and certification of unexpected pediatric deaths . As suchnvssrestricteddata@cdc.gov.The data analyzed in this study is subject to the following licenses/restrictions: privacy or ethical restrictions imposed by the United States Centers for Disease Control. Requests to access these datasets should be directed to JB conceptualized and designed the study, carried out analysis, and drafted the initial manuscript. VC obtained Argentine infant mortality data, reviewed, and revised the manuscript. JS and JZ refined the analysis, reviewed, and revised the manuscript. AS and CP critically reviewed and revised the manuscript. JO conceptualized the study, refined analysis, reviewed, and revised the manuscript. All authors approve the final manuscript as submitted.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Hydatid cyst is a parasitic infestation that is usually observed in the liver and lungs. The localization in the brain and the heart is exceptional. Here, we report a 11-year-old boy who was diagnosed to have two large hydatid cysts of the heart and brain. We discuss this unusual presentation of hydatid cyst and its management. By reporting a rare case of brain and cardiac concomitant localization of the hydatid cyst, we underlie this atypical clinical presentation and treatment difficulties.A hydatid cyst is a parasitic illness that is frequently seen in rural areas where husbandry is widely practiced. It can affect any organ and is usually observed in the liver (∼75%) and lungs (∼20%) . The locWe received an eleven-year-old boy with Down's syndrome and mental retardation and psychiatric trouble (hyperexitability). His parents noticed dyspnea and decreased exercise tolerance. The family lives in a rural area in companion with domestic animals.The boy cannot express due to mental disorder. On physical examination, he was irritable. However, his parents reassured us that he was always like this with strangers. Cardiopulmonary auscultation was normal. Electrocardiogram showed sinus rhythm with 110 beats per minute and systolic ventricular hypertrophy (Sokolow score at 37 mm), with a negative T wave . FrontalOn abdominal ultrasound, no cysts were observed in the liver, kidneys, or spleen. Hydatid serology was positive , ELISA was positive, and optic density was 1.034 (threshold 0.275)). We started preoperative albendazole (at a posology of 15 mg/kg/day or 400 mg per day), and we decided to proceed with surgical removal. Two weeks after the diagnosis of cardiac hydatid cyst, the patient made a severe neurological impairment and was admitted to the emergency for symptoms of increased intracranial pressure, nausea, and vomiting. A brain-CT demonstrated a very large cerebral cyst with signs of mass effect . The carWe were planning to remove the cardiac hydatid cyst one month after the brain surgery. Unfortunately, the patient had a shock and died immediately after the first surgery.Echinococcus genus. The most common form worldwide including Morrocco is cystic echinococcosis that is chiefly caused by Echinococcus granulosus. It is endemic in Mediterranean countries, the Middle East, South America, and Australia [Hydatid cyst is a parasitic infestation caused by the larval stage of the different species of the tapeworm ustralia .In Morrocco, the incidence of cystic echinococcosis is 5.2 cases per 100,000 inhabitants with a predominance in females (sex ratio M/F = 0.66) and young adults (59.1% of hydatidosis have been diagnosed in patients aged 15 to 49 years) [Echinococcus is complex. The worm has a life cycle that requires definitive hosts and intermediate hosts. Definitive hosts are normally carnivores such as dogs and cats while intermediate hosts are usually herbivores such as sheep or cattle. Echinococci are transmitted to intermediate hosts via the ingestion of eggs as humans do, whereas they are transmitted to definitive hosts by means of eating infected, cyst-containing organs. Humans are accidental intermediate hosts that become infected by handling soil or dog excrement that contains eggs or by ingestion of food contaminated by the ova of the parasite [Like many other parasitic infestations, the course of parasite .The potential risk factors of cystic echinococcosis are the regional epidemic, the rural environment with hygiene practices, social conditions, education, and the young age. In fact, 29% of the cases were found in children younger than 14 years .The liver and lungs are the organs most affected by parasitosis. Hepatic hydatidosis is by far the most common 75%), followed by lung locations (20%). Still, hydatidosis can be found in any site of the body: brain, muscle, heart, kidney, spleen, peritoneum, and so on . The hyd%, followBrain localization is usually single, supratentorial, and intraparenchymal. The cysts do not produce serious symptoms until they grow to large dimensions. A cyst's clinical symptoms depend on its localization and the dimensions of the lesion in the central nervous system. Headaches and throwing up are the most frequently observed symptoms , 9.Symptoms develop slowly, and neurological deficits generally appear in the late period as a result of an increase in intracranial pressure. Papillary edema is frequently seen in children, while focal symptoms, such as hemiparesis, paraphasia, hemianopsia, and seizures, are frequently observed in mature individuals and depend on the localization of the cyst , 9.Psychiatric disorders  have also been reported in the literature. In our patient, perhaps, his irritability and agitation are related to his cerebral hydatid cyst, but this was difficult to prove because of his mental retardation. He later presented with signs of intracranial hypertension .A clinical diagnosis is made according to epidemiological findings, the patient's history and clinical symptoms, any morphological lesions that are discovered by ultrasonography (US), CT, and MRI, and serological tests , 4.The tests for diagnosis of hydatidosis include detection of IgE and IgG by western blot and molecular analysis of the excised tissues. Sequencing of the DNA polymerase chain reaction of contents from the cyst could also be performed as more specific test , 4.Management of disseminated echinococcal disease is complex, which requires a multidisciplinary approach. Hydatid disease should be treated with either albendazole and surgery or albendazole and PAIR  to extract the cyst without any complications , 12.As of high frequency of recurrent hydatid disease after treatment with only surgery or only albendazole, multidisciplinary approach is recommended, and continuing medical treatment for at least 3 months postoperatively is also suggested . In patiIn our case, we started with the medical treatment, and then we performed the cerebral hydatid cyst surgery given the urgency as the patient presented with signs of cerebral engagement. An ablation of the cardiac hydatid cyst was planned in a second time. Unfortunately, the postoperative shock state probably due to anaphylactic shock took the patient away.In the literature, causes of rapid clinical decline involve a wide range of mechanisms including anaphylaxis (with or without cyst rupture), cardiac outflow obstruction or conduction tract disturbance, pulmonary and cerebral embolism, pericarditis, cardiac tamponade, myocardial ischemia, pulmonary hypertension, peritonitis, hollow organ perforation, intracerebral mass effect, obstructive hydrocephalus, seizures, and cerebral ischemia/infarction. The autopsy helps determine the exact cause of death. It was not performed on our patient because the family refused , 16.When a hydatid cyst is found, whatever the localization is, it is necessary to assess the extension by a brain-CT, chest X-ray, echocardiography, and abdominal echography. Atypical localization can be found and can change the therapeutic vision, especially in children who live in endemic regions. Medical treatment must be started without delay along with surgical removal of all cysts if possible.


