Observational studies have identified various associations between neuroimaging alterations and neuropsychiatric disorders. However, whether such associations could truly reflect causal relations remains still unknown.n = 9,725 to 1,331,010); (2) 110 diffusion tensor imaging (DTI) measurement ; (3) 101 region-of-interest (ROI) volumes, and investigate the causal relationship between brain structures and neuropsychiatric disorders by two-sample Mendelian randomization. Among all DTI-Disorder combinations, we observed a significant causal association between the superior longitudinal fasciculus (SLF) and the risk of Anorexia nervosa (AN) . Similar significant associations were also observed between the body of the corpus callosum  and Alzheimer’s disease . By combining all observations, we found that the overall p-value for DTI − Disorder associations was significantly elevated compared to the null distribution , especially for DTI − Bipolar disorder (BP) (λ = 2.64) and DTI − AN (λ = 1.82). In contrast, for ROI-Disorder combinations, we only found a significant association between the brain region of pars triangularis and Schizophrenia  and no overall p-value elevation for ROI-Disorder analysis compared to the null expectation.Here, we leveraged genome-wide association studies (GWAS) summary statistics for (1) 11 psychiatric disorders (sample sizes varied from As a whole, we show that SLF degeneration may be a risk factor for AN, while DTI variations could be causally related to some neuropsychiatric disorders, such as BP and AN. Also, the white matter structure might have a larger impact on neuropsychiatric disorders than subregion volumes.The online version contains supplementary material available at 10.1186/s12864-021-07661-8. Neuroimaging study is the most widely used procedure for studying brain disorders . Many neSeveral case-control studies with large sample sizes , 9 have N = 17,706 and 19,629) and twelve neuropsychiatric disorders , we implemented a two-sample MR approach to detect the causal relationship between white matter (WM) structures (diffusion tensor imaging [DTI]), brain subregion volumes (region of interest [ROI]), and neuropsychiatric disorders. An overview of the study design is illustrated in Fig. Despite the longitudinal analysis focusing on the high-risk status, an alternative method for addressing the challenge of causality is Mendelian Randomization (MR) . MR has P < 5 × 10− 8 in DTI GWAS [P < 0.05/1320): superior longitudinal fasciculus Axial Diffusivity (SLF.AxD) – the risk of Anorexia nervosa (AN) . Another DTI-Disorder pair, body of corpus callosum Fractional Anisotropy (BCC.FA) − Alzheimer disease (AD), was close to reaching SW significance . Both associations had relatively consistent results across instruments   DTI-Disorder pairs and 973/1212 (101*12) ROI-Disorder pairs had at least one strong instrument  . The exiP value for all DTI-Disorder pairs and compared them to the null uniform distribution ; this result persisted after removing heterogeneous DTI-Disorder pairs (those with Cochran’s P < 0.05)  or outlier instruments (SNPs with MR-PRESSO P < 0.05) . When we analyzed each disease separately  and AN (pp for λ: 0.012) were not due to the bias inherent in the data or method. Additionally, heterogeneous DTI-Disorder pairs generally had non-significant MR results and did not contribute to inflation  and were analyzed by MR. In the IVW analysis, we found no SW significant results  . The SMR-HEIDI test detected a significant MR effect in the same direction  with no evidence of colocalization pleiotropy (HEIDI P = 0.84). We estimated that per 1-SD increment in normalized PT volume, the risk of SCZ decreased by 52 % (OR = 0.48). In conclusion, these results suggested a potential causal relationship between PT and SCZ. However, the validation of this relationship requires more work on potential pleiotropy.Similar to the DTI-Disorder analysis, we also assessed the ROI-Disorder association. 973/1212 (101*12) RD pairs had at least one strong instrument (SNP with P = 0.12) and outliers (KS P = 0.07). However, IVW p-value for SCZ showed significant inflation , and the result was significantly impacted by heterogeneity  Fig. a and 4b.Our study’s top MR result was a novel risk factor for AN—namely, decreased SLF.AxD. A few studies have reported a decreased SLF integrity in AN patients , 24, butThe roles of BCC in AD and PT in SCZ—2 marginally significant results from our MR analysis—have received more attention in the literature than SLF in AN. However, both MR results should be interpreted with caution. BCC atrophy is widely observed in AD patients even at an early stage and reflects Wallerian degeneration and myelin breakdown . HoweverP values. Future GWAS with a larger sample size, both for neuroimaging polymorphism and neuropsychiatric disorders, will provide a better chance to improve our understanding in this field.There were some limitations to this study. Firstly, classic MR methods largely depend on high heritability and strong exposure instruments , 28. HowIn conclusion, our analysis results demonstrate that, in general, WM structures make a more significant contribution to the etiology of neuropsychiatric disorders—especially BP and AN—than brain subregion volumes. SLF.AxD was causally related to AN; marginally significant relationships were also found between BCC.FA and AD and between PT and SCZ.We obtained publicly available GWAS summary statistics for DTI, ROI, and neuropsychiatric without collecting any individual information. Ethics approval was obtained in each of the original studies; therefore, no further ethics approval was needed for the current study.The genetic instruments for DTI measurements have been previously described . BrieflyWe collected GWAS summary statistics from the following neuropsychiatric studies on European cohorts: 1) Alzheimer disease (AD) ; (2) Att AlzheimeP < 5 × 10− 8 as strong instruments for MR; measurements without a strong instrument were discarded. We removed SNPs with linkage disequilibrium (LD) r2 ≥ 0.001 for each measurement using reference LD data from the 1000 Genomes Project [For each DTI and ROI measurement, we retained single nucleotide polymorphisms (SNPs) with  Project . Data ha Project . Since mWe calculated the variance in phenotype explained by each instrument byWhere EAF was the effect allele frequency, β was the effect size, N was the sample size, and se(β) was the standard error of effect size. The F statistic was then denoted as2 and F were used to evaluate power for each instrument. For each RD and DTI-Disorder pair, we calculated the overall MR power using mRnd tool [RRnd tool , assuminFor DD/RD pairs with at least two instruments, we performed a meta-analysis of each instrument’s MR effect using the inverse variance–weighted (IVW) method. The results were considered preliminary results and were used for downstream analyses. For the top IVW findings, we additionally applied weighted mode , weightep-value was adjusted by the Bonferroni method by numbers of all DTI-Disorder pairs (1320) or ROI-Disorder pairs (1212).Since both IVW and Wald ratio results were taken into account, the p-value for heterogeneity; those with outlier(s) were reanalyzed by IVW after removing the outlier(s). We also applied leave-one-out tests for all top findings to further evaluate the effects of unknown outliers.The intercept of the Egger regression was used as an indicator of potential horizontal pleiotropy, while modified Cochran’s Q for IVW and Rucker’s Q for Egger regression  were useP < 5 × 10− 8 for each neuropsychiatric disorder as instruments. The absence of a reverse MR effect (IVW P > 0.05) was considered as evidence for the validity of directionality.For all MR results, we tested the reverse MR effect  by selecting SNPs with P values, we shuffled SNP labels for BP and AN 1,000 times to carry out a permutation test. Permutation P < 0.05 was considered evidence for significant inflation. These tests were also separately applied to each disease and repeated after removing heterogeneous results (those with Cochran’s P < 0.05) or outlier SNPs (those with MR-PRESSO P < 0.05).To assess the general contribution of DTI (ROI) polymorphisms to neuropsychiatric disorder, we pooled the IVW P values for all DTI-Disorder (RD) pairs and compared them to the null uniform distribution using quantile-quantile plots. A positive bias (inflation) from uniform distribution was considered as evidence for a general contribution. The significance of inflation was evaluated with the Kolmogorov–Smirnov (KS) test, while the extent of inflation was assessed with the inflation factor λ, which was calculated by chi-square regression using the GenABEL R package . Since tAdditional file 1. Summary statistics for all instrument variables after data harmonization.Additional file 2. Full results for DTI-Disease association analysis.Additional file 3. Full results for ROI-Disease association analysis.Additional file 4. Funnel plots for top MR findings, leave-one-out results for top DTI-Disorder pairs, general contribution of DTI to neuropsychiatric disease after sensitivity test adjustment, Rank-Rank overlaps between MR effect and heterogeneity for ROI-Disease analysis.


