We hereby report a rare case of pseudoaneurysm of the left Inferior epigastric artery following extended totally extraperitoneal (e-TEP) repair for bilateral inguinal hernia. The patient developed swelling and pain in the lower abdomen one month following surgery. He was diagnosed to have a pseudoaneurysm of the left inferior epigastric artery with significant collection in the retro rectus plane. The pseudoaneurysm was thrombosed using Thrombin injection under ultrasound guidance. He was subsequently taken up for laparoscopic pseudo aneurysm excision with hematoma evacuation and ultrasound-guided transfascial ligation of the inferior epigastric artery with mesh explantation. The pseudoaneurysm was successfully treated and at follow-up, the patient’s symptoms were resolved. One of the rare complications of surgery of the abdominal wall includes a pseudoaneurysm of the inferior epigastric artery (IEA) with less than 20 cases reported so far . With thWe present a case of a 45-year-old gentleman, with no comorbidities who was admitted with abdominal pain and swelling following Laparoscopic extended totally extraperitoneal inguinal hernia repair done one month ago. The patient was found to have a collection of about 700mL over the mesh on ultrasound and mesh infection was suspected. On further evaluation by contrast-enhanced CT of the abdomen, he was found to have a pseudoaneurysm of size 3x3cm of the left IEA with hematoma of about 700ml anterior to the mesh Figure .The pseudo aneurysm was thrombosed using thrombin injection under ultrasound guidance by our interventional radiologist Figures , 3.Subsequently, two days later, the patient was taken up for a laparoscopic pseudoaneurysm excision with transfascial ligation of the left IEA. Hematoma evacuation and mesh explantation was done as a large hematoma can serve as a nidus for mesh infection. The pseudo aneurysm was very friable and adherent to the hematoma hence it was excised Figure .Following the excision of the pseudoaneurysm, the IEA could not be traced due to altered anatomy from previous surgery. Transfascial ligation of IEA was done under ultrasound guidance. The mesh was removed to reduce the chance of infection as there was some focus of infection around the mesh Figure .He was discharged with a drain and daily drain output was monitored. The drain was in decreasing trend and was removed on post operative day 5. The patient was counseled regarding the chances of hernia recurrence and the need of surgery if there were any recurrence in the future.The IEA arises from the external iliac traversing down the posterior wall of the rectus sheath between 4 cm and 8 cm from the midline. The IEA is thus prone to injury on any procedure on the abdominal wall. Incomplete disruption of the vessel wall results in pseudoaneurysms resulting in a partial thickness dilatation due to ligation or trauma. The patient may be asymptomatic or present with a swelling in the lateral abdominal wall with or without pain. On clinical examination, a bruit might be heard over the swelling. They might be detected by color Doppler sonography . In openIn minimally invasive surgery, methods like transillumination, which helps in port placement under direct vision, help in reducing injury to the vessels to 2% . UnfortuDuring trocar entry, we must keep in mind that the epigastric vessels traverse the abdominal wall around 4 to 8 cm lateral to the midline and almost parallel to it. Steering clear of this area on either side of the midline will ensure safe entry into the abdomen without injury to the epigastric vessels [A high degree of suspicion is always required to rule out uncommon complications. Pseudoaneurysm of the IEA is one such complication - rare but having high morbidity. Based on our experience with the current case and existing literature, any lateral swelling following a laparoscopic procedure, a pseudoaneurysm to the IEA must be considered as a differential diagnosis. Early detection by imaging and multimodality timely intervention can result in good outcomes for affected individuals.


White matter abnormalities have been identified in major depressive disorder (MDD). Although several diffusion tensor imaging studies found decreased fractional anisotropy (FA) in MDD, the effect of antidepressants (AD) treatment on white matter integrity has been insufficiently studied.We sought to examine the effect of AD treatment of MDD on white matter, using DTI, in responders compared to nonresponders.We included 25 individuals with MDD (HAMD >/=20) without inflammatory, unstable medical/neurological conditions or prolonged duration (> 1 year),or AD or anti-inflammatory treatment >/=1 week preceding first evaluation. Evaluation before treatment and at 16 weeks included depression rating scales, a cognitive battery, inflammatory markers and MRI. Desvenlafaxine was initiated at 50mg with a possible increase to 100mg at 8 weeks.Changes included: increased volume in responders in the right Inferior Fronto-Occipital fasciculus (p=0.0315) and Superior Longitudinal Fasciculus part 3 (p=0.0050); in remitters in the right Inferior Fronto-Occipital fasciculus (p=0.0359) and Superior Longitudinal Fasciculus part 2 (p<0.05) and 3 (p=0.0481); decreased volume in responders in the left Superior Longitudinal Fasciculus part 1 (p=0.0147) and left Corona Radiata(p<0.05); and in remitters in the left Superior Longitudinal Fasciculus part 1 (p=0.0109) and the Corpus Callosum part 5 (p<0.05); decreased FA in the right Cortico Spinal Tract in remitters (p=0.0175) and responders (p=0.0272), and an increase in FA in the left Uncinate Fasciculus in nonremitters (p=0.0493). These results lose significance following Bonferroni correction.Overall, AD treatment of MDD was not associated with significant changes in FA, whole brain, or specific tract volume in this study.This research was funded by Pfizer Canada.


Main outcome measures were first non-invasive tear film break-up time (F-NITBUT), bulbar redness (BR), Schirmer test, and nasal palpebral angle measurement. The associations with gestational age (GA), birth weight (BW), and BW percentile, retinopathy of prematurity (ROP), ROP treatment, and other perinatal factors were evaluated using regression analyses. Results: 489 eyes of 255 preterm and 277 eyes of 139 full-term individuals  were included. Of these, 33 participants (56 eyes) had a history of spontaneously regressed ROP and 9 participants (16 eyes) had a history of ROP treatment. After adjustment for age and sex, lower F-NITBUT (<20 s) was associated with ROP treatment . Lower GA correlated with increased bulbar redness  and increased length of wetting in the Schirmer test . Furthermore, low GA was associated with narrowing of the nasal palpebral angle  adjusted for age and sex, but not when considering ROP in the multivariable model. Conclusion: Our analyses indicate that perinatal history affects ocular surface properties, tear production and lid geometry in adults born term and preterm. This might indicate that affected persons have a predisposition to diseases of the corneal surface such as the dry eye disease.Background/Aims: This study aimed to analyze the effects of perinatal history on tear film properties and lid geometry in adults born preterm. Methods: The Gutenberg Prematurity Eye Study (GPES) is a German prospective examination of adults born preterm and term aged 18 to 52 years with Keratograph Preterm delivery leads to an abrupt change in the surrounding fetal environment and may result in ocular changes, especially in those with immediate exposure to the environment such as the ocular surface. Indeed, children born preterm have altered ocular morphology, including a steeper corneal geometry , a smallThere are different hypotheses and models explaining the effects of an altered corneal geometry. For example, Fielder et al. hypothesized that the lower extrauterine temperature leads to a decreased flattening of the cornea after preterm birth , whereasDry eye disease is a multifactorial disease of the tears and ocular surface leading to discomfort, an unstable tear film, and visual disturbance , with upPrecis: This study investigated the long-term effects of prematurity on dry eye disease parameters and lid geometry in adulthood. The results indicate that the more preterm individuals are born, the more frequently alterations of ocular surface occur.Key messages of the article:−What is already known on this topic?Prematurity is associated with altered ocular morphology and functioning in childhood and adulthood, so we investigated whether perinatal factors have long-term effects on the ocular surface and lid configuration in adulthood.−What does this study add?ROP treatment is linked to reduced tear film break-up time later in life. Furthermore, low gestational age is associated with increased bulbar redness, longer Schirmer strip measurement, and a narrower nasal lid angle.