Elevated middle cerebral artery peak systolic velocity and risk of death in donor twin affected by twin-twin transfusion syndrome but not twin anemia-polycythemia sequence.

OBJECTIVES: To determine the association between elevated (> 1.5 multiples of the median (MoM)) middle cerebral artery (MCA) peak systolic velocity (PSV) and fetal demise of the donor twin in pregnancies complicated by twin-twin transfusion syndrome (TTTS) in the absence of twin anemia-polycythemia sequence (TAPS). Secondary objectives were to evaluate if donor or recipient MCA-PSV is associated with a risk for their corresponding fetal death, and to compare the proportion of donor fetuses with low MCA pulsatility index (PI) among donor twins with high MCA-PSV and those with normal MCA-PSV to evaluate the contribution of blood-flow redistribution to the fetal brain in donor twins with high MCA-PSV. METHODS: This prospective cohort study included TTTS cases that underwent laser surgery between 2011 and 2022 at a single center. TAPS cases were excluded from the study. Multivariable and Poisson regression analysis were performed to explore the association between isolated elevated donor MCA-PSV and fetal demise, adjusted for TTTS stage, selective fetal growth restriction (sFGR) and other confounders. RESULTS: Of 660 TTTS cases, donor MCA-PSV was not recorded in 48 (7.3%) cases. Of the remaining 612 patients, nine (1.5%) were lost to follow-up and 96 TAPS cases were excluded; thus, 507 cases were included in the study. High donor MCA-PSV was seen in 6.5% (33/507) of cases and was an independent risk factor for donor fetal demise (adjusted relative risk (aRR), 4.52 (95% CI, 2.72-7.50)), after adjusting for confounders. Regression analysis restricted to each Quintero TTTS stage demonstrated that high donor MCA-PSV was an independent risk factor for fetal demise of the donor in Quintero Stage II (aRR, 14.21 (95% CI, 1.09-186.2)) and Quintero Stage III (aRR, 3.41 (95% CI, 1.82-6.41)). Donor MCA-PSV in MoM was associated with fetal demise of the donor (area under the receiver-operating-characteristics curve (AUC), 0.69; P < 0.001), but recipient MCA-PSV in MoM was not associated with fetal demise of the recipient (AUC, 0.54; P = 0.44). A higher proportion of donor twins in the group with high MCA-PSV had a low MCA-PI compared to the group with normal MCA-PSV (33.3% vs 15.5%; P = 0.016). CONCLUSIONS: Elevated donor MCA-PSV without TAPS prior to laser surgery for TTTS is associated with a 4-fold increased risk for donor fetal demise, adjusted for sFGR, TTTS stage and other confounders. Doppler evaluation of donor MCA-PSV prior to laser surgery may help stratify TTTS staging to evaluate the risk of donor fetal demise. © 2024 International Society of Ultrasound in Obstetrics and Gynecology.

Fetal surgery for open neural tube defect with severe ventriculomegaly.