To compare the clinical efficacy and safety of arthroscopic internal drainage for the treatment of unicameral popliteal cysts with or without cyst wall resection.This was a retrospective case–control study of 73 patients diagnosed with unicameral popliteal cysts from January 2012 to January 2019 who received arthroscopic treatment. The study included 38 cases with cyst wall resection (CWR group) and 35 cases with cyst wall preservation (CWP group). The CWR group consisted of 14 men and 24 women with an average age of 51.8 years, while the CWP group consisted of 13 men and 22 women with an average age of 52.0 years. All patients were examined for intra‐articular lesions and communicating ports by magnetic resonance imaging (MRI) prior to surgery, and recurrence of cysts was evaluated at the last follow‐up examination. Rauschning and Lindgren grade (R–L grade) and Lysholm score were used to evaluate clinical outcomes. In addition, operation time and complications were recorded.P > 0.05). The last follow‐up MRI scans showed that in the CWR group, the cyst disappeared in 25 cases and shrunk in 13 cases. In the CWP group, the cyst disappeared in 22 cases, shrunk in 12 cases and persisted in one case. There was no obvious difference in recurrence rate between the two groups . At the last follow‐up, there were no differences in the R–L grade (P = 0.630) and Lysholm score  between the two groups. Compared with the CWP group, operation time was significantly prolonged in the CWR group . In the CWR group, three cases occurred fluid infiltration under the gastrocnemius muscle, which improved after pressure bandaging and cold compress. In another three cases, hematoma was found. The incidence of complications in the CWR group was markedly higher than that in the CWP group . During the follow‐up period, none of the patients developed serious complications such as neurovascular injury, deep venous thrombosis, or infection.The average length of follow‐up was 24.2 months . There were no considerable differences in age, gender, cyst size, Lysholm score, R–L grade and concomitant intra‐articular cases between the CWR group and CWP group prior to surgery (For unicameral popliteal cysts, arthroscopic internal drainage combined with resection of the cyst wall did not further improve the clinical outcomes or reduce the recurrence rate, while prolonging the operation time and increasing the possibility of complications. This paper evaluated the necessity of additional removal of the capsule wall after arthroscopic internal drainage in the treatment of popliteal cyst, and concluded that resection of the capsule wall would not produce better outcomes. The body of research by Rauschning and Lindgrenet al.Popliteal cyst is a common cystic lesion around the knee joint, most frequently characterized by expansion of the gastrocnemius‐semimembranosus bursaet al.Popliteal cysts may be divided into primary and secondary cysts based on the different pathogenesis. Secondary popliteal cysts are most common in adultsPosterior open surgery has traditionally been used for symptomatic popliteal cysts with ineffective conservationvs arthroscopic internal drainage only have been used successfully in the treatment of popliteal cysts by different scholars, and their research has already shown some promising results. However, to our knowledge, the majority of studies have independently evaluated the efficacy of internal drainage combined with cyst wall resection or arthroscopic drainage only, but few controlled trials have been designed to compare the outcomes of the two surgical procedures.Arthroscopy has been widely used in the treatment of popliteal cystsIn this study, we retrospectively analyzed the outcomes of arthroscopic internal drainage combined with cyst wall resection compared with arthroscopic internal drainage combined with cyst wall preservation in the treatment of unicameral popliteal cysts. The aims of this study were to: (i) compare differences in operative time and clinical efficacy between cyst wall resection and cyst wall preservation; (ii) describe recurrence of popliteal cysts in patients with or without cyst wall preservation and clarify whether additional cyst wall resection is necessary after arthroscopic internal drainage; and (iii) report the incidence of complications between the two groups to compare the safety of the two surgical approaches.This retrospective case–control study was conducted at the Department of Orthopedics in the Second Affiliated Hospital of Shanxi Medical University from January 2012 to January 2019. The protocol for the study has been approved by the Ethics Committee of the Second Affiliated Hospital of Shanxi Medical University and conforms to the provisions of the Declaration of Helsinki. Written informed consent to participate was obtained from all patients.The inclusion criteria were: (i) patients with symptomatic unicameral popliteal cysts based on concomitant intra‐articular lesions and communication between the cysts and the articular cavity observed during preoperative MRI; (ii) treatment with arthroscopic internal drainage combined with cyst wall resection; (iii) treatment with arthroscopic internal drainage; (iv) R–L grade, Lysholm score, recurrence, complication were compared; (v) retrospective case–control study.The exclusion criteria were: (i) previous arthroscopic or open surgery for cysts; (ii) formation of an internal septum leading to a multilocular cyst; (iii) co‐occurring ligament injury, rheumatoid arthritis, infectious arthritis, or gouty arthritis; (iv) co‐occurring diabetes mellitus, hypercoagulable state, or chronic thrombotic disease of lower limbs; (v) postoperative surgery for other diseases; (vi) no complete follow‐up.Eighty‐eight patients diagnosed with popliteal cysts were retrieved from the medical records system. A total of 76 patients met the inclusion criteria. Thirty‐nine cases were treated by arthroscopic internal drainage combined with cyst wall resection, while 37 cases were treated by arthroscopic internal drainage only. One case in the CWR group received surgical treatment for appendicitis 3 months after the operation, while in the CWP group, one case was lost to follow‐up and one case refused to undergo MRI after the operation. All three patients were excluded from the study. The remaining 73 cases (including 38 cases in the CWR group and 35 cases in the CWP group) were included in the analysis. There were 27 men and 46 women with an average time of onset of 12.8 months (range 6 to 24 months). The popliteal cysts were located in the right knee in 33 cases and in the left knee in 40 cases. All operations were performed by the same senior author.After spinal or general anesthesia, arthroscopic surgery was performed with the patient placed in supine position. A tourniquet applied at the base of the thigh was used to control bleeding and improve vision of the surgical incision.Routine anterolateral and anteromedial approaches have been established to explore and treat intra‐articular lesions  Fig. .After treatment of intra‐articular lesions, the lens entered the posteromedial compartment through the space between the posterior cruciate ligament and the posterior horn of the medial meniscus through the intercondylar fossa at 90° flexion of the knee joint Fig. . The firA shaver and probe were used alternately to find the opening fissure of the gastrocnemius‐semimembranous bursa at the articular capsule folds behind the femoral medial condyle Fig. . After cFollowing surgery, the joint cavity was washed and the incision was closed following conventional procedures with no drainage tube. An elastic bandage was used to apply pressure to the sutured area.The position of patients and surgical methods of cyst drainage under arthroscopy were identical to those of the CWP group.After internal drainage, the lens was transferred from the anterolateral portal to the PM portal, and extended from the posteromedial side of the medial head of the gastrocnemius muscle to the interior of the cyst, exposing the smooth inner surface of the capsule wall Fig. . FurtherThe PM portal was used to observe the cyst under arthroscopy. The HPM portal was used for the arthroscopic surgery Fig. . A shaveFollowing surgery, the joint cavity was washed and the incision was closed following conventional procedures with no drainage tube. An elastic bandage was used to apply pressure to the sutured area.The medical charts were reviewed to obtain clinical data, including cyst size, intraoperative findings, duration of surgery. Recurrence and complications were recorded during the follow‐up visit. R–L grade and Lysholm score were used to evaluate the preoperative status and postoperative outcome.Rauschning and Lindgren grade (0–3) is used to evaluate knee joint symptoms in patients with popliteal cysts, according to swelling, pain, instability, limitation of movement, and ability to work and participate in sports. The Rauschning and Lindgren grading is as follows: grade 0 – no swelling or pain, no limitation of range of motion, no instability or weakness, no limitation in work or sports participation; grade 1 – slight swelling and discomfort after strenuous exercise, slight weakness and <1 cm muscular atrophy, negligible limitations to range of motion (<10 degrees), patient is restricted from hard labor and elite sports participation; grade 2 – moderate swelling, pain following moderate exertion, slight or moderate instability and 1–2 cm muscular atrophy, slight limitation to range of motion (10°–20°), patient is restricted from physical work and is permitted limited participation in sports; grade 3 – considerable swelling, severe pain interfering with daily activities, pain at rest, disabling instability, contractures and >2 cm muscular atrophy, limited range of motion (>20°), joint may be nonfunctional due to derangement, no participation in sportsThe Lysholm Knee Scoring Scale is a patient completed questionnaire commonly used to assess the performance and activity restrictions both before and after arthroscopic knee surgery. It consists of eight items: limpness , support , locking , instability , pain , swelling , stair climbing , squatting . The total score is the sum of each response to the eight items. Maximum score is 100 points, which means no symptoms or disability. Scores are categorized as excellent (95–100), good (84–94), fair (65–83), or poor (<64)Ultrasound or MRI was performed on all patients before surgery to confirm the presence of a popliteal cyst and detect the associated intra‐articular pathology. At the last follow‐up, an MRI scan was performed to determine if the cyst had recurred. Complications were also recorded. The results were expressed as disappearance, shrink, and persistence, of which the persistence was identified as recurrence.P‐value <0.05 was considered statistically significant.All statistical analyses were performed using SPSS software . The continuous variables with normal distribution were displayed as mean ± SD deviation. Independent sample t‐tests were used to compare continuous data between groups. Categorical variables were presented with absolute frequencies (n) and percentages (%). Pearson chi‐square test or a Fisher's exact probability test were used to compare count data. The rank variables were examined by Wilcoxon rank sum test. All statistical tests were two‐sided and were evaluated at the significance level of 5%, a P = 0.247). Symptoms associated with popliteal cysts had disappeared in most patients by the last follow‐up examination.All patients underwent follow‐up examinations in the outpatient department. The average follow‐up period was 24.2 months . The mean follow‐up times of the CWR group and the CWP group were 24.8 months  and 23.5 months , respectively. The subgroup data were presented in Table P = 0.624), gender distribution (P = 0.979), cyst size (P = 0.512), Lysholm score (P = 0.096), and R–L grade (P = 0.360).A total of 73 cases of popliteal cysts was investigated, 38 cases in the CWR group and 35 cases in the CWP group. Baseline characteristics for patients in the two group were listed in Table In all cases, correlative intra‐articular lesions were treated, and the two‐way communication mechanism between the posteromedial compartment and the cyst was restored under arthroscopy. In the CWR group, the cyst wall was completely dissected through the high posteromedial portal combined with internal drainage decompression. In the CWP group, only internal drainage decompression was performed and the cyst wall was preserved.P = 0.990)   Fig. ; cartilaP = 0.630).According to the Rauschning and Lindgren grade, the distributions of the CWR group at the final follow‐up were as follows: grade 0 in 26 patients, grade I in 11 patients, and grade II in one patient. The relevant findings in the CWP group at the final follow‐up were: grade 0 in 23 patients, grade I in eight patients, and grade II in four patients Fig. . There wP = 0.071)  Table .vs 2.9%, P = 0.899)   and between meniscus tear and popliteal cysts (P = 0.01). In this study, the most common intra‐articular pathology detected under arthroscopy was medial meniscus injury (69.6%).Although the etiology of popliteal cyst is still unclear, it is generally believed that intra‐articular pathology plays an indispensable role in the formation of popliteal cyst. Some studieset al.et al.In addition, valve mechanism is also a key factor in the persistence of popliteal cyst. Kim et al.At present, proper treatment of the cyst wall has brought new challenges to the arthroscopic treatment of popliteal cysts. Interestingly, there are currently few controlled studies on cyst wall resection and preservationet al.et al.et al.Numerous researchers prefer complete cyst wall resection. Chen To our knowledge, resection of the cyst wall increases operation time and the possibility of concomitant injury. The popliteal neurovascular bundle, which is usually on the outer side of the cyst, is the main neurovascular structure at risk during surgery. Large cysts often compress the adjacent popliteal artery and vein, resulting in slight displacement of blood vessels. Therefore, when using a shaver to remove the inner cyst wall, light suction should be applied to avoid drawing blood vessels and nerves into the shaver, especially when the cyst has extended to the posterolateral side. In addition, removal of the cyst wall requires the confirmation of an additional posteromedial portal, which is the accumulation of experience and puts forward higher surgical requirements for surgeons.Based on our experience, when there is a septum in the capsule, we recommend that experienced surgeons plane the cyst wall to reduce the potential for recurrence caused by the septumOur research has several limitations. First, we have designed a retrospective control study, but the inherent limitation of retrospective study should be considered. Second, the follow‐up period was relatively short and cysts could recur at a later time. In addition, our small sample size may limit the statistical power of the study. Due to these factors, the conclusion reached may be biased. These limitations need to be addressed by conducting a multi‐center, long‐term follow‐up randomized control study with a large sample population in the future.In conclusion, for unicameral cysts, resection of the cyst wall is not recommended, because it does not benefit in terms of clinical outcomes and recurrence rate compared with retaining the cyst wall; on the contrary, it increases the operation time and the probability of complications.