−How might this study affect research or practice?Perinatal history affects the ocular surface, tear production, and lid geometry in adults born term and preterm, which might predispose affected persons to diseases of the corneal surface and dry eye disease in later life.The Gutenberg Prematurity Eye Study (GPES) is a single-center cohort study at the University Medical Center of the Johannes Gutenberg University Mainz in Germany (UMCM) that recruits individuals that (i) have been born preterm or at term between 1969 and 2002 and (ii) were between 18 and 52 years of age at study enrolment. According to these design elements, the study is a retrospective cohort study with a prospective acquisition of follow-up data. For the GPES, every preterm newborn with a GA ≤ 32 weeks and every second randomly chosen preterm newborn with GA 33–36 weeks was contacted and invited to participate. From each month from 1969 to 2002, 6  randomly selected full-term subjects with a birth weight between the 10th and 90th percentile were also invited to serve as controls as reported earlier ,22,23,24® 5M  and a medical history interview. Furthermore, their medical records documenting the perinatal and postnatal history were assessed.The study examinations were performed between 2019 and 2021. The flow chart for eligibility and recruitment efficacy proportion is shown in Written informed consent was obtained from all participants before their entry into the study and the GPES complies with Good Clinical Practice (GCP), Good Epidemiological Practice (GEP), and the ethical principles of the Declaration of Helsinki. The study protocol and documents were approved by the local ethics committee of the Medical Chamber of Rhineland-Palatinate, Germany .The medical histories were assessed from medical records stored at the UMCM. Data were collected regarding GA (weeks), birth weight (kg), presence of ROP, stage of ROP, ROP treatment, placental insufficiency, preeclampsia, maternal smoking during pregnancy and breastfeeding. Birth weight percentiles were also calculated according to Voigt et al. .For descriptive analysis, participants were allocated to group 1: full-term participants (GA ≥ 37 weeks), group 2: preterm participants with GA between 33–36 weeks without ROP, group 3: preterm participants with GA between 29–32 weeks without ROP, group 4: preterm participants with GA ≤ 28 weeks without ROP, group 5: preterm participants with GA ≤ 32 weeks with postnatal ROP without ROP treatment and group 6: preterm participants with GA ≤ 32 weeks with postnatal ROP and ROP treatment as reported earlier ,22. In t® 5M  to measure the non-invasive tear film break-up time (first: F-NITBUT) and grade of break-up time. Furthermore, the software of the Keratograph® 5M measures the nasal and temporal conjunctival areas, detects conjunctival blood vessels and calculates redness grade. Values for the mean global bulbar redness consist of values from temporal and nasal bulbar redness. The limbal nasal and limbal temporal redness values are subcategories of the nasal and temporal bulbar redness, respectively. Lid geometry was determined by analyzing photographs of the anterior segment and measuring the palpebral fissure and the nasal palpebral angle. Each parameter was controlled for outliers.Each participant was examined with a KeratographTear production was measured by the Schirmer test. In every participant, the distance of the tears to travel along the length of a paper test strip was measured  without Covariates were factors that may have affected the main outcome measures such as sex , age (years), GA (weeks), birth weight (gram), birth weight percentile, ROP (yes), ROP treatment (yes), placental insufficiency (yes), preeclampsia (yes), breastfeeding (yes), and maternal smoking during pregnancy (yes).Only participants with successful measurement of the tear film break-up time were included. Each measurement was checked for correctness and centration and excluded if considered invalid. Participants with a history of corneal or cataract surgery were excluded as this may have contributed to an altered ocular surface.https://www.R-project.org/; package “quantreg” (accessed 10 January 2022).The main outcome measures were non-invasive tear film break-up time, bulbar redness, length of wetting in the Schirmer test I, and nasal palpebral angle. Descriptive statistics were computed for these measures stratified by clinical group. Absolute and relative frequencies were calculated for dichotomous parameters; the mean and standard deviation were calculated for approximately normally distributed variables, otherwise median and interquartile range. Categorical data were compared with the chi-square test, with not-normally distributed continuous parameters compared with the Mann–Whitney U-test. Linear regression models in the case of normal distribution with general estimating equations (GEE) were used to assess associations and account for correlations between corresponding eyes. For non-normally distributed parameters, quantile regression was performed including only right eyes (Schirmer I test). Binary logistic regression analyses were conducted for reduced F-NITBUT (<20 s). First, univariate analyses of the main outcome measures and sex , age (years), GA (weeks), birth weight (kg), birth weight percentile, ROP (yes), ROP treatment (yes), placental insufficiency (yes), preeclampsia (yes), breastfeeding (yes) and maternal smoking during pregnancy (yes) were computed. Then, only parameters associated in the univariate analyses were included in model #1 with additional adjustment for sex and age. In a further model, the potential effect of ROP occurrence (yes) and/or ROP treatment (yes) were analyzed. Birth weight was excluded in the multivariable models to avoid collinearity which was strong between GA and birth weight. This was an explorative study, so there was no adjustment for multiple testing. Calculations were performed using commercial software , R Core Team (2020), R: A language and environment for statistical computing and R Foundation for Statistical Computing, Vienna, Austria. URL The present analysis included 489 eyes of 255 preterm and 277 eyes of 139 full-term individuals . Overall, there were 277 eyes of 139 participants with GA ≥ 37 weeks (group 1), 256 eyes of 129 participants with a GA between 33–36 weeks without ROP (group 2), 133 eyes of 70 participants with a GA between 29–32 weeks without ROP (group 3), 28 eyes of 14 participants with a GA ≤ 28 weeks without ROP (group 4), 56 eyes of 33 participants with a GA between 24–32 weeks with ROP without treatment (group 5), and 16 eyes of 9 participants with a GA between 24–32 and with postnatal treatment for ROP (group 6). Of the ROP-treated group, five (nine eyes) participants underwent laser coagulation, while four (seven eyes) participants had cryocoagulation. The recruitment efficacy proportion for each group is presented in p = 0.032; p = 0.034; group 2) and the group with untreated ROP participants  and in the ROP treated participants  compared to the full-term control group (group 1) , GA 29–32 weeks without ROP , and GA ≤ 28 weeks without ROP , and descriptively increased in participants with GA ≤ 32 weeks with ROP without treatment  and with ROP treatment  compared to the full-term control group (group 1) (Participants treated for ROP showed a lower F-NITBUT (group 1) . Furthergroup 1) . Parametp = 0.024) and ROP treatment (p = 0.009). After adjustment for sex and age and the additional inclusion of ROP occurrence and treatment, ROP treatment  but not ROP occurrence was associated with F-NITBUT < 20 s. In the univariable analyses, Bulbar redness was associated with GA (p = 0.004), birth weight (p = 0.003), and ROP occurrence (p = 0.05). After adjustment for sex and age in model #1, GA (p < 0.001) was still associated with bulbar redness. In model #2, a low GA revealed an association  with bulbar redness but not ROP occurrence.In the association analyses, first univariable analyses were performed. Associated parameters were then included in model #1 without the inclusion of ROP occurrence and ROP treatment. In a second multivariable model, ROP occurrence and treatment were additionally included if they were associated in the univariable model. Models #1 and #2 were additionally adjusted for sex and age. First tear film break-up time (<20 s) correlated in univariable analyses with ROP occurrence (p < 0.001), birth weight (<0.001), and placental insufficiency (p = 0.029) in univariable analyses. In multivariable model #1, the Schirmer test results were still associated with gestational age  and placental insufficiency .The measurement in the Schirmer test was associated with GA (p = 0.002), birth weight (p < 0.002), ROP occurrence (p = 0.002), and preeclampsia (p = 0.040). After adjustment for sex and age, GA (p = 0.011) and preeclampsia (p = 0.034) showed both associations. In model #2, GA and ROP treatment showed no association, while preeclampsia was associated   .The present study provides new data describing the long-term effects of prematurity, ROP, and perinatal factors on ocular surface health in adults born preterm. Our study shows that prematurity correlated with an increase in bulbar redness, increased length of wetting in the Schirmer test, and a narrower nasal palpebral angle. Furthermore, ROP treatment was associated with a tear film break-up time lower than 20 s. Overall, this data indicates that adults born preterm may have altered ocular surface homeostasis.This study provided new insights regarding the long-term effects of perinatal history on ocular surface characteristics. It is well known that preterm birth and the postnatal occurrence of ROP are linked to an altered organ morphology in childhood, adolescence, and adulthood. The Wiesbaden Prematurity Study observed that prematurity was linked with a steeper corneal curvature, while postnatal ROP occurrence and treatment were linked to a shorter anterior chamber depth . In congWhile Raffa and colleagues  observedIndividuals affected by dry eye diseases suffer from ocular discomfort, burning, instable tear film, and visual disturbance that can lead to inflammatory damage of the ocular surface . They maOne limitation of the present study is the single-center hospital-based study design. Furthermore, other lid parameters were not investigated, such as frequency of blinking in different environments, horizontal lid aperture, and temporal lid aperture. Invalid or missing keratograph examinations may further limit the present data. Moreover, the number of individuals with a history of ROP and ROP treatment was low, which must be considered during the data interpretation. A further limitation is the missing data about tissue status and function of the meibomian gland in the present study which should be examined in future studies.The strengths are that this study was one of the largest cohorts of adults born preterm at different GA with and without ROP. Detailed assessment of perinatal history from medical records enabled a comprehensive data analysis of the perinatal effects on the ocular surface, with all measurements and validation steps blinded with respect to GA and other perinatal factors.In conclusion, our analyses indicate that perinatal history affects the ocular surface later in life. Preterm birth was associated with increased bulbar redness, increased length of wetting in the Schirmer test, and a narrower palpebral angle, while ROP treatment was associated with a reduced tear film break-up time of less than 20 s, suggesting that affected persons may be predisposed to diseases of the corneal surface in later life, such as dry eye disease.