OBJECTIVE: Prenatal open neural tube defect (ONTD) repair is performed to decrease the risk of needing treatment for hydrocephalus after birth and to preserve motor function. Some centers may not consider patients to be candidates for surgery if severe ventriculomegaly is present and there is no expected benefit in risk for hydrocephalus treatment. This study sought to compare the postnatal outcome of fetuses with ONTD and severe ventriculomegaly (ventricular width ≥ 15 mm) that underwent prenatal repair with the outcome of fetuses with severe ventriculomegaly that underwent postnatal repair and fetuses without severe ventriculomegaly (< 15 mm) that underwent prenatal repair. METHODS: This was a retrospective study of fetuses with ONTD that underwent prenatal or postnatal repair between 2012 and 2021 at a single institution. The cohort was divided into two groups based on preoperative fetal ventricular size: those with severe ventriculomegaly (ventricular width ≥ 15 mm) and those without severe ventriculomegaly (< 15 mm). Fetal ventricular size was measured by magnetic resonance imaging before surgery using the standardized approach and the mean size of the left and right ventricles was used for analysis. Motor function of the lower extremities was assessed at the time of referral by ultrasound and if flexion-extension movements of the ankle were seen it was considered as preserved S1 motor function. Postnatal outcomes, including motor function of the lower extremities at birth and the need for a diversion procedure for hydrocephalus treatment during the first year after birth, were collected and compared between groups. Multivariate regression analysis was used to adjust for potential confounders. RESULTS: In this study, 154 patients were included: 145 underwent fetal surgery (101 fetoscopic and 44 open hysterotomy) and nine with severe ventriculomegaly underwent postnatal repair. Among the 145 patients who underwent fetal surgery, 22 presented with severe ventriculomegaly. Fetuses with severe ventriculomegaly at referral that underwent prenatal repair were significantly more likely to need hydrocephalus treatment by 12 months after birth than those without severe ventriculomegaly (61.9% vs 28.9%, P < 0.01). However, motor function assessment at birth was similar between both prenatal repair groups (odds ratio, 0.92 (95% CI, 0.33-2.59), P = 0.88), adjusted for the anatomical level of the lesion. The prenatal repair group with severe ventriculomegaly had better preserved motor function at birth compared to the postnatal repair group with severe ventriculomegaly (median level, S1 vs L3, P < 0.01; proportion with S1 motor function, 68.2% vs 11.1%, P < 0.01). Fetuses with severe ventriculomegaly that underwent prenatal repair had an 18.9 (95% CI, 1.2-290.1)-times higher chance of having intact motor function at birth, adjusted for ethnicity, presence of club foot at referral and gestational age at delivery, compared with the postnatal repair group. There was no significant difference in the need for hydrocephalus treatment in the first year after birth between prenatal and postnatal repair groups with severe ventriculomegaly (61.9% vs 87.5%, P = 0.18). CONCLUSIONS: Although fetuses with ONTD and severe ventriculomegaly do not seem to benefit from fetal surgery in terms of postnatal hydrocephalus treatment, there is an increased chance of preserved motor function at birth. Results from this study highlight the benefit of prenatal ONTD repair for cases with severe ventriculomegaly at referral to preserve motor function. © 2024 International Society of Ultrasound in Obstetrics and Gynecology.

Ambulation after in-utero fetoscopic or open neural tube defect repair: predictors for ambulation at 30 months.

OBJECTIVES: To compare the ambulatory status of a cohort of children who had undergone prenatal repair of an open neural tube defect (ONTD) using one of two different methods (fetoscopic or open hysterotomy) with that of a cohort who had undergone postnatal repair, and to identify the best predictors of ambulation at 30 months of age. METHODS: This was a retrospective review of a cohort of children who underwent ONTD repair either prenatally (n = 110), by fetoscopic surgery (n = 73) or open hysterotomy surgery (n = 37), or postnatally (n = 51), in a single tertiary hospital between November 2011 and May 2023. The cohort comprised a consecutive sample of cases who had undergone ONTD repair in-utero following Management of Myelomeningocele Study (MOMS) trial criteria and cases who had undergone postnatal repair, meeting the same criteria, which were also followed up after birth at the same institution. Motor function assessment by ultrasound was recorded at referral, 6 weeks after prenatal repair, or after referral in postnatally repaired cases, and at the last ultrasound scan before delivery. Clinical examinations to assess motor function at birth and at 12 months were retrieved from records. Intact motor function was defined as first sacral myotome (S1) motor function. Ambulatory status data at each follow-up visit were collected. The proportion of children who were able to walk independently after 30 months of age was compared between those who had undergone fetoscopic vs open prenatal surgery and between prenatal (by either fetoscopic or open surgery) and postnatal ONTD repair. Logistic regression analyses were performed to identify predictors for independent ambulation. RESULTS: After 30 months, the proportion of infants who were able to walk independently was higher in prenatally vs postnatally repaired cases (51.8% vs 15.7%, P < 0.01), and there was no difference between those with fetoscopic (52.1%) vs open (51.4%) prenatal repair (P = 0.66). In the prenatally repaired group, having intact motor function at 12 months (adjusted odds ratio (aOR), 9.14 (95% CI, 2.64-31.63), P < 0.01) and at birth (aOR, 4.50 (95% CI, 1.21-16.80), P = 0.02) were significant predictors of independent walking at 30 months; an anatomical level of lesion below L2 at referral (aOR, 1.83 (95% CI, 1.30-2.58), P = 0.01) and female gender (aOR, 3.51 (95% CI, 1.43-8.61), P < 0.01) were also predictive for this outcome. CONCLUSIONS: Prenatally repaired cases of ONTD have a better chance of being able to walk independently at 30 months than do those who undergo postnatal repair. In patients with prenatally repaired ONTD, ambulatory status at 30 months can be predicted by observing a low lesion level at referral (below L2) and intact motor function postnatally. These results have implications for parental counseling and planning for supportive therapy in pregnancies affected by ONTD. © 2024 International Society of Ultrasound in Obstetrics and Gynecology.

