Previous studies showed that intrauterine growth restrictions, resulting in smaller body size at birth, are associated with altered development and the risk of age-related diseases in adult life. Thus, prenatal development may predict aging trajectories in humans. The study aimed to verify if body size at birth is related to biological age in adult men. The study sample consisted of 159 healthy, non-smoking men with a mean age of 35.24 (SD 3.44) years. Birth weight and length were taken from medical records. The ponderal index at birth was calculated. Biological age was evaluated based on serum levels of s-Klotho, hsCRP, DHEA/S, and oxidative stress markers. Pregnancy age at birth, lifestyle, weight, cortisol, and testosterone levels were controlled. The results showed no relationship between birth size and s-Klotho, DHEA/S level, inflammation, or oxidative stress. Also, men born as small-for-gestational-age (N = 49) and men born as appropriate-for-gestational-age (N = 110) did not differ in terms of biological age markers levels. The results were similar when controlled for pregnancy week at birth, chronological age, BMI, testosterone, or cortisol level. The results suggest that there is no relationship between intrauterine growth and biomarkers of aging in men aged 30–45 years from the affluent population. There are also studies showing the relationship between lowered birth weight and altered gonadal development5, earlier age at menarche6, and higher risk of reproductive disorders7. Furthermore, birth weight is positively associated with postnatal growth and adult height8, and negatively with adult obesity risk9. The observed effects extend across the normal range of birth weight, have been described in populations of different ages, sex, and ethnic origin, and occur independently of the duration of gestation or adult weight10.A large body of evidence links impaired fetal growth and smaller body size at birth with altered development and worsened adult health. The majority of the research focuses on the negative relationship between birth size and the risk of cardio-metabolic diseases and their physiological forerunners, such as hypertension, dyslipidemia, and impaired glycemia11. The mechanism underlying these adaptations may result from the altered functioning of the key endocrine axes that condition life history (LH) trajectories, such as the hypothalamic–pituitary–adrenal axis, hypothalamic–pituitary–gonadal axis, and growth hormone-insulin-like growth factor axis in small for gestational age (SGA) children, resulting in alterations in age at menarche, growth, or age at onset of cardio-metabolic diseases14. Thus, early-life exposures seem to impact a range of systems that are crucial for LH pace and trade-offs, which often have hormonal underpinnings, and the relationship between birth size and the risk of chronic disease may result from the altered pace of aging15.It has been suggested that these relationships result from programming, a process whereby a stimulus or insult at a critical period in development results in permanent adaptation of the organism’s structure and physiology affecting its development across ontogenesis17. As a result, there is a marked variation in the rate of an individual’s biological aging and the age when we experience chronic diseases (e.g. cardio-metabolic diseases) and declining capacities 20. Also, birth size may be linked with biological age in healthy adult individuals which in consequence may lead to various risks of chronic disease development. Recent research reported a negative relationship between birth weight and DNA methylation in men but not in women of 20.8–22.5 years21 or in epigenetic age acceleration over the first 3 years of life22. Another study showed contradictory results for various DNA methylation clocks in young and middle-aged adults23 or no relationship between birth weight and telomere length24. Including other than DNA-based measures of biological age in the studies on early developmental origins of aging trajectories may help to understand these contradictory results.Across the lifespan, the consequences of individual differences in genetic endowment, cellular biology, hormonal axes functioning, and life experience accumulate, driving the divergence of biological age from chronological age for some people26 and negatively with the risk of neurodegenerative disease27, hypertension28, triglycerides levels29, and chronic inflammation30.There are many physiological markers of biological age, including specific proteins, hormones, oxidative stress, or inflammation level. One such specific protein is α-Klotho whose level is positively associated with slowing the aging process and longevity32. Although it is suggested that the main role of DHEA/S is due to being a precursor of sex hormones, some studies suggest that DHEA/S per se may have preventive and therapeutic properties against many age-associated diseases35 and their levels correlate positively with muscle mass and strength36, bone mineral density37, skin condition38, cognitive functioning39, cardiovascular health40, glucose tolerance41, lower oxidative stress42 and the risk of autoimmune disease43.Among the hormonal markers of biological age, dehydroepiandrosterone (DHEA) and its sulfated metabolite (DHEA-S) are one of the most important. Concentrations of these hormones in humans typically decrease steadily with age, although showing inter-individual variability, approaching a nadir (c.a. 20% of the peak concentration) at approximately 65–70 years, the age at which many diseases of aging become markedly more prevalent44. Their negative effects are neutralized by antioxidant defenses, and when the antioxidant defenses are reduced, oxidative stress occurs resulting in oxidative damage to various cell molecules. This damage increases and accumulates with age causing progressive damage and functional decline46. Oxidative stress is involved in several age-related conditions, such as cardiovascular disease47, neurodegenerative diseases48, diabetes49, cancer50, and also is related to shorter lifespan51.Another physiological marker of biological age is oxidative stress level. Free radicals are produced in the mitochondrial respiratory chain, an oxidative burst of neutrophils, macrophages, dendritic cells, and monocytes, or as a response to environmental factors54. Similarly, 8-epi-prostaglandin F2α (8-epi-PGF2α) is a major F2-isoprostane formed during lipid oxidation and a reliable marker of oxidative stress55. Elevated levels of 8-epi-PGF2α correlate positively with glucose levels, HOMA-IR index value, and risk of diabetes, hypertension, dyslipidemia, and cancer57. Furthermore, 8-hydroxy-2′-deoxyguanosine (8-OHdG) is the most commonly observed ROS-induced oxidative DNA lesion that may induce mutations in replicating DNA and is a biomarker of oxidative DNA damage58. 8-OHdG level is often used as a marker of age-related oxidative damage accumulation61 linked with increased risk of carcinogenesis62, metabolic syndrome63, or neurodegenerative diseases64.Among a wide range of oxidative stress markers, protein carbonyls (PCs) are one of the key products of protein oxidation in cells and tissues. Elevated PCs level has been detected in elders and several aging-related diseases including neurodegenerative and cardiovascular diseases, cancer, and diabetes65, which can be also perceived as markers of biological age. A chronic inflammatory state is involved in the pathogenesis of most age-associated diseases67, a robust risk predictor for cardiovascular68, neurodegenerative69, autoimmune diseases70, osteoporosis65, and cancer71.Aging is also associated with immune dysfunction that coexists with an upregulation of the inflammatory response that occurs with age, resulting in a low-grade chronic systemic proinflammatory state. The latter is illustrated by a two- to four-fold increase in the levels of C-reactive protein (CRP) or interleukin (IL)-6Thus, the study aims to verify if the birth size is related to biological age as measured based on s-Klotho, adrenal hormones (DHEA/S), oxidative stress , and inflammation levels (hsCRP).Descriptive statistics are presented in Table p = 0.04, Cohen’s d = 0.33). Men who practiced sport had higher testosterone level  compared to men who did not practice sport  (t(157) = 1.97, p = 0.05, Cohen’s d = − 0.31). The two groups did not differ in terms of the other markers of biological age or chronological age (in each case p > 0.23). Men who smoked in the past and men who have never smoked did not differ in terms of markers of biological age (in each case p > 0.24). S-Klotho level was lower in men who drank alcohol more often  = 5.06, p = 0.007, η2 = 0.06). These three groups did not differ in terms of other markers of biological age (p > 0.11).Men who practiced sport had a lower level of hsCRP  compared to men who did not practice sport  (t(157) = − 2.09, DHEA, DHEAS-S levels, and the composite index of biological age were negatively correlated with age. hsCRP was positively related to adiposity and the composite index of biological age was negatively related to adiposity. DHEA/S and composite index of biological age were also positively related to cortisol levels. hsCRP correlated negatively with testosterone levels Table .Table 2TBirthweight was positively related to pregnancy week at birth and TAC levels and negatively with cortisol level. The ponderal index was not related to any controlled variable Table .Table 3Tp > 0.28).The results of zero-order correlations showed that the s-Klotho level showed no relationship between birth weight or ponderal index and markers of biological age Table . Also, tp = 0.96, η2 < 0.001) or ponderal index  = 0.23, p = 0.80, η2 = 0.003).S-Klotho level was not related to birth weight or ponderal index when controlled for pregnancy week at birth and frequency of the alcohol drinking. S-Klotho level was only related to the frequency of alcohol drinking Table . There wp = 0.49, η2 = 0.01) or ponderal index  = 0.12, p = 0.88, η2 = 0.001). There was also no difference in the mean DHEA-S levels between men from the three terciles of birthweight  = 0.48, p = 0.62, η2 = 0.006) or ponderal index  = 0.30, p = 0.74, η2 = 0.004).DHEA level was not related to birth weight or ponderal index when controlled for pregnancy week at birth, age, adiposity, and cortisol level . There was no difference in the mean inflammation levels between men from the three terciles of birthweight  = 0.47, p = 0.63, η2 = 0.006) or ponderal index  = 0.31, p = 0.73, η2 = 0.006).hsCRP level was not related to birth weight or ponderal index when controlled for pregnancy week at birth, adiposity and regular physical activity. Inflammation was positively related only to adiposity level (Model 1 and 2—Table 2 = 0.002) or ponderal index  = 0.91, p = 0.41, η2 = 0.01).OS level was not related to birth weight or ponderal index when controlled for pregnancy week at birth and TAC (in order to account for a possible impact of antioxidant capacity on the relationship between birth size and oxidative stress level Table . There w2 = 0.01) or ponderal index  = 0.29, p = 0.40, η2 = 0.004).The composite index of biological age was also not related to birth weight or ponderal index when controlled for chronological age, adiposity, and cortisol level. Biological age was negatively related to adiposity level and positively to cortisol level Table . There wThe results of this study showed no relationship