Filar cysts are frequently found on neonatal ultrasound and are physiologically involuting structures with natural resolution. Hence, there has been no previous histologic correlation. Ventriculus terminalis is a focal central canal dilation in the conus medullaris and usually not clinically significant. Extra-axial cyst at the conus–filum junction connected to ventriculus terminalis is extremely rare, especially when associated with tethered lipomatous filum terminale and with progressive cyst enlargement.A Caucasian female neonate with abnormal gluteal cleft had ventriculus terminalis cyst with an extra-axial cyst at the conus–filar junction and taut lipomatous filum on ultrasound examination and magnetic resonance imaging. This persisted at 6-month follow up imaging. In light of the nonresolving extra-axial mass and thick taut lipomatous filum, the child underwent L1–L3 osteoplastic laminectomies. The extra-axial cyst expanded after bony decompression and furthermore on dural opening; visualized on ultrasound. It communicated with the central canal and was documented with intraoperative photomicrographs. It was excised and filum sectioned. Histological immunostaining of the cyst wall showed neuroglial and axonal elements. The child did well without deficits at 4-year follow up with normal urodynamics.Progression dilation of ventriculus terminalis and extra-axial conofilar cyst with tethered lipomatous filum will likely progress to clinical significance and require surgical intervention. The embryologic basis for this pathology is discussed, with literature review. Incidental cystic mass at the conofilar junction is frequently found at the neonatal lumbar ultrasound (US) examination and termed as filar cyst (FC). FC is considered a physiologic involuting structure with expected natural resolution , 2. The A neonate Caucasian girl, a product of an uncomplicated pregnancy, was found to have asymmetric gluteal crease. Neurological examination was normal, and subsequent urodynamics study was also normal. Spine ultrasound at 1 day of age showed a cystic mass overlying the conofilar junction at the L3 level measuring 12 × 5 × 5 mm . In their retrospective review of 418 spine MRIs (age 5 days to 20 years), Coleman et al.  found foAre the ventriculus terminalis and filar cyst different entities or ends of the spectrum with the same pathophysiology? We believe the latter and these are representing the embryologic variation of the distal spinal cord Fig. . Both thDuring the canalization of the equinal cord, vacuoles form at many sites and coalesce into the canal with great viability. The ependymal-lined cyst/canals in the conus are variable and may communicate with the central canal or remain as an isolated cavity , 7. AcceVentriculus terminalis and filar cyst are transitional and should involute. Persistence and enlargement of associated extra-axial cysts and other equinal cord anomalies such as tethering of the cord warrants close observation for the development of cauda equina symptoms and progressive enlargement. Surgical intervention may be necessary.


As the conformity of a medial ball-in-socket total knee arthroplasty (TKA) provides intrinsic anterior-posterior (A-P) stability, surgeons cannot rely on the manual examination of sagittal laxity to identify the optimal insert thickness. Instead, the present study determined whether measuring tibial axial orientation in extension and 90° flexion with an insert goniometer could identify the optimal thickness that, when implanted, provides high postoperative function. In twenty-two patients that underwent unrestricted caliper-verified kinematic alignment (KA) with a PCL retaining implant, two surgeons measured tibial orientation in extension and 90° flexion with 10, 11, 12, and 13 mm thick insert goniometers. Each TKA had one insert thickness that restored either the maximum external tibial orientation in extension, the maximum internal tibial orientation at 90° flexion, or both relative to 1 mm thinner and thicker inserts. In addition, the 6-month median [interquartile range] Forgotten Joint Score of 73 (54–87) and Oxford Knee Score of 42 (38–45) indicated high satisfaction and function. In conclusion, surgeons using a medial ball-in-socket TKA design can measure external tibial orientation in extension and internal tibial orientation at 90° flexion with an insert goniometer. Furthermore, implanting an insert with the thickness that provided the maximum orientation values resulted in high postoperative function, thereby personalizing PCL tension. A total knee arthroplasty (TKA) should restore the native or healthy knee’s resting length and tension of the posterior cruciate ligament (PCL) throughout the range of motion to provide stability and to not over or under constrain the knee . An overA common assumption in TKA is that an implant design that achieves closer to native knee kinematics will provide better outcomes and lower revision rates . One desAs the medial ball-in-socket insert allows internal-external tibial rotation rather than A-P translation, a method that measures tibial axial rotation instead of sagittal laxity might be able to select the optimal insert thickness ,10,12. IThe insert goniometer is an inexpensive instrument for measuring the degree of tibial orientation. The insert has an angular scale that records tibial orientation at the intersection with a sagittal line on the medial condyle of the trial femoral component ,19 Figu. The devFinally, it is necessary to provide supportive evidence that the thickness selected by the insert goniometer is ‘optimal’ by determining whether the patient reports high satisfaction and function as measured with validated follow-up patient-reported outcome scores. For example, values representing high satisfaction and function for the Forgotten Joint Score  of 80 and 70 points indicate negligible and minor knee function restrictions, respectively . For theAccordingly, the present study evaluated twenty-two patients who underwent unrestricted caliper-verified kinematic alignment (KA) with a medial ball-in-socket implant design and PCL retention to determine whether measurements of tibial orientation can select the optimal insert thickness. The first hypothesis was that the surgeon could identify the optimal insert thickness as the one that provided either the maximum external tibial orientation in extension, maximum internal tibial orientation at 90° flexion, or both relative to inserts 1 mm thinner and thicker. The second hypothesis was that implanting the optimal insert thickness resulted in high satisfaction and function at 6 months.Our institutional review board approved the retrospective study (Pro00054838). Two surgeons performed unrestricted caliper-verified kinematic alignment (KA) and PCL retention with a medial ball-in-socket and flat lateral articulation using a mid-vastus exposure . From April 2021 to June 2021, one-time use insert goniometers were used on a first-come, first-serve basis in twenty-two patients based on the availability of sterile 3-D printed 10, 11, 12, and 13 mm thick inserts in sizes 3, 4, and 5 for left and right tibial baseplates . Each paThe following steps using trial components determined the preliminary insert thickness. First, the surgeon placed the knee at 90° flexion and palpated the PCL to verify that it was intact. Next, the surgeon verified that the knee was hyperextended a few degrees, like the pre-arthritic knee. When the knee had a flexion contracture, either a thinner insert was used, or the posterior capsule was manually released by gently hyperextending the TKA. With the TKA in maximum extension, the surgeon verified that the varus-valgus (V-V) laxity was negligible. With the knee in 15–30° flexion, the surgeon verified a ~3–4 mm gap in the lateral compartment and a ~1 mm gap in the medial compartment. A 1 mm thinner insert was used when anterior lift-off of the insert from the trial baseplate occurred at 90° flexion, which indicated an over-tensioned PCL  Forgotten Joint Score was 73 (54–87) and Oxford Knee Score was 42 (38–45).The present study of a medial ball-in-socket insert measured axial tibial orientation as a substitute for manual A-P laxity assessment to identify the optimal insert thickness, thereby personalizing ligament and PCL tension after unrestricted caliper-verified KA TKA. One important finding was that each TKA had one  insert thickness that restored either maximum external tibial orientation in extension or maximum internal tibial orientation at 90° flexion relative to 1 mm thinner and thicker inserts. A second was that implanting the optimal insert thickness achieved high satisfaction and function at 6-months as measured by the Forgotten Joint Score and Oxford Knee Score.The insert goniometer is inexpensive, requires little change in the surgical workflow, and allows a quantitative selection of the optimal insert thickness. When an insert increases external orientation in extension or internal orientation in 90° flexion, or both, the thickness is closer to optimal. When an insert decreases external or internal orientation or both, the thickness is farther from optimal. Selecting an insert that provides negligible V-V laxity in extension, ~3–4 mm lateral and ~1 mm medial gap in 30° flexion, and no lift-off of the insert at 90° flexion restores native tibial compartment forces by default without input from a tibial force sensor ,20,23,25Identifying the optimal insert thickness has potential kinematic benefits. In the present study, the optimal insert restored a mean of 7° of external tibial orientation in extension, which is the ‘screw home motion’ or locking mechanism of the native knee . In addiAccording to published criteria, the insert goniometer’s selection of the optimal thickness restored high satisfaction and function at 6-months. The median Forgotten Joint Score of 73 is expected to increase with prolonged follow-up and was between the 80 and 70 point cut-offs associated with negligible and minor knee function restrictions, respectively ,29. SimiThe present study has several limitations. First, the reliability of the insert goniometer’s orientation measurement could depend on the TKA conditions. The conditions in the present study included a mid-vastus exposure that promoted patella tracking, a medial ball-in-socket and lateral flat insert conformity like the native knee, PCL retention, and components set coincident to the patient’s pre-arthritic joint lines with KA. An insert with a less conforming medial compartment than a 1:1 ball-in-socket loses 2° of internal rotation at 90° flexion . An inseIn summary, an insert goniometer is an inexpensive tool that, when used with a medial ball-in-socket implant design, provides quantitative guidance into personalizing ligament and PCL tension when performing unrestricted caliper-verified KA TKA. In addition, knowing the difference in tibial orientation in extension and at 90° flexion between insert thicknesses can identify the thickness with the maximum orientation at each knee position and help the surgeon select the optimal insert thickness within a tolerance of ±1 mm, which restores high function.