The findings support BHT as a potentially interesting pharmacological tool for dissecting PIN trafficking and auxin transport.The activity of polarly localized PIN-FORMED (PIN) auxin efflux carriers contributes to the formation of auxin gradients which guide plant growth, development, and tropic responses. Both the localization and abundance of PIN proteins in the plasma membrane depend on the regulation of PIN trafficking through endocytosis and exocytosis and are influenced by many external and internal stimuli, such as reactive oxygen species, auxin transport inhibitors, flavonoids and plant hormones. Here, we investigated the regulation of endosomal PIN cycling by using a Brefeldin A (BFA) assay to study the effect of a phenolic antioxidant ionol, butylated hydroxytoluene (BHT), on the endocytosis and exocytosis of PIN1 and PIN2. BHT is one of the most widely used antioxidants in the food and feed industries, and as such is commonly released into the environment; however, the effect of BHT on plants remains poorly characterized. Preincubation of Arabidopsis seedlings with BHT before BFA treatment strongly enhanced the internalization of PIN1 into BFA compartments. After the simultaneous application of BHT and NAA, the NAA effect dominated PIN internalization suggesting the BHT effect occurred downstream to that of NAA. Washing seedlings with BHT after BFA treatment prevented the release of PIN1 from BFA compartments back to the plasma membrane, indicating that BHT application inhibited PIN1 exocytosis. Overall rates of PIN2 internalization were less pronounced than those of PIN1 in seedlings pre-incubated with BHT before BFA treatment, and PIN2 exocytosis was not inhibited by BHT, indicating a specific activity of BHT on PIN1 exocytosis. Comparison of BHT activity with other potential stimuli of PIN1 and PIN2 trafficking [e.g., H Environmentally responsive plant growth requires the integration of diverse physiological responses. Many environmental stresses induce the formation of reactive oxygen species (ROS), the response to which often includes the biosynthesis of antioxidants that influence growth and development through their effect on plant hormones. Among these, auxins are prominently involved through their formation of instructive concentration gradients. These gradients are generated by PIN-FORMED (PIN) auxin efflux facilitator proteins, which may be asymmetrically localized to various sides of the cell, but always in the direction of auxin flux . This poPIN gene family is represented by eight members whose protein products show a partially overlapping expression pattern that builds a dynamic network to allow differential regulation of auxin distribution among different cell types , GNOM, by activation of an ADP-ribosylation factor . The locabp1 mutants  preferentially inhibits recycling, whereas a high concentration (50 μM) also stops the targeting of vesicles to the vacuole for degradation . Thus, bIn agreement with experiments which used 50 μM BFA , the eff2O2) or a ROS-induced stress . One mM H2O2 inhibited the exocytosis of both PIN1 and PIN2  showed that PIN1 was internalized in to BFA compartments and, upon withdrawal of BFA, PIN reappeared at the plasma membrane in a manner which was independent of protein synthesis . Becausereatment , and thaBHT is one of the most widely used antioxidants in the food industry and has been extensively investigated in animal systems and in terms of human health ; howeverWe suggest three alternative hypotheses to explain the modulation of PIN trafficking by BHT observed in our investigation. The first hypothesis is that BHT acts as an antioxidant and indirectly regulates PIN trafficking by ROS scavenging. The second hypothesis is that BHT acts as a prooxidant to produce ROS that then affect PIN trafficking. The third hypothesis is that BHT acts directly on some as yet unidentified molecular targets to modulate PIN trafficking.2O2 inhibited exocytosis   and the is roots .2O2 act in a similar manner on PIN1 exocytosis (2*– (superoxide)  , whereaseroxide) .2O2 do not support the idea that the activity of BHT on PIN trafficking is not related to its potential prooxidant activity.Based on the potential for the production of ROS in an aqueous medium at the root surface and the fact that ROS inhibit exocytosis , this hy2O2 and BHT activities provide further support for the conclusion that the mode of BHT action cannot be explained by its pro-oxidant activity.Interestingly, hydrogen peroxide inhibits exocytosis but also stimulates endocytosis, as observed by its effects in the absence of BFA . By contThe inhibitory effect of BHT on PIN1 exocytosis resembles that of the auxin transport inhibitors NPA and TIBA. Early studies on the PIN trafficking machinery showed that TIBA and NPA blocked the transfer of PIN1 from the BFA compartments to the membrane that occurred during cell washing after BFA treatment . HoweverThe activity of auxin transport inhibitors on auxin transport activity has been attributed to their binding to the multi-drug resistant ABCB type transporters, a plasma membrane aminopeptidase, and other proteins (including PINs themselves) . The sentt4  Heynh. Columbia (Col-0) and PIN1:PIN1:GFP  salts and 1% sucrose, pH 5.7] and 15 g l–1 agar-agar (Merck). After stratification overnight at 4°C in darkness, plates were transferred to a growth chamber  for seed germination and maintained in a vertical position. Experiments were performed on 4-day-old seedlings in 24-well cell-culture plates in liquid AM medium. For the evaluation of BFA-induced PIN internalization, Arabidopsis seedlings were pre-treated for 30 min in AM containing 10 μM 1-NAA, 200 μM BHT, or 1mM GSH. Pre-treatments were followed by 45 min of concomitant treatment with chemicals and 25 μM or 50 μM BFA. BFA was initially dissolved in dimethylsulfoxide (DMSO) at 50 mM. Control treatments contained an equal amount of DMSO. For the evaluation of the direct effect of BHT on PIN endocytosis, seedlings were treated for 30 min in AM containing 200 μM BHT. For the evaluation of PIN exocytosis from BFA-bodies to the plasma membrane (exocytosis), 4-day-old Arabidopsis seedlings were pretreated with 50 μM BFA  for 45 min. BFA was removed by washing for 2 h with 0.5 MS medium containing appropriate chemicals .PIN1:GFP  seeds weInsitu Pro; Intavis).Immunolocalization of Arabidopsis roots was carried out as described previously . Rabbit Confocal images were taken using a Zeiss LSM 510 NLO confocal laser scanning microscope. Alexa Fluor 488 and GFP were excited with a 488 nm argon laser line in combination with a 500–550 band-pass filter. Alexa Fluor 555 was excited with a helium-neon 543 nm laser (HeNe laser) in conjunction with a 575-long-pass filter. The confocal microscopy images were quantitatively analyzed using Imaris 7.5.6 software (Bitplane AG). The fluorescence signal was detected using the “create surface” tool, and the fluorescence signal was calculated at the plasma membrane and in the BFA bodies. The level of signal internalization  was calculated as the ratio between intensity of the intracellular fluorescence signal and the intensity of the total fluorescence signal and expressed as a percentage. For every root, the estimation of the level of PIN internalization was based on 20–32 and 10–18 cells for PIN1 and PIN2, respectively. Quantification of PIN1 and PIN2 signal in plasma membrane was performed along defined linear region of interest (ROI) drawn crossing cells using ImageJ. We used 5–10 roots for every treatment. Averages for every root were used for statistical analysis.For root length measurements Arabidopsis seedlings were grown on vertically oriented plates in a growth chamber under the standard conditions described above. Seedlings were grown for three days on control medium and then transferred onto new plates containing the same medium with a reduced percentage of agar (0.8% instead of 1.5%) and supplemented with BHT at 0, 10, 100, 500, or 1000 μM. The seedlings were then grown for another two days and the length of the main root was measured by scanning at 24 h and 48 h after seedling transfer and using ImageJ software .Data were statistically analyzed by analysis of variance (one-way ANOVA). When significant treatment effects were identified by ANOVA, Fisher’s protected LSD test was used to compare the individual means .All datasets generated for this study are included in the article/supplementary material.IP and KP conceived the project. IP, MP, and WT wrote the manuscript. VB performed the experiments and analyzed the data.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Many maternal factors are known to be associated with adverse birth outcomes, but studies about paternal factors yielded inconsistent conclusions. The study was to assess whether paternal factors are associated with low birth weight (LBW), preterm birth (PTB), and small for gestational age (SGA).A birth cohort study was conducted in 2010–2012 at the Gansu Provincial Maternity and Child Care Hospital, the largest maternity and childcare hospital in Lanzhou, China. Paternal age, ethnicity, educational level, height, weight, smoking, and drinking were collected. Birth outcomes and pregnancy complications were extracted from the medical records.2  and paternal education which above college  were associated with a lower rate of SGA.During the study period, 10,121 participants were included; the overall prevalence of LBW, PTB, and SGA was 7.2, 9.9, and 7.8%, respectively. Paternal higher height , higher weight (P for trend < 0.001), and higher BMI (P for trend < 0.001) could decrease the rate of LBW. Paternal higher education  and higher weight  were associated with lower rate of PTB. Fathers who smoked more than 6 pack-years were associated with PTB . Paternal BMI > 23.9 kg/mPaternal low education is independently associated with PTB and SGA. Paternal heavy smoking is associated with PTB. Low paternal weight/BMI is independently associated with LBW, PTB, and SGA.The online version contains supplementary material available at 10.1186/s12884-020-03492-9. Various adverse birth outcomes including low birth weight (LBW), preterm birth (PTB), and small for gestational age (SGA) are associated with increased neonatal morbidity and mortality , and eveStudies that investigated the relationship between paternal factors and adverse birth outcomes have reached inconsistent results. Some studies observed that advanced paternal age was associated with an increased risk of LBW  and PTB Compared with Beijing, Shanghai and Guangzhou, Lanzhou is an economically underdeveloped