Preterm birth can lead to impaired language development. This study aimed to predict language outcomes at 2 years corrected gestational age (CGA) for children born preterm.We analysed data from 89 preterm neonates (median GA 29 weeks) who underwent diffusion MRI (dMRI) at term-equivalent age and language assessment at 2 years CGA using the Bayley-III. Feature selection and a random forests classifier were used to differentiate typical versus delayed (Bayley-III language composite score <85) language development.The model achieved balanced accuracy: 91%, sensitivity: 86%, and specificity: 96%. The probability of language delay at 2 years CGA is increased with: increasing values of peak width of skeletonized fractional anisotropy (PSFA), radial diffusivity (PSRD), and axial diffusivity (PSAD) derived from dMRI; among twins; and after an incomplete course of, or no exposure to, antenatal corticosteroids. Female sex and breastfeeding during the neonatal period reduced the risk of language delay.The combination of perinatal clinical information and MRI features leads to accurate prediction of preterm infants who are likely to develop language deficits in early childhood. This model could potentially enable stratification of preterm children at risk of language dysfunction who may benefit from targeted early interventions.A combination of clinical perinatal factors and neonatal DTI measures of white matter microstructure leads to accurate prediction of language outcome at 2 years corrected gestational age following preterm birth.A model that comprises clinical and MRI features that has potential to be scalable across centres. It offers a basis for enhancing the power and generalizability of diagnostic and prognostic studies of neurodevelopmental disorders associated with language impairment.Early identification of infants who are at risk of language delay, facilitating targeted early interventions and support services, which could improve the quality of life for children born preterm. Ambalavanan et al.11 reported that neurodevelopmental impairment at 18–22 months CGA was predicted by combining sex, respiratory illness severity, and enlarged ventricular size, periventricular leukomalacia, or porencephalic cyst on cranial ultrasound. Vesoulis et al.12 developed a tool for prediction of risk of neurodevelopmental impairment at 18–24 months CGA. This tool comprised of ventilator days, mode of delivery, exposure to antenatal corticosteroids, retinopathy of prematurity (ROP) requiring surgery, and magnetic resonance imaging (MRI) findings .Nonetheless, a few studies have built and validated tools for prediction of the composite outcome of neurodevelopmental impairment at 2 years corrected gestational age (CGA) for children born preterm. Tyson et al.13 evaluated the predictive value of structural MRI and DTI variables for classification of very preterm infants at high versus low risk of language delay. They developed a model for prediction of language delay that included DTI variables in three brain regions and achieved 89% sensitivity and 86% specificity. Ball et al.14 revealed that distinct patterns of brain structure and microstructure following preterm birth are linked to specific clinical and environmental factors, and these patterns correlate with neurodevelopmental outcome at 18–24 months CGA. Language outcome was associated with specific neuroanatomic variation, which was linked to age at scan, need for continuous positive airway pressure, birth weight, GA at birth, parenteral nutrition, surfactant administration, and mechanical ventilation.However, deficits in different developmental domains require different therapies and targeted support strategies. Thus, tools for stratification of children at high risk of impairment in specific developmental domains would be valuable. Recently, Vassar et al.15 demonstrated that histogram-based variables derived from DTI , which represent generalized water content and myelination, can be used as biomarkers of microstructural white matter alterations associated with preterm birth. The advantage of the histogram-based framework is that it is fully automated, captures generalized white matter dysmaturation that characterizes the encephalopathy of prematurity, is computationally inexpensive compared with tract-specific approaches, and has high inter-scanner reproducibility.16In view of this evidence, we hypothesized that a combination of clinical, environmental, and imaging factors derived from DTI that capture generalized white matter dysmaturation would potentially enhance the prediction of language outcomes at 2 years CGA following preterm birth. Blesa et al.A prediction tool that combines clinical data and imaging biomarkers for early language development is lacking, and yet timely identification of future language deficits has clinical and research implications, because it could stratify infants at most need for early interventions. Here we aimed to develop a machine learning model that accurately predicts typical versus delayed language outcomes at 2 years CGA using a parsimonious feature set derived from clinical, demographic, and histogram-based variables computed from neonatal brain DTI.17 Selection from the larger cohort was based on availability of diffusion MRI (dMRI) scans at term-equivalent age and 2-year language outcome. Ethical approval was obtained from the UK National Research Ethics Service (NRES), South East Scotland Research Ethics Committee (NRES numbers 11/55/0061 and 13/SS/0143). Written informed consent from parents/carers was obtained for all neonates. Exclusion criteria for the study were congenital anomalies, chromosomal abnormalities, congenital infections or major overt parenchymal lesions , and post-haemorrhagic ventricular dilatation. Infants with a contraindication to MRI at 3 Tesla were also excluded.Participants were selected from a longitudinal cohort of preterm neonates born at ≤33 weeks of gestation at the Royal Infirmary of Edinburgh between February 2012 and August 2015.19 GA (based on first trimester ultrasound),18 birth weight,20 maternal age,21 primiparity,19 twin status,20 maternal body mass index (BMI),22 medical history of maternal depression,23 administration of a complete course of antenatal corticosteroids for foetal lung maturation (defined as two doses 24 h apart), any antenatal corticosteroid exposure,20 administration of antenatal magnesium sulfate (MgSO4) for neuroprotection,24 mode of delivery ,19 total days requiring intubation while in the neonatal intensive care unit (NICU),18 bronchopulmonary dysplasia (defined as oxygen requirement at ≥36 weeks CGA),26 late-onset sepsis  bacterial pathogen isolated from blood culture or (b) blood culture growing coagulase-negative staphylococcus, along with one or more signs of generalized infection, and treatment with intravenous antibiotics for ≥5 days),20 necrotizing enterocolitis ,28 ROP treated with laser therapy,29 and type of infant feeding at discharge from the neonatal unit .30 All infants had placental histopathology performed and histological chorioamnionitis was defined using an established system.31 Maternal level of education 20 and socioeconomic status of the family, operationalized as Scottish Index of Multiple Deprivation 2016 (SIMD16) quintile, where 1 indicates the most deprived and 5 indicates the least deprived (https://www2.gov.scot/Topics/Statistics/SIMD), were also included.The selection of clinical and demographic features included in models was guided by extant literature linking biological and environmental exposures with neurocognitive development in preterm infants. Specifically, we studied the contribution towards prediction of language outcome at 2 years CGA of the following features: sex,Infants underwent a brain MRI scan at term-equivalent age (38–42 weeks GA) without sedation, during natural sleep after having been fed and swaddled. Vital signs were monitored throughout the scan, and hearing protection was provided for all neonates . All scans were supervised by a physician and a paediatric nurse trained in neonatal resuscitation.b = 750 s/mm2) single-shot, spin-echo, echo planar imaging volumes collected in the axial plane with 2 mm isotropic voxels .A Siemens MAGNETOM Verio 3-Tesla MRI clinical scanner  and 12-channel phased-array head coil were used to acquire dMRI data consisting of 11 T2-weighted and 64 diffusion-weighted  as the response variable. The clinical cut-off of 85 (i.e. 1 SD below the mean) was used in order to assign children into two distinct groups, thus creating a binary outcome; children whose score was <85 were considered to have moderate-to-severe language impairment, while scores ≥85 were considered as normal range or higher.40All children took part in a developmental assessment with a trained clinician at 2 years CGA  using the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III).41 (b) ReliefF expRank,43 and (c) random forests (RF) variable importance.44 The Boruta algorithm is a wrapper feature selection technique built around the RF learner, which uses Z score as the importance measure. In other words, it measures the importance of each feature by dividing the average loss of accuracy among all trees by the standard deviation of the accuracy loss. The basic idea of the ReliefF algorithm is to assign a ‘weight’ value to all features of a data set based on how well their values distinguish between the instances that are near to each other and thus how useful they are in predicting the response variable. The important features will have a large weight, while the redundant ones will have a low weight. In RF variable importance, variable importance is computed using the mean decrease in Gini index. We can measure the total amount that the Gini index is decreased by splits over a given feature, averaged over all trees. A large value indicates an important feature. In all cases, we obtain a feature ranking indicating in descending order their contribution towards prediction of the response variable. The final feature subset for each feature selection algorithm was selected using leave-one-out cross-validation (LOOCV), using only the training data set in each cross-validation iteration and following the process described by Tsanas et al.45 Subsequently, the selected feature subset was presented into a RF classifier46 in order to predict the binarized language composite score. Partial dependence plots (PDP)47 were constructed in order to assess how the selected features influence the prediction of the RF classifier. To quantify the strength of the association between the selected features, we used correlation analysis .We compared three feature selection algorithms: (a) Boruta,48 which has been previously used in similar unbalanced applications in the healthcare domain.53 We found that SMOTE yields the best results, which are presented in the paper. SMOTE is a training data enrichment method, where the minority class is over-sampled by creating new synthetic samples, to create a balanced data set. For each minority class sample, the k minority class nearest neighbours were identified  and synthetic