A large proportion of neonatal deaths in India are attributable to low birth weight (LBW). We report population-based distribution and determinants of birth weight in Bihar state, and on the perceptions about birth weight among carers.A cross-sectional household survey in a state representative sample of 6007 live births born in 2018–2019. Mothers provided detailed interviews on sociodemographic characteristics and birth weight, and their perceptions on LBW (birth weight <2500 g). We report on birth weight availability, LBW prevalence, neonatal mortality rate (NMR) by birth weight and perceptions of mothers on LBW implications.Bihar state, India.Women with live birth between October 2018 and September 2019.A total of 5021 (83.5%) live births participated, and 3939 (78.4%) were weighed at birth. LBW prevalence among those with available birth weight was 18.4% (95% CI 17.1 to 19.7). Majority (87.5%) of the live births born at home were not weighed at birth. LBW prevalence decreased and birth weight ≥2500 g increased significantly with increasing wealth index quartile. NMR was significantly higher in live births weighing <1500 g  and 1500–1999 g  than those weighing ≥2500 g . Assuming proportional correspondence of LBW and NMR in live births with and without birth weight, the estimated LBW among those without birth weight was 35.5% (95% CI 33.0 to 38.0) and among all live births irrespective of birth weight availability was 23.0% (95% CI 21.9 to 24.2). 70% of mothers considered LBW to be a sign of sickness, 59.5% perceived it as a risk of developing other illnesses and 8.6% as having an increased probability of death.Missing birth weight is substantially compromising the planning of interventions to address LBW at the population-level. Variations of LBW by place of delivery and sociodemographic indicators, and the perceptions of carers about LBW can facilitate appropriate actions to address LBW and the associated neonatal mortality. Data on birth weight documented for a representative sample of live births including neonatal deaths.Documentation of birth weight based on recall, which is of reasonable quality based on the global criterion.Perceptions of caregivers on low birth weight documented in the same population.Global nutrition targets include a 30% reduction in low birth weight  prevalence between 2012 and 2030.10South Asia, with India as its largest component, was estimated to have the highest LBW prevalence for any region in the world in 2015 as per the most recent global update on LBW prevalence which provided country-level estimates.8 9 11In this background, we report on a population-based assessment of birth weight in the Indian state of Bihar, which is among the most populous Indian states accounting for a significant burden of neonatal mortality.8 11For the survey, a state representative sample of 6000 live births was selected using a multistage sampling approach from 37 of the 38 districts of Bihar state, excluding the Lakhisarai district. In the first stage, 70 functioning community/primary health centres (CHC/PHC) were randomly sampled with probability proportional to population size from a total of 445 functioning CHC/PHCs, with each catering to an average of 84 villages. In the next stage, five villages were selected from the catchment area of each of the selected CHC/PHC using the village list available in the Census 2011.The mother/caregiver of each identified live birth was contacted for a detailed interview irrespective of whether the baby was currently alive. Details on the sociodemography, the pregnancy, delivery and postnatal care of the eligible live birth were documented. Specifically, for the analysis reported in this paper, birth weight was recorded from the mother or caregiver of the child based on their recall. We also documented the mother/caretaker’s perception of the birth weight for each live birth , and whether the mother/caretaker perceived low birth weight in a baby to be an indication of sickness, and if so why. Furthermore, the possible reasons for LBW in babies, how to prevent LBW and if the mother/caretaker thought if the delivery process was different based on the birth weight were also documented. The questionnaire was developed in English and then translated into Hindi , after which it was back-translated into English to ensure the accurate and relevant meaning and intent of the questions. Pilot testing of the questionnaires was carried out and modifications made as necessary. Data were collected between November 2019 and January 2020 using Open Development Kit by interviewers trained in study procedures. Data entered were scrutinised using the internal consistency checks built in to detect and correct errors using standardised procedures to meet the data quality. To further improve data quality, spot checks were conducted by the supervisors in 10% of the households and back checks were done in 15% of the households. At least three attempts were made to reach out to all the eligible live births.We tested the quality of birth weight data by using the criteria used for the report on the global LBW prevalence estimates.14We categorised birth weight into five categories for analysis: <1500 g, 1500–1999 g, 2000–2499 g, <2500 g (LBW), and 2500 g or more. We present birth weight prevalence per 100 live births for these five categories with 95% CIs, and also for not being weighted at birth, and for birth weight could not be recalled considering all live births irrespective of birth weight availability. We then report birth weight prevalence for these five birth weight categories considering only the live births for whom birth weight was available. Among these, the prevalence and mean birth weight with SD is also reported by maternal age, maternal education, wealth index, sex of the baby, length of the pregnancy, place of delivery and based on live birth survival. Wealth index was estimated using the standard questions and methods used in the National Family Health Survey.We explored the association of neonatal and postneonatal mortality with birth weight. Based on the difference in neonatal mortality rates between live births for whom birth weight was available versus those for whom birth weight was not available, we also report proportionately adjusted LBW prevalence in those with birth weight available to estimate the LBW prevalence in those with birth weight not available. In addition, a variety of perceptions of the caregivers about LBW are reported. All analysis was performed using STATA V.13.1 software .Patients or the public were not involved in the design, or conduct, or reporting, or dissemination plans of our research.We identified 6007 live births representative of the Bihar state between October 2018 and September 2019 from 5852 women aged 15–49 years in 55 475 households. Detailed interview was available for 5021 (83.6%) live births, majority (98.2%) of whom were singleton births, 2614 (52.1%) were boys, 2870 (57.2 %) were born in a public health facility and 150 (3%) were currently not alive. Of the 5021 live births, 3939 (78.4%) were weighed at birth but birth weight could not be recalled for 292  live births.2, p=0.008), maternal education  and place of delivery  as shown in Considering the 3647 live births with birth weight available, 52% of all birth weight values fell on 2500 g, 3000 g or 3500 g; 1.6% live births weighed at least 4500 g and 0.36% of birth weights were either at 250–500 g or 5500 g. This indicates data to be of reasonable quality, as the heaping was less than the criteria for poor quality data. Significant variation was seen in the reporting of birth weight values of 2500 g, 3000 g and 3500 g by maternal age , <2500 g of LBW was 13.3% (95% CI 12.4 to 14.3) and of live births not weighed at birth was 21.5% (95% CI 20.4 to 22.7) as shown in 10.1136/bmjopen-2022-061934.supp2Supplementary dataAmong live births with birth weight available, the mean birth weight was 2848.2 g with SD of ±647.2 g , and wasThe prevalence of LBW was 18.4 (95% CI 17.1 to 19.7), and that of birth weight <1500 g was 1.5 (95% CI 1.1 to 1.9), of 1500–1999 g was 4.1 (95% CI 3.5 to 4.8) and of 2000–2400 g was 12.8 (95% CI 11.8 to 13.9) as shown in Of the 670 LBW babies, the parents of 463 (69.1%) live births were informed by the health provider that the baby was weak/LBW. This proportion was 87.2% for the 203 live births with birth weight of <2000 g and 94.3% for 53 live births with birth weight of <1500 g. Considering the 190 facility live births with birth weight <2000 g, live births at public facility (84%) were significantly less likely to be informed by the health provider of the baby being weak/having LBW as compared with those born in a private sector facility .A total of 150 (3.0%) live births were not currently alive of whom 114 (76%) had died during the neonatal period . The neoMothers were the predominant respondent in the survey (99.8%). A total of 3527 (70.2%) mothers considered LBW to be a sign of sickness/illness. Among these 3527 women, 2988 (84.2%) perceived it as a risk of developing other illnesses, 1764 (50%) considered it a risk for weak growth and 433 (12.3%) perceived it as having an increased probability of death . Among the 1350 (26.9%) women who did not consider LBW to be a sickness in a newborn, 1308 (96.9%) felt that the baby would gain weight after birth and hence there was nothing to worry. Majority  of the mothers thought that LBW baby needed extra care; and the extra care practices commonly reported  were oil massage (76.4%), exclusive breast feeding (74.3%), seeking healthcare advice (46.6%) and keeping the baby warm (31.2%).We present the estimates for birth weight prevalence across various categories in the Indian state of Bihar, including LBW prevalence which is essential for tracking progress towards the national and global nutrition targets. These estimates are presented in two ways—including and excluding live births based on birth weight availability—to highlight the need for improved birth weight availability to arrive at robust understanding of LBW prevalence for appropriate action both within the health system and the community. Sociodemographic distribution of live births for whom birth weight was not available can facilitate formulating specific actions in these populations to improve birth weight availability. Notably, the perceptions of mothers regarding reasons for LBW and its implications can provide a framework for developing relevant actions to improve care of LBW babies and possible actions to reduce LBW prevalence.Birth weight was missing for one out of four live births in this population. Extrapolating our findings to the estimated 2.5 million live births in 2019 in Bihar, 543 000 live births were not weighted at birth and recall was not available for 146 600. Although home births accounted for only 22% of all live births in this population, these accounted for majority of the live births who were not weighted at birth. Therefore, until facility births can be increased further in the long-term that could result in increased birth weight measurement, tracking LBW as a priority target is not possible unless urgent targeted efforts are made in the short-term to engage with the health providers who assist with home births to improve birth weight availability.Overall, birth weight data in our study was of reasonable quality as per the criteria used in the recent report on global estimation of LBW prevalence.The LBW prevalence estimated was 18.4% considering only live births with birth weight available, and 23% in all live births by proportionately adjusting for those who did not have birth weight available based on their higher neonatal mortality rate. Even though the adjustment made for neonatal mortality is fairly simplistic, the extent of variation in LBW prevalence with this adjustment conveys the enormous implications of non-availability of birth weight for the planning of interventions and to appropriately allocate resources to address LBW at the population-level. Those without birth weight accounted for one-third of all neonatal deaths, and birth weight availability was less than half for the live births who had died on day 0. Importantly, the LBW prevalence was estimated to be almost twice among live births for whom birth weight was not available versus those for whom birth weight was available. This finding is of significance as we have previously reported that 50% of all neonatal mortality in the state to be in 0–2 days of birth, with 35% of them not weighted at birth.A significant focus of neonatal health programmes is on caring for the small and sick newborns, and communication with the carer/family is an integral part for their meaningful participation.22–27The finding of decrease in prevalence of LBW and increase in birth weight ≥2500 g with increasing wealth index quartile is not surprising, given that maternal undernutrition is associated with poor maternal-fetal outcomes including LBW.11 30–34Documentation of birth weight based on recall in this study could be considered a limitation; however, these data were of reasonable quality using the global criterion.Significant efforts are needed in India beyond what has been done so far to increase the availability and quality of birth weight in order to improve robustness of LBW estimates, which can help planning of appropriate interventions and investments to address this important risk factor of neonatal mortality. Without robust birth weight estimates, India may not be able to address neonatal mortality effectively to meet the Sustainable Development Goal by 2030.