Role of gestational age at time of placental laser surgery in outcomes of twin-to-twin transfusion syndrome.

OBJECTIVE: There are conflicting data on whether fetoscopic laser photocoagulation of placental anastomoses (FLP) for treating twin-to-twin transfusion syndrome (TTTS) is associated with lower rates of overall survival. The objective of this study is to characterize survival and other associated morbidity after FLP across gestational ages of FLP. METHODS: This is a secondary analysis of prospectively collected data on patients with monochorionic-diamniotic twins that had FLP for TTTS at two centers between 2011 and 2022. Patients were divided into gestational age epochs for FLP before 18 wks, 18 0/7 - 19 6/7 wks, 20 0/7 - 21 6/7 wks, 22 0/7 - 23 6/7 wks, 24 0/7 - 25 6/7 wks and after 26 wks. Demographic characteristics, sonographic characteristics of TTTS and operative characteristics were compared across the gestational age epochs. Outcomes including overall survival, preterm delivery, preterm prelabor rupture of membranes (PPROM), intrauterine fetal demise (IUFD) and neonatal demise (NND) were also compared across gestational age epochs. Multivariate analysis was performed by fitting logistic regression models for these outcomes. Kaplan-Mejer curves were constructed to compare the interval from PPROM to delivery for each gestational age epoch. RESULTS: There were 768 patients that met inclusion criteria. The dual survival rate was 61.3% for FLP performed prior to 18 weeks compared to 78.0% - 86.7% across later gestational age epochs. This appears to be related to increased rates of donor IUFD following FLP performed before, versus after 18 weeks (28.0% vs. 9.3% - 14.1%). Rates of recipient IUFD/NND and donor NND were similar regardless of gestational age of FLP. Rates of PPROM were higher for earlier FLP, ranging from 45.6% for FLP before 18 weeks to 11.9% for FLP at 24 - 26 weeks gestational age. However, the gestational age of delivery was similar across gestational age epochs with a median of 31.7 weeks. In multivariate analysis, donor loss was independently associated with FLP before 18 weeks after adjusting for selective fetal growth restriction, Quintero stage and other covariates. PPROM and PTD were also associated with FLP before 18 weeks after adjusting for cervical length, placental location, trocar size, laser energy and amnioinfusion. CONCLUSION: FLP performed at earlier gestational ages is associated with lower overall survival, which is driven by higher risk of donor IUFD, as opposed to differences in PPROM or PTD. Counseling regarding survival should account for gestational age of presentation. This article is protected by copyright. All rights reserved.

MAIT Cells in the Bone Marrow of Patients with Aplastic Anemia.

Mucosal-associated invariant T cells (MAIT cells) are a subset of T cells with innate, effector-like properties that play an essential role in the immune response to microbial infections. In humans, MAIT cells are detectable in the blood, liver, and lungs, but little is known about the frequency of these cells in the bone marrow. Also, the pathogenic role, if any, of MAIT cells in the development of aplastic anemia, a disease with an exquisite origin in the bone marrow, is currently unknown. We investigated the frequency and clinical relevance of bone marrow MAIT cells in a cohort of 14 patients (60.6 ± 23 and 57% women) with aplastic anemia. MAIT cells in the bone marrow samples obtained at diagnosis were evaluated by flow cytometry, and their association with various blood cell parameters and the patients' clinical features was analyzed. MAIT cells were detectable in the bone marrow of all patients, with considerable variations among them. Bone marrow MAIT cells expressing the activator receptor natural killer group 2D - NKG2D (NKG2D+ MAIT cells) were significantly more abundant in the specimens of the aplastic anemia patients than in patients with bone marrow failure distinct from aplastic anemia. In addition, the NKG2D+ MAIT cells positively correlated with whole blood cell counts (WBC), platelet counts, and neutrophil counts, as well as with various inflammatory markers, including neutrophil-to-lymphocyte rate (NLR), platelet-to-lymphocyte rate (PLR), and systemic inflammatory index (SII). In functional studies, bone marrow CD34+ hematopoietic cells exposed to phytohemagglutinin or bacterial-derived lipopolysaccharide and acetyl-6-formylpterin upregulated MR1 (major histocompatibility complex, class I-related, known to interact with MAIT cells) and MICA/B (MHC class I chain-related gene A, a ligand of NKG2D) proteins on their cell surface, suggesting that under stress conditions, CD34+ hematopoietic cells are more likely to interact with NKG2D+ MAIT cells. In addition, NKG2D+ MAIT cells upregulated perforin and granzyme B in response to their interaction with recombinant MICA protein in vitro. This study reports for the first time the frequency of MAIT cells in the bone marrow of patients with aplastic anemia and assesses the potential implications of these cells in the pathogenesis or progression of aplastic anemia.