between birth size and physiological markers of biological age in men between 30 and 45 years. Birth weight but not the ponderal index was only positively related to TAC level and negatively to cortisol level. Furthermore, the levels of biological age markers were mainly related to lifestyle factors, adiposity, and testosterone level. hsCRP was negatively related to physical activity and testosterone level and positively to adiposity. The S-Klotho level was negatively related to the frequency of alcohol drinking. DHEA and DHEA-s were negatively related to age and positively to cortisol levels.75. In human adults with a mean age of 43.04 years, birth weight was inversely associated with p21 gene expression but not with p16 expression, markers of cellular senescence. What is interesting, the expression of p21 but not p16, was positively correlated with BMI gain at 29 years and current BMI76. In men, lower birth weight predicted advanced biological aging based on epigenetic clocks21. Furthermore, no association was found between birth weight and telomere length in humans78. Masterson et al.79 showed that heavier birth weight was associated with longer telomere length but the relationship was attenuated by maternal age at birth and probably rather related to childhood growth. Other studies show that BMI in childhood may be more important for senescence than birth size81. In this study, no relationship between birthweight and biological age was found as measured as a composite index of physiological markers of biological age.The results of the previous research on the relationship between birth size and senescence showed contradictory results. Animal studies have shown that growth restriction during pregnancy and subsequent catch-up growth diminishes telomere length in rats that ultimately have also a reduced life span82 and at variance with previous studies which showed that birth weight was negatively associated with adolescent or adult CRP levels85. However, previous research has also shown that this relationship may be mediated by an elevated body fat mass among individuals with lower birthweight87. Birth weight-adult inflammation risk is mediated by later BMI and BMI change and inflammatory risk related to birthweight can be offset by weight loss88. However, in our study, although hsCRP level was positively related to body adiposity, physical activity, and testosterone level, these factors did not moderate the relationship between birth weight and inflammation level. Other studies suggest that breastfeeding89, life-course socioeconomic status90, and diet91 are important factors in moderating the relationship between birth weight and adult inflammation. Also, the role of such modifiers as sex or age is still unclear92. We cannot exclude the possibility that some lifestyle factors that were not controlled in our study might impact the relationship between inflammation and birth size.We also found no relation between birth weight and inflammation level, also when body adiposity was controlled. This result is in line with sparse studies showing no relationship between birth size and inflammation93. No research, so far investigated if the relationship persists to adulthood. What is interesting, the s-Klotho level was also not related to physiological markers of cardiometabolic risk in this group94. This is in line with other research showing no relationship between s-Klotho level and health outcomes97. It is possible that the role of s-Klotho as a marker of biological age may depend on age and may be more valid in older individuals98 Also, other research suggested sex differences in the relationship between the s-Klotho level and health components99 that might be explained by different profiles of sex hormones and the interaction between s-Klotho and testosterone or estradiol levels101. However, the physiological effects of sex steroid hormones on klotho levels have not been completely elucidated and require further studies. Furthermore, the only factor related to klotho level was the frequency of alcohol drinking which is in line with the previous research104. Quintero-Platt et al.105 observed higher s-Klotho levels among alcoholics than in controls, but these differences were dependent on the presence of cirrhosis. This higher s-Klotho plasma levels in cirrhotic patients could be due to a pathologic status, where the liver function is impaired, and thus not applicable to healthy individuals. Several studies showed an increase in s-Klotho plasma levels in diabetics106, patients with acromegaly107, and patients with autosomal dominant polycystic kidney disease108. However, it is also important to note that many studies show a positive correlation between s-Klotho and markers of health and biological age110, also in patients with various disorders111.We found no relationship between birth size and s-Klotho level in adult men. Previous research has shown that newborns with SGA have lower levels of klotho112 On the other hand, higher DHEAS levels at 7 years old were also associated with lower birth weight and higher adiposity113. Although, experimental data in animals and recent human observations have suggested that an alteration in the set point of the hypothalamic–pituitary–adrenal axis entails important long-term change that occurs in association with reduced fetal growth33 we did not observe the relationship between DHEA/S level and birth weight in men of 30–45 years. We only confirmed that DHEA/S level was only inversely related to chronological age and positively to cortisol level.We also found no relationship between size at birth and DHEA/S level in adult men. Most of the research on the relationship between birth size and adrenal androgens level was conducted in children or young adults and the results are equivocal. For instance, previous research showed a relationship between birth size and DHEA and DHEAS levels in women but not in men of age 18–22 years115 we found no relationship between birth size and OS level in men of 30–45 years old. Previous research showed increases in oxidative stress markers in SGA children118 and male rats exposed to maternal protein restrictions119 or placental insufficiency116. The mechanisms of oxidative stress programming may be through directly modulating gene expression or indirectly through the effects of certain oxidized molecules, which could be compensated by increased antioxidant levels114. Interestingly, we found a positive relationship between birth weight, but not ponderal index, and serum total antioxidant capacity. Animal studies suggest that the antioxidant expression and activity are up-regulated in the IUGR (intrauterine growth restriction) rats that are normotensive in young adulthood, implicating a compensatory mechanism that may be protective against the generation of reactive oxygen species in adult IUGR rats119. Also, human studies have shown that SGA children have elevated OS markers and also some antioxidants120. Possibly, oxidative stress in adults born as small for gestational age can be attenuated by elevated antioxidant levels.Many known or suspected causes or conditions associated with adverse (poor or excessive) fetal growth or preterm birth have been associated with oxidative stress (OS). Although OS may be one of the mechanisms linking impaired fetal growth with certain chronic diseases in adulthoodThis research study has several methodological strengths. Study subjects were homogeneous in terms of age and ethnic background. Information on birth weight and gestational age at birth was drawn from data recorded by hospital or clinic staff in the maternal and child health handbook. Several methodological limitations of the current study should also be clarified. First, the study had a cross-sectional design, thus we cannot exclude the influence of various factors that could impact the relationship during ontogeny. Second, biological age markers were assayed only once. Despite the rigorous study protocol, we cannot exclude the possibility of some intra-individual variability in the measured markers. Finally, the relatively small sample size may limit the statistical power of the analysis, and small differences in biological age as a function of birth weight may not have been detected.This study was a part of a broader project on factors related to men’s health. All methods were carried out by relevant guidelines and regulations and were reviewed and approved by the Commission of Bioethics at Wroclaw Medical University (nr 222/2019). All men signed written informed consent for participation in the study.age = 36.14 ± 3.53) were recruited from an urban Polish population after the initial screening to exclude chronic and acute health problems. Information on birth parameters was available for 183 men. From this sample, 24 men were excluded due to the following reasons: (1) chronic diseases—e.g. diabetes (N = 3); (2) regular smoking (N = 8); (3) CRP > 10 mg/l, indicating ongoing inflammation (N = 1); (4) incomplete measurements of physiological markers of biological age (N = 12). Health status was evaluated based on inflammation, blood morphology, and self-reported health and none of the participants exhibited symptoms of infection. Thus, the final analyses were conducted on 159 healthy men of mean age 35.24 ± 3.42 years (29.83–44.29 years). An a priori power analysis was conducted using G*Power126 for minimum sample size estimation. Results indicated the required sample size to achieve 80% power for detecting a medium effect at a significance criterion of α = 0.05 and five predictors is 92 for the regression analysis. Thus, the obtained sample size of N = 159 is adequate to test the study hypothesis.Information on the ongoing study was posted in local newspapers, on social media, and broadcasted on the local radio. 209 men .Participants were asked to refrain from physical activity, heavy meals, and alcohol for 24 h before the study visit. A fasting blood sample was taken between 7:30 a.m. and 9:00 a.m. for blood biochemical and hormone analyses. In addition to serum markers of biological age, also testosterone and cortisol levels were measured. Age-related decline in testosterone levels is linked with increased vulnerability to multiple chronic diseasesThe participants completed a questionnaire about demographic data, current and past health problems, medications, smoking, and alcohol drinking patterns. Among the participants, 28 individuals declared that they had regularly smoked in the past (quit at least one year before the visit) and 131 stated that they had never smoked. Participants were also asked about the level of physical activity: the number and length (in minutes) of training per week and the type of sport practiced. The types of sports activities practiced by the participants were comparable in terms of intensity . The participants were divided into two categories: (1) physically active (N = 86), which included individuals who declared regular physical activity at least 60 min/week; and (2) inactive (N = 73) i.e. with no regular sport activity. There were no professional sportsmen in the study sample. Participants were also asked how often they drink alcohol and based on their answers they were divided into three groups: (1) rarely—i.e. once per month or less often (N = 40), (2) sometimes—i.e. 2–4 times per month (N = 72), (3) often—i.e. 2–3 times per week (N = 47).3 and expressed in kg/m3. The ponderal index value below 2.0 indicates asymmetrical intrauterine growth restrictions. We controlled for pregnancy week at birth, as it may impact the birth size also of children born in term124.Information on participants’ birth weight and length, and health condition at birth was obtained from the medical records . The ponderal index at birth was calculated as birth 0.1 × weight/(birth length)Blood samples were centrifuged and serum was collected and stored at − 80 °C until the analyses. Sample preparation and all test procedures followed the manual supplied with each ELISA kit.