area located in Northwest China. At present, no study has assessed the perinatal outcomes in Northwest China using a large birth cohort. Therefore, the aim of this study was to assess whether paternal factors are associated with LBW, PTB, and SGA.A birth cohort study was conducted in 2010–2012 at the Gansu Provincial Maternity and Child Care Hospital, the largest maternity and childcare hospital in Lanzhou, China . The stuUpon obtaining written consent, five residents trained in epidemiology at the Yale School of Public Health conducted in-person interviews at the hospital using a standardized and structured questionnaire (Supplementary File 2) was calculated from paternal weight and height data were measured by nurses after the newborns were delivered, with the fathers paying a visit to the mothers. Smokers were defined as men who smoked 1 or more cigarettes per day for at least 1 month before deliveries. Drinker was defined as men who were exposed to alcohol at least one time per week on average before deliveries. Based on tertiles of, height, and weight, packyear, drinking times per year were classified into three groups. The first tertiles were used as reference groups.Information on paternal characteristics was also collected through the questionnaire and confirmed by the fathers, including age, height, weight, reproductive and medical histories, smoking, alcohol consumption, occupational and residential histories were collected within 1 to 3 days after delivery. Paternal age was defined as the age of father in completed years at the time of their child’s birth. Paternal body mass index (BMI) , hypertensive disorders during pregnancy (yes or no), family’s average monthly income , smoking during pregnancy (yes or no), and gestational week (only for LBW). Adjustment for cesarean delivery of the current birth (yes or no), maternal gestational diabetes (yes or no), maternal alcohol consumption (yes or no), and infant gender  did not result in changes in the observed associations and thus were not included in the final models. Two-sided P-values < 0.05 were considered statistically significant. All statistical analyses were carried out using SAS 9.4 .All data were managed using EpiData 3.0 . The continuous data were tested for normal distribution using the Kolmogorov-Smirnov test. Continuous data are presented as mean ± standard deviation and analyzed using the Student t-test or ANOVA with the Tukey’s post hoc test , or as median (range) and the Mann-Whitney U test . Categorical variables are presented as frequencies and were analyzed using the Fisher’s exact test. Multiple logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (95%CI) for the associations between paternal characteristics and birth outcomes. Based on the literature , 15, then = 323), stillbirth (n = 53), and missing information on infant gender (n = 36) and birth weight (n = 43), and missing information on father’s factors (n = 34) or women with more than one exclusion conditions, 10,121 participants were included in the analysis.A total of 14,535 pregnant women came to the hospital for delivery, of whom 176 were judged to be ineligible for the study . Thus, a total of 14,359 eligible women were approached for participation. Of those, 3712 refused to participate and 105 did not complete in-person interviews, which yielded 10,542 (73.4%) women who completed in-person interviews. After exclusion of women who had multiple births . Compared with the control group, young paternal age, small paternal stature, paternal smoking, and paternal drinking were not associated with LBW. Interesting, father who liked drinking beer and red wine was associated with LBW , although these findings were based on only 3 LBW cases and should be cautiously interpreted.The overall prevalence of LBW was 7.2%. As shown in Table P for trend < 0.0001, were associated with a lower rate of PTB. In addition, father who smoked more than 6 pack-years was associated with PTB . There were no significant associations regarding age, height, or drinking.The overall prevalence of PTB was 9.9%. Table > 1.75 m had a lower risk of SGA  compared with men with a height < 1.71 m. Compared with infants born with normal weight, the fathers whose BMI was > 24 kg/m2 were associated with a lower rate of SGA . There were no significant associations regarding age, weight, smoking, or drinking.The overall prevalence of SGA was 7.8%. The associations between paternal factors and SGA are shown in Table 2) is associated with a low risk of LBW, PTB, and SGA, our study also suggested that paternal smoking is associated with a high risk of PTB. The previous studies that investigated the association between paternal age and adverse birth outcome provided conflicting results. It was reported significant associations between younger paternal age and PTB [To our knowledge, the present study is the first to comprehensively examine the effect of paternal factors on the risk of a wide range of adverse perinatal outcomes  in a Chinese population. It supports the hypothesis that paternal lower education and lower weight are associated with a higher incidence of PTB and SGA. Moreover, high paternal BMI , but fathers who were taller were associated with a decreased risk of LBW (P for trend = 0.0013), independently from maternal height. This is supported by the literature [A recent study documented that maternal height contributes to the intrauterine environment and to infant growth and gestational age, which may overcome the influence of paternal genes. In order to rule out the effect of maternal height, we stratified the subjects by maternal height but did not found any interaction between paternal height and adverse birth outcomes (terature , but theterature . The effterature .Regarding paternal weight and BMI on birth weight, we observed an association between paternal weight and LBW, as supported by previous studies , 23. UnlAs for the paternal lifestyle habits, although previous studies  paid morIn addition, our study found no significant association between paternal alcohol consumption and adverse birth outcomes, which was similar to the literature . Up to nThe etiologies of adverse birth outcomes are multifactorial and not completely understood yet –35. In tThe interpretation of the results of this study must take into account its limitations. First, in relation to the ascertainment of exposure, the data regarding the father were mostly self-reported except for height and weight, therefore prone to recall bias. Second, selection bias might have occurred as some fathers were less willing to co-operate in the birth cohort study or were absent when we interviewed the women. A meta-analysis of studies that used biochemical measurements to validate self-reported smoking behavior found that the self-reporting of smoking was generally reliable . UnfortuDespite these shortcomings, our study has some strengths. The first is the exclusion of multiple births and stillbirths, minimizing the potential differences in health effects of birth weight and gestation age. Secondly, all participants were Chinese, minimizing differences in genetic susceptibility to birth weight and gestation age. Third, we collected and controlled potential confounding factors in the analysis. Information on birth outcomes and maternal complications during pregnancy was obtained from the medical records, minimizing misclassification.This is the first study in China to show low paternal education and low weight are associated with a higher incidence of PTB and SGA. Paternal overweight was associated with lower LBW, PTB, and SGA. Paternal smoking is associated with high risk of PTB. These associations could provide clues to the etiology of these conditions. Further scientific and epidemiologic studies are needed to elucidate the mechanism of how paternal factors influence fetal developmental processes.Additional file 1: Supplementary File 1. Questionnaire


Birth weight plays an important role in infant mortality and morbidity, child development, and future health of the child. Reports showed that low birth weight is one of the critical issues in Gugare zone that causes many babies short-term and long-term health consequences and tends to have higher mortality and morbidity. This study examined and identified the determinants of weight of children at birth in Gurage zone.The survey or the information has been collected on a total of 735,109 reproductive mothers in Gurage zone. Children with age less than 59 months were considered in this study. Ordinal logistic regression techniques used for data analysis using maternal and sociodemographic variables as explanatory variables and size of a baby at birth as the response variable and statistical package for social science (SPSS) version 23 and STATA were used for data analysis purpose.According to our study, from the sampled children, 30.1%, 44.4% and 25.5% were small in size, medium in size and large in size, respectively. Mater-nal related variables were statistically significant like uneducated mother , mothers who get antenatal visit care 2–3 times , source of drinking water  and malaria affected mothers .Children from rural mothers, uneducated families, mothers who did not get more antenatal care visits, poor families, mothers who drink non -improved water, mothers who are affected by malaria during pregnancy, teen-ager mothers are small in size at birth. One of the poor outcomes of pregnancy that has caught the attention of the World Health Organization (WHO) is the size of children at birth which is directly related to low birth weight. A child’s birth weight or size at birth is an important indicator of the child’s vulnerability to the risk of childhood illnesses and the child’s chances of survival. Children whose birth weight is less than 2.5 kilograms, or children reported to be “very small” or “smaller than average”, have a higher than average risk of early childhood death .Birth weight is affected to a great extent by the mother’s own fetal growth and her diet from birth to pregnancy, and thus, her body composition at conception. Mothers in deprived socio-economic conditions frequently have low birth weight infants. In those settings, the infant’s low birth weight emerges primarily from the mother’s poor nutrition and health over a long period of time. During pregnancy, the higher prevalence of specific and non-specific infections, or from pregnancy complications, underpinned by poverty aggravates the situation. Physically demanding work during pregnancy also contributes to poor fetal growth .Low birth weight infants are 2 times more