Management of large placental chorioangioma: two-port laser approach for fetal intervention.

OBJECTIVES: There is a paucity of literature providing evidence-based guidelines for the management of large placental chorioangioma (≥ 4 cm in diameter). The objectives of this study were to compare outcomes between patients managed expectantly and those undergoing in-utero intervention and to describe the different in-utero techniques used for cessation of blood flow to the tumor and the associated outcome. METHODS: This was a retrospective cohort study of 34 patients referred for the management of large placental chorioangioma in a single center between January 2011 and December 2022, who were managed expectantly or underwent in-utero intervention. In-utero intervention was performed when the fetus developed any signs of impending compromise, including high combined cardiac output (CCO), worsening polyhydramnios or abnormal fetal Doppler velocimetry findings. Interventions included radiofrequency ablation (RFA), interstitial laser ablation (ILA) and single-port or two-port fetoscopic laser photocoagulation (FLP). Treatment selection was dependent on the proximity of the tumor to the umbilical cord insertion (UCI) and placental location. The two-port technique was performed in patients with a chorioangioma with large feeding vessels (≥ 3 mm) located in the posterior placenta, in which one port was used for occlusion using bipolar forceps and the other port was used for laser photocoagulation of the feeding vessels downstream. The single-port technique was used for chorioangioma with small feeding vessels (< 3 mm) located in the posterior placenta. ILA or RFA was performed in cases with an anterior placenta. Supportive treatments, including amnioreduction and intrauterine transfusion (IUT), were performed for worsening polyhydramnios and suspected fetal anemia based on middle cerebral artery Doppler flow studies, respectively. Comparative statistical analysis between cases undergoing expectant management vs in-utero intervention was performed. Descriptive details were provided for patients who underwent in-utero intervention. RESULTS: Thirty-four cases of large chorioangioma were evaluated, of which 25 (73.5%) were managed expectantly and nine (26.5%) underwent intervention. The frequency of polyhydramnios was significantly higher in the intervention group compared with the expectant-management group (66.7% vs 8.0%, P < 0.001). The live-birth rate among expectantly managed cases with large chorioangioma was significantly higher compared with that in cases that underwent in-utero intervention (96.0% vs 62.5%, P = 0.01). In the intervention group, preoperative CCO was elevated in all cases with available information and preoperative hydrops was present in 33.3% (3/9) of cases. One patient experienced fetal demise following IUT prior to planned FLP. Among the remaining eight patients, four underwent two-port FLP, two underwent single-port FLP, one underwent ILA and one underwent both ILA and RFA. All three cases in which hydrops was present at the time of intervention resulted in fetal demise. CONCLUSIONS: In-utero interventions aimed at cessation of blood flow in the feeding vessels are a therapeutic option for the management of cases with large chorioangioma. The two-port percutaneous technique appears to improve the efficiency of FLP when a large chorioangioma with large feeding vessels is located in the posterior placenta. We propose that in-utero interventions for large chorioangioma should be initiated prior to the development of fetal hydrops. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Outcome of laser photocoagulation in monochorionic diamniotic twin pregnancy complicated by Type-II selective fetal growth restriction.