This study identifies that poor outcomes in EDS pregnancies differ depending on the maternal and the fetal EDS status. These insights into maternal and fetal association with certain poor pregnancy outcomes in pregnancies complicated by EDS can further guide physicians in educating, managing, and treating these women during pregnancy.The majority of research papers published on obstetrical outcomes in Ehlers-Danlos syndrome (EDS) have focused on the contribution of maternal EDS to the risk of poor pregnancy outcomes. The purpose of our study was to further clarify the fetal versus maternal contribution of EDS to poor pregnancy outcomes. A web-based, anonymous questionnaire was developed to collect pregnancy histories of families with a member with EDS. The survey was disseminated via social media through the Ehlers Danlos National Foundation. Population descriptors  and pregnancy descriptors  were collected. To identify fetal and maternal contribution of EDS to poor pregnancy outcomes, three groups were compared based on maternal or infant diagnosis (EDS versus non-EDS). The rate of birth complications, treatment for preterm birth, and occurrence of preterm birth, as well as gestational age at preterm birth, were different depending on maternal/ infant EDS status, and these differences were significant when comparing infant EDS status but not when comparing maternal EDS status. The occurrence of PPROM is increased in the non-EDS mother/EDS infant group compared to both EDS mother/non-EDS infant and EDS mother/EDS infant groups (38.9%, 12.5%, 14.8%, The online version contains supplementary material available at 10.1007/s43032-022-00992-1. The Ehlers-Danlos syndromes (EDS) are a clinically and genetically heterogeneous group of 13 heritable connective tissue disorders characterized by skin hyperextensibility, joint hypermobility, and tissue fragility .The majority of research papers published on obstetrical outcomes in EDS have focused on the contribution of maternal EDS to the risk of poor pregnancy outcomes. These population-based studies, which include the most common maternal EDS types, identify a relationship between EDS and poor pregnancy outcomes –5. When The first paper to associate poor outcomes in EDS pregnancies with the EDS status of the infant was published in 1966, prior to the first classification of EDS into types , 13. In We developed a survey to collect pregnancy outcome information for pregnancies involving mothers and/or infants with EDS to further clarify fetal and maternal status, and the association to poor pregnancy outcomes and birth complications.A web-based, interactive, anonymous questionnaire was developed on Survey Monkey to collect pregnancy histories of families with a member with EDS. An open, non-randomized format with branching components was employed, along with a comment section for respondents to clarify information given. The person responding to the survey is referred to as “respondent.” The respondent then answers questions regarding herself and her offspring. Generational data was combined into “mother/maternal” and “infant/baby/fetal.” The survey was disseminated via social media through the Ehlers-Danlos National Foundation. Responses were collected from March through May of 2016.Our local ethics committee, the Women & Infants Hospital Institutional Review Board, ruled that no formal ethics approval was required for our survey, and as such, consent was not necessary. For exempt studies that were approved prior to 2019, as this study was, the applicable regulation falls under 45 CFR 46.101. The study was determined to qualify for exempt category b2.Quantitative data collected included both population descriptors and pregnancy descriptors. Population descriptors such as age, gender, EDS diagnosis, and age of diagnosis were self-reported. Our exclusion criteria included surveys from male respondents, and repeat IP addresses. Pregnancy descriptors such as number of pregnancies, number of live births, and gestational age at birth were self-reported, while descriptors of ante-, intra-, and post-partum preterm birth complications were chosen from a list of subcategories. For this study, the poor pregnancy outcomes we focused on were birth complications, cesarean delivery, treatment for preterm birth (PTB), and occurrence of PTB, defined as a gestational age of less than 37w0d.Data analysis was conducted on the continuous variable of gestational age using Kruskal–Wallis (three groups) and Wilcoxon (two groups) tests, due to the variable’s non-normal distribution. Categorical variables such as pregnancy/birth complications were analyzed with the chi-square test. The entire sample was analyzed first as three groups , followed by subgroup analyses contrasting infant status into two groups (EDS or non-EDS) and maternal status into two groups (EDS or non-EDS) to determine the association between maternal and fetal status and poor pregnancy outcomes and complications associated with preterm delivery. Risk ratios and 95% confidence intervals (CI) were calculated for the 2 × 2 tables.A total of 1704 responses were collected, representing 22 countries. A copy of the survey is presented in Supplemental File The majority of respondents (56.5%) were 18–40 years old, followed by 38.3% between 41 and 60 years old, 3.7% > 60 years old, and 1.6% < 18 years old. Of those respondents, 87.9% have EDS. Respondents’ diagnoses included all types of EDS: type III—hypermobility was the most common (69.5%), followed by type I or II—classical (11.3%), and type IV—vascular (3.2%)  outcomes such as miscarriage, stillbirth, and termination of pregnancy reported by mothers with EDS, than by mothers without EDS regardless of the offspring’s EDS status . Thus, three groups emerged: EDS mother/EDS infant, EDS mother/non-EDS infant, and non-EDS mother/EDS infant. Poor pregnancy outcomes in these three groups are presented in Table Next, to identify the association of fetal versus maternal diagnosis of EDS to poor pregnancy outcomes, two groups were compared: one based on maternal diagnosis (EDS versus non-EDS), and the other based on fetal diagnosis (EDS versus non-EDS). When mothers with EDS were compared to mothers without EDS, no difference was observed between the groups for proportions of birth complications, cesarean delivery, treatment for PTB, occurrence of PTB, or mean gestational age. When the groups were compared based on the infant’s diagnosis (EDS versus non-EDS), an increased rate for each category except cesarean delivery was observed in the infants with EDS compared to infants without EDS Table .Table 2Pp = 0.007) higher percentage of PPROM in mothers without EDS compared to mothers with EDS .The ten most frequently reported categories of ante-, intra-, and post-partum complications associated with pregnancies resulting in preterm birth are presented in Table This study is the first to describe self-reported gestational outcomes in pregnancies complicated by Ehlers-Danlos syndrome.Our study revealed that women with EDS report more pregnancy outcomes such as miscarriage, stillbirth, and abortion compared to women without EDS who give birth to children with EDS. Previous studies have also shown a higher rate of spontaneous abortions, miscarriages, and stillbirths in the 3 most common EDS subtypes compared to the general population , 5, 7, 8The acquisition of data regarding both the maternal and infant EDS status allowed conclusions to be drawn regarding maternal versus fetal association to the observed outcomes. Our data demonstrate that the percentage of birth complications as well as the percentage of pregnancies treated for preterm birth is highest in pregnancies in which both the mother and the infant have EDS, and the gestational age at preterm birth is lowest in this group, while the rate of preterm birth is highest in mothers without EDS who have infants with EDS. A possible explanation for these findings is that pregnancy complications unrelated to preterm birth may be more common in women with EDS, and treatment for preterm birth may be higher as they may be observed more closely during pregnancy than women without EDS. This closer clinical observation and rate of intervention to prevent preterm birth in EDS mothers is likely not equivalent to that experienced by non-EDS mothers, since they may not be considered at risk if it is not known that they are carrying an EDS infant. EDS-related preterm birth is likely driven by fetal contribution. Early case studies have similarly concluded that infants with EDS were more likely to be born prematurely than their siblings without EDS , 17.Previous studies have shown that phenotypically healthy women with a history of recurrent PPROM have connective skin abnormalities reminiscent of EDS , that prWhile previous studies have indicated an association, our study is the first to demonstrate the importance of the infant EDS genotype compared to the maternal genotype in PPROM. Another important question, which is beyond the sample size of this study, is whether the risk of PPROM is dependent on the EDS subtype.Our data also shows that mean gestational age at PTB is associated with the EDS status of the infant but not the EDS status of the mother. This again suggests that PTB may be driven by fetal EDS, possibly related to the altered composition of the fetal membranes secondary to the genetic abnormalities associated with EDS. However, a caveat to these findings is that the differences found in the mean gestational age may not be clinically relevant.Our survey was conducted prior to the revised EDS classification in 2017 . Since hWhile the data gathered from this survey are based on participants’ recollection of past events, previous studies have shown that maternal recall of obstetric data is a valid method for data collection, and that a correlation exists between the severity of the obstetric complication and recall accuracy –24. AlthThis study describes the outcomes of pregnancies affected by EDS, as well as identifying the key concept that outcomes differ depending on whether it is the mother, the infant, or both who have EDS. These insights into maternal versus fetal association to adverse pregnancy outcomes in pregnancies complicated by EDS can further guide physicians in educating, managing, and treating pregnant women with EDS-related pregnancies.Supplementary file1 (24.3 KB)Below is the link to the electronic supplementary material.