samples were introduced along the line segments joining any or all of the k minority class nearest neighbours. Model validation was implemented using LOOCV. LOOCV involves holding out a single observation to be used as the test set, while the learner is trained using the remaining n − 1 observations . The process is repeated n times and each time a different observation from the original data set is used as the test set. The result is n estimates of the test error. The final test error rate is the average of these n test error estimates. The accuracy of the model was assessed by constructing a confusion matrix, which is a contingency table of the observed and predicted classes. Missing data for both numeric and categorical features were imputed using multiple imputation by chained equations (five imputed data sets were created in each LOOCV iteration),55 based only on the information in the training set independently within each LOOCV iteration. Data analysis was conducted in R. The R packages used were: tidyverse, dplyr, caret, randomForest, CORElearn, Boruta, mice, ggplot2, DMwR, Hmisc, RGraphics, grid, gridExtra, and gridGraphics.The data set is imbalanced since only 16% of the study group had a language composite score <85. To overcome the class imbalance problem in the data set, we explored different data balancing techniques: under-sampling of the majority class, over-sampling of the minority class, and the synthetic minority over-sampling technique (SMOTE),Two-year language data and dMRI of the brain at term-equivalent age were available from 89 children; demographic and clinical characteristics of the study population are presented in Table Figure Table Finally, we repeated the analysis to investigate separately the performance of the model when presented only with either clinical or MRI features, which led to reduced model performance. As shown in Table We developed a parsimonious machine learning model that accurately identifies preterm infants who are likely to develop language impairment in early childhood. We explored the predictive value of 24 clinical, demographic, and brain imaging features and found that a robust subset of eight clinical characteristics and imaging biomarkers best predicts a language composite score <85 on the Bayley-III: PSFA, PSRD, PSAD, twin status, administration of an incomplete course of antenatal corticosteroids, no exposure to antenatal corticosteroids, male sex, and feeding with exclusive formula milk or mixed formula and breast milk. Overall, we demonstrated out-of-sample balanced accuracy: 91%, sensitivity: 86%, and specificity: 96%.56 where they performed very competitively against many established feature selection approaches. In general, we would expect a wrapper or embedded method to perform better for a particular choice of a classifier, although it might not necessarily generalize very well with the choice of different classifiers.Feature selection was conducted by comparing three feature selection algorithms: (a) Boruta, (b) ReliefF expRank, and (c) RF variable importance. Feature selection methods can be broadly considered into three main categories: filter, wrapper, embedded methods. Filter feature selection methods work independently of a statistical learner relying on the general statistical properties of the data and thus select a feature subset that is not tuned or optimized towards a specific learning algorithm. Wrapper methods take a particular machine learning method into account in order to choose the best subset of the original features. They evaluate multiple models by training and testing in the feature space, thus optimizing the performance of the particular machine learning model that was used. Embedded methods choose the subset of features while the learning model is being constructed. This means that the resulting feature subset is specific to a particular learning algorithm. We chose to use a feature selection algorithm from each main category for our exploration; ReliefF is a filter technique, Boruta is wrapper feature selection technique built around the RF learner, and RF variable importance is an embedded method. The use of ReliefF and the RF importance have been extensively used and validated in many different applications and we have previously conducted a thorough empirical study15 are predictive of impaired language development at 2 years CGA. We explored the predictive value of whole-brain measures of PS DTI metrics, instead of tract-specific segmentations, because preterm brain dysmaturation is a substantially generalized process,57 and language development draws on broad cognitive capacities. We have found that the probability of language delay is higher with increased PSFA, PSRD, and PSAD. These features are consistent with delayed myelination, less coherent white matter organization, and altered axonal integrity in the preterm brain.58 Previous research has also shown that abnormalities in brain structure following preterm birth are correlated with long-term neurodevelopmental outcome.59Our findings suggest that PSFA, PSRD, and PSAD, which detect generalized white matter microstructural alterations in preterm infants compared to infants born at term,60 and language delay61 at 2 years CGA. Language delay in twins can be attributed to postnatal environmental factors;63 twins receive a less focussed and less elaborated communicative interchange with their parents than do singletons. Thorpe et al.62 compared families with twins to families with pairs of closely spaced singletons. This study found that language delay in twins compared to singletons may be explained by patterns of parent–child interaction and communication. Antenatal corticosteroid administration is associated with lower risk of language deficits, which has been previously proved by research.12 Our findings suggest that male sex is a risk factor for language impairment in early childhood, consistent with previous studies that have associated male sex with poorer neurodevelopmental outcome following preterm birth.19The data show that twin status is associated with increased risk of impaired language development. This finding is consistent with studies in the extant literature which have found that multiple pregnancy is associated with neurodevelopmental impairment30 and in the general population breast milk intake in infancy is associated with improved performance on intelligence tests.64 In line with this, we found that exclusive breastfeeding is associated with improved language outcomes compared to formula feeding or mixed breast and formula feeding. It is surprising that GA at birth was not included in the final feature set. However, its influence on long-term outcome may be captured by PSRD and PSAD, which are strongly correlated with GA at birth.15Moreover, previous work has shown that exclusive breast milk feeding in the weeks following preterm birth can enhance brain development,16 meaning that they can be easily obtained for preterm neonates who undergo a dMRI scan at term-equivalent age and can be used for multi-centre studies. Thus, our model comprises features that can be easily obtained for future clinical application.This study is the first to investigate the use of PS DTI metrics as predictors for language development in the preterm population. The advantage of using these image biomarkers is that their calculation is fully automated, computationally inexpensive, and has high inter-scanner reproducibility,12 However, deficits in different developmental domains require different interventions. Therefore, tools for timely identification of children at risk of impairment in specific developmental domains are valuable. The developed model predicts language deficits at 2 years CGA. Recently, a model was developed for classification of very preterm infants at high versus low risk for language delay, which achieved 89% sensitivity and 86% specificity.13 That model included DTI variables in three brain regions: MD of right sagittal stratum and right inferior occipital gyrus and AD of right lingual gyrus. However, whole-brain calculation of DTI variables is computationally expensive; hence, we investigated the predictive value of histogram-based variables derived from DTI. We have shown that combining DTI metrics with perinatal factors, along with the use of advanced machine learning techniques, can further improve identification of children at risk of language impairment.Hitherto, few studies have focussed on developing and validating prediction models for early neurodevelopmental outcomes for children born preterm. Most tools predict the composite outcome of neurodevelopmental impairment.The main strength of our study is that we had a longitudinal cohort of preterm infants that is deeply phenotyped with brain imaging and biological information that enabled us to investigate a large number of clinical, demographic, social, and DTI variables. We acknowledge some limitations in our study. The sample size is relatively small, and this is a single-centre study, so despite our best efforts with standard model validation techniques to assess model generalization we would need to further validate findings in a different cohort. Nonetheless, the study population was fairly representative of NICU populations in terms of comorbidities that have been associated with long-term neurodevelopmental outcomes. In addition, cortical grey matter was not assessed in this study. We focussed on alterations in white matter microstructure, since it is the most consistently abnormal finding in preterm infants, by measuring a functionally tractable property using a tool that is readily applied to clinical image data. Future studies could aim to validate our model in additional external cohorts and also apply machine learning techniques for prediction of motor, cognitive, and social–emotional outcomes for children born preterm.A combination of clinical perinatal factors and neonatal DTI measures of white matter microstructure best predict language impairment at 2 years after preterm birth. This model has the potential to enable clinicians identify infants who are at risk of language delay, thus facilitating targeted early intervention and support services. The model comprises clinical and MRI features that have potential to be scalable across centres, so it offers a basis for enhancing the power and generalizability of diagnostic and prognostic studies of neurodevelopmental disorders associated with language impairment.Supplementary abbreviations