likely to die during their first 28 days of life than normal birth weight infants . Low birSmall size of children at birth is one of the critical issues in Ethiopia that causes many babies short-term and long-term health consequences and tend to have higher mortality and morbidity . Only 5 As the Gurage zone health officer report indicates, the weight of about quarter (25%) of the new born children in Gurage zone is below average or smaller than average and this small weight exposes children to extremely high rates of morbidity and mortality. Thus this study intended to identify the risk factor for small size of children at birth.The study has been conducted in Gurage zone which is found in south nation, nationalities and peoples’ region (SNNPR), Ethiopia. According to Gurage zone health care office, the total population in this zone is estimated to be 1,609,908 and among this 735,109 are women in reproductive age (15–49), so the target population for this study was women in reproductive age . The study was conducted among Gurage zone women, who have children less than five years from September to February, 2017.Stratified, multi-stage sampling technique was employed to include study participants in to the research. The study area was first stratified in to urban and rural places since residency is known to affect the prevalence of size of children at birth. The total 15 woredas of the study area were stratified in to two strata, urban and rural, each containing 2 town administrates and 13 woredas, respectively.Then in the first stage, one town administrative (Butajira), two rural woredas (Abeshige and Gumer) were selected proportionally, based on the number of woredas in each stratum through lottery method. In the second sampling stage, simple random sampling technique was used to take households from each of the selected three woredas, by taking into account the number of households in each of the sampled woreda, until the calculated sample size in the respective woreda was reached to achieve the sample size of 897 households in total.The data for this study were collected by organized questionnaire with recorded birth weight, if available from written records or mother’s recall, for all births in the five years preceding the study. Birth weight may not be known for many babies, and particularly for babies delivered at home and not weighed at birth, the mother’s estimate of the baby’s size at birth was also obtained.This study tried to include the most important and expected determinants of child size at birth from various literatures. The explanatory variables at individual and household levels included place of residence, mothers’ education level, wealth index of family, family size, frequency of antenatal visit during pregnancy, sex of child, birth order, previous birth interval, vaccination during pregnancy, abortion status of mothers, age at first birth, frequency of listening to radio, Malaria history of mothers, source of drinking water, and use of contraceptive.Ordinal logistic regression was used to analyze the data in this study because the size of child at birth is ordered. Specifically, proportional odds model (POM) was employed .Ethics approval and consent to participate. The ethical clearance was obtained from Wolkite University, Research Ethics Review Committee. The survey was commenced after obtaining permission from Gurage Zonal Health Department and District Council. Informed verbal consent was obtained from each study subject. Each respondent was informed about the objective of the study and assurance of confidentiality.From the sampled children, 30.1%, 44.4% and 25.5% are small in size, medium in size and large in size, respectively. The distribution of small size of baby at birth or low birth weight by key characteristics of the child, mother, and household among children whose mothers were interviewed is shown in The result of univariable ordinal logistic regression analysis indicated that the variables sex (p=0.312), abortion history (p=0.136), economic source of family, and frequency of watching TV (p=0.445), were not significant. Hence, the final multivariable model excludes insignificant variables from the analysis. Accordingly, the deviance-based chi-square test provided a chi-square value of 360.582 (p=0.000) for the final model which would imply that the model is good fit as compared to the intercept only model. Furthermore, the chi-square value is not significant .Therefore, there is not enough evidence to reject the null hypothesis for the final model. Thus, the proportional odds assumption appears to match the final model.When the proportional odds model is used in the analysis of ordinal data, the coefficients of the explanatory variables in the model are interpreted as the logarithm of the ratio of the odds of the response variable. This means that estimates of this odds ratio, and corresponding confidence intervals can be easily found from the fitted model. The discussion and interpretation of the parameters corresponding to the variables which are found significant in the final model as shown in βj)=exp(−.13)=0.878) indicates that urban children are 0.878 times less likely to be small child at birth as compared to rural children holding all other variables constant. The odds ratio could be as low as 0.9166 and as high as 1.4181 with 95% confidence. The study is consistent with Mwabu (2006) that birth weights are lower in rural than in urban areas (The result indicates that place of residence is a significant covariate. The estimated odds ratio (exp(From Mothers’ education level is a significant predictor of size of child at birth. The estimated odds ratio OR=1.29) implies that children from uneducated mothers’ are 1.29 times more likely to be small size at birth as compared to child from mothers’ with education level in secondary and above (Reference category) keeping all other covariates constant. This figure can go up 1.568 and down to 0.996 with 95% confidence. This result is consistent with Tuntiseranee et al. (1999) that maternal education is a significant factor increasing the risk to deliver LBW baby even after adjustment for possible confounding factors such as maternal age, parity, obstetrical anamnesis and prenatal care level . The stu implies In our study, antenatal visit care  was found a statistically significant variable associated with size of child at birth. The odds ratio for pregnant women who get antenatal visit 2–3 times is OR=0.77 which implies that children from mothers who get antenatal visit care 2–3 times during pregnancy period are 0.77 times less likely to be small size at birth as compared to child from mothers who do not get any antenatal visit care keeping all other covariates constant. Mothers who get complete antenatal visit care can give normal child. The study is consistent with Alexan-dar and korenbrot 1995) and Hollandar (2017) that mothers received 4 or more antenatal care during pregnancy gave birth to higher birth weight babies in comparison to mothers who received less than 4 antenatal care visits , 12. The95 and HoThe model results portrayed that source of drinking water is a significant variable. Children from households with non-improved source of drinking water are not normal in size during birth. Children from mothers who drink river water are 1.65 times more likely to be small size at birth as compared to children from mothers who drink piped water (p<0.027 and OR=1.65). And children from mothers who drink from hole water are 2.32 times more likely to be small size at birth as compared to children from mothers who drink piped water (p<0.000 and OR=2.32) when other factors are constant. The study agrees with Dharma lingam et al. (2010) who conducted a study in India using national survey data investigated the association between the mother’s nutritional status and birth weight of her newborn. They found that safe drinking water was an important determinant for size of children at birth. Pure sanitation conditions are linked with size of children at birth, even indirectly, since such conditions are associated with greater number of infectious and parasitic diseases, which in turn contributed towards diminishing the health status of baby .The model result also showed that wealth index (Income of the household) is a significant predictor for size of children at birth. The estimated odds ratio for high wealth index and medium wealth index  indicate that children from rich families are 0.60 times less likely to be small size at birth and children from medium income families are 0.733 times less likely to be small/medium size at birth as compared to children from poor families keeping other variables constant. The result of this study agrees with Ipadeola et al. (2013) that wealth index is positively associated with child’s weight at birth .The health condition of pregnant mother has statistically significant effect on the size of children at birth. Pregnant mothers who are affected by malaria bring forth small child. Children born from malaria affected mothers are 1.41 times more likely to be small size at birth than children born from healthy mothers. The result is consistent with Siza 2008) which stats that malaria (14.8%)  indicates that children born from mothers whose age at birth is 21 years and above are 0.37 times less likely to be small size at birth as compared to children from mother age bellow 16 years keeping other variables constant. The odds ratio could be as low as 0.294 and as high as 0.473 with 95% confidence. The study is consistent with EDHS (2011) that low birth weight is more common among children of the youngest mothers, age less than 20 (13 percent) and older mothers, age 35–49 (17 percent). Children born to very young mothers (<20 years) were most likely to be reported as small . TeenageAccording to the study, place of residence, mother’s level of education, birth order of the child, source of drinking water, abortion history of mother, frequency of antenatal care visit, vaccination during pregnancy, frequency of listening to radio, malaria history of mothers, age of mothers at birth and previous birth interval of child are all important in reducing the incidence of small size at birth. Children from rural mothers, uneducated families, mothers who did not get more antenatal care visits, poor families, mothers who drink nonimproved water, mothers who are affected by malaria during pregnancy, teenager mothers are small size at birth or they are not normal at birth. Size of children at birth and mothers’ pregnancy problem are directly related in this study.