® Code no 27998; with inter-assay and intra-assay coefficient of variation less than 11.4% and less than 3.5% respectively with assay sensitivity of 6.15 pg/ml), following the manufacturer’s protocol. Calibrators (standards supplied with the kit) and serum samples were assayed in duplicate and the average absorbance value was used to calculate hormone concentration. The standard curve was created by plotting mean absorbance values for each standard (Y axis) against its concentration (X axis). Total s-Klotho concentration was calculated in relation to the standard curve, multiplied by the dilution ratio, and expressed in pg/ml.Serum soluble circulating Klotho (s-Klotho) level was measured with enzyme-linked immunosorbent assay (ELISA) using commercial kits (IBLSerum 8-epi-PGF2α level was assayed with an Elabscience competitive-ELISA kit (cat. No E-EL-0041) with intra- and inter-CV less than 7%. Protein carbonyls were assayed with a MyBioSource ELISA kit (cat. No MBS3802635). DNA/RNA oxidative damage was assayed with a Cayman ELISA kit (cat. No 589320) with inter- and intra- CV less than 12%. The kit allows to measure of DNA/RNA oxidative damage, asses 8-OH-dG from DNA, 8-OHG from RNA, and 8-hydroxyguanine from either DNA or RNA.Serum hsCRP level was measured using a DEMEDITEC ELISA kit (cat no 740011) with inter- and intra- CV less than 6.3% and 6.9% respectively.Serum DHEA and DHEA-S levels were assayed using a DEMEDITEC competitive ELISA kit. DHEA (cat no DEH3344) level was measured with inter- and intra-CV less than 6.9% and less than 6.9% respectively. DHEA-S (cat no DEH3366) level was measured with inter- and intra-CV less than 12.2% and less than 6.8% respectively.Serum total antioxidant capacity (TAC) was assayed with a Cayman ELISA kit (cat. No 709001), with an inter-assay CV is 3% and an intra-assay CV is 3.4%. The kit allows for assessing of aqueous- and lipid-soluble antioxidants, thus the combined antioxidant capacities of all its constituents including vitamins, proteins, lipids, glutathione, uric acid, etc. were assessed.Serum cortisol level was measured using a DEMEDITEC ELISA kit (cat no DEH3388) with inter- and intra-CV less than 9.2% and less than 7.2% respectively.Serum samples and calibrators (and controls if supplied with a kit) were assayed in duplicate in all ELISA tests. Absorbance  was measured using a microplate reader (ASUS UVR340) with at λ recommended by each manual. The calculation of results was based on the calibration curve . The average value of sample concentration (from duplicate measures) was used in analyses.®) using a Cobas analyzer and expressed in ng/ml.Quantitative measurement of total testosterone was evaluated by a certified analytical laboratory  and averaging for each individual the three Z scores.An aggregate measure incorporating oxidative stress markers should more accurately assess the levels of antioxidant potential and OS than a single biomarkerSimilarly, an aggregate measure of biological age was calculated by Z scoring each biomarker  and averaging for each individual the seven Z scores. Z scores of hsCRP and oxidative stress markers were multiplied by − 1 to account for the inverse relationship with biological age. The higher values of this composite measure indicated younger biological age.94, the t-test was used to verify if participants who smoked in the past (N = 28) and participants who have never smoked (N = 131) differed in terms of markers of biological age. T-test was also used to verify if participants classified as physically active (N = 86) and participants classified as inactive (N = 73) differed in terms of markers of biological age. ANOVA was used to verify if participants differed in terms of levels of s-Klotho and cardiometabolic risk markers levels depending on how often they drink alcohol: (1) rarely (N = 40); (2) sometimes (N = 72); (3) often (N = 47). Tukey test was used as a post-hoc test. Pearson correlation was to verify if birth weight and ponderal index are related to controlled variables .Similarly, as in our previous studyFirst, the relationship between birth parameters and biological age markers levels was verified with Pearson correlation analysis. The mean levels of markers of biological age were compared between men classified as small-for-gestational-age  and men classified as appropriate for gestational age  using a T-test. Participants were divided into three groups according to the values of terciles of birth weight: (1) the first tercile ; (2) the 2nd tercile ; (3) the 3rd tercile . Participants were also divided into three groups according to the values of terciles of ponderal index: (1) the first tercile ; (2) the 2nd tercile ; (3) the 3rd tercile . ANOVA was used to compare the differences between the three groups divided according to terciles of birth weight and ponderal index in terms of markers of biological age. Then, a simple linear regression model was used to test the association between levels of biological age markers. In each regression analysis, the pregnancy week at birth was controlled as it may impact an individual’s birth size. We controlled also other factors related to the markers of biological age such as chronological age, body adiposity, alcohol use, testosterone and cortisol level, and physical activity. The predictors for each analysis were selected based on the results of the t-test and Pearson correlation analysis for the relationship between biological age markers and potential confounders.p < 0.05.Analyses were performed with Statistica 12.0 software. The results were interpreted as statistically significant if Supplementary Information.


Chylolymphatic cyst, variant of mesenteric cyst, is a rare entity. Clinical presentation and radiological features are not characteristic, so diagnosis can be made finally on histopathology. We report an extremely rare case of giant chylolymphatic cyst measuring >15 cm. A 2-year-old female presented with abdominal pain and vomiting. On examination, a ill-defined and firm mass was palpable just below umbilicus. Positron emission tomography-computed tomography scan revealed a large ill-defined lesion, which measured 16 × 13.2 × 6.7 cm in size and was seen in relation to the abdominal mesentery. Provisional diagnosis of mesenteric cyst was made. Laparotomy revealed multiple lymphatic cysts of variable size arising from the mesentery of proximal ileum. Histopathology examination confirmed the presence of a giant chylolymphatic cyst. Chylolymphatic cysts are rare entity and should be kept in mind while diagnosing a pediatric case of abdominal cysts. Mesenteric cysts are a rare entity and chylolymphatic cyst, a variant of mesenteric cyst is even more rare. Literature regarding chylolymphatic cyst presenting in adult population is frequently available but not so in pediatric population. Moreover, clinical presentation and radiological features are not characteristic, so through our case report and literature review, we compiled the usual presentation, morphological features, and management of these cases for better and accurate diagnosis in future. We herein report an extremely unusual case of giant chylolymphatic cyst involving mesentery in a 2-year-old female child.We report a case of 2-year-old female child who presented with complaints of pain in abdomen for 3 days and 2 episodes of nonbilious vomiting. On examination, vitals were stable. A vague mass was palpable just below umbilicus with ill-defined margins and firm surface. A Ultrasonography whole abdomen was performed, and there was evidence of multicystic intra-abdominal lesion. Positron emission tomography-computed tomography scan revealed a large ill-defined infiltrative mass lesion seen in relation to the abdominal mesentery, centered within the mesocolonic fat. The lesion measured 16 × 13.2 × 6.7 cm in size involving almost the entire abdominal cavity and demonstrate no significant contrast enhancement (Fig. A chylolymphatic cyst is a rare variant of a mesenteric cyst with a prevalence of 1 per 20 000 children (These cysts are thought to originate from isolated or ectopic lymphatic channels due to accumulation of both chyle and lymph in the small bowel mesentery. The accumulation in these channels results from an imbalance between the inflow and outflow of fluid .Chylolymphatic cysts are diagnosed by 10 years of age in 25% of cases (Chylolymphatic cyst has varied presentation, it may be asymptomatic and may present with abdominal distension or may be associated with complications such as intestinal obstruction, volvulus, infection, rupture of the cyst, or obstruction of the urinary or biliary tract .In most of these cases, prior diagnosis of the chylolymphatic cyst was difficult as no characteristic features were present on radiographs. Abdominal radiographs usually reveal air fluid levels in dilated loops of bowel only when associated with intestinal obstruction caused by compression of the adjacent bowel from the enlarged cyst or may be caused by mesenteric volvulus. Fujita et al  describeMost cases of the chylolymphatic cyst are managed by surgical excision of cyst with or without bowel resection. Others include enucleation or drainage of cyst. Lee et al  suggesteHistopathology is important as it is not only confirmatory but also helps to exclude other differentials such as cystic lymphangioma, lymphoepithelial cyst, and multilocular peritoneal inclusion cysts. Cystic lymphangioma has distinct histology, the smooth muscle and lymphatic spaces are lacking in the wall of cyst. Some literature has considered chylolymphatic cysts to be a variant of mesenteric cysts, while other considered it as a type of cystic lymphangioma. Multilocular peritoneal inclusion cyst is differentiated from chylolymphatic cyst by presence of mesothelial cells ,7. DiffeOn extensive search on PubMed with keywords “paediatric chylolymphatic cyst” only 12 articles were found representative of 17 patients Table ,7–14.Chylolymphatic cyst of size >15 cm are considered as giant chylolymphatic cyst. Of reviewed cases of pediatric chylolymphatic cysts, only 2 are giant chylolymphatic cysts. In the evaluated series of pediatric chylolymphatic cyst most common presentation was with abdominal pain and other symptoms include vomiting, abdominal distension, constipation, acute intestinal obstruction, severe back pain, and scrotal swelling. Our case presented with complaints of pain in abdomen and vomiting.On follow-up of our case, there was no recurrence. In the evaluated series, there was no recurrence in any of the case except in 5 cases where no follow-up was done.Chylolymphatic cysts area rare entity and should be kept in mind while diagnosing a pediatric case of abdominal cysts. In evaluated series, the most common presentation was abdomen distention and abdominal pain. Treatment involves excision of cyst with or without resection of bowel. Diagnosis is usually made on histopathological examination.