OBJECTIVES: To evaluate the outcome of monochorionic diamniotic (MCDA) twins complicated by Type-II selective fetal growth restriction (sFGR) who underwent fetoscopic laser photocoagulation and to validate a previously proposed subclassification system for Type-II sFGR in a large multicenter cohort. METHODS: This retrospective multicenter cohort study included all MCDA twins complicated by Type-II sFGR who underwent laser photocoagulation of placental anastomoses at four large tertiary fetal-care centers between 2006 and 2020. Cases were subclassified according to a recently proposed system based on Doppler evaluation of the ductus venosus (DV) and middle cerebral artery (MCA) into Type-IIA (normal DV flow and MCA peak systolic velocity (PSV) of the growth-restricted fetus) or Type-IIB (absent or reversed flow in the DV during atrial contraction and/or MCA-PSV ≥ 1.5 multiples of the median of the growth-restricted fetus). Demographic characteristics and pregnancy outcomes were compared between the groups. Data are presented as mean ± SD or n (%) as appropriate. P-values < 0.05 were considered statistically significant. RESULTS: A total of 98 patients with MCDA twins met our inclusion criteria, with 56 subclassified as Type IIA and 42 as Type IIB. Demographic characteristics were similar between the groups; however, Type-IIB cases had a significantly earlier gestational age at diagnosis and at laser surgery, as well as larger intertwin estimated fetal weight discordance, which may be a reflection of disease severity. Postnatal survival of the growth-restricted fetus to 30 days of age was significantly lower in Type-IIB compared to Type-IIA cases (23.8% vs 46.4%; P = 0.034). CONCLUSIONS: In MCDA twins complicated by Type-II sFGR and treated with laser photocoagulation of placental anastomoses, preoperative Doppler assessment of the DV and MCA helped identify a subset of patients at increased risk of demise of the growth-restricted fetus following intervention. This study provides valuable information for guiding surgical management and patient counseling. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Effect of preoperative low-normal cervical length on perinatal outcome after laparotomy-assisted fetoscopic spina bifida repair.

OBJECTIVE: To determine if preoperative cervical length in the low-normal range increases the risk of adverse perinatal outcome in patients undergoing fetoscopic spina bifida repair. METHODS: This was a retrospective cohort study of patients who underwent fetal spina bifida repair between September 2014 and May 2022 at a single center. Cervical length was measured on transvaginal ultrasound during the week before surgery. Eligibility for laparotomy-assisted fetoscopic spina bifida repair was as per the criteria of the Management of Myelomeningocele Study, although maternal body mass index (BMI) up to 40 kg/m2 was allowed. Laparotomy-assisted fetoscopic spina bifida repair was performed, with carbon dioxide insufflation via two 12-French ports in the exteriorized uterus. All patients received the same peri- and postoperative tocolysis regimen, including magnesium sulfate, nifedipine and indomethacin. Postoperative follow-up ultrasound scans were performed either weekly (< 32 weeks' gestation) or twice a week (≥ 32 weeks). Perinatal outcome was compared between patients with a preoperative cervical length of 25-30 mm vs those with a cervical length > 30 mm. Logistic regression analyses and generalized linear mixed regression analyses were used to predict delivery at less than 30, 34 and 37 weeks' gestation. RESULTS: The study included 99 patients with a preoperative cervical length > 30 mm and 12 patients with a cervix 25-30 mm in length. One further case which underwent spina bifida repair was excluded because cervical length was measured > 1 week before surgery. No differences in maternal demographics, gestational age (GA) at surgery, duration of surgery or duration of carbon dioxide uterine insufflation were observed between groups. Cases with low-normal cervical length had an earlier GA at delivery (median (range), 35.2 (25.1-39.7) weeks vs 38.2 (26.0-40.9) weeks; P = 0.01), higher rates of delivery at < 34 weeks (41.7% vs 10.2%; P = 0.01) and < 30 weeks (25.0% vs 1.0%; P < 0.01) and a higher rate of preterm prelabor rupture of membranes (PPROM) (58.3% vs 26.3%; P = 0.04) at an earlier GA (mean ± SD, 29.3 ± 4.0 weeks vs 33.0 ± 2.4 weeks; P = 0.05) compared to those with a normal cervical length. Neonates of cases with low-normal cervical length had a longer stay in the neonatal intensive care unit (20 (7-162) days vs 9 (3-253) days; P = 0.02) and higher rates of respiratory distress syndrome (50.0% vs 14.4%; P < 0.01), sepsis (16.7% vs 1.0%; P = 0.03), necrotizing enterocolitis (16.7% vs 0%; P = 0.01) and retinopathy (33.3% vs 1.0%; P < 0.01). There was an association between preoperative cervical length and risk of delivery at < 30 weeks which was significant only for patients with a maternal BMI < 25 kg/m2 (odds ratio, 0.37 (95% CI, 0.07-0.81); P = 0.02). CONCLUSIONS: Low-normal cervical length (25-30 mm) as measured before in-utero laparotomy-assisted fetoscopic spina bifida repair may increase the risk of adverse perinatal outcomes, including PPROM and preterm birth, leading to higher rates of neonatal complications. These data warrant further research and are of critical relevance for clinical teams considering the eligibility of patients for in-utero spina bifida repair. Based on this evidence, patients with a low-normal cervical length should be aware of their increased risk for adverse perinatal outcome. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Prediction of dual survival following fetoscopic laser photocoagulation for twin-twin transfusion syndrome.