Low birth weight is a significant index for survival, intrauterine growth, and mortality in infants. Thus, this study is aimed at determining the prevalence of low birth weight in Iranian infants through a systematic review and meta-analysis. I2 index, and data analysis was done using Comprehensive Meta-Analysis software.  This study was performed by meta-analysis from January 2000 to December 2019. The studies relevant to the topic have been obtained through search in databases of Scopus, ScienceDirect, SID, Magiran, Barakat Knowledge Network System, Medline (PubMed), and Google Scholar. Heterogeneity of the studies has been assessed by the P < 0.05).  By investigating 14 articles and 93924 infants, the total prevalence of low birth weight in infants in Iran was achieved at 8.5% (95% CI: 7.3-9.9%) according to the meta-analysis; the most prevalence of low birth weight was in infants in Hamedan at 19.1% (95% CI: 21.2-17.2%) in 2007, and the lowest prevalence of low birth weight was in infants in Tonekabon at 4.2% (95% CI: 3.4-5.2%) in 2005, and also, by increasing the sample size, the prevalence of low birth weight increases, by which the difference is statistically significant ( Due to the high prevalence of low birth weight in infants in Iran, health policy-makers must take effective attempts in order to reduce it in infants. Intrauterine growth restriction (IUGR) refers to a condition in which an unborn baby is smaller than it should be because it is not growing generally inside the womb. Delayed growth puts the baby at risk of specific health problems during pregnancy and delivery and after birth. They include low birth weight; difficulty handling the stresses of vaginal delivery; decreased oxygen levels; hypoglycemia; low resistance to infection; low Apgar scores; meconium aspiration, which can lead to breathing problems; trouble maintaining body temperature; and abnormally high red blood cell count –5.A common cause is a problem with the placenta. The placenta is the tissue that joins the mother and fetus, carrying oxygen and nutrients to the baby and permitting the release of waste products from the baby. The condition can also occur as the result of specific health problems in the mother, such as advanced diabetes; high blood pressure or heart disease; infections such as rubella, cytomegalovirus, toxoplasmosis, and syphilis; kidney disease or lung disease; malnutrition or anemia; sickle cell anemia; smoking; drinking alcohol; or abusing drugs –6.Low birth weight is the most important factor determining survival and an essential marker of intrauterine growth. It is also one of the most straightforward and most general health indices in each society and is a crucial index in infant mortality –3. ApproIn addition to spiritual and mental problems, the high costs of caring and treatments of LBW infants at birth are borne by their families, who often belonged to vulnerable society segments ; out of LBW infants are more susceptible to risks such as cerebral palsy, mental retardation, neural defects, pulmonary diseases, sudden death syndrome, and complications caused by hospitalization at intensive care units in comparison to healthy weight infants –12. In tSince low birth weight increases the rate of mortality, disability, and many diseases in childhood and adulthood, and since performing interventional studies to reduce the prevalence of low birth weight in infants require accurate and consistent information to prevent problems and complications of LBW, the question of this research is on the rate of the total prevalence of LBW in infants in Iran. This study is aimed at determining the incidence of LBW in infants in Iran through a systematic review and meta-analysis.This was a systematic review and meta-analysis done by extraction of results of conducted studies in the context of the prevalence of LBW in infants in Iran and consisted of articles published in domestic and foreign journals and literature review in databases of ScienceDirect, Scopus, SID, Magiran, Medline (PubMed), Barakat Knowledge Network System, and Google Scholar from Jan 2000 to Dec 2019. The literature review has been performed by using keywords of low-birth weight, infants, and Iran and also probable combinations in English and Persian language. Therefore, literature review in Persian-language databases has been done by using mentioned Persian-language keywords, and for literature review in English-language databases, the English equivalent words of low birth weight, birth, neonates, and Iran were used, and also, for searching in Google Scholar, every two words in Persian and English language have been used, and logical operators of AND and OR in combination have been applied in order to have complete access to all the articles. Therefore, the operator of OR has been applied to investigate common names in the cases such as (Low birth weight OR Low-Birth-Weight Infant OR Infant LBW) and (neonates OR Infant OR Newborn), and also, the operator of AND has been applied between keywords of (Low birth weight AND neonates) through matching the words in the MeSH browser.Firstly, all the articles were gathered by using selected keywords, and after finishing the literature review, a list consisting of articles' abstracts was prepared.After hiding the characteristics of articles, including the journal name and authors, the full texts have been provided to reviewers. Each article was studied by two independent reviewers. In case of rejection, the reason for refusal has been mentioned. In case of a lack of consensus between the two reviewers, the article was reviewed by a third reviewer, and the third reviewer's opinion was considered.Articles in English and Persian language with cross-sectional design in the context of prevalence and frequency of LBW in Iranian infants were eligible to be enrolled in the study, and other review studies, case-control studies, cohort, and interventional studies were excluded from the article list. In this study, a review of gray literature, evidence, and documents not printed and published due to any reason was aimed at searching keywords in Google search and reviewing topic-relevant websites.Then, investigated studies were evaluated based on the 4-stage process of PRISMA 2009 consisting of identification of articles, screening, assessing the criteria for accepting the articles, and finally assessing the included articles in the meta-analysis.In order to assess the studies, the STROBE checklist was used. This checklist consisted of 22 sections, by which 18 items of it are general and are used for all observational studies including cohort, case-control, and cross-sectional studies, and 4 items of it are specified, which is related to the type of study, and include various aspects of methodology such as the study's objectives, appropriate determination of sample size, type of study, sampling method, study population, data gathering method, description of variables, the way samples were evaluated, data gathering tools, objectives assessed in the study, applied statistical test, and report of the results. Accordingly, the maximum score for qualitative assessment was considered 32, and articles with scores of lesser than 14 were considered poor based on assessment and evaluation and were excluded from the study.I2 test. Generally, heterogeneity has classified into three classes: heterogeneity less than 25% (low heterogeneity), between 25 and 75% (moderate heterogeneity), and more than 75% (high heterogeneity). Data were analyzed by Comprehensive Meta-Analysis software . The probability of publication bias in the results has been evaluated by a Funnel plot and by using the Egger test at the significance level of 0.05, and also, to assess the impacts of active potential factors in the heterogeneity of studies, a metaregression test has been used in two elements of sample size and the year the study was performed in.The prevalence of LBW in infants for each study conducted in Iran was achieved; heterogeneity of the studies has been investigated by the The results are based on conducted researches on the prevalence of LBW in Iranian infants, consisting of published articles in domestic and foreign journals. Literature review was done to 95 articles in databases of Magiran, SID, and Barakat Knowledge Network System, 185 articles in Medline (PubMed), 321 articles in ScienceDirect, 72 articles in Scopus, and 461 articles in Google Scholar, and 1134 articles were obtained based on the 4-stage process of PRISMA 2009 . Then, 1I2 test, and based on this test, the value of 96% was achieved and is a representative of high heterogeneity in entered studies; therefore, the random effects model was used to combine the studies' results; obtained results from evaluation of publication bias in the studies were assessed by the Egger test (P = 0.537).Heterogeneity in articles was assessed by the ger test  by whichThe total number of samples entered in the study was 93924 infants, and the overall prevalence of LBW in Iranian infants based on meta-analysis has been achieved at 8.5% (95% CI: 7.3-9.9%). The highest incidence of LBW was in infants in Hamadan at 19.1% (95% CI: 17.2-21.2%)  in 2007,P < 0.05). P = 0.820).To investigate the impacts of active potential factors in the heterogeneity of prevalence of LBW in infants in Iran, a meta-regression test has been used on two factors of sample size and year of investigation Figures  and 5. BBased on the results obtained from this study and investigations on 93924 infants, the total prevalence of LBW in infants in Iran according to the meta-analysis was achieved at 8.5%. The World Health Organization (WHO) reported incidence of LBW in sub-Saharan Africa at 15%, in the Middle East and northern Africa at 11%, in East Asian countries at 10%, in southern Asia at 33%, in Latin America at 9%, in developed countries at 6%, and developing countries and the whole world at 18% and 17%, respectively –30.Other studies show that the prevalence of LBW inborn infants was 15% in Kenya, 8% in Ethiopia, 13.6% in Saudi Arabia, and 6% in the United States .The studies showed that most of the LBW infants are with intrauterine growth retardation, which can be due to nutritional deficiency, low maternal age, and lack of pregnancy care , 33, andThese studies report that factors such as trauma to the mother's abdomen leading to preterm labor, membrane rupture, placental abruption or detachment, and uterine detachment and also factors such as nicotine and tobacco and alcohol use, low economic status of the family, low maternal weight, anemia, inappropriate diet, sexually transmitted diseases, and mental diseases can be of most important factors leading to LBW in infants –35.The main symptom of IUGR is a small size for gestational age baby. Specifically, the baby's estimated weight is below the 10th percentile or less than that of 90% of babies of the same gestational age. Depending on the cause of IUGR, the baby may be small all over or look malnourished. They may be weak and pale and have loose, dry skin. The umbilical cord is often thin and dull instead of thick and shiny –35.LBW's importance is due to the birth of girls with LBW, by which they are going to be mothers with a higher probability of giving birth to infants with LBW. In other words, delivery of LBW infants has transmitted intergeneration –39.This condition in various conducted studies in low economic status or areas showed a higher prevalence of LBW so that the incidence of LBW was 39.1% in India's slum area, 36.8% in impoverished regions in Bangladesh, and 20.9% in rural areas of most Asian countries .Due to the relatively high prevalence of LBW in Iran, it is necessary to increase the maternal health rate through care processes before and after labor, appropriate nutrition, and prevention of iron deficiency anemia and also through an increase in awareness of parents and mothers by mass media and developing care programs for mothers during pregnancy, and obligation on referral to health centers for mothers and implementing pregnancy care provide the basis for a decline in LBW in infants in-country, and also by equipping and promoting quality of intensive care units in the country, the fundamental basis for hospitalization and treatment of premature and LBW infants would be provided.The most important limitations of the current study are the lack of access to the full texts of articles and the low quality of some articles.Given the high prevalence of LBW in infants in Iran, health policy-makers must produce effective policies to take sufficient management attempts, including periodical care for pregnant mothers and infants.