Preterm birth (PTB) is one of the most important problems that pose dilemmas for both the obstetrician and neonatologist, placing a heavy burden psychologically and financially on the families involved, and triggering high socio-economic costs to the public healthcare. The rate of PTB in Asian countries has been ranked at top globally. To reduce the PTB rate, to promote the prevention and intervention for PTB, and to better understand the pathophysiology underlying PTB, the Preterm Birth International Collaborative Australia branch (PREBIC-AA) was launched in 2017. A series scientific activities including organizing annual research symposiums has been planned and organized among Australasian countries. Here we briefly updated the current progress in clinical management and translational research on PTB in Australasian countries that have been participated in PREBIC-AA. The Preterm Birth International Collaborative (PREBIC) is composed of leading researchers, clinicians, and clinical academics from Europe, Asia, North America, South America, and Australia, and its mission is to improve the quality of life of preterm infants and reduce the birth defects of children. Facilitated by Dr. Nanbert Zhong, who was the president of PREBIC at the time, the PREBIC-Australasia (PREBIC-AA) branch was launched on October 27, 2017, at the First PREBIC-Australasia Symposium, held in Haikou, Hainan Province . HoweverWhile further COVID disruptions continued throughout 2021, the International Symposium of PREBIC-AA resumed as a virtual meeting on December 18th, 2021. More than 100 participants attended the meeting from China, Japan, Korea, Australia, India, and the United States. The symposium was a mix of clinical physicians, experts and enthusiasts who are working on preterm birth and related complications. Informative lectures toward understanding of the etiology and biological markers of preterm birth, respectively were invited. Topics also covered the latest research progress made toward improving our knowledge on the fundamental basic research of preterm birth, augmented by multi-disciplinary fields like obstetrics, neonatology, pediatrics, perinatology, genetics, neurology, immunology, imaging, radiology, pathology, laboratory medicine, cell biology, molecular biology, and bioinformatics, to help us move forward toward finding tangible solutions as translational outputs for this unmet problem.Preterm birth, defined as delivery before 37 weeks' gestation, is the leading cause of death in children younger than 5 years worldwide . DespiteBesides the accurate reports on prevalence of preterm birth worldwide, an increasing number of countries have their own detailed domestic research on PTB.via a meta-analysis   in 2019. Babies born with low birth weight ranged from 6.2% in 2009 to 6.6%  in 2019 , 16.Extremely preterm birth can lead to neonatal death, even if those who survive will be involved in the greater risk of a variety of potential consequences in all organ systems for the physical, neurodevelopmental, and behavioral development of these children  17–22).–22.17–22An omics-based “Two-Hit” hypothesis was introduced by Dr. Nanbert Zhong. The “1st-Hit” is genetic predisposition determined by the DNA sequence that can be studied with genomic approach. Gene-environmental interaction presents as the “2nd-Hit” that may result in epigenetic or epigenomic alterations. Metabolomic and microbiomic factors are the common environmental factors, which may impact gene transcription and result in transcriptomic and proteomic changes. To profile integrated “omics” may help investigate the pathogenic mechanism underlying spontaneous preterm birth. Proteomic study on preterm premature rupture of membrane (pPROM) demonstrated that extracellular matrix has been altered in preterm fetal membranes due to proteolysis. Metabolism was also altered in preterm fetal membranes. The molecular changes in the fetal membranes provided a significant molecular signature for pPROM in preterm syndrome , althougIt has been difficult to fully understand preterm birth because of its heterogeneities in the definition, pathophysiologic heterogeneities, etiologic heterogeneities, genetic heterogeneities, and environmental heterogeneities. Professor Ramkumar Menon emphasized the needs for international collaborative efforts to reduce the incidence of PTB. A meta-analysis including 217 studies on maternal biomarkers of preterm birth from 1965 to 2010 shows that a total of 116 different biomarkers have been reported in spontaneous preterm . The hugAlthough spontaneous preterm birth is a complex phenotype and multifactorial adverse pregnancy, cervical dysfunction plays an important role in the pathology. The cervix is generally composed of collagen-based extracellular matrix and some fibroblasts, muscle cells, glandular cells, vascular cells, and immune cells, but the proximal part has more muscle cells than the distal part. The cervical canal runs along its length and connects the cavity of the body of the uterus with the lumen of the vagina. The openings are known as the internal os and external os , respectively. The internal os of the cervix is different from the nearby tissues in histological structure and imaging location. Some scholars predict that muscle cells near the internal os would function as sphincters and play a role in the funneling phenomenon seen in ultrasound . NumerouPreterm birth is clinically divided into spontaneous preterm delivery and iatrogenic preterm delivery. Infection and infection-derived activation of the inflammatory response are thought to be the leading risk factor of spontaneous preterm birth. The molecular triggers and mechanisms underlying the activation of immune pathways associated with the induction of preterm birth remain poorly understood. Innate immune cells  and adaptive immune cells  are jointly involved in preterm birth. Similar to term birth, idiopathic preterm birth is preceded by selective accumulation of decidual macrophages, the depletion of which protects pregnant mice from LPS-induced preterm birth . Mast ce4 until 34–36 weeks of gestation has often been performed for preterm labor. For example, among all patients with preterm labor, 28.7% have been reported to receive intravenous infusion of ritodrine for ≥ 28 days , an observational tertiary hospital-based pregnancy cohort in the North of India, funded by the Department of Biotechnology, Ministry of Science and Technology, was presented to discovery of molecular signatures of PTB using integrated multi-omic approaches. The cohort has reported proteomic changes in maternal saliva, and high vaginal fluid obtained serially along pregnancy, using the state-of-the-art label-free proteomics (SWATH-MS) approach. Detailed protein-protein interaction network analysis has revealed a list of proteins associated with maternal immune modulation, metabolism, host defense mechanism and tissue remodeling, organ development microbial defense in salivary and high vaginal fluid analysis respectively , 41. TowIn this report, we explored the current situation, research hotspots, and therapy strategies in China, Korea, Japan, Australia, and India. Despite the medical technology becoming more advanced in the last few decades, preterm birth rate had continued to increase from 9.8% in 2000 to 10.6% in 2014 globally, which equates to an estimated 14.84 million live preterm births in 2014. The authoritative statistics of “Top 10 countries for the number of preterm births in 2014” showed that four of the top 5 countries are from Asia and they accounted for 6.6 million (44.6%) of preterm births globally. This places a heavy psychological and financial burden on the families of preterm infants and associates with high socio-economic costs to the healthcare system. The goal for healthcare professionals and governments is to improve the above situation of preterm birth, reduce preterm birth rate and prevent potential consequences of preterm birth. However, high-level evidence-based clinical and basic researches to assist the community medical institutions and primary care givers to standardize diagnosis and treatment for preterm birth is inadequate, which may be the most needed scientific improvements in the Australasian context. The scarce high-quality preterm birth research is partly attributable to varieties of challenges related to study training, support, funding, ethics committees, effective health management systems as well as local collaboration. Therefore, global collaborations and multihospital and community cohorts need to be established for validation of the molecular signatures that have to date been associated with PTB. A multidisciplinary global approach in search of molecular and or clinical markers is required. Development and validation of predictive tools for preterm birth that could be implemented in a clinical setting would be a step further in reducing the rate of PTB and its related complications post-birth both in mother and child.NZ had full access to all the manuscript and had final responsibility for the decision to submit for publication. All authors designed the manuscript, collected data, revised, and approved the report.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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.The article represents the views of the authors only, and not the views of their institutions.