Choledochal cysts are congenital malformations of the biliary tract that involve aberrant configurations of the pancreaticobiliary ductal system. The pathology exists on a spectrum from fusiform dilation of the common bile duct to multiple dilations involving the intra- and extrahepatic bile ducts with potential risks of malignant transformation and hepatic fibrosis. Advancements in ultrasound technology have increased the incidence of prenatal diagnosis of choledochal cysts. Here, we present the case of a prenatally diagnosed initially asymptomatic Type I choledochal cyst with rapid progression in the neonatal period to a complete gastric outlet obstruction within the first month of life. We demonstrate the feasibility of cyst resection and reconstruction with Roux-en-Y hepaticojejunostomy in the neonatal age group. Finally, we discuss management of the case based on evolving imaging findings and laboratory evidence of impending liver dysfunction. Choledochal cysts (CCs) are rare and usually benign abnormalities consisting of a single or multiple dilations of the intra- or extrahepatic bile ducts. Though the exact cause of these malformations is unknown, a commonly accepted etiology is an anomalous junction between the pancreatic and common bile duct (CBD), resulting in reflux of pancreatic fluid into the CBD leading to weakening of the bile duct wall and cyst formation , 2. WhilA 41-year-old woman, gravida 7, para 2, aborta 4, had a routine prenatal ultrasound at 28 weeks, 6 days which showed a large fusiform-shaped cyst in the fetal abdomen extending from the porta hepatis to the descending duodenum, concerning for a Type I CC. Fetal MRI on the same day showed the cyst measuring 2.6 × 1.1 × 3.3 cm, along with mildly dilated intrahepatic ducts which appeared to be communicating with the cyst. No other prenatal malformations were observed and aside from a maternal history of idiopathic thrombocytopenic purpura, the pregnancy was otherwise uneventful. A female infant was born at 38 weeks gestational age by cesarean section due to failure to progress and non-reassuring fetal heart tones. Apgar scores upon delivery were 9 and 9 at 1 min and 5 min, respectively. Her physical exam was benign with a soft abdomen and no palpable masses or jaundice. Abdominal ultrasound redemonstrated the cystic malformation, now measuring 3.3 × 2.3 × 6.7 cm with associated intrahepatic biliary ductal dilation. Laboratory results after birth showed total bilirubin (TB) 6.4 and direct bilirubin (DB) 0.3. Prior to discharge from the neonatal intensive care unit on day of life (DOL) one, the parents were informed of a need for subsequent surgical intervention, though not in the emergent setting given the infant’s lack of symptoms.On DOL 22, the patient presented for a routine outpatient follow-up. She was tolerating feeds and stooling normally at home; her exam was unremarkable aside from mild abdominal distention. Laboratory results at that time showed TB 1.6 (0.3–1.2) and DB 0.8 (0–0.4). An magnetic resonance cholangiopancreatography (MRCP) was subsequently obtained on DOL 36 which revealed progression of the cyst, now measuring 5.1 × 4.2 × 10.8 cm, associated with a markedly distended stomach and decompressed small bowel . The cysIntraoperatively, a large cystic structure, noted to be the CC, was identified spanning the right upper and lower quadrants down to the pelvis, displacing surrounding tissue. Following the cholecystectomy, the CC was freed circumferentially, identifying and preserving the right hepatic artery. Once the cyst was able to be elevated off of the portal structures, the decision was made to drain the cyst. The cyst was entered at the level of the common hepatic duct below the bifurcation, and significant bilious sludge was aspirated. Once the cyst was drained, it was excised from just proximal to the bifurcation of the left and right hepatic ducts to the distal CBD which was oversewn after clear identification of the pancreatic duct . ReconstFig. 4A-Fig. 4C-CCs are congenital malformations of the biliary tract that involve aberrant configurations of the pancreaticobiliary ductal system. The most widely accepted classification was proposed by Todani and colleagues in 1977 and describes five types of CC: Type I as a fusiform or cystic dilation of the CBD, Type II as a true diverticulum of the CBD, Type III as a choledochocele protruding into the duodenum, Type IV as dilation of the intra- and extrahepatic bile ducts and finally Type V, or Caroli’s disease, as fusiform or saccular dilation of intrahepatic ducts . While iHamada et al.  previousA previous review by Lugo-Vicente et al.  showed tin extremis [. Liver dysfunction is not always apparent and requires laboratory confirmation [This case highlights the challenge in management of asymptomatic patients with progressive CC growth. Indolent growth without any overt symptoms may mask the potential severity of the disease and patients may present extremis . Liver dirmation . BecauseNone declared.None.


Fertility decline characterised by inter-birth intervals remains rather slow or stall in many countries of sub-Saharan African (SSA). Non-adherence to optimal inter-birth intervals often occasioned by low prevalence of contraceptive use and high fertility desires often lead to poor maternal and child health outcomes. Additionally, information on the influence of contraception and fertility desire on interval between first and second births (SBI) is rarely available. This study therefore aimed to examine the influence of fertility desire and contraception on SBI among women in four SSA countries.We analysed cross-sectional data on women aged 15–49 years who participated in the recent Demographic and Health Surveys in DR Congo, Ethiopia, Nigeria and South Africa. Semi-parametric Cox proportional hazards regression was employed for the analysis at 5% significance level.The median time to second birth was 34 months in DR Congo; 35 months, Nigeria; 42 months, Ethiopia; and 71 months, South Africa. About 70% of the women desired additional child(ren) and two-thirds have never used contraceptive in both Nigeria and DR Congo. The hazard of second birth was significantly lower among women who desired additional child(ren) compared to desired for no more child in DR Congo , Ethiopia  and South Africa . Women who had never used contraceptive were 12%, 20% and 24% more likely to lengthen SBI than those who were current users in DR Congo, Nigeria and South Africa respectively. DR Congo and Nigerian women were about two times more likely to shorten SBI compared with their South African counterparts. Other significant determinants of SBI include ethnicity, rural residential, age and marital status at first birth, wealth and employment status.Findings showed differentials in the linkage between second birth interval and the desired fertility and contraception by country, demonstrating the importance of context. The contribution of these factors to second birth interval requires country context-specific attention if further decline in fertility and poor health outcomes associated with sub-optimal inter-birth interval is to be attained in SSA. Even though fertility decline in most of the world’s high-fertility regions is remarkable, sub-Saharan African (SSA) remains the region with the highest total fertility rate (TFR). The SSA current TFR is estimated at 4.8 births per woman . BesidesStudies have linked the postponement of all higher-order births, including the second birth as a driver of SSA fertility decline , 6. UsuaThe optimal length of SBI and other inter-birth intervals is usually three to five years, while at least 2 years is ideal before the next conception after birth –13. Non-Generally, the optimal inter-birth interval could be achieved through effective use of contraceptive. Many studies have shown that effective use of contraceptive impacted positively on inter-birth interval lengthening –19. ThisHowever, information on the effect of contraception and fertility desire on interval between first and second births is rarely documented. Yet there is evidence of inconsistency between desired fertility and contraceptive behaviour . There iSurveys (DHS) conducted in four SSA countries: DR Congo DHS (2013/14 DRCDHS), Ethiopia DHS (2016 EDHS), Nigeria DHS (2018 NDHS), South Africa DHS (2016 SADHS). The DHS is cross-sectional in design and provide population-based health indicators to assist policymakers and programme managers in designing and evaluating programs and strategies for improving the health of a country's population. The data, collected by trained field workers, contain self-reported information on the sexual and reproductive health history of the sampled women.Currently, the four countries have diverse population sizes: DR Congo (90 million), Ethiopia (115 million), Nigeria (206 million) and South Africa (60 million); these constitute the largest population in middle, eastern, western, and southern regions of SSA . The groIn these countries, the DHS employs a stratified two-stage cluster sampling technique using the sampling frame containing the enumeration areas (EAs). In the first stage, clusters (otherwise known as EAs) are selected using a probability proportional-to-size approach per stratum. At the second stage, households are selected as the secondary sampling units using a systematic sampling per cluster. Women of childbearing age who reside in the respective countries were the study participants. A detailed description of the sampling design and strategies has been previously reported –35.Of the 18,827, 15,683, 41,821, 8514 women aged 15–49 years who participated in the 2014 DRCDHS, 2016 EDHS, 2018 NDHS, 2016 SADHS respectively, 13,884, 10,114, 29,296, 6039 had had at least one birth and were included in the current study. These were the participants who had reported at least one singleton childbirth as of the survey date.Outcome variable The dependent variable of interest was the time elapsed between first and second childbirth among women in the selected countries. Women who did not have second childbirth as at the time of the survey were right-censored and were coded 0; otherwise, 1 in the analysis.Independent variables The key independent variables were contraceptive use and fertility desire. Use of contraceptive was derived from the questions asking women to indicate “whether they ever used anything or tried to delay or avoid getting pregnant” and their “current contraceptive use by method type”; this was categorised as “never-, former-, or current-use” of any means to delay/stop pregnancy/childbirth. Fertility desire, derived from the questions asking women to indicate whether they desired more children were re-categorised as “no-more, want, or undecided”. Based on existing empirical studies [ studies , 36, othSurvival analysis methods were used for the analysis. The “failure time” for women who have had second birth was the SBI. The “censored time” for the women without second birth yet was time since the first-birth and interview date. The Kaplan–Meier survival method was used to describe the women’s time to second birth while the log-rank test was employed to examine the association between SBI duration and the individual explanatory variables. Semi-parametric Cox proportional hazard (CPH) regression was thereafter used to evaluate the effect of contraceptive use and fertility desire on SBI amidst other variables controlled for, in each of the selected countries.Model expression The CPH model can be written as:Xj, p—number of explanatory variables, t isUsually, the relationship between hazard, H(t) and survival, S(t) functions is expressed aswheret; f(t) is the probability density function of the survival time T, defined as the probability