Fathers may affect expectant mothers’ daily living situations, which in turn might influence pregnancy outcomes. We investigated the association between paternal violent criminality and risk of preterm birth (≤36 weeks).We conducted a register-based study with all live singleton births in the Swedish Medical Birth Register from 1992 to 2012, linked with records of paternal violent crime convictions from the National Crime Register from 1973 to 2012.Paternal violent criminality was associated with increased risk of preterm birth and lower gestational age. The association was especially pronounced among infants of reoffenders: men convicted of three or more violent crimes . Maternal half sibling-comparisons, an analytic approach controlling for maternal factors stable across pregnancies, also suggested increased risk of preterm birth and lower gestational age when exposed to a violently reoffending father compared to a father without violent criminal convictions .Persistent paternal violent criminality was associated with increased risk of preterm birth, even after controlling for maternal characteristics that did not change between pregnancies. Preterm birth is the leading cause of infant mortality worldwide. Although there are several known risk factors for preterm birth, the aetiology for most preterm births remains elusive . MaternaThe expectant father is an integral part of the psychosocial and physical environment of the pregnant woman, and may thereby influence the pregnancy . PartnerViolence is a severe global public health problem . Having By cross-linking national Swedish registers, we explored whether a father’s conviction status increases the risk of preterm birth and shortens gestational age. To test whether maternal characteristics partly explained possible associations, we also compared maternal half-siblings whose fathers differed by conviction status.Data from longitudinal national medical and social registers in Sweden were linked using the person-unique national identification numbers, assigned to each Swedish resident. After data linkage, personal identification numbers were replaced with non-traceable distinctive identifiers to secure anonymity.n = 2,039,050). Fathers were identified by linkage to the Multigeneration Register, which record biological and adoptive parents of all Swedish residents. Subjects with unidentified or foreign-born parents were excluded from the study population , due to different durations of living in Sweden, related to the likelihood of having criminal record. After excluding births with non-minor malformations  and those missing gestational age data (n = 996), the study population consisted of 1,478,703 singleton births. Additional sampling for maternal half-sibling comparisons is described in Fig. All live singleton births from January 1, 1992 to December 31, 2012 and their mothers were identified from the Swedish Medical Birth Register (SMBR) . The ninth version (ICD-9) was used up until 1996, and the tenth version (ICD-10) was used thereafter.Information on paternal criminal conviction status was derived from the Crime Register and categorized as having no criminal conviction, having a violent criminal conviction, and having another non-violent criminal conviction  and moderately preterm (32–36 weeks) birth. We defined a spontaneous preterm birth as having a preterm birth with spontaneous onset of delivery or a maternal diagnosis of preterm rupture of the membranes . Medically indicated preterm birth was defined as having an induced onset of delivery, including a caesarean section.We collected information on maternal age, parity, height, smoking status, body weight, country of birth, family situation at first antenatal care visit, and year of delivery from the SMBR. Maternal criminal conviction status was also obtained from the Crime Register and categorized as no criminal conviction, a violent criminal conviction and a non-violent criminal conviction, respectively. Data on dispensable household income per person the calendar year before childbirth, paternal age, maternal and paternal education until the year of childbirth, were collected from the Swedish Income and Enumeration Survey, held by Statistics Sweden. We did not collect data on neighbourhood context, as previous research suggests that neighbourhood context does not directly affect criminality or preterm birth in the Swedish context , 16.In the Swedish judicial system, even severe mental illness does not exclude criminal sentencing. Thus, some of the crimes were conducted under influence of psychiatric disorder. Paternal and maternal psychiatric diagnoses , alcohol use , and drug use  diagnoses were collected from the National Patient Register covering all inpatient admissions (recorded from 1973 onwards) and non-primary outpatient care (information available from 2001 onwards).In population analysis, we first compared births exposed to paternal non-violent and violent criminal convictions to births fathered by men without criminal convictions. Secondly, we compared births fathered by those convicted of 1–2 and 3 or more violent offences, respectively, to those without criminal convictions. In these two analyses, we used logistic regression models with cluster robust estimation of standard errors, adjusting for calendar year of birth, parity, maternal and paternal age (in quadratic forms), maternal and paternal education. We also performed linear regression models of the same variables to estimate the mean differences in gestational age (βs) between the groups. Thirdly, we compared risks of spontaneous or medically indicated preterm birth and risks of very or moderately preterm birth using multinomial logistic regression models.Sibling comparisons between the exposed infant and his/her unexposed maternal half-sibling allowed controlling for stable maternal confounders. Fixed effect linear  and logistic regression  modelling was performed to estimate βs and ORs of preterm birth of exposed infant in comparison to his/her unexposed maternal half-sibling, whose father had no criminal conviction status. Cluster robust estimation of standard errors was used in fixed effect models to account for independence between maternal half-siblings, with Huber/White/sandwich estimator and bootstrap estimator being used in fixed linear and logistic regression, respectively. In addition to variables adjusted in population analysis, further adjustment was made for pregnancy-specific covariates of quintiles of household income per person, maternal body mass index (BMI) and smoking status in early pregnancy.Stratified analysis was conducted to explore potential modification of cohabitation situation on paternal violent criminality. We also tested for multiplicative interactions between paternal violent criminal conviction status  and family situation.Data management was performed using SAS 9.4 . All statistical analyses were performed using STATA.Table Table ≥3–0.79 [− 0.96 to − 0.62] vs. β 1–2 -0.29 [− 0.40 to − 0.18], respectively).Table Table ≥3 1.27 [0.91 to 1.78], OR 1–2 0.93 [0.71 to 1.21]).The findings for reoffending fathers and shortened gestational age remained (β − 0.91 [− 1.51 to − 0.31]) when comparing infants of reoffending fathers to his/her maternal half-sibling(s) fathered by men with no criminal conviction  and family situation on the odds ratio scale showed In this national cohort study of 1.5 million births, having a father convicted of violent crime, and especially a father who was repeatedly convicted, was associated with increased risk of preterm birth or shortened gestational age. The association was particularly pronounced for spontaneous preterm birth before 32 gestational weeks. The association between repeated paternal violent crime and shorter gestational age was confirmed when controlling for all invariant maternal characteristics shared between half-siblings.Partner conviction status, used as a novel social indicator, may affect preterm birth risk in several ways. Explanations of the association include, but is not limited to, the mother herself being a victim of physical intimate partner violence –14. HaviPaternal psychiatric illness cannot easily be disentangled from violent crime , 19. In Previous studies showed that conviction status may restrict the social and economic potential for both the offender himself and the remaining family , 22. PreComparing pregnancies of the same mother allowed us to control for maternal invariant characteristics such as health risk behaviour and psychiatric morbidity that might correlate with the father’s conviction status. Analyses of exposure-discordant maternal half-siblings were hampered by statistical power, but did not essentially change the associations between paternal violent criminality and preterm birth. This further underscores the possible influence of a father with repeated violent convictions on the physical and psychosocial environment of the mother and the foetal environment.The national register design of this study minimized selection and recall bias, which are major problems in previous studies of violence and preterm birth. The large sample size provided opportunities for analysing preterm birth subtypes, which might be more aetiologically informative. We also performed sibling comparisons which controlled for fixed maternal factors (i.e. factors not changing between