Of the 407 singleton-pregnant women, 21 infants were diagnosed with macrosomia. After adjusting confounders, we found that each unit increase in prenatal ozone exposure caused 8.80% [ORozone90%CI: 0.912 ] decreased risk of macrosomia, but the splined ambient ozone exposure data was not statistically associated with birth weight, which is probably due to the limited sample size. In conclusion, prenatal ozone exposure is associated with decreased risk of macrosomia but is weakly linked to birth weight.Studies have shown that prenatal ozone exposure is associated with an increased risk of adverse pregnancy outcomes, among which abnormal birth weight is a detrimental factor for diseases in adulthood, but the association between birth weight and ozone is inconclusive. Herein, we conducted this study by enrolling 407 couples of pregnant women and collected their demographical materials, their exposure to ambient ozone was assessed according to the place of their residence. The hourly monitored ozone was first averaged to the daily level, then monthly and whole-gestationally levels. After adjusting confounders, we processed a multivariate generalized addictive analysis to predict the association between prenatal ozone exposure and birth weight. We also divided the cohort into two categories according to whether the infant met the standard of macrosomia, and the occurrence of macrosomia was studied via univariate and multivariate logistic regression analyses as extreme conditions of the effects of ozone exposure on birth weight. We found that the ground-level ozone in Jinan changed with temperature periodically, higher in summer and lower in winter. Over the past 8 years from 2014, the ambient ozone increased by 1.74 μg/m Birth weight has long been studied as a crucial indicator reflecting the health status of the newborn, and it is also recognized as an indicator potentially associated with many diseases in adulthood. Low birth weight (LBW), for example, is defined as a newborn weighing <2,500 g, for whom there are increased risks of perinatal morbidity and cardiovascular and metabolic diseases in adulthood , 2. In c3) has intrinsically increased with climate change, and ozone pollution is gradually becoming an essential constituent of air pollution which challenges the physical inner homeostasis of human beings. Generally, ozone in the air is not directly emitted but is generated by photochemical reactions in the troposphere, in which sunlight and ozone-precursors such as nitrogen oxides (NOx), volatile organic compounds (VOCs), and carbon monoxide (CO) are involved. Driven by climate change, the rate of temperature change often accelerates along with altitude rises, and temperatures above 4,000 meters have warmed 75 percent faster than at altitudes below 2,000 meters over the past 20 years  under sunlight, and ozone in the troposphere occupies 10% of the total number of ambient ozone . Commonlchnology , for date slight . In Antae slight .For human beings, ozone is a well-defined oxidizing agent, and breathing ground-level ozone can result in a series of adverse health effects, including induction of respiratory symptoms, decrements in lung function, and inflammation of airways , 22. NotTo investigate the impacts of prenatal ambient ozone exposure on birth weight, we analyzed the variation of atmospheric ozone levels over the last 8 years, based on which we established statistical models toward the occurrence of macrosomia as extreme conditions. These results would facilitate the risk qualification of prenatal ozone exposure on birth weight and contribute to its intervention.The study protocol was reviewed and approved by the Ethics Committee of Maternal and Child Health Care Hospital of Shandong Province, Jinan, China. The information used in this study was anonymous, and no individually identifiable records exist.MICE package in R software.This study was adopted in the Maternal and Child Health Care Hospital of Shandong Province, where 407 couples with singleton birth pregnant women from 2018 to 2019 were enrolled. The details of the subjects were collected from the electronic medical record system and questionnaires, including maternal age, pre-pregnancy body mass index (BMI), height, weight, age at menarche, menstrual status, education background, history of gestation, parity, abortion, and live birth, paternal smoking and drinking status, gestational age, sex of the newborn, and fetal weight. The criteria for excluding samples were traveling out over 30 days during pregnancy, being conceived by human-assisted reproduction techniques, being diagnosed with a congenital disability at the neonatal screening stage, and conceived at <18 or >45 years old. The missing values of the final dataset were randomly imputed by the According to birth weight, the infants are divided into three categories: the normal birth weight group includes babies born weighing between 2,500 and 4,000 g, low birth weight is defined as a baby born weighing <2,500 g, and macrosomia refers to birth weight beyond 4,000 g regardless of gestational age.https://aqicn.org/. The data were collected from 2014 to 2021, during which the prenatal ozone exposure level is calculated based on the daily averaged ozone from the first day of pregnancy confirmation to the day of delivery. In parallel, the meteorological parameters of local temperature and wind direction and speed were acquired from the NOAA Integrated Surface Database (ISD), available through worldmet package in R software. The long-term trend of atmospheric ozone level was analyzed through Theil–Sen method.In line with our previous study , the houAccording to previous studies , we collt-test for continuous variables and a chi-square test or Fisher exact probability test for categorized variables.All demographical variables of the study subjects and their corresponding atmospheric ozone exposure levels were integrated into one dataset. The continuous variables were represented as mean and standard deviation, the categorized variables were shown as frequency with correlated percentage. According to birth weight, we divided the cohort into two groups, where the macrosomia group were infants weighing ≥4,000 g, and the non-macrosomia group were babies weighing <4,000 g. The differences between these two groups were compared through a p-value <0.05 were reserved. Also, the area under the receiver operator characteristic curve (AUC) was generated to test the robustness of the results of multivariate logistic regression analysis. Finally, the generalized additive model analysis was conducted to explore the linearity of ozone exposure and birth weight, where all demographical variables and ozone exposure data were involved, of which BMI and ozone were shown as splined items.Three statistical models were built to evaluate the effect of ozone exposure on birth weight, where macrosomia was set as a dependent variable in logistic regression analyses, and birth weight was employed as a continuous variable in the generalized additive model. In detail, the univariate logistic analysis was conducted based on the prenatal ozone exposure level and confounders of birth weight, each time one factor was independently involved in the statistical model. By simultaneously enrolling the prenatal ozone exposure data and all confounders of birth weight in one model, the multivariate analysis was built to adjust the bias of demographical variables, and only items with p-value <0.10 were considered statistically significant unless otherwise indicated.The visualization, description, comparison, and modeling of data were processed using R software version 4.1.0 for Windows. The differences between groups of 2), wind speed, and temperature changed periodically during the study period. For ozone and temperature, they were consistently higher in summer and lower in winter. In contrast, the ambient SO2 levels and wind speed changed in the opposite way. The average level of ozone was 74.00 ± 5.72 μg/m3, ranging from 57.59 to 91.05 μg/m3. The Theil-sen trend analysis showed that ambient ozone elevated from 2014 to 2021 by 1.74 μg/m3 each year. In combination with wind direction and speed, ambient ozone was visualized using a polar plot. As shown in As shown in 2 (ranging from 15.24 to 35.76), the gestational age was 39.60 ± 0.99 weeks (ranging from 37 to 41.57), and the birth weight was 3408.00 ± 378.91 g . The menstrual cycle of 18.18% of study subjects was irregular, and over 90% of women were educated at middle or higher levels. The occurrences of historical gestation, parity, and abortion were 41.77, 34.64, and 2.21%. Of the 407 newborns, 21 babies weighing >4,000 g were diagnosed with macrosomia. A total of 210 babies were boys, and 197 babies were girls, occupying 51.60 and 48.40% of total infants, respectively. For paternal factors, 19.41 and 17.20% of participants confirmed the consumption of cigarettes and alcohol.In total, 407 couples were involved in this study, they were 30.05 ± 3.60 years old on average, and 13.41 ± 1.02 years old at menarche, ranging from 19 to 42 and 10 to 18. The average BMI was 21.51 ± 2.99 kg/mp < 0.05), but the ambient ozone exposure level was lower and statistically significant at 0.10 level.According to birth weight, the cohort was divided into two groups: the macrosomia group and the non-macrosomia group. The differences in all demographical variables and ozone exposure levels were compared and shown in Rozone 90%CI = 0.934 ].Three statistical models were built to investigate the association of prenatal ozone exposure, birth weight, and macrosomia. Utilizing the binary categorized birth weight (macrosomia vs. non-macrosomia) as a dependent variable, the univariate logistic regression analysis was first adopted by enrolling the demographical variables and ambient ozone exposure data, one factor each time. As shown in BMI 90%CI = 1.251 ; ORGestationalage 90%CI = 1.906 ], while each unit increase of ambient ozone exposure decreased the risk of macrosomia by 8.80% [ORozone 90%CI = 0.912 ]. The robustness of the multivariate logistic regression model was tested through ROC analysis in To adjust the bias of demographical variables, we adopted the multivariate logistic regression analysis by simultaneously employing all demographical variables and ambient ozone exposure data. As shown in the right side of The generalized additive model was built to study the linearity of ozone exposure level and birth weight, where continuous birth weight was involved as the dependent variable. By splining the ambient ozone exposure data and BMI, we found maternal age, gestational age, fetal gender, and the splined BMI could affect the increase in birth weight . As showAmbient ozone has been demonstrated as an emerging air pollutant that is associated with increased prevalence of various physical disorders, but few studies have been done regarding its effect on adverse pregnancy outcomes. Given the crucial role of birth weight that has been documented as an early life indicator for many childhood and adulthood diseases, we conducted this study primarily aiming to figure out the role of prenatal ambient ozone exposure on the decrease of birth weight and the occurrence of macrosomia as extreme conditions. We find that ambient ozone concentration is increasing over recent years, and prenatal exposure to increased ambient ozone is associated with decreased risk of macrosomia, but results of the multivariate generalized addictive model suggested a negative response of splined ambient ozone exposure on birth weight, but increased gestational age and splined pre-pregnancy BMI are found to cause a linear increase of birth weight.3 per year over the past 8 years, which should be an alarm for the increased physical disorders related to peroxidation in this area.The meteorology variation and climate change are factors affecting tropospheric ozone, and three dominant pathways have been defined by Lu's team, of which the natural emission of ozone precursors is affected by climate-sensitive natural sources such as lightening and biosphere, and the change of solar radiation, temperature, and humidity affect the chemical process of ozone generation and degradation . In line3 increase in O3 exposure level causes an increased risk of low birth weight by 1.025  folds for the first trimester and 1.033  folds for second trimester , P < 0.05] , situated in Tianjin, China, Juan Chen found that high levels of PM 2.5 exposure during pregnancy were associated with increased risk of preterm birth and low birth weight . In Austh weight . In our  < 0.05] .3 per year. After adjusting confounders primarily demographical variables, we find each unit increase in prenatal ozone exposure level causes 0.912  decreased risk of macrosomia, but the splined ambient ozone exposure level is not statistically associated with birth weight which is probably due to limited study population.Based on the ambient ozone monitoring data between 2014 and 2021, we show the variation of ozone with wind speed and temperature between seasons and identified its increasing trend of 1.74 μg/mThe 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 Ethics Committee of Maternal and Child Health Care Hospital of Shandong Province. The Ethics Committee waived the requirement of written informed consent for participation.Project administration, methodology, data curation, and writing—original draft by CZ. Investigation and validation by JT. Validation by LM. Resources by CD. Conceptualization, resources, supervision, writing-review and editing, and funding acquisition by LZ. All authors contributed to the study conception and design, commented on previous versions of the manuscript, read, and approved the final manuscript.This work was financially supported by the Initial Scientific Research Fund of Young Talent in the Maternal and Child Health Care Hospital of Shandong Province (ISRFYT-2019-001). The funders had no role in study design, data collection, interpretation, or the decision to submit the work for publication.