OBJECTIVE: To develop a model based on factors available at the time of diagnosis of twin-twin transfusion syndrome (TTTS) for predicting the probability of dual twin survival following fetoscopic laser photocoagulation (FLP) using a machine-learning algorithm. METHODS: This was a retrospective study of data collected at two university-affiliated tertiary fetal centers between 2012 and 2021. The cohort included monochorionic diamniotic twin pregnancies complicated by TTTS that underwent FLP. Data were stratified based on survival 30 days after delivery, and cases with dual survival were compared to those without dual survival. A random forest machine-learning algorithm was used to construct a prediction model, and the relative importance value was calculated for each parameter that presented a statistically significant difference between the two study groups and was included in the model. The holdout method was applied to check overfitting of the random forest algorithm. A prediction model for dual twin survival 30 days after delivery was presented based on the test set. RESULTS: The study included 537 women with monochorionic diamniotic twin pregnancy, of whom 346 (64.4%) had dual twin survival at 30 days after delivery and were compared with 191 (35.6%) cases that had one or no survivors. Univariate analysis demonstrated no differences in demographic parameters between the groups. At the time of diagnosis, the dual-survival group had lower rates of estimated fetal weight (EFW) < 10th centile for gestational age in the donor twin (56.4% vs 69.4%; P = 0.004), intertwin EFW discordance > 25% (40.8% vs 56.5%; P = 0.001) and anterior placenta (40.5% vs 50.0%; P = 0.034). Comparison of Doppler findings between the two groups demonstrated significant differences in the donor twin, with a lower rate of pulsatility index (PI) > 95th centile in the umbilical artery and ductus venosus and a lower rate of PI < 5th centile in the fetal middle cerebral artery in the dual-survival group. Relative importance values for each of these six parameters were calculated, allowing the construction of a prediction model with an area under the receiver-operating-characteristics curve of 0.916 (95% CI, 0.887-0.946). CONCLUSIONS: We developed a predictive model for dual survival in monochorionic twin pregnancies following FLP for TTTS, which incorporates six variables obtained at the time of diagnosis of TTTS, including donor EFW < 10th centile, intertwin EFW discordance > 25%, anterior placenta and abnormal PI in the umbilical artery, ductus venosus and middle cerebral artery of the donor twin. This clinically applicable tool may improve treatment planning and patient counseling. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Implication of chromosomal microarray analysis prior to in-utero repair of fetal open neural tube defect.