pregnancies).Although we used sibling analysis to further control for unmeasured maternal factors shared between siblings, confounders which vary between siblings may lead to more biased results . We furtPaternal violent crime conviction status is not only a strong proxy for paternal violent behaviour. All men who commit violent crimes are not reported, apprehended, prosecuted or convicted, and many of the crimes included in our indicator could be related to specific situations outside the family sphere. Thus, our findings are not generalizable to all intimate partner violence, the effect of which requires more precise information on partner relationship.This large national register study suggested that criminal behaviour or violence, even when not strictly measured as intimate partner violence, is a risk factor for preterm birth. The association between persistent paternal violent crime and preterm birth, especially very preterm birth, suggests that paternal violent and antisocial behaviour might affect the next generation even before birth. Future estimation of the public health repercussions of violence need to take preterm birth and its long-term health consequences into account.It is important that health care professionals are aware of the possible link between paternal violence, maternal stress and preterm birth. Antenatal care consists of 10–12 visits to a midwife and is offered free of charge with 99% coverage in Sweden . ScreeniPaternal violent criminal conviction status is associated with increased risk of preterm birth. Half-siblings without a violent father have lower preterm birth risk than their half-sibling(s) with a convicted father. The association between paternal conviction status and risk of preterm birth deserves more attention from antenatal care providers and public health workers. Risk factors of expectant fathers requires further examination, especially regarding violent behaviour, poor mental health, and adverse social conditions.Additional file 1: Table S1. Definition of violent crime according to the Swedish Penal Code (Ds 1999:36). Table S2. Conviction status of the father and odds ratios (ORs) of spontaneous/medically indicated very (≤31 weeks) preterm birth and moderately (32–36 weeks) preterm birth . Table S3. Modification of family situation on paternal violent criminality status .


Observational studies from large datasets are becoming more common in neonatology. In this review, we highlight the importance of the denominator in study design and interpretation including examples of bias from source data, weight-based categories, age-related bias, and diagnosis-based denominators. Observational studies from “big data” sources are important for generating hypotheses and for doing comparative effectiveness studies when randomized controlled trials are not feasible. In neonatology, we are fortunate to have several high-quality datasets, including from National Institute of Child Health and Development , the CanClinically relevant insights have been reported from all of these sources, and these studies are becoming more common every year. Therefore, we must be intentional in the design and interpretation of findings from these sources. Critical review of these studies tends to focus primarily on the observational numerator—such as how the exposure or outcome is defined or how to account for confounding factors. We feel that the denominator deserves similar scrutiny. Our goal with this review is to demonstrate how the denominator can be a hidden source of bias in retrospective observational research. A better understanding of these issues can help both clinicians and researchers in applying appropriate context to this type of data. Ascertainment bias refers to bias that results from the sampling method. All of the neonatal databases have specific enrollment criteria for an infant to be included in the dataset. Notably, these criteria are unique to each dataset, and these differences can have important ramifications on study design. In 2015, Rysavy et al. [This issue extends to the other end of the gestational age spectrum as well. The criteria for inclusion of larger and more mature infants in many of these datasets select for infants who are also ill enough to require critical or intensive care. This is a minority of term infants , and so,One method to account for this is to include an unrelated but similar diagnosis that can act as an internal control. When we reviewed the changing prevalence of gastroschisis, we used the prevalence of patients with omphalocele to act as an internal control. We assumed two similar gastrointestinal anomalies would vary in a similar way if referral or care parents explained the changes. We found that the prevalence of gastroschisis changed in significant ways but the prevalence of omphalocele was much more consistent .Gestational age is not the only cause of bias in source data. Cohorts derived from Children’s Hospital NICUs have a referral bias in that the infants admitted to their sites are more likely to have complex diagnoses or require specialized care . The effStudies of infants with a poor prognosis  can have ascertainment bias from several sources: prenatal diagnosis may result in pregnancy termination, and infants who are receiving palliative care may receive care in the NICU. These factors complicate comparisons between datasets and can limit overall study generalizability, so it is essential to understand the context of source data. In neonatology, it is common to define infant categories based on birth weight. Study cohorts will select for very low birth weight (VLBWs) or extremely low birth weight infants (ELBWs). Although these definitions are based on objective measures that are accurate, reliable, and easily reproducible, we find this classification a problematic source of bias for several reasons. First, VLBW infants represent an extremely heterogeneous group . The morSecond, the gestational age at birth VLBW infants is not normally distributed. Because of this, more mature and larger infants are over represented in VLBW cohorts. For example, in a VLBW cohort from the Pediatrix CDW, almost half of infants are greater than 29 weeks and the ratio of 28 week infants to 23 infants is 3:1 . One metA third concern with weight-based classification for premature infants is bias introduced by small-for-gestational-age infants. Older studies suggested that growth restriction, presumably caused by some process that accelerates fetal maturity, may actually improve some morbidities such as respiratory distress syndrome . HoweverFor these reasons, we prefer to use gestational-age-based categories , despitComplications can also arise in any denominator that is age-dependent due to skews in distribution of NICU stay and/or timing of death. The characteristics of the study cohort included in an age-based study cohort changes dramatically with duration of NICU stay. For example, the incidence of early onset sepsis is dependent on the denominator. Most blood cultures are done in the first 3 days after birth a, and thMortality poses a similar problem. In premature infants, mortality rates are the highest in the first few days after admission and every day that these babies survive, they are more likely to go home alive . As a reSometimes, in order to further explore disease incidence of progression, investigators will define their cohort as infant with a specific diagnosis. However, bias can be introduced by changes in the evaluation or classification of the disease of interest. This leads to a denominator that changes over time or among studied groups.We recently described changes in the frequency of patent ductus arteriosus (PDA) diagnosis in premature infants . In thatAnother example comes from disease incidence of intraventricular hemorrhage (IVH) in preterm infants. There is substantial variation in diagnostic cranial ultrasound (CUS) in higher gestational age groups  29 week. As these two cases illustrate, changes in disease incidence or measurement must be considered potential sources of bias when the denominator is based on a diagnosis. Big data research is important. The large sample sizes are almost always able to discern statistically significant relationships. Randomized trials are not available or feasible for many pressing clinical questions in our field. These examples come from the Pediatrix Clinical Data Warehouse . The sou