There is no global consensus as to which standards are the most appropriate for the assessment of birth weight and length. The study aimed to compare the applicability of regional and global standards to the Lithuanian newborn population by sex and gestational age, based on the prevalence of small or large for gestational age (SGA/LGA).Analysis was performed on neonatal length and weight data obtained from the Lithuanian Medical Birth Register from 1995 to 2015 . Their distributions by gestation and sex were estimated using generalized additive models for location, scale, and shape (GAMLSS), and the results were compared with the INTERGROWTH-21st (IG-21) standard to evaluate the prevalence of SGA/LGA (10th/90th centile) at different gestational ages.The difference in median length at term between the local reference and IG-21 was 3 cm–4 cm, while median weight at term differed by 200 g. The Lithuanian median weight at term was higher than in IG-21 by a full centile channel width, while the median length at term was higher by two channel widths. Based on the regional reference, the prevalence rates of SGA/LGA were 9.7%/10.1% for boys and 10.1%/9.9% for girls, close to the nominal 10%. Conversely, based on IG-21, the prevalence of SGA in boys/girls was less than half (4.1%/4.4%), while the prevalence of LGA was double (20.7%/19.1%).Regional population-based neonatal references represent Lithuanian neonatal weight and length much more accurately than the global standard IG-21 which provides the prevalence rates for SGA/LGA that differ from the true values by a factor of two. The health status of a newborn is reflected by its body size at birth. Therefore, the assessment of birth weight and length by applying appropriate standards not only plays an essential role in good clinical care but is also sustainable with an increasing evidence of preventable adverse growth-related outcomes .When considering neonatal body size, two groups with an increased risk for negative perinatal outcomes and future cardio-metabolic changes have been identified : infantsMoreover, a range of recent publications established the relationship between the preterm newborn body's parameters at birth, postnatal growth restriction and later growth failure with short- and long-term health consequences –7.Thus, from a clinical perspective, the priority would be to reduce health effects related to size at birth by providing a preventive and promotive care, and monitoring for complications . AdequatAt present, several types of charts for growth assessment of premature newborns are available. One of the commonly used types is intrauterine growth charts based on cross-sectional anthropometric measurements taken from infants of varying gestational ages at birth presented as the gold standard for premature infant growth . HoweverAnother point of debate is the choice between customized and population-based references. Proponents of customized charts claim that they improve the prediction of adverse perinatal outcomes and differentiate better between “small-but-healthy” infants and growth-restricted ones , 15. OppA similar discussion arises when choosing between the regional or global references , 18–21. Considering all the above, in this study, we have set several objectives: (a) to construct the national birth weight/length reference values and curves for Lithuanian newborns from 22 to 42 GA weeks; (b) to compare the results with the recently adopted global IG-21 , 20 stanBirth data from the Lithuanian Medical Data of Births for the period of 1995–2015 were retrieved from the Health Information Center of the Institute of Hygiene in Vilnius, Lithuania, including liveborn singletons of between 22 and 42 completed weeks of gestational age (GA). We excluded multiple births, stillbirths, infants with undetermined sex or major congenital malformations and syndromes, and those with incomplete data. Also, the cases where weight or length were more than 3 standard deviations (SD) from the mean, following WHO standards , were ext (BCT) distribution. It can be used to model excess kurtosis over the normal distribution (leptokurtic data) when the Box-Cox transformation fails to transform the data close to normality due to the presence of kurtosis. The BCT distribution is defined by a power transformation, νY, which follows a truncated t distribution that is shifted and scaled. The truncated t distribution has a degrees of freedom parameter, τ. The BCT distribution is characterized by four parameters and is denoted as BCT . The parameters µ, σ, ν and τ may be interpreted as relating to location (median), scale (centile-based coefficient of variation), skewness (power transformation to symmetry) and kurtosis (degrees of freedom), respectively.The LMS method estimates growth reference centiles by modelling any skewness present in the measurement distribution . It assuGeneralized additive models for location, scale, and shape (GAMLSS) were fitted to obtain the centile  reference values and curves of birth weight/length by GA and sex separately . The LMSTwo published standards of the IG-21 project , 20 wereThe sample size of our study  increaseOur study constructed the 3rd, 10th, 25th, 50th, 75th, 90th, and 97th smoothed centile curves according to gestational age and sex for birth weight and length of Lithuanian newborns –5. The vThe 3rd, 50th and 97th Lithuanian birth weight centiles by sex and gestation were similar to those of IG-21 at extremely early gestations (24–27 weeks), especially for boys and the 97th centile , 3. WithFor birth length, the median and lower IG-21 centiles were close to the Lithuanian centiles at early gestations, while the higher centiles differed by almost a full centile channel, i.e., 1.0–1.5 cm , 5. In lA total of 9.7% 30,859) boys were SGA based on the Lithuanian 10th centile, compared to 4.1% based on the IG-21 10th centile, less than half the prevalence . Similar0,859 boyIn contrast, the incidence of LGA was 10.1% 31,972) for boys based on the Lithuanian 90th centile as against 20.7% using the IG-21 90th centile, i.e., more than double . Similar1,972 forGrowth centiles as clinical tools for assessing the infant's physical status have gained much importance in recent years. The choices between global or regional, and between customized and population-based growth references or growth standards for different populations are under debate , 30. TheOur study revealed slightly better agreement in the main centiles of extremely preterm newborns –5. HowevMoreover, a larger discrepancy was observed starting from the late preterm period  with certain disparities evident in mean newborn weight and length data at term –5. NotewIn addition, the insights drawn from the comparison of centiles between the studies when supplemented with the categorization of newborns as SGA/LGA  demonstrIn addition to the strengths mentioned above, our study has some limitations. Using these growth centiles for monitoring postnatal growth of preterm infants may not be realistic or ideal, because they do not reflect the initial water and weight loss that occurs in infants during the first 2–3 weeks , 42. UndIt should also be noted that IG-21 was designed to become an international standard and included only low-risk pregnancies with women whose health and nutritional needs were met and who received adequate antenatal care in 8 socioeconomically stable developing or developed countries such as Lithuania. The data of our study included all births regardless of maternal socioeconomic status. Therefore, we believe that the main findings of our study would be even more pronounced if we had only applied the same inclusion criteria as IG-21. There are around 15% of ethnic minorities in Lithuania and Lithuanian newborns were found to be the biggest in size in comparison to newborns of other ethnic groups . What isIn conclusion, the global standard IG-21 should be considered with caution, as requiring validation before implementation. Instead, the findings of our study advocate the use of regional population-based neonatal centiles that more accurately represent the size of the Lithuanian newborn population. Furthermore, the prevalence of SGA/LGA at different gestations depending on the instrument used reveals the clinical importance of using local standards to benefit the most vulnerable infant populations.


Deoxynivalenol (DON), one of the most prevalent mycotoxins, has been found to cause fetal growth retardation in animals. However, limited evidence exists regarding its effects on pregnant women.Maternal urinary concentration of total DON (tDON) and free DON (fDON) in the second trimester was measured using liquid chromatography with tandem mass spectrometry. Provisional daily intake (PDI) of DON was calculated based on tDON concentration. Linear and logistic regression models were used to evaluate the association between DON exposure levels and birth weight, birth length, and the risk of small for gestational age (SGA).P-trend < 0.001) and 63.02 g  for fDON (P-trend = 0.004) in the highest tertile. Each unit increase in Ln-tDON and Ln-fDON was also inversely associated with birth weight. Furthermore, compared to those who did not exceed PMTDI, pregnant women whose PDI exceeded PMTDI had lower birth weight  and birth length , and a higher risk of SGA  in their offspring. Similar associations with birth weight, birth length, and SGA were found when comparing the highest tertile of PDI to the lowest tertile .Among 1538 subjects, the median concentrations of tDON and fDON were 12.1 ng/mL and 5.1 ng/mL, respectively. The PDI values revealed that the median DON intake was 0.7 µg/kg bw, and 35.9% of the total population exceeded the provisional maximum tolerable daily intake (PMTDI) of 1 µg/kg bw. Compared with the lowest tertile, birth weight decreased by 81.11 g  for tDON (Maternal DON exposure is related to decreased birth weight. Our findings implicate that DON exposure during pregnancy may cause fetal growth faltering, and measures should be taken to reduce DON exposure in pregnant women.The online version contains supplementary material available at 10.1186/s12916-023-03011-5. Fusarium species commonly found in cereal crops such as wheat, barley, and maize  was found. Moreover, we performed the analysis using creatinine-adjusted DON levels, and the results showed that the association between urinary DON and birth weight remained statistically significant  compared with women who were in the lowest tertile. In addition, women whose PDI exceeds PMTDI were more likely to deliver an SGA baby . We did not find any relationships between provisional daily DON intake and LBW or PTB  for SGA, but there was not statistically significant. However, pregnant women in the highest tertile of PDI displayed about 1.62-fold increased risk of SGA  or baby boys, the interaction between maternal age and maternal DON exposure  on birth weight was statistically significant . Notably, this is the first epidemiological study to suggest a possible dose–response relationship between DON exposure and adverse birth outcomes. Specifically, our findings demonstrated that maternal urinary DON levels and provisional daily DON intake were positively associated with lower birth weight. Furthermore, pregnant women with a PDI of DON exceeding the PMTDI had a 1.48-fold increased risk of delivering SGA offspring.The levels of DON among pregnant women in the present study were moderately high compared to those in other countries. More than 90% of pregnant women in our study had detectable levels of total DON in their urine, with a median concentration of 12.1 ng/mL or 13.5 ng/mg creatinine, indicating relatively high DON levels. In a study conducted in Bangladesh, only about half of the pregnant women had detectable levels of DON, with mean concentrations of 0.86 ng/mL or 2.14 ng/mg creatinine . AnotherCurrently, only one cohort study has evaluated the association between serum DON levels and adverse birth outcomes in 483 pregnant women at 8–24 weeks of gestation in rural Ethiopia. However, this study did not find a statistically significant association . The serOur findings reveal that dietary DON exposure during pregnancy may lead to the exposure of DON in early life, resulting in fetal growth retardation. Smaller size or relative thinness at birth and during infancy have been associated with increased rates of coronary heart disease, stroke, type 2 diabetes mellitus, adiposity, metabolic syndrome, and osteoporosis in adult life . So giveThere are several possible biological mechanisms that may explain the effect of DON on growth faltering. The first is that DON may interfere with the nutritional efficiency of maternal intestinal absorption, which could affect fetal weight gain , 35. EveSeveral limitations in the present study should be mentioned. First, though we performed a multivariate analysis model to adjust for potential confounders, there were unmeasured confounders that could affect exposure concentrations and infant birth outcomes. Second, we only measured DON in the urine but not in the blood. Studies have demonstrated that urinary DON biomarkers have been shown to be a good indicator of the body’s burden to assess DON exposure , 45. ThiIn summary, higher DON exposure during pregnancy may be associated with lower birth weight and birth length, and a higher risk of SGA in their offspring. More attention and measures for policy maker are needed to reduce deoxynivalenol exposure in Chinese pregnant women.Additional file 1: Fig.S1. Flowchart of the study population for analysis. Fig.S2. Scatterplot of urinary free DON (fDON) and urinary total DON (tDON), all in logarithmic scale . Table S1. Maternal and neonatal characteristics for the study population, urine available and unavailable subjects.a. Table S2. Associations of maternal urinary creatinine-corrected DON levels (ng/mg Creatinine) during pregnancy with birth outcomes. Table S3. Associations of maternal urinary DON levels (ng/mL) during pregnancy with the risk of low birth weight and preterm birth. Table S4. Associations of maternal urinary DON levels (ng/mL) during pregnancy with the risk of low birth weight and preterm birth.