that a woman has her second childbirth per unit time in a short interval expressed as:The F(t) is the cumulative probability that a woman has her second birth before time ni is the number of women who were exposed to the risk of having second birth, censored women inclusive, before ith survival time (ti) and li is the number of women who had second birth at ti, then Eq. .If then Eq.  below esp < 0.15) based on the log-rank test in addition to the main independent variables. The Wald test using the deviance statistic, − 2log likelihood (− 2LL), was used to select the best model with the least value being adjudged as more adequate.The unadjusted CPH model was used to explain the association between each of the main independent variables including the other covariates and SBI. Using the Wald test to assess the significance of the interplay between the key variables (contraceptive use and fertility desire), the statistically significance of the interaction term was not uniform across the studied countries (this was not presented). Thus, having confirmed non-violation of the proportional hazard assumption, two adjusted CPH models were fitted. Model 1 constitutes only the key independent variables and model 2 includes all the significant variables (j which indicates the changes in the expected time to second birth due to a unit change in the jth predictor) suggest the tendency of hazard to second birth; thus, HR > 1 indicates higher hazard and HR < 1 lower hazard. The data was weighted to adjust for differences in population sizes of each region of the selected countries. All analyses were carried out at a 5% level of significance, using STATA 14 SE.The hazard ratios (HR) including their 95% confidence intervals are reported. The exponentials of the coefficients  or never used contraceptive in each of these countries. Only 30.3% of the women desired additional child(ren) and 22.4% never used contraceptive in South Africa; half never used contraceptive (50.8%) and nearly three-fifths desired additional child (56.7%) in Ethiopia. Most women desired additional child(ren) but never use contraceptive in Nigeria (45.3%), DR Congo (43.9%), Ethiopia (29.6%); but few, in South Africa (5.9%) Tables , 2.More than 80% of the women in DR Congo 81.5%), Ethiopia (80.5%) and Nigeria (84.1%), compared to only three-quarters in South Africa (66.5%), had second birth as of the survey date  differences in their respective survival curves category except for sex  and the survival status of the first child (DR Congo and South Africa).The SBI duration did not vary considerably by fertility desire nor contraception in Nigeria and DR Congo. The two countries had relatively similar duration of SBI among women who desired another child ; DR Congo, 34 (33–34) months) or never used contraceptive ; DR Congo, 33 (33–34) months). In the other two countries, the median time to second birth was longer among women who desired additional child ; South Africa, 105(96–115) months) compared to those who wanted no more. However, relative to women who currently used contraceptive, shorter and longer SBI durations were respectively observed among Ethiopian (36 vs 53 months) and South African (78 vs 69 months) women who never used contraceptive. By and large, the median time to second birth was 34 (33–34) months in DR Congo; 35(35–35) months, Nigeria; 42 (41–42) months, Ethiopia; and 71 (70–73) months, South Africa  even after controlling for fertility desire; however, the hazard became non-significant when other studied variables were adjusted for  compared to male in Ethiopia. Of note, DR Congo and Nigerian women were about two times more likely to shorten SBI compared to their South African counterparts Table .This study was aimed to explore the impact of contraceptive use and fertility desire on time to second childbirth duration in SSA. The observed median time to second birth in this study suggests that inter-birth interval remains sub-optimally short in DR Congo and Nigeria, long in South Africa and optimal in Ethiopia. Even though the finding indicates relatively optimal SBI, a few studies conducted in Ethiopia have reported a high prevalence of sub-optimally short birth interval , 38. ThiStudies have rarely explored the impact of fertility desire and contraceptive use on SBI. The observed shortest duration of SBI in DR Congo and longest in South Africa relative to their respective fertility rate among the studied countries attest to the submission that the higher the TFR the more shortened the inter-birth interval and vice versa. Relative to DR Congo, nearly equivalent SBI duration was observed among women in Nigeria. A similar finding was reported earlier . The neaUnlike DR Congo, Ethiopia and Nigeria, the prevalence of unmet need for contraceptive was low among women in South Africa (5.9%). The possible explanation could be the high uptake of contraceptive in South Africa in relation to other SSA countries. Other researchers have alluded to these findings . In addiOf note, the effect of fertility desire on SBI remains unchanged even after controlling for contraceptive use alone and other variables including contraceptive use, respectively. The finding suggests that the effect of fertility desire on SBI is independent of other variables’ influence, contraceptive use inclusive. Studies have demonstrated the strong relationship between the desire for more children and birth interval , 30. On Other determinants of SBI duration include residence, ethnicity and marital status at first birth in all selected countries; others such as age, religion, education, wealth status and employment status, and first birth survival and sex are country-specific predictors. For instance, being a rural resident and a married woman respectively increased the hazard of having second childbirth early; being aged ≥ 25 years increased the tendency of having a lengthened SBI across all the considered countries but Nigeria. This corroborates early literature . FurtherA few limitations were observed in this study. One, the study design is cross-sectional in which a causal relationship between the variables and time to second birth cannot be established. Two, there may be a possibility of recall bias due to self-reported data extracted from the original dataset without any means of verification. Nonetheless, the study has been strengthened using a large nationally representative dataset. Besides, the strength of the work includes the provision of information on how fertility desire and contraceptive use impacted the second birth interval in SSA, which is rarely documented.Evidence of sub-optimal short and long duration of SBI was observed among women in most sub-regions of SSA. The findings demonstrate country context-specific variation in fertility desires and contraception effect on SBI among women in SSA. While desired for additional child(ren) was strongly associated with SBI in DR Congo, Ethiopia and South Africa; contraceptive non-use was positively related to SBI in Nigeria, Ethiopia and South Africa. Fertility effect on SBI is not only independent of contraceptive use status but also independent of other included important variables. Other predictors—the place of residence, ethnicity, age, marital status at first birth, religion, education, wealth status and employment status, and first birth survival and sex—have also been identified to impact on second birth interval. Relevant policymakers should strengthen and intensify context-specific family planning campaign aimed to address the low uptake of contraceptives and associated challenges of unmet need for contraception. Also, context-specific strategies and policies aimed at containing the associated challenges of densely populated countries through advocacy for low fertility desire should be promoted. These may have a far-reaching impact on women’s fertility desire, contraceptive use, adherence to the optimal inter-birth interval, and consequently improved maternal and child health.


Metastatic deposits from primary ovarian malignancy can manifest as cystic masses in the liver. In endemic areas, hydatid disease is an important differential in all cases of cystic hepatic masses. We report a case of a 55-year-old lady who presented with progressive abdominal distension and was diagnosed with primary ovarian high-grade serous carcinoma. Imaging revealed concurrent lesions in the liver that were thought to be metastatic deposits but was later diagnosed as hydatid cyst based on radiologic features and serology. We report this rare case to highlight the importance of suspecting a hydatid cyst in endemic areas and its varied manifestations. Echinococcus granulosus [Hydatid cyst is a zoonotic disease caused by the larvae of anulosus . The cananulosus . Humans anulosus . It is uanulosus . It is ianulosus ,4. The hanulosus . We repoEchinococcus IgG ELISA affirmed the diagnosis of hydatid disease. On USG, the hydatid cyst was classified as type CE3b (multilocular cysts with daughter cyst in the solid matrix). She was treated with pre-operative PO albendazole (400 mg BD x 28 days) with concurrent three cycles of three-weekly neoadjuvant chemotherapy (paclitaxel with carboplatin) for high-grade serous ovarian carcinoma following which interval debulking surgery with hepatic hydatid cyst drainage and excision of the cyst was done. Histopathological examination of the hepatic cystic tissue specimen confirmed the diagnosis of hydatid cyst with the demonstration of outermost reactive pericyst and inner acellular laminated membrane, i.e., ectocyst  and an abdominal mass (8 x 4 cm) in the hypogastrium. The pelvic mass had a firm consistency with side-to-side mobility and an impalpable lower border. A contrast-enhanced computed tomography (CECT) of the abdomen and pelvis revealed a well-defined enhancing complex solid-cystic mass in the pelvis (9 x 7.9 x 10.3 cm) and multiple cystic lesions in the liver with enhancing double-layered cyst-wall with basal hydatid matrix/sand Figure . Ultraso Figures , 2B and  Figures . She hasOvarian cancer is among the most common cancers in women with a considerable burden in developing countries like India . Most ofEchinococcus spp. is used for the serological diagnosis of hydatid cyst. ELISA has good sensitivity for making a diagnosis of liver hydatid cyst [Ovarian cancer can directly extend into the peritoneum or metastasize to the bowel, liver breast or spleen -11. In ttid cyst  with IgGtid cyst .Although both USG and CECT-scan have good sensitivity for diagnosing hydatid cyst, USG is preferred for staging as it is cost-effective whereas CT is preferred for delineating the number, size, and location of the hepatic cyst ,15. USG In summary, we report a case of an elderly woman who was diagnosed with primary ovarian malignancy and incidentally detected hepatic hydatid cyst masquerading as metastatic deposits. The clinical, radiological, and serologic evaluation helped clinch the diagnosis of hydatid cyst. We report this rare case to highlight the need for suspicion of hydatid cyst in patients from endemic areas in light of relevant radiological and serologic findings.