Bronchogenic cysts are speculated to arise from abnormal budding of the foregut tissue during embryogenesis. Around 90% of mediastinal bronchogenic cysts are asymptomatic, and a small percentage of them present with chest pain and dyspnea. Pericardial effusion is one of the manifestations described; however, pericarditis has not been widely reported. We describe a case of a bronchogenic cyst in a 19-year-old female with an initial presentation of pericarditis due to mechanical impingement. There was an associated trace to small pericardial effusion. The bronchogenic cyst was planned to be excised; however, it could only be partially excised due to its adherence to the left atrium. Bronchogenic cysts are thin-walled, fluid- or mucus-filled cysts that result from anomalous development of the ventral foregut. They are most often found in the mediastinum or lung , with a A 19-year-old Caucasian female with no medical history presented with chest pain, substernal in location that was radiating to her back. She described the pain as worsening when lying flat and with deep inspiration, with improvement on sitting upright. It was associated with shortness of breath, nausea, and vomiting. Her social history was significant for tobacco use of half a pack for two years and occasional marijuana use.At presentation, the chest X-ray showed abnormal bulging of the right mediastinal contour, suggestive of a mediastinal mass Figures , 2. The The patient was immediately started on a high dose of ibuprofen at 600 mg three times a day, colchicine 0.6 mg twice a day, and pantoprazole sodium 40 mg twice a day before meals for clinical suspicion of pericarditis. This intervention improved her symptoms within two days. Cardiothoracic surgery service was consulted, and a computed tomography (CT) chest with intravenous contrast was performed to better delineate the bronchogenic cyst morphology. It showed a 7.5 cm x 6.8 cm x 6.3 cm fluid-filled thin-walled subcarinal mass consistent with a bronchogenic cyst Figures . SubsequUpon follow up one month later, a repeat echocardiogram was performed, which revealed a trace to a small amount of pericardial effusion without evidence of tamponade, and an evidence of thickening near the left atrial wall due to known remnants of the bronchogenic cyst Figure .Bronchogenic cysts commonly arise in the mediastinum due to abnormal budding of the ventral diverticulum of the foregut between the 26th and 40th days of intrauterine life . In the Clinical manifestation may range from being asymptomatic to compression, infection, pneumothorax, hemorrhage, or rupture . If sympBronchogenic cysts are filled with fluid  containiDifferential diagnoses of a bronchogenic cyst include gastrointestinal duplication cyst, cystic pulmonary sequestration, cystic teratoma, mesothelium-lined cyst, posttraumatic cyst, and hydatid cyst .For symptomatic patients, treatment is usually by complete resection which prevents complications, whereas in asymptomatic patients, there is some controversy regarding resection. Studies show that approximately 45% of asymptomatic cysts at diagnosis, if followed over time, develop symptoms and have a 0.7% risk of malignant transformation . Based oThe type of surgical approach is decided on a case-to-case basis. Open thoracotomy is preferred over VATS in the setting of major adhesions to vital structures. Even when performing a thoracotomy, complete excision maybe not feasible at times in order to avoid structural damage to the involved organs. In these situations, subtotal resection is performed along with cauterization .The majority of the bronchogenic cysts are asymptomatic and discovered incidentally on routine imaging studies. Symptoms arise when the cyst gets infected or if there is any tracheobronchial or cardiac compression. As there is high variability in their location, the presentation of the symptomatic bronchogenic cysts is highly inconsistent. Various imaging modalities are available to obtain a pre-operative diagnosis, including chest X-ray, chest CT scan, and cardiac MRI. Surgical excision is both diagnostic and potentially curative and is recommended even in asymptomatic cases to avoid the development of future complications including malignant transformation.


Bronchopulmonary dysplasia (BPD) is the most common complication of prematurity and significantly contributes to mortality and morbidity with few predictive biomarkers. Given that nitrites have been implicated in pathways associated with lung disease, we hypothesized that nitrite levels would be altered in the airways of premature infants diagnosed with BPD.This was a prospective cohort study of extremely low birth infants (< 28 weeks’ gestation) at the University of Alabama at Birmingham. Nitrite levels from tracheal aspirates (TAs) were compared between intubated and ventilated infants with BPD and gestation matched full term (FT) controls. TA derived nitrite levels from day one after birth were also compared between preterm infants who did and did not develop BPD.p < 0.05). There was a trend for increased nitrite levels on postnatal day one in infants that developed BPD compared to infants that did not develop BPD (p = 0.05).Infants with BPD were found to have significantly elevated nitrite levels in their tracheal aspirates compared to gestation matched FT controls (In conclusion, nitrite levels are significantly increased in airways of infants with BPD. Data from a larger cohort are needed to further support the utility of nitrite for BPD prediction.Not applicable. Bronchopulmonary dysplasia (BPD) is a common morbidity of preterm infants for which few biomarkers exist. Development of BPD results from a multitude of factors including inflammation, hyperoxia, disrupted pulmonary angiogenesis, and microbial dysbiosis. In addition to a paucity of biomarkers that predict disease, few therapies prevent disease development. Nitric oxide (NO), as well as precursors to NO production, have been evaluated as potential markers of disease and therapies for prevention.Nitric oxide a signaling molecule produced throughout the airway, has many physiologic roles in the lung including vasodilatation and anti-inflammation. Moreover, in addition to other angiogenic growth factors, NO influences both pre- and postnatal pathways critical to lung development including airway branching morphogenesis and alveolarization , 2. NitrBronchopulmonary dysplasia in preterm infants is associated with pulmonary vascular remodeling and pulmonary hypertension, which in turn contributes to morbidity and mortality. Given the physiologic and developmental roles of NO which may ameliorate the contributory factors of inflammation and pulmonary vascular maldevelopment to BPD pathogenesis, NO has been extensively studied as a potential therapy for BPD prevention. In animal models inhaled NO improved gas exchange and angiogenesis , howeverWe conducted a prospective cohort study at the University of Alabama Regional Neonatal Intensive Care Unit between 2015 and 2017. TAs were collected from three different patient populations: inborn or outborn extremely preterm infants  at birth or within 6 h of birth before surfactant administration, infants with BPD that were 36 weeks’ PMA and remained intubated, and gestational age matched full term controls. Samples taken at birth were compared between infants that did or did not develop BPD based on clinical outcome of severe BPD at 36 weeks’ PMA. Samples from infants 36 weeks’ PMA with BPD were compared to samples from gestational age matched full term infants that served as best available controls and were collected within 6 h after birth in infants intubated secondary to non-respiratory clinical indication . Institutional Review Board granted waiver of consent given that TA samples were collected from routine care. Demographic and clinical characteristics were collected from enrolled patients using the electronic medical record. The physiologic definition of BPD [TA samples were collected as per unit protocol, as described in our previous publications . Prior tp < 0.05, Fig. p = 0.05, Fig. Samples were taken at birth from 20 extremely preterm infants, at 36 weeks’ PMA in five infants with BPD, and at birth in five full term gestational age matched controls. In samples taken at birth, infants that developed BPD had a lower gestational age (23.7 vs 26.3 weeks) and weight (515 g vs 780 g). Full term infants were 37 weeks’ gestation at birth with a median birth weight of 3330 g. Additional characteristics for these infants are reported in Table Parallel NO production has emerged as a pathway critical to cardiopulmonary homeostasis through nitrite induced pulmonary vasodilation under hypoxic stress, protection from ischemia reperfusion damage, and regulation of vascular function . StudiesIn the present study, infants with BPD had higher airway nitrite when compared to gestational-age matched controls. This suggests that NO synthesis and/or potentially NO that is biologically available from nitrite reduction is increased in the airways of these infants, which could result from airway exposure to hyperoxia and NO production by airway epithelia or leukocytes. Peroxynitrite, known to cause lung tissue injury, forms from superoxide radicals and NO and may subsequently decompose and increase nitrite in the preterm airway. Previous observational studies have reported elevated 3-nitrotyrosine levels and a trend for elevated nitrite levels in infants that developed BPD suggesting that markers of NO metabolism and peroxynitrite formation may serve as predictors for BPD in preterm infants , 14. In n = 7) had improvements in oxygenation and a reduction in the oxygen index [Nitrite supplementation may also have therapeutic benefit. In wild type mice exposed to prolonged hypoxemia, both nitrate and nitrite supplementation prevented pulmonary vascular remodeling and improved pulmonary hypertension . Ethyl nen index . If incrDue to the small sample size of the current study, it remains unclear whether airway nitrite levels at birth could serve as a predictive biomarker for BPD. Comparing TA nitrite at additional postnatal time points in infants that do and do not develop BPD may also warrant investigation. Given prior studies suggesting NO bioavailability may both predict and treat lung disease, further study of a larger cohort is needed.