In vitro and in vivo studies have shown that certain cytokines and hormones may play a role in the development and progression of type 2 diabetes (T2D). However, studies on their role in T2D in humans are scarce. We evaluated associations between 11 circulating cytokines and hormones with T2D among a population of sub-Saharan Africans and tested for causal relationships using Mendelian randomization (MR) analyses.n = 2790). We used 35 genetic variants previously associated with at least one of these 11 cytokines and hormones among non-T2D individuals as instrumental variables in univariable and multivariable MR analyses. Statistical significance was set at 0.0045 (0.05/11 cytokines and hormones).We used logistic regression analysis adjusted for age, sex, body mass index, and recruitment country to regress levels of 11 cytokines and hormones  on T2D among Ghanaians, Nigerians, and Kenyans from the Africa America Diabetes Mellitus study including 2276 individuals with T2D and 2790 non-T2D individuals. Similar linear regression models were fitted with homeostatic modelling assessments of insulin sensitivity (HOMA-S) and β-cell function (HOMA-B) as dependent variables among non-T2D individuals . IL-RA was partly mediated via BMI (30-34%), but GIP was not. Inverse variance weighted MR analysis provided evidence for a causal effect of adipsin on T2D , though these associations were not consistent in all sensitivity analyses.Circulating GIP and IL-1RA levels were associated with T2D. Nine of the 11 cytokines and hormones (exceptions GLP-1 and IL-6) were associated with HOMA-S, HOMA-B, or both among non-T2D individuals. Two-stage least squares MR analysis provided evidence for a causal effect of GIP and IL-RA on HOMA-S and HOMA-B in multivariable analyses (GIP ~ HOMA-S The findings of this comprehensive MR analysis indicate that circulating GIP and IL-1RA levels are causal for reduced insulin sensitivity and increased β-cell function. GIP’s effect being independent of BMI suggests that circulating levels of GIP could be a promising early biomarker for T2D risk. Our MR analyses do not provide conclusive evidence for a causal role of other circulating cytokines in T2D among sub-Saharan Africans.The online version contains supplementary material available at 10.1186/s13073-023-01263-7. The global burden of type 2 diabetes (T2D) is high and rising and disproportionally affects African-ancestry populations. In the USA, African Americans have a 1.6 times higher prevalence of T2D than European Americans .The reasons for the disproportionate burden of T2D among African-ancestry populations are not completely understood. Inflammatory processes have been implicated in the development and progression of T2D . Such anMendelian randomization (MR) analysis leverages genetic variants as instrumental variables to improve causal inference in observational studies. Specifically, MR studies are less affected by limitations such as unmeasured confounding and reverse causation because of the random distribution of genotypes at conception. MR studies assessing causality for the relationship between cytokines and hormones with T2D are limited. Wang et al. found evidence for a causal effect of leptin levels on T2D in European-ancestry individuals , while fHere, we aimed to (1) evaluate the association between 11 circulating cytokines and hormones with T2D-related phenotypes, and (2) infer causality in these associations using MR analyses in a population of sub-Saharan Africans.The Africa America Diabetes Mellitus (AADM) study is the longest-running genetic epidemiology study of T2D in sub-Saharan Africa. The study enrolled over 6000 sub-Saharan African adults aged 25 years and above with T2D and adults without T2D  from university medical centres in Nigeria, Ghana, and Kenya. The study design and procedures have been described in detail elsewhere –24. In b2 (kg/m2).Demographic data including age and sex were obtained through structured questionnaires. Height and weight were measured in light clothing and body mass index (BMI) was calculated as weight/heightFasting serum and plasma samples were obtained by trained personnel. Fasting glucose concentration was measured in mg/dl using the enzymatic reference method with hexokinase on a Roche analyzer. Eleven circulating cytokines and hormones, namely adipsin, leptin, visfatin, PAI-1, GIP, GLP-1, ghrelin, resistin, IL-6, IL-10, and IL-1RA were measured using multiplex bead-based flow cytometric immunoassays according to the manufacturer’s instructions . These commercial kits measure the levels of cytokines and hormones reported to be involved in obesity and diabetes pathophysiology. Data were collected using Bio-Plex 200®System  equipped with Bio-Plex Manager™ Software . IL-6, IL-10, and IL-1RA were analysed in a subset of participants using enzyme-linked immunosorbent assay (ELISA) .https://www.dtu.ox.ac.uk/homacalculator/). HOMA-S is the reciprocal of HOMA-IR (insulin resistance) as calculated using the linear set of equations. Both HOMA-S and HOMA-B were calculated for non-T2D individuals only as the measures are deemed not to be valid in the presence of T2D.T2D was defined using the American Diabetes Association (ADA) criteria, i.e. a fasting glucose of ≥ 126 mg/dl (≥ 7.0 mmol/L), or an oral glucose tolerance test (OGTT) 2-h post load value of ≥ 200 mg/dl (11.1 mmol/L) on more than one occasion, or the reported use of glucose-lowering medication as prescribed by a physician confirmed by review of clinical records. The updated Homeostatic Model Assessment (HOMA) was used through the University of Oxford HOMA2 calculator to estimate insulin sensitivity (HOMA-S) and β-cell function (HOMA-B). The updated HOMA model is a computer model that derives HOMA-S and HOMA-B as percentages of a normal reference population rather than linear approximations  and R studio (version 2022.12.0) , 27. Themeasures . The ordP-value ≤ 1 × 10 −6) and imputed using the African Genome Resources Haplotype Reference Panel via the Sanger Imputation Service. Genome-wide quantitative linear regression analyses were performed for all cytokines and hormones separately with adjustment for age, sex, T2D, the first three principal components (PCs), and a genetic relatedness matrix [P-value of < 5 × 10−7 were subsequently selected as potential instruments. We then grouped these SNPs into genetic loci using pairwise linkage disequilibrium (LD) analysis. This procedure, commonly known as “LD clumping” was performed separately for each cytokine and hormone. The PLINK 1.9 software [2 threshold of < 0.1 and all unrelated AADM participants as the LD reference. The SNPs with the lowest P-value in each clump were selected as independent instruments. We used the mRnd online web tool to calculate the power of the MR analyses with these selected instruments for an α of 0.05 and a true causal effect size of β = 0.2 for the HOMA measures and OR = 1.5 for T2D [For each cytokine and hormone, instruments were derived from previously published genome-wide association analyses among AADM study participants without T2D . In bries matrix . For inssoftware  was used for T2D .AER package [n = 2790), each cytokine was regressed on its genetic instruments. The fitted values of these regressions were subsequently used in regression with HOMA-S and HOMA-B as dependent variables.To estimate the univariable effect of each of the cytokines and hormones on the continuous outcomes HOMA-S and HOMA-B, the two-stage least squares (2SLS) method was used through the ivreg function of the  package . In thesn = 5066), the inverse variance weighted (IVW) method as implemented in the MendelianRandomization R package was used for multi-SNP instruments, while for single-SNP instruments (i.e. IL-6) the Wald ratio was used [Q and the I2 statistic for the IVW analyses as an assessment of heterogeneity. In addition, we performed MR-Egger and weighted median analyses. These analyses could only be performed for cytokines and hormones with three or more genetic instruments. MR-Egger corrects for pleiotropy by assuming that the pleiotropic effects of each instrument follow a normal distribution with a mean of zero and a variance that can be estimated from the data [For the univariable T2D MR analysis , those produced by the gut , and those produced by immune cells . While univariable MR analysis estimates the total (i.e. indirect and direct) effect of each cytokine on the outcomes, multivariable MR estimates the direct effect of each cytokine on the outcomes.AER R package, which first regressed the cytokines and hormones per group  on the genetic variants in a multivariate multiple linear regression. In the second stage, the HOMA outcome was regressed linearly on the fitted values of each of the cytokines and hormones. We additionally performed causal mediation analysis using the mediation R package on any statistically significant cytokines or hormone to examine whether their effect on HOMA-S and HOMA-B is mediated through BMI [Multivariable 2SLS analyses for HOMA-S and HOMA-B were also performed using the ough BMI .MendelianRandomization R package to perform multivariable MR for the T2D outcome via the IVW method using a fixed effects model. We performed similar sensitivity analyses as for the univariable MR analyses: the IVW method using a random effects model, the multivariable MR-Egger method, and the multivariable median-based method.We used the mr_mvivw function from the Out of the total 5066 individuals, 2790 were non-T2D individuals and 2276 were affected by T2D Table . As expeP-value of 0.0045 (0.05/ 11 cytokines and hormones). The reverse of HOMA-S was seen for HOMA-B, with inverse associations for IL-10 and resistin and positive associations for all other cytokines and hormones.Most cytokines and hormones were associated with the HOMA measures, the proxies for the hallmarks of T2D, insulin sensitivity (HOMA-S), and β-cell function (HOMA-B). All cytokines and hormones except for GLP-1 and IL-6 were associated with HOMA-S  and one unit higher levels of ORQ transformed IL-1RA was associated with 1.34 higher odds .Two out of the eleven cytokines and hormones were associated with T2D, namely GIP and IL-1RA  association analysis using univariable 2SLS analyses Figs. . GeneticI2 statistic (90.8%) and Cochran’s Q (21.8) for the fixed effects IVW adipsin model were suggestive of variation across genetic instruments . No evidence for a causal effect of any of the other cytokines or hormones on T2D was found  and HOMA-B  lost Bonferroni-corrected statistical significance. Given the substantial role of adiposity in the development of glycaemic dysfunction and insulin resistance, we performed mediation analyses to explore whether the causal effect of GIP and IL-1RA may be partially mediated through BMI. We did not find evidence for BMI mediating the effect of GIP on HOMA-S , but BMI did mediate 30.8% of the effect of