The median gestational age (GA) and birthweight (BW) were significantly lower in BPD vs. non-BPD neonates . Serum sRAGE at birth in all 124 preterm and term infants significantly correlated with BW  and GA . Among those born at <32 weeks, median serum sRAGE levels at birth were significantly lower in infants with BPD than without . Receiver operating characteristic analysis for sRAGE levels at birth in infants with and without BPD revealed that the area under the curve was 0.724 . However, serum RAGE levels were not associated with severity of BPD. Serum sRAGE levels at birth were significantly correlated with BW and GA. Furthermore, serum sRAGE levels at birth could serve as a biomarker for predicting BPD, but not its severity.Bronchopulmonary dysplasia (BPD) is a common cause of pulmonary disease in preterm infants. The soluble receptor for advanced glycation end products (sRAGE) is implicated in the development of various pulmonary diseases. The objectives of the current study were to investigate perinatal factors associated with serum sRAGE levels at birth and to establish whether serum sRAGE could be a biomarker for BPD. This retrospective single-center study was conducted at Fukushima Medical University Hospital's Department of Pediatrics Neonatal Intensive Care Unit from April 2014 to September 2020. Mechanically ventilated or oxygenated neonates born at <32 weeks gestational age and healthy control neonates were included in this study. Serum sRAGE levels in cord blood were measured using an enzyme-linked immunosorbent assay. Eighty-four preterm infants born at <32 weeks and 40 healthy infants were identified. The 84 born at <32 weeks were categorized as BPD ( Bronchopulmonary dysplasia (BPD) is a common cause of pulmonary disease in preterm infants, with long-term respiratory and neurodevelopmental consequences , 2. BPD The receptor for advanced glycation end-products (RAGE) is a cell surface protein that has been implicated in various conditions, including atherosclerosis, diabetic nephropathy, and pulmonary disease –7. RAGE We hypothesized that serum sRAGE at birth could serve as biomarker for BPD. The objectives of the present study were to correlate perinatal factors with serum sRAGE levels at birth in preterm and healthy infants and to evaluate whether serum sRAGE at birth could be a biomarker for BPD.This retrospective single-center study was conducted at Fukushima Medical University Hospital's Department of Pediatrics Neonatal Intensive Care Unit (NICU) from April 2014 to September 2020. This research was approved by the Institutional Review Board of Fukushima Medical University, which is guided by local policy, national law, and the World Medical Association Declaration of Helsinki. As our human subjects were neonates, informed consent was solicited from parents or other legal guardians, and documented in writing.2 (fraction of inspired oxygen) ≤ 0.30 at 36 weeks PMA; severe BPD was defined by also needing supplemental oxygen at 36 weeks PMA and needing mechanical ventilation and/or FiO2 > 0.30  28. Data for analysis included gestational age (GA), phenotypic sex, body weight at birth (BW), invasive mechanical ventilation at DOL 28, supplemental oxygen at DOL 28, respiratory distress syndrome (RDS), being small for gestational age (SGA), Apgar scores, and various maternal complications including chorioamnionitis (CAM), premature rupture of membranes (PROM), and hypertensive disorders of pregnancy (HDP). CAM was defined by histological diagnosis. BPD was defined in accordance with the National Institutes of Health consensus definition for infants . Infants2 > 0.30 . SGA was2 > 0.30 .Using serum samples of cord venous blood at birth stored at −80°C until assay, serum sRAGE levels were measured using an enzyme-linked immunosorbent assay  according to manufacturer's protocol. Specifically, a monoclonal antibody raised against the extracellular domain of human RAGE was used to capture sRAGE from serum. Captured sRAGE was detected with a polycloncal antihuman sRAGE antibody. After washing, plates were incubated with streptavidin-HRP, developed with appropriate substrate, and OD450 was determined using an ELISA plate reader .U-test was used to compare continuous variables, and the χ2 test was used for nominal variables. The Kolmogorov-Smirnov test was used to judge the normality tests of distribution of serum sRAGE levels at birth-frequency. The Kruskal–Wallis test was used for comparing intergroup variances among non-BPD and BPD subdivided as mild, moderate, and severe. Correlations between GA, BW, and serum sRAGE levels were evaluated using Spearman's correlation coefficient. Multivariate analysis was used to determine perinatal factors significantly associated with serum sRAGE levels at birth. Furthermore, we also performed multivariate analyses to determine factors significantly associated with BPD as potential confounding factors such as BW, GA, invasive mechanical ventilation at DOL 28, Apgar score at 1 min <3, oxygen supplementation at DOL 28, and serum sRAGE levels at birth in premature infants born at <32 weeks, adjusted for mechanical ventilation using stepwise regression. Receiver operating characteristic (ROC) analysis and its area under the curve (AUC) were applied to quantify independent risks for BPD. Data analysis was performed with SPSS (version 21.0) and GraphPad Prism version 8 software.All data are presented as medians. The Mann–Whitney P < 0.05 were considered to be statistically significant.P < 0.001, 634 vs. 952 g, P < 0.001, respectively). Apgar score at 1 min <3 occurred in BPD infants more often than non-BPD infants . Oxygen supplementation and invasive mechanical ventilation at DOL 28 were more likely in BPD infants than in non-BPD infants. There were no significant differences between control and BPD infants by sex, antenatal steroid usage, SGA, PDA, CAM, HDP, or PROM (P = 0.0195). Levels of sRAGE at birth in 124 preterm and term infants were significantly correlated with BW  and GA   . As showP = 0.0005). Next, we performed multivariate analysis to explore risk factors associated with BPD (P = 0.014), BW (P = 0.015), and serum sRAGE (P = 0.028) levels at birth significantly correlated when analyzed using stepwise regression. ROC analysis for sRAGE levels at birth in infants with and without BPD revealed that the AUC was 0.724  (As shown in with BPD . GA (P == 0.001) .As shown in To the best of our knowledge, this is the first study to reveal that lower serum sRAGE levels at birth among those born at <32 weeks gestational age is an independent risk factors for BPD. This result is consistent with emerging data implicating lower sRAGE in the pathogenesis of lung disease . Benjamin = 12) of infants born at <30 weeks, whereas our cohort included 74 infants born at <30 weeks. On the other hand, sRAGE levels have been associated with increased inflammation in both the mother and the infant at birth (This also appears to be the first study to correlate serum sRAGE levels at birth with other perinatal factors in neonates. Gestational age and birthweight were positively correlated with serum sRAGE levels. However, previous research suggested that plasma sRAGE levels at birth were negatively correlated with gestational age , contrarat birth . In humaat birth . We alsoat birth , 28.Egron et al. suggested that serum sRAGE levels in children with bronchitis were negatively correlated with age during the first year of life , and thaThere are several limitations in our study, including its single-center sample size and retrospective nature. Specifically, the number of severe BPD infants was too small for any correlations to emerge akin to those seen in adults with severe pulmonary disease. To generalize our observations, a larger sample size including multiple centers would be needed. We could not find a significant association between serum sRAGE levels and the severity of BPD. In adult pulmonary disease such as chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis, blood sRAGE is significantly decreased , 31. ThiIn conclusion, our study suggested that serum sRAGE levels at birth were significantly correlated with birth weight and gestational age and could serve as a biomarker for predicting BPD, however, not as a biomarker for severity of BPD. The mechanism by which serum sRAGE at birth is lower in BPD infants awaits further elucidation.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Institutional Review Board of Fukushima Medical University. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.HG designed the study, carried out the analyses, drafted the manuscript, and reviewed and revised the manuscript. HO, KN, and MH critically reviewed the initial draft and provided ongoing scientific and editorial guidance. KS, HI, and KM carried out the analyses and reviewed the manuscript. HM, KO, MS, and YK collected the samples and reviewed the manuscript. All authors approved the final manuscript as submitted and agree to accountable for all aspects of the work.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Subjects were 31 healthy term neonates who did not require resuscitation. Thirteen neonates were delivered vaginally (VD group) and 18 were delivered by elective caesarean section (CS group). Absolute oxyhaemoglobin, deoxyhaemoglobin, and total haemoglobin concentrations were measured continuously by TRS; oxyHb × 100/totalHb (ScO2) (%) and CBV (mL/100 g brain tissue) were also calculated. Measurements were started as soon as possible after birth, obtained from 1 to 2 min after birth, and continued until 15 min after birth. CBV was significantly higher in the VD group than in the CS group in the 4 min after birth but not thereafter. There were no significant between-group differences in ScO2 and SpO2. These findings indicate that there is a difference in cerebral haemodynamic patterns in the first 4 min after delivery between term neonates by mode of delivery when CBV is monitored by TRS.Cerebral haemodynamics during the immediate transition period in neonates may differ depending on whether delivery is vaginal or by caesarean section. However, these differences have never been confirmed by near-infrared time-resolved spectroscopy (TRS). Therefore, the purpose of this study was to compare cerebral blood volume (CBV) and cerebral haemoglobin oxygen saturation (ScO Newborn infants are subjected to a dramatic environmental change at the time of birth and must adapt rapidly to life in the extrauterine environment. The transition from foetal to newborn life is a major physiological challenge that all humans must overcome to survive. In almost all cases, the transition to pulmonary breathing at birth occurs without impediment.1, suggesting that early neonatal cardiovascular patterns may differ according to mode of delivery.However, adaptation of cardiac function after birth is affected by many factors during the perinatal period. Differences in foetal perfusion related to the mode of delivery  may influence foetal haemodynamics. Umbilical arterial adenosine and catecholamine concentrations have been found to differ significantly between neonates born vaginally and those born by caesarean section2. These two non-invasive continuous monitoring methods enable measurement of the arterial oxygen saturation (SpO2) and heart rate. However, few studies have investigated whether there are any differences in neonatal haemodynamic patterns according to mode of delivery when using these parameters5.The neonatal resuscitation guideline now recommends routine monitoring with pulse oximetry/electrocardiography12. We have previously reported a difference in the pattern of cerebral haemoglobin (Hb) oxygen saturation (ScO2) during the first 15 min after birth according to whether delivery is vaginal or by caesarean section14. In contrast, Urlesberger et al. found no differences in regional oxygen saturation in the brain according to mode of delivery6.There is increasing interest in additional monitoring of neonates during the immediate transition period using near-infrared spectroscopy (NIRS). NIRS is non-invasive and can detect changes in oxyhaemoglobin (oxyHb) and deoxyhaemoglobin (deoxyHb) concentrations in cerebral tissue. There have been several reports on use of NIRS to measure cerebral oxygenation via the tissue oxygenation index or regional saturation of oxygen in neonates during the immediate transition after birth7. Near-infrared time-resolved spectroscopy (TRS) is a unique method for calculating not only quantitative ScO2 but also CBV; it uses a light-absorption coefficient without inducing changes in light-absorbing materials, such as oxygenated Hb and indocyanine green, because the respective