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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. 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Retinopathy of prematurity (ROP) is a biphasic vaso-proliferative disease that has the potential to cause blindness. In addition to prematurity and hyperoxia, perinatal infection and inflammation have been reported to play a critical role in the pathogenesis of ROP. The aim of this study was to assess the association between placental inflammation and the severity of ROP.A retrospective study of infants  born at the King Edward Memorial Hospital, a tertiary perinatal center in Western Australia.p < 0.001), exposure to postnatal steroids , and receipt of platelet transfusion .A total of 878 infants were included in this study . The presence of maternal chorioamnionitis appeared to show signs of an association with reduced odds of severe ROP: mild chorioamnionitis OR=0.43  and severe chorioamnionitis OR=0.68 . A strong association was observed for oxygen supplementation at 36 weeks (OR: 5.16; Maternal chorioamnionitis or fetal chorioamnionitis was associated with reduced odds of severe ROP. A strong association was found in infants who needed oxygen supplementation at 36 weeks and those who required steroids or platelets in the postnatal period. Retinopathy of prematurity (ROP) is a biphasic vaso-proliferative disease of the retina that almost exclusively affects preterm infants. Prematurity, in combination with relative hyperoxia after birth, leads to the arrest of physiological vascular development, involving obliteration and suppression of developing vessels (phase I). As the retina develops further, the metabolic demand exceeds supply, resulting in relative hypoxia and the excessive production of vascular growth factors and neovascularization (phase II) . Severe Recent studies have shown that in addition to prematurity and hyperoxia, perinatal infection and inflammation may play a critical role in the pathogenesis of ROP . Acute iThe effects of inflammatory mediators and growth factors such as interleukin-1β can significantly increase the activity of hypoxia-inducible factor (HIF-1α) . In addiClinical data on the association between placental histopathology and retinal outcomes in very preterm infants are conflicting , 6. ThisIn this study, we aimed to characterize the relationship between placental histology and ROP in a cohort of preterm infants < 30 weeks.This retrospective cohort study analyzed data from very preterm infants admitted to the only tertiary perinatal center in Western Australia.The electronic records of all infants born with a gestational age (GA) of 22 + 0 to 29 + 6 weeks delivered at or transferred to the study center were assessed for availability of placental histology and ROP disease classification. We excluded infants whose placentas were not available for histologic assessment.Demographic characteristics and known risk factors for ROP, including sepsis, duration of oxygen requirement, duration of mechanical ventilation, and other common neonatal outcomes, were extracted from electronic databases where they were routinely recorded.Histological examination of the placenta was performed as part of routine clinical care from pregnancies delivering at < 30 weeks’ GA. The findings were reported by a single senior placental histopathologist who was blinded to the clinical outcomes. Sections of the chorioamniotic membranes, umbilical cord, chorionic plate, and placenta were analyzed by one perinatal pathologist throughout the study period using an adaptation of a widely accepted semiquantitative scoring system. The presence and degree of maternal inflammation was defined by neutrophilic infiltration of the cellular chorion, of the membranes, or of the chorionic plate. The incidence and severity of fetal inflammation were defined by neutrophilic infiltration from the fetal vessels into the umbilical vessels or the chorionic plate vessels. Funisitis was defined as inflammation of the umbilical cord arising from the fetal vessels .All neonates born < 31 weeks postmenstrual age, regardless of birth weight, and all neonates with birth weight < 1,250 grams, regardless of postmenstrual age at birth, were screened for ROP as part of routine care.–31 weeks postmenstrual age in infants born at < 27 weeks GA and at 4–5 weeks postnatal age in infants born at 27–32 weeks GA. After the first evaluation, if the infant did not have ROP, the neonate was evaluated at 2–4-week intervals until full vascularization. If the patient had an active or rapid progressive lesion, evaluation was more frequent, depending on the clinical findings.The screening examination for ROP followed the guidelines proposed by the American Academy of Ophthalmology and Pediatrics and the Association for Pediatric Ophthalmology and Strabismus . The firROP status was recorded for each infant on the basis of the International Committee for the Classification of Retinopathy of Prematurity (ICROP) guidelines , 11. In Following the extraction of data from medical records, the data were structured in the form of one record (row) per child. Descriptive statistics  were calculated for the extracted demographic and clinical variables and are presented by ROP classification. Bivariate assessments of the associations between clinical variables and ROP classification were carried out using a chi-squared test followed by ordinal regression [where odds ratios and 95% confidence intervals  are reported]; the Student's t-test was used for comparison of continuous  data between groups. Further assessment of the association between clinical risk factors and the incidence of severe ROP was carried out using logistic regression. Given the limited size of the dataset, only a minimal set of known confounders were adjusted for in the model , while the placental histopathology variables were entered into the model in turn and then together; ORs with 95% CIs are reported. Post-hoc analysis of a combined maternal and fetal variable with three levels  was carried out in an effort to further understand the relationship between these variables and ROP. All analyses were conducted using R .–2). Forty-eight infants needed treatment for ROP, in 31 of whom signs of plus disease were present. Consistent with known risk factors, infants with plus disease were smaller  than those without. Patient flow and distribution according to ROP stage are depicted in Among newborns identified as eligible during the study period , placental histology and ROP outcome data were available for 878 infants. There were 49 infants with stage 3 or more severe disease and 829 infants with milder disease (stage 0p < 0.001), exposure to postnatal steroids , and receipt of platelet transfusion . In our cohort, more mature gestational age  and higher birth weight  were associated with decreased odds of severe ROP, and male sex was associated with increased odds  of severe ROP based on a logistic regression model (with only these three variables included).Descriptive statistics for demographic and clinical variables, by ROP classification, are given in After controlling for GA, birth weight, and sex, the presence of maternal chorioamnionitis appeared to show signs of an association with reduced odds of severe ROP: mild chorioamnionitis OR=0.43  and severe chorioamnionitis OR=0.68 . While the confidence intervals included 1, the ORs were relatively large in magnitude and somewhat consistent across the levels of maternal chorioamnionitis. After controlling for GA, birth weight, and sex, the presence of fetal chorioamnionitis in the “chorionic plate” appeared to show a significant association with reduced odds  of severe ROP.post-hoc combined variable for maternal or fetal chorioamnionitis suggested a reduced risk of severe ROP with just one type of chorioamnionitis  or both maternal and fetal chorioamnionitis together , acknowledging that both confidence intervals included 1. The addition of placental organisms isolated to the model suggested that this variable had little association with severe ROP . The addition of funisitis to the model also suggested that this had little association with severe ROP .When the effects of maternal and fetal chorioamnionitis were examined in the model together , there wThe relationship between placental inflammation and risk for ROP has been studied in both clinical and experimental setups. A systematic review by Mitra et al. did not show any association between CA and ROP (any stage) or with severe ROP (stage 3 or higher) . The autp = 0.01) and infant-level (p = 0.005) inflammation with the presence of ROP disease (p = 0.014) and inflammation in Wharton's jelly  were independent protective factors against ROP. It is postulated that with the progression of acute histologic chorioamnionitis, there is a decrease in the level of the intact form of insulin-like growth factor binding protein 1, ultimately affecting IGF-1 bioavailability  for mild chorioamnionitis and 0.68  for severe chorioamnionitis. Owen et al. recently reported that acute placental inflammation, analyzed by severity, revealed significant inverse associations for both maternal-level  (p = 0.029)  . This is= 0.029) .n = 1217), both maternal and fetal inflammatory markers together posed a significant risk for severe ROP (p = 0.03)  .In our cohort of infants, neither early- nor late-onset sepsis had a significant effect on incidence of ROP. The numbers were too small to examine whether sepsis was associated with a higher incidence of plus disease. Wang et al., in a systematic review that had large heterogeneity, found that sepsis increased the risk of ROP in preterm infants . Al-Essap < 0.001) in our cohort. A recent review that included 19 studies concluded that there was an association between platelet deficiency and severe ROP, but this review could not estimate a critical threshold . The authors of the ELGAN study  reported that the co-occurrence of bacteria in the placenta and inflammation increased the risk of ROP in Zone 1. If either of these presented alone, it did not increase the risk . In our hreshold .p < 0.001). A similar piece of research involving a retrospective study of 75 infants using a multivariate logistic regression identified “total dosage of systemic steroids” as a risk factor predicting treatment warranting ROP. On receiver operating characteristic (ROC) curve analysis, a cut-off value of 8.95 mg/kg steroid was found to be significant  models and its molecular pathogenesis, and this does not represent the patient cohort that we see in the clinical world . We needA major strength of this study is the large sample size and the fact that the data included detailed histological assessment of the placenta, including microbiological data. One of the key limitations of this study is its retrospective nature and the exclusion of infants due to a lack of placental histopathology findings. Zone-specific details could have provided more information about the effect of chorioamnionitis on the developing retina.After controlling for GA, birth weight, and sex, the presence of maternal chorioamnionitis or fetal chorioamnionitis on its own appears to show signs of an association with reduced odds of severe ROP. When the effects of maternal and fetal chorioamnionitis were examined in the model together, there was some attenuation of the effect. The results of the addition of isolated placental organisms or funisitis to the model suggest that these variables are not associated with severe ROP. As reported in the literature, a strong association with increasing severity of ROP was observed in infants who needed oxygen supplementation at 36 weeks and who needed steroids and platelet transfusion in the postnatal period.