IL-1RA on HOMA-S . Similarly, BMI was not a mediator in the effect of GIP on HOMA-B , but it was a mediator in the effect of IL1-RA on HOMA-B .The causal effect of GIP on HOMA-S and HOMA-B that we observed in the univariable analyses was independent of other gut-produced hormones  and had a regression coefficient of − 0.67 for HOMA-S and 0.59 for HOMA-B Figs. C and 3. P-value of 0.006. The multivariable IVW estimate when excluding this potentially pleiotropic instrument was not statistically significant . None of the other cytokines or hormones showed evidence of a causal effect on T2D independent of other cytokines and hormones.The multivariable MR analyses for T2D showed that the statistically significant estimate of adipsin on T2D with the fixed effect IVW and median methods was independent of other cytokines and hormones produced by adipose tissue Table . HoweverWe examined the role of 11 circulating cytokines and hormones previously implicated in T2D in predominantly non-human studies. Circulating levels of nine out of the 11 cytokines and hormones were associated with insulin sensitivity and eight with β-cell function among non-T2D individuals. In addition, GIP and IL-1RA were associated with T2D. Furthermore, MR analyses provided evidence for an independent causal effect of circulating GIP levels on insulin sensitivity and β-cell function that was not mediated through BMI and an independent causal effect of IL-1RA on insulin sensitivity and β-cell function that was partially mediated through BMI. For all other cytokines and hormones, no robust evidence for a causal association with insulin sensitivity, β-cell function, or T2D was found.The plausibility of a causal effect of fasting circulating GIP on reducing insulin sensitivity and promoting β-cell function is supported by evidence from other studies , 40. GIPThe role of GIP in insulin secretion is closely linked with GLP-1 but we found no evidence of a causal effect of circulating GLP-1 levels on insulin sensitivity, β-cell function, or T2D. In fact, neither circulating nor genetically predicted GLP-1 was significantly associated with any of these traits. This result may be a consequence of analysing fasting measures in this study as GLP-1 has a more potent action on postprandial insulin secretion in healthy individuals . In addiP2RX7 gene was found to be associated with an increase in IL-1RA levels among T2D patients [The effect of IL-1RA on insulin sensitivity and β-cell function that we found in our study population of sub-Saharan Africans is in line with findings from some studies but in contrast with others. While MR analyses by Nowak et al. were in the same direction of effect as our findings, they did not find evidence for a causal association between IL-1RA and insulin sensitivity . Neitherpatients , which ipatients , whereaspatients . In our If our findings of a causal effect of GIP and IL-1RA on insulin sensitivity and β-cell function are confirmed by other studies, there are potential implications for prevention of T2D development. Monitoring of circulating levels could serve as biomarkers for early detection and risk assessment as elevated levels of GIP and IL-1RA could signal increased risk for reduced insulin sensitivity and increased β-cell function. Increased β-cell function often precedes β-cell failure in T2D development . In addiSERPINE1 gene as instrumental variables [RETN SNPs and did not find evidence for an effect of these SNPs on insulin sensitivity [Our null findings for other circulating cytokines and hormones are consistent with other MR studies that have investigated some of these cytokines and hormones in other populations. Wang et al. did not find evidence for a causal effect of leptin levels on T2D or HOMA measures using data from European-ancestry participants  and Songariables . The cauariables , 60 was sitivity . More brsitivity , suggestLimitations of our analytic strategy are worth noting. Firstly, we employed a one-sample approach for the MR analyses with the HOMA measures as outcomes, which can lead to increased false positive findings in the presence of weak instruments. We attempted to mitigate this possibility by assessing F-statistics and excluding potentially problematic instruments. We note that no other genetic epidemiological cohort with data on the same circulating cytokines and hormones among sub-Saharan Africans exists. This situation presents a challenge considering instrumental variable assumptions are more likely to be violated when two samples represent different ethnic groups . This alIn conclusion, this MR study using a sample of sub-Saharan Africans provides evidence for a causal effect of circulating GIP and IL-1RA levels on insulin resistance and β-cell function in non-T2D individuals and suggests that circulating levels of several other cytokines and hormones that have previously been reported in relation to T2D are not causal. While the effect of IL-1RA was partially mediated through BMI, the effect of GIP was not, suggesting that circulating GIP levels could be explored further as a potential biomarker for the development of insulin resistance. Given the few GWAS on circulating cytokines and hormones in general and among sub-Saharan African populations in particular, such studies are needed to expand and further validate these findings in sub-Saharan African and other populations.Additional file 1. Associations of individual genetic instruments with cytokines and hormones. Additional file 1 shows the effect sizes and P-values for the associations of all 35 genetic instruments with each of the 11 cytokines and hormones in Table S1. Figure S1 in this file shows the variant-specific estimates as well as the univariable inverse variance weighted (IVW), MR-Egger, and weighted mediation estimates for each of the 11 cytokines and hormones on type 2 diabetes as outcome.


Several cytokines including leptin were associated with maternal body weight , smoking habits , or gestational diabetes . Conclusions: In a general cohort of pregnant women, the intake of fatty acids influenced the balance between pro- and anti-inflammatory molecules together with weight gain, smoking habits, and gestational diabetes.Background: During pregnancy, the balance between pro-inflammatory and anti-inflammatory responses is essential for ensuring healthy outcomes. Dietary Fatty acids may modulate inflammation. Methods: We investigated the association between dietary fatty acids as profiled on red blood cells membranes and a few pro- and anti-inflammatory cytokines, including the adipokines leptin and adiponectin at ~38 weeks in 250 healthy women. Results: We found a number of associations, including, but not limited to those of adiponectin with C22:3/C22:4 (coeff −1.44;  During pregnancy, the woman’s body undergoes significant immune changes to support fetal implant and development, including an increase in certain immune cells and alterations in immune function that involve both pro-inflammatory and anti-inflammatory responses, which work together to promote maternal–fetal tolerance and fetal growth. A controlled inflammatory response helps to facilitate implantation and early placental development, and is characterized by the recruitment of immune cells, such as natural killer cells and macrophages, to the site of implantation, as well as the production of pro-inflammatory cytokines . HoweverIn parallel, the woman’s body also experiences metabolic changes to accommodate the increased metabolic demands of fetal growth and development . In earlReduced insulin sensitivity is deemed as a condition of low-grade systemic inflammation and can contribute significantly to worsening the physiological inflammation that characterizes pregnancy.Dietary lipids can have a significant impact on inflammation through directly influencing the immune system  while woConsuming excessive amounts of saturated (SFAs)  and tranFor these purposes, we measured circulating levels of specific molecules, namely adipokines and cytokines, which play an important role in immune function, inflammation, and metabolism, and whose imbalance has been found to contribute to the development of pregnancy-related complications such as GDM, pre-eclampsia, preterm birth and fetal growth restriction. We selected for testing molecules reflecting different facets of inflammation, and our list of molecules included adiponectin, leptin, soluble cluster of differentiation 14 (sCD14), soluble tumor necrosis factor receptor II (sTNFR-II), IL-6, IL-8, IL-10, monocyte chemoattractant protein 1 (MCP-1), endotoxin, and human intercellular adhesion molecule 1 (ICAM-1).The “Feeding Low-Grade Inflammation and Insulin Resistance of the Fetus” study ,10, a poThe “Feeding” study was approved by the Ethical Committees of the “Ospedale Pediatrico Bambino Gesù” (OPBG) and the SCH. The study was in accordance with the national and international regulations, and the Declaration of Helsinki (2000). All pregnant women who participated in this study signed an informed consent.2, and the obesity-status-classified [The women’s anthropometrics were estimated  at baselassified  GDM was assified .We calculated the gestational weight gain (GWG) as the difference between the pre-pregnancy weight to the weight at the time of delivery, and defined adequate GWG in relation to pre-pregnancy BMI , or as inadequate or excessive if the weight gain was below or exceeded values recommended for pre-pregnancy BMI classes, respectively.We collected sociodemographic  and anthropometric variables of both parents. Finally, we estimated the newborns’ with the following variables: body weight (BW); body length (BL); and head circumference (HC) at birth. Standard deviation scores (SDS) for infant weight and height were calculated following the Italian Neonatal Study Chart .Fasting blood samples were withdrawn from all the participants at week ~38. Red blood cells were isolated from the serum within 2 h, and erythrocyte membranes were isolated using a standard procedure. Briefly, after plasma centrifugation , RBCs were added with acid citrate dextrose, washed with distilled water (10:1), centrifuged  four times, and then were frozen at −80 °C and immediately stored.