light-reduced scattering and absorption coefficients can be determined by resolving the photon diffusion equation15. We have already demonstrated that TRS can stably measure cerebral haemodynamics despite the dramatic physiological changes that occur during labour in the transition period16. However, there are still no reports on the differences in absolute CBV patterns in healthy term neonates according to mode of delivery.NIRS can also measure the changes in cerebral Hb concentration (tHb) and cerebral blood volume (CBV), with some work showing a decrease in CBV in term neonates in the first 15 min after birthIn this study, we hypothesised that changes in CBV would be less in infants delivered by elective CS than in those who delivered vaginally and, investigated the changes in absolute CBV during the immediate transition period in healthy infants according to whether delivery was vaginal or by elective caesarean section and how the CBV pattern differed between the two modes of delivery.Thirty-seven healthy term infants were delivered vaginally n = 17) or by elective caesarean section (n = 20) at Kagawa University Hospital during the study period. Two neonates delivered by caesarean section were excluded because of the need for respiratory support after delivery and four neonates delivered vaginally were excluded because of an abnormal μs′ value, leaving 31 infants for analysis   [. There was also no significant difference between the groups in SpO2 , and then tended to be higher in the VD group until about 12 min after birth [ between the VD and CS groups. The oxyHb concentration tended to be higher in the VD group than in the CS group at 2.5–3.5 min after birth. However, there was no difference in deoxyHb concentration between the groups.2 including SpO2, but it was not significantly different between these delivery modes. This is the first study to show that CBV is a cerebral haemodynamic parameter that is significantly affected by mode of delivery in the neonate. Furthermore, this was the first time TRS using probes with a bent tip was applied to neonates and the procedure was determined to be feasible during the transition period after birth.The two main findings of this study were as follows: (1) CBV was significantly higher in the VD group than in the CS group in the first 4 min after delivery but decreased thereafter during the first 15 min in both groups and (2) there was an increase in ScO17. Our study showed a decrease in CBV within 15 min after birth not only in CS, but also in VD, consistent with those previous studies. These decreases in CBF and CBV during postnatal transition may have significant clinical implications, although the relation between CBF and CBV in neonates remains unclear. Schwaberger et al. speculated that the cause of this reduction in CBF was an increase in arterial oxygen content and/or changes in shunting through the ductus arteriosus during the transition period7. We speculate that another factor that may contribute to the decrease in CBV within the first 15 min after birth is clamping of the umbilical cord postpartum. In a study in newborn lambs by Polglase et al., CBF increased rapidly within the first 60 s after cord clamping and remained elevated throughout the entire ventilation period. The authors attributed the rapid increase in CBF to a combination of haemodynamic responses to clamping of the umbilical cord 18.Schwaberger et al. reported a decrease in CBV within 15 min of birth in healthy neonates delivered by caesarean section, and Noori et al. demonstrated a decrease in cerebral blood flow (CBF) in preterm infants after birth using Doppler sonography21. Uterine contractions result in a decline in foetal PaO2 by approximately 25%, but the majority of appropriately grown, healthy, term foetuses are able to withstand this effect. This hypoxia stimulated the brain stem to increase both the parasympathetic and sympathetic outflow, which induces profound peripheral vasoconstriction. This leads to hypertension and increases the descending aortic pressure, which in turn increases the right ventricular afterload, encouraging passage of blood from the right atrium through the foramen ovale into the left atrium and then the left ventricle, thereby increasing blood flow into the ascending aorta as well as cerebral blood flow22. In one previous report, CBV was increased by labour and pushing during the second stage of labour, and the change in CBV after birth in our study is consistent with that report19. Such hypoxia to the degree caused by labour is not a serious problem in the process of birth, because the foetus responds to physiological compensations; therefore, blood gas data after birth was in the normal range. This is similar to previous reports that UApH does not differ by mode of delivery6. However, elective CS without labour might not show these compensatory reactions as is the case with labour before birth in vaginal delivery. CBF might not increase and thus there will be less of an increase in CBV.In this study, CBV was significantly higher in the VD group than in the CS group during the first 4 min after birth but was similar in the two groups by 10–15 min after birth. A possible explanation for the higher CBV within the first 4 min after birth could be the hypoxia that occurs during labour and passage through the birth canal, which causes the marked antepartum difference between normal vaginal delivery and elective caesarean section. There are a few reports on cerebral haemodynamics during labour25. One study showed that when acute hypoxia is detected by chemoreceptors in the carotid body, there is an increase in sympathetic and parasympathetic outflow from the brain stem, which triggers an increase in CBF and cerebral perfusion22.TRS can determine the absolute total Hb value, which consists of oxyHb and deoxyHb. In this study, the finding of a higher oxyHb in our VD group indicates that vasodilation in the cerebral arterial circulation might be more marked in neonates delivered vaginally than in those delivered by elective caesarean section. Furthermore, sympathetic activation by certain stressors, such as mechanical compression of the head, can promote incretion of catecholamines, and the foetus becomes ready for birth while maintaining its cerebral haemodynamics. There are some reports on the foetal response to hypoxia that focus on cerebral haemodynamics and oxygenation2, between the two delivery modes, it tended to be higher in the VD group than in the CS group at 5 min after birth. Pichler et al. found significantly higher ScO2 in a VD group than in a CS group at 4 and 5 min after birth. They speculated that this difference in ScO2 may reflect differences in CBF, likely as a result of cerebral autoregulation, which may be caused by the difference in arterial oxygen content between VD and CS8. The reason why there was no significant difference in ScO2 in our study within 5 min after birth was that oxyHb tended to be higher in VD than in CS, but deoxyHb had the same decreasing pattern in both groups.Although there was no significant difference in ScO26. In contrast, Almaazmi et al. reported that HR was almost identical in healthy term infant regardless of mode of delivery9. We speculate that the lack of significant differences between the two groups may be attributable to arrested labour in their study. CBV depends on cardiac output and vascular resistance. When HR is used as a measure of cardiac output, the difference in HR suggests that CBV differs by mode of delivery. However, in this study, we measured only cerebral haemodynamics and oxygenation; we did not measure systemic haemodynamics except for HR. We checked the venous blood gas in all neonates 2 h after birth and calculated CBV but could not obtain neonatal blood gas measurements immediately after birth as an indicator of the stress caused by delivery. Furthermore, the number of neonates was too small to define a range of CBV. The early CBV data obtained at around 2 min did not provide enough information about the initial process of cerebral haemodynamic adaptation to the extrauterine environment. In our next study, we will measure these data earlier such as before cord clamping throughout delivery. Healthy neonates born by vaginal delivery had a significantly higher CBV than those born by elective caesarean section in the immediate transition period, although there was no significant difference in ScO2. This difference in CBV between the two delivery modes may reflect a difference in cerebral arterial vasodilation, which may be more pronounced in response to hypoxia during passage through the birth canal in neonates born by vaginal delivery. CBV has the potential to be a useful parameter for understanding the initial process of cerebral haemodynamic adaptation after birth.HR was higher in the VD group than in the CS group in this study, which is consistent with previous reportsThis prospective observational study was performed at Kagawa University Hospital and involved term neonates  born by vaginal delivery or elective caesarean section, which was performed under spinal anaesthesia, between October 2012 and April 2019.2.After cord clamping, which is performed routinely after 30 s, the neonates were placed in a supine position and breathed room air on the resuscitation table under an overhead heater. A neonatologist observed the transition of each newborn infant and recorded Apgar scores at 1 and 5 min. Resuscitation was performed in accordance with the Neonatal Cardiac Pulmonary Resuscitation 2015 guidelines. A portable three-wavelength TRS system  was used. As soon as possible after delivery, another neonatologist attached the TRS optical probe to the newborn’s forehead on the right side and obtained measurements continuously for 15 min .The following exclusion criteria were applied: (1) a need for any form of respiratory support, such as oxygen, continuous positive airway pressure, or artificial ventilation; (2) hospitalisation due to hypoglycaemia or infection; (3) emergency caesarean section because of obstructed labour and foetal distress; and (4) abnormal optical properties in reference to our previous published data28 to calculate the absorption coefficient (μa) and the reduced scattering coefficient (μs′) values of the head at wavelengths of 762, 800, and 836 nm.TRS uses a time-correlated single-photon counting technique for detection. The system was controlled by a computer through a digital I/O interface that consisted of a three-wavelength  picosecond light pulser as the pulse light source, a photon-counting head for single-photon detection, and signal-processing circuits for time-resolved measurement. The re-emission profiles observed at each measurement point were fitted with the photon diffusion equation proposed by Patterson et al.In each iterative calculation, the photon diffusion equation was calculated in reflectance mode and was convoluted with the instrumental response; it was then fitted to the observed re-emission profile. After determination of the µa and µs′ values at the three wavelengths, the oxyHb and deoxyHb concentrations were calculated from their respective absorption coefficients using the following equations, based on the assumption that the background absorption was due to 85% (by volume) water.In these equations, 2, and CBV values were calculated as follows:Hb is the molecular weight of Hb , tHb is the venous Hb concentration (g/dL), and Dt is the brain tissue density (1.05 g/mL).We used a source optical fibre bundle with a diameter of 1 mm and a detector optical fibre bundle with a diameter of 3 mm, both with a 90° bent tip and numerical aperture of 0.29 , a linear mixed model was used to analyse the difference between the CS and VD groups at each time point. This is because there are differences in the number of time points measured in different cases. A model was constructed with the parameters measured over time as the dependent variable, subjects as a random factor, and time, groups, and their interaction terms (time × group) as fixed factors. For each estimate, the least squares mean and its 95% confidence interval (CI) were calculated. Statistical analyses of CBV, ScO2, SpO2, and HR were performed using SPSS for Windows version 24.0 . A two-sided P value < 0.05 was considered statistically significant.For the parameters measured over time . A The study was approved by the Regional Committee on Biomedical Research Ethics of Kagawa University  and conducted in accordance with the Declaration of Helsinki. The parents of all neonates enrolled in the study provided written informed consent before delivery after receiving a full explanation of the research.