® Peachtree Corners, GA, USA, Human soluble Cluster of Differentiation 14 ELISA Kit, Catalog #: ELH-CD14; detection range 6–6000 pg/mL; sensitivity 6 pg/mL); sTNFR-II ; IL-6 ; IL-8 ; IL-10 ; MCP-1 ; endotoxin ; and ICAM-1 .Serum was stored for the later assay of the following adipokines and cytokines: human total adiponectin/Acrp30 Quantikine ELISA ; leptin ; sCD14 , or median and inter-quartile range (IRQ) as appropriate. A correlation plot was used to evaluate the correlation between FAs and cytokines (R corplot package version 0.92).As cytokines were found to be not normally distributed , we analyzed their association to FAs with quantile regression for the 50th quantile (median), a method that is applied when the conditions of linear regression are not satisfied and that is robust to outliers.A quantile regression model for each cytokine and FAs one by one at the time was fitted while adjusting for confounders. We considered as confounders variables: maternal age, smoking, GDM, hypertension, gestational age, gestational weight gain, and maternal weight at week 38.p-value < 0.1 of the previous models and the above confounders. Finally, we assessed, in a quantile regression mediation model, three distinct clinical variables , to explore their possible mediating roles in the association between FAs and cytokines, resulting in significant associations in the univariate quantile regressions.For each cytokine, a multiple quantile regression model was fitted by including each FA associated with the cytokine with a The same approach was used to explore the association of patterns between the FAs and the cytokines, i.e., TFAs , SFAs , PUFAs , and PUFAs .Mediation analysis was performed with mediation R package version 4.5.0, and quantile regression with the quantreg R package version 5.94. Heatmap plot was performed with theheatmap.2 function from gplots package version 3.1.3.Il-6 was assessed in 390 women from the whole cohort of 847 women. IL-8 was evaluated in 496 women, while all the other cytokines were examined in 525 women. To keep the relevant IL-6 and IL-8 data in our analysis, we only enclosed the data of 250 women who had complete datasets of FAs and cytokines. No significant differences were found in the lipid RBC membrane profile and cytokine milieu between women with complete and incomplete datasets see . Table 1We reported the mean values and quartiles of the FAs in Several statistically significant associations between FAs and cytokines were found, as reported in p < 0.1 , while adjusting for confounding . Final models are reported in Multiple quantile regression was used to model relationships between each cytokine and the FAs that resulted in significant associations in the quantile regression reported above with Conducting mediation analysis is beneficial to identify the mechanisms behind an observed relationship between an independent variable and a dependent variable through the inclusion of a third variable, known as a mediator. Rather than a direct relationship between the independent and the dependent variable, a mediation model proposes that the independent variable influences the mediator, which in turn influences the dependent variable, as displayed in We evaluated the three distinct variables, namely insulin, pre-pregnancy BMI, and GWG in a quantile regression mediation model to investigate their possible mediating roles in the regulation of the inflammatory patterns for all the pairwise combinations of FA and cytokines that resulted in significant associations in the previous models. Despite several pairwise effects between FAs, cytokines, and clinical variables being found significant, the mediation analysis revealed no relevant mediating roles of the clinical variables in the inflammatory patterns, suggesting that the pairwise effect between fatty acids and cytokines plays a predominant role in the inflammatory effects .The findings we obtained in this study demonstrate that dietary FAs contribute to maintaining the balance between pro-inflammatory and anti-inflammatory responses during pregnancy. In doing so, they favor healthy pregnancy outcomes. It is worth noting that associations of single dietary FAs and circulating cytokines were found to be independent of the obesity status, of the amount of weight gain during pregnancy, and of the insulin levels as the mediation analysis demonstrated. Indeed, differently from what we expected, there was no mediation of body weight, weight gain, or insulin levels found in the association between fatty acids and inflammation. FAs, with regard to SFAs and n-3 PUFAs, are known to influence both sides of insulin metabolism, sensitivity, and glucose-induced insulin secretion ,6. NeverCD14, TNF-RII, and ICAM-1 to be negatively associated with SFAs. TNF-RII was also found to be negatively associated with MUFA levels. No association emerged with PUFAs. Furthermore, several adipokines and cytokines, i.e., adiponectin, were associated with single FAs, but indexes of adiposity were the best predictors for others such as leptin.It is also important to highlight that in our analysis we looked at the association with inflammatory molecules of single FAs but also of groups of FAs, namely SFAs, PUFAs, and TFAs. We selected for investigation a few molecules that affect different paths of inflammation and the immune response, and whose circulating levels have been associated with pregnancy and fetus-related health outcomes ,2. At muFirst, we focused on leptin and adiponectin, whose circulating levels are influenced by the fat mass that is secreted by the adipose tissue. Circulating leptin increases throughout pregnancy, with the highest levels observed in the third trimester owing to the greater body fat stores. Conversely, adiponectin levels decrease ,18.Leptin plays an important role in regulating the energy balance and metabolism, including insulin sensitivity. It affects several physiological processes that are important for pregnancy, such as placental development and function, fetal growth, and development through promoting angiogenesis, and by stimulating the release of insulin-like growth factor-1. Leptin also helps to regulate placental function by increasing the uptake of glucose and amino acids by the placenta . In our Adiponectin is thought to play a role in maintaining healthy pregnancy outcomes by regulating insulin sensitivity, maternal glucose and lipid metabolism, reducing inflammation, and promoting proper placental function, fetal growth, and development . Low levsCD14 is a protein that is released into circulation from immune cells, including monocytes and macrophages, and plays an important role in the immune response, as well as in inflammation and metabolism. Its levels have been found elevated in women with pre-eclampsia and in those who deliver preterm [ preterm . sCD14 h preterm , and sin preterm .Endotoxin is a component of the outer membrane of Gram-negative bacteria and the most powerful activator of the immune system. This molecule crosses the placenta and activates the fetal immune system. Endotoxin exposure during pregnancy has been associated with preterm birth, pre-eclampsia, and fetal growth restriction . EndotoxThere was also a trend for a positive association found between the nervonic-acid C24:1 and levels of both IL-6 and IL-10. Nervonic acid is among the group of cerebrosides which account for approximately 40% of the total FAs in sphingolipids . IL-6 isIL-10 is an anti-inflammatory cytokine that is generated by the placenta, and it helps to maintain a balance between the maternal immune system and the developing fetus. IL-10 levels are elevated during pregnancy, particularly in the third trimester .IL-8 acts as a chemoattractant to white blood cells, particularly neutrophils, to the site of infection or inflammation. IL-8 is produced by the placenta and helps to regulate the growth and development of blood vessels in the placenta. Levels can be elevated during pregnancy, particularly in cases of preterm labor and delivery . In our MCP-1 concentrations were found to be positively associated with C16:0 levels, a SFA which is known to worsen insulin sensitivity and potentiate glucose induced insulin secretion, hence favoring hyperinsulinemia .TNFR-II, significantly elevated levels of the latter molecule were observed in association to GDM. sTNF-R acts as a decoy receptor for TNF. It binds to TNF and prevents it from binding to its cell surface receptors, which can reduce the level of inflammation in the body. There are two types of sTNF-R: sTNF-RI and sTNF-RII, which have different affinities for TNF. During pregnancy, the levels of sTNF-R can be affected. TNF-alpha is involved in several processes during pregnancy, including implantation, placental development, and maintenance of pregnancy [While no associations were found between FAs and levels of regnancy . Howeverregnancy .The only significant association of ICAM-1 at the multivariate quantile model observed was inverse with levels of the SFA myristic acid. ICAM-1 has been implicated in the adhesion and migration of trophoblast cells and in the regulation of angiogenesis. Increased levels of ICAM-1 have been found in the placentas of women with pre-eclampsia, and the molecule has been implicated in the pathogenesis of fetal growth restriction .Findings of our study confirm that there may be complex interactions between different biomarkers during pregnancy, and that changes in the FA levels have downstream effects on the levels of cytokines and other biomarkers of inflammation in pregnant women from a general population on a free diet and no n-3 PUFA supplementation.Studies in the literature mostly have investigated beneficial effects of n-3 PUFAs supplementation during pregnancy on maternal and neonatal outcomes . SupplemStrengths of our study include the profiling of fatty acids on the erythrocyte membranes as markers of dietary intake of lipids during pregnancy instead of referring to plasma levels or to dietary recall. Furthermore, we investigated a population that was a general one on a free diet. Nevertheless, several of the associations that we have described are of an uncertain significance and, owing to the cross-sectional design of study, the causative direction of these relationships cannot be established. Longitudinal studies of healthy and unhealthy women tracking the dietary intake of fats and levels of cytokines along the whole pregnancy are warranted to better understand the effects of dietary FAs on the mother’s health and on the pregnancy outcomes, including the time of delivery. Indeed, we limited our investigation to healthy women, and owing to economical restrains we assessed FAs and inflammatory molecules at the end of the pregnancy. By study design, we excluded women who gave birth before 38 weeks of gestation from the study, although it would have also been of interest to investigate these associations in such groups too. Reduced levels of n-3 PUFAs  and incrOur findings demonstrate the importance of maternal diet during pregnancy to maintain maternal metabolic profile and fetus sustainability. These findings are important when designing dietary strategies to optimize maternal metabolism during pregnancy for a successful pregnancy outcome. The study provides important insights into the complex interplay between different biomarkers during pregnancy and highlights the need for a holistic approach to studying maternal health. Further research is needed to fully understand the implication of these associations, and to explore the potential mechanisms underlying the observed effects.


Stimulating infants to elicit a cry at birth is common but could result in unnecessary handling. We evaluated heart rate in infants who were crying versus non-crying but breathing immediately after birth.crying or non-crying but breathing within 30 s after birth were included. Background demographic data and delivery room events were recorded using tablet-based applications and synchronised with continuous heart rate data recorded by a dry-electrode electrocardiographic monitor. Heart rate centile curves for the first 3 min of life were generated with piecewise regression analysis. Odds of bradycardia and tachycardia were compared using multiple logistic regression.This was single-centre observational study of singleton, vaginally born infants at ≥33 weeks of gestation. Infants who were 1155 crying and 54 non-crying but breathing neonates were included in the final analyses. There were no significant differences in the demographic and obstetric factors between the cohorts. Non-crying but breathing infants had higher rates of early cord clamping <60 s after birth (75.9% vs 46.5%) and admission to the neonatal intensive care unit (13.0% vs 4.3%). There were no significant differences in median heart rates between the cohorts. Non-crying but breathing infants had higher odds of bradycardia  and tachycardia .Infants who are quietly breathing but do not cry after birth have an increased risk of both bradycardia and tachycardia, and admission to the neonatal intensive care unit.ISRCTN18148368. However, international resuscitation algorithms disagree on whether Non-crying but breathing infants have increased risk of bradycardia, tachycardia and neonatal intensive care admission compared with crying infants.While waiting for further studies assessing the role of stimulation in non-crying but breathing infants, these newborns should be monitored carefully for clinical deterioration.does not cry during the first minute after birth warrants evaluation as the globally important Helping Babies Breathe (HBB) neonatal resuscitation algorithm uses lack of cry alone to direct further actions in newborn resuscitation.2The transition to air breathing at birth is a seminal physiological event essential to the onset of pulmonary gas exchange and postnatal survival.Lung fluids play a critical role in early fetal lung development but represent an obstacle to lung expansion and gas exchange post delivery.5Lung recruitment at birth also plays a key role in cardiovascular transition and pulmonary blood flow. Lung aeration increases arterial oxygen content with subsequent decrease in local pulmonary vascular resistance, while shift of liquid from the alveoli to perialveolar tissue triggers a neurally mediated global increase in pulmonary blood flow.With clamping of the umbilical cord and closure of right-to-left shunts, pulmonary venous return becomes the sole source of left intracardiac volume.9crying or non-crying but breathing immediately after birth.For low-resource settings, simple clinical signs are needed for identifying infants in need of resuscitation. We previously demonstrated higher risk of neonatal mortality among neonates who were not crying immediately after birth.This was a secondary analysis of a single-centre prospective observational study conducted over months (28 May–28 October 2019) at Western Regional Hospital, Pokhara, Nepal.Deliveries were attended by a nurse-midwife or a skilled birth attendant with on-call support from a general medical doctor, paediatrician and obstetrician when needed.12All live-born vaginally delivered singleton neonates at or beyond 33 weeks of gestation or with birth weight of >2500 g were eligible for this study.Crying newborns were defined as those who cried within approximately 30 s after birth.Non-crying but breathing newborns were defined as those who did not cry but were noted to be breathing within the same period.All newborns who were non-crying and non-breathing after birth were excluded from this study.Research nurses not part of the clinical care team recorded delivery room observations including periods of breathing and time of cord clamping using a purpose-designed application .Following thorough drying, a NeoBeat newborn HR meter  was placed on the abdomen of the newborn.Information from the Liveborn and SUSTAIN apps were extracted separately and cleaned. Unique identification numbers provided for each participant facilitated synchronisation of data for final analysis.For the final data analysis, we excluded participants’ data when the birth was registered in the Liveborn app more than 10 s after the actual birth; time of birth was not provided; or if there was too little (<30 s), too late (>60 s after birth) or too inconsistent HR data.Maternal and infant demographics, mode of delivery, birth weight, small for gestational age status , gestational age, sex and timing of cord clamping (early <60 s and late ≥60 s after birth) were collected from patient records. A list of maternal and obstetric complications considered is presented in 10.1136/bmjpo-2023-001886.supp1Supplementary data2 test.Means in the two cohorts were compared using independent samples t-test and medians by non-parametric median test. Proportions were compared by Pearson’s χHR data for the crying and non-crying but breathing groups from 10 s until 180 s after birth were analysed using centile curves at 3rd, 10th, 25th, 50th, 75th, 90th and 97th centiles. The curves were smoothed using piecewise cubic spline fitting. Median HRs at two serial time points were compared every 15 s using Mann-Whitney U test with post hoc Bonferroni correction of p values to adjust for repeated measures (p=0.05/12=p≤0.004 for significance).The ORs of bradycardia and tachycardia were explored by logistic regression. Time of cord clamping, gestational age in weeks, birth weight in kilogram and obstetric complications including abnormal fetal HR were included as covariates. Results are presented as aOR with 95% CI.Cumulative proportion of neonates with bradycardia (HR <100 beats/min for ≥1 s) and tachycardia (HR ≥200 beats/min for ≥1 s) in the crying and non-crying but breathing groups were presented using a generalised additive model with 95% CI of continuous data recorded every second.Analyses were performed using R V.4.1.2  and MATLAB R2021a .No patient was involved in this study.During the study period, 3578 deliveries took place at the hospital, of which 1028 were not assessed for eligibility. Of the 2550 births observed, Liveborn was not used in 368 neonates; 57 resulted in a fresh stillbirth and 34 neonates had a gestational age less than 33 weeks. Of the neonates observed with Liveborn, 882 were excluded due to issues with the HR data, Liveborn application or gestational age. Among the 1209 neonates included in the final analyses, 1155 were classified as crying and 54 as non-crying but breathing immediately after birth .There was no significant difference in maternal age, parity or ethnicity in the two cohorts. Infants in the two groups had similar birth weight, gestational age, sex distribution and median Apgar scores at 1 and 5 min . ObstetrNon-crying but breathing infants had a higher proportion of early cord clamping than crying infants  and were more often admitted to the neonatal intensive care unit  .The smoothed 3rd, 10th, 25th, 50th, 75th, 90th and 97th HR centiles in crying and non-crying but breathing groups are displayed in The aOR of bradycardia during the first 180 s after birth was increased in the non-crying but breathing cohort compared with the crying cohort . Similarly, the aOR of tachycardia was increased to 2.86  .The median duration of bradycardia was 7 s (interquartile range [IQR] 4-16 s) and that of tachycardia 11 s (IQR 6-25 s). A total of 6/54 (11.1%) and 48/1155 (4.2%) infants were ever bradycardic, and 6/54 (11.1%) and 71/1155 (6.1%) were ever tachycardic in the non-crying and crying groups, respectively. Bradycardia and tachycardia largely affected separate infants; only one infant was both bradycardic and tachycardic within the first 180 s after birth.A comparison of the cumulative proportion of infants with bradycardia and tachycardia in the crying and non-crying but breathing groups is presented Crying confers physiological advantage over quiet breathing for clearance of lung liquids at birth. This single-centre observational study compared HR in 1155 crying and 54 non-crying but breathing neonates during the first 3 min after birth. There was no difference in the median HR between the two groups, but a larger proportion of non-crying but breathing neonates displayed an unstable HR pattern of either bradycardia  or tachycardia . Non-crying but breathing infants also had a higher risk of admission to the neonatal intensive care unit.et al,Previous papers have presented centile curves for neonatal HR.Another cause of bradycardia in newborns is hypoxia-induced vagal reflex.Results of this study have potential implications for neonatal resuscitation algorithms and clinical practice. Current resuscitation guidelines are inconsistent in whether breathing or crying should guide the need for resuscitation . The HBB20Differentiating well breathing from less effective respiratory effort is challenging, and saturation measurement or abdominal breathing monitoring is not always available in low-income settings. Findings of this study, along with previous research showing higher odds of mortality among non-crying but breathing infants as compared with those who were crying at birth,Outcome data of the study were measured with NeoBeat HR monitor that has been shown to record efficient and reliable HR data.Evaluating breathing patterns in a newborn can be difficult, and complex systems using flow measurement, video and audio recordings are required for confident classification.do not cry are at increased risk of cardiopulmonary instability and should therefore be monitored closely.Crying is a simple clinical indicator of likely adequate lung recruitment facilitating normal physiological transition at birth. Infants who are breathing but


Small vessel disease (SVD) causes most spontaneous intracerebral haemorrhage (ICH) and is associated with widespread microstructural brain tissue disruption, which can be quantified via diffusion tensor imaging (DTI) metrics: mean diffusivity (MD) and fractional anisotropy (FA). Little is known about the impact of whole-brain microstructural alterations after SVD-related ICH. We aimed to investigate: (1) association between whole-brain DTI metrics and functional outcome after ICH; and (2) predictive ability of these metrics compared to the pre-existing ICH score.Sixty-eight patients (38.2% lobar) were retrospectively included. We assessed whole-brain DTI metrics (obtained within 5 days after ICH) in cortical and deep grey matter and white matter. We used univariable logistic regression to assess the associations between DTI and clinical-radiological variables and poor outcome . We determined the optimal predictive variables (via LASSO estimation) in: model 1 (DTI variables only), model 2 (DTI plus non-DTI variables), model 3 (DTI plus ICH score). Optimism-adjusted C-statistics were calculated for each model and compared (likelihood ratio test) against the ICH score.p = 0.010) and white matter MD  were associated  with poor outcome. Discrimination values for model 1 (0.67 [95% CI 0.52–0.83]), model 2 (0.71 [95% CI 0.57–0.85) and model 3 (0.66 [95% CI 0.52–0.82]) were all significantly higher than the ICH score (0.62 [95% CI 0.49–0.75]).Deep grey matter MD (OR 1.04 [95% CI 1.01–1.07], Our exploratory study suggests that whole-brain microstructural disruption measured by DTI is associated with poor 6-month functional outcome after SVD-related ICH. Whole-brain DTI metrics performed better at predicting recovery than the existing ICH score.The online version contains supplementary material available at 10.1007/s00415-023-11592-7. The ICH score was designed to predict short-term (30-day) mortality and has limited predictive performance for longer-term functional outcome, with C-statistics ranging from 0.74 to 0.82 for 6-month functional outcome ), have no prior history of stroke and had small ICH volumes (median volume 7.1 ml [IQR 3.2–13.7]). We found that although DTI metrics were associated with excellent (6-month mRS 0–1) outcome prediction, they did not statistically improve prediction over the ICH score alone. Despite no major differences in terms of pre-ICH mRS between included and excluded patients Below is the link to the electronic supplementary material.