OBJECTIVE: In-utero repair of open neural tube defects (ONTD) is an accepted treatment option with demonstrated superior outcome for eligible patients. While current guidelines recommend genetic testing by chromosomal microarray analysis (CMA) when a major congenital anomaly is detected prenatally, the requirement for an in-utero repair, based on the Management of Myelomeningocele Study (MOMS) criteria, is a normal karyotype. In this study, we aimed to evaluate if CMA should be recommended as a prerequisite for in-utero ONTD repair. METHODS: This was a retrospective cohort study of pregnancies complicated by ONTD that underwent laparotomy-assisted fetoscopic repair or open-hysterotomy fetal surgery at a single tertiary center between September 2011 and July 2021. All patients met the MOMS eligibility criteria and had a normal karyotype. In a subset of the pregnancies (n = 77), CMA testing was also conducted. We reviewed the CMA results and divided the cohort into two groups according to whether clinically reportable copy-number variants (CNV) were detected (reportable-CNV group) or not (normal-CMA group). Surgical characteristics, complications, and maternal and early neonatal outcomes were compared between the two groups. The primary outcomes were fetal or neonatal death, hydrocephalus, motor function at 12 months of age and walking status at 30 months of age. Standard parametric and non-parametric statistical tests were employed as appropriate. RESULTS: During the study period, 146 fetuses with ONTD were eligible for and underwent in-utero repair. CMA results were available for 77 (52.7%) patients. Of those, 65 (84%) had a normal CMA and 12 (16%) had a reportable CNV, two of which were classified as pathogenic. The first case with a pathogenic CNV was diagnosed with a 749-kb central 22q11.21 deletion spanning low-copy-repeat regions B-D of chromosome 22; the second case was diagnosed with a 1.3-Mb interstitial deletion at 1q21.1q21.2. Maternal demographics, clinical characteristics, operative data and postoperative complications were similar between those with normal CMA results and those with reportable CNVs. There were no significant differences in gestational age at delivery or any obstetric and early neonatal outcome between the study groups. Motor function at birth and at 12 months of age, and walking status at 30 months of age, were similar between the two groups. CONCLUSIONS: Standard diagnostic testing with CMA should be offered when an ONTD is detected prenatally, as this approach has implications for counseling regarding prognosis and recurrence risk. Our results indicate that the presence of a clinically reportable CNV should not a priori affect eligibility for in-utero repair, as overall pregnancy outcome is similar in these cases to that of cases with normal CMA. Nevertheless, significant CMA results will require a case-by-case multidisciplinary discussion to evaluate eligibility. To generalize the conclusion of this single-center series, a larger, multicenter long-term study should be considered. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Decreased expression of T-cell-associated immune markers predicts poor prognosis in patients with follicular lymphoma.

We previously examined the utility of rituximab-bendamustine (RB) in patients with follicular lymphoma (FL) exhibiting less than optimal responses to 2 cycles of the R-CHOP chemotherapy regimen. The aim of this study was to identify molecular biomarkers that can predict prognosis in RB-treated patients in the context of the prospective cohort. We first analyzed the mutational status of 410 genes in diagnostic tumor specimens by target capture and Sanger sequencing. CREBBP, KMT2D, MEF2B, BCL2, EZH2, and CARD11 were recurrently mutated as reported before, however none was predictive for progression-free survival (PFS) in the RB-treated patients (n = 34). A gene expression analysis by nCounter including 800 genes associated with carcinogenesis and/or the immune response showed that expression levels of CD8+ T-cell markers and half of the genes regulating Th1 and Th2 responses were significantly lower in progression of disease within the 24-mo (POD24) group (n = 8) than in the no POD24 group (n = 31). Collectively, we selected 10 genes (TBX21, CXCR3, CCR4, CD8A, CD8B, GZMM, FLT3LG, CD3E, EOMES, GZMK), and generated an immune infiltration score (IIS) for predicting PFS using principal component analysis, which dichotomized the RB-treated patients into immune IIShigh (n = 19) and IISlow (n = 20) groups. The 3-y PFS rate was significantly lower in the IISlow group than in the IIShigh group (50.0% [95% CI: 27.1-69.2%] vs. 84.2% [95% CI: 58.7-94.6%], P = .0237). Furthermore, the IIS was correlates with absolute lymphocyte counts at diagnosis (r = 0.460, P = .00355). These results suggest that the T-cell-associated immune markers could be useful to predict prognosis in RB-treated FL patients. (UMIN:000 013 795, jRCT:051 180 181).

Chlorpromazine cooperatively induces apoptosis with tyrosine kinase inhibitors in EGFR-mutated lung cancer cell lines and restores the sensitivity to gefitinib in T790M-harboring resistant cells.

We previously reported that the antipsychotic drug chlorpromazine (CPZ), which inhibits the formation of clathrin-coated vesicles (CCVs) essential for endocytosis and intracellular transport of receptor tyrosine kinase (RTK), inhibits the growth/survival of acute myeloid leukemia cells with mutated RTK (KIT D816V or FLT3-ITD) by perturbing the intracellular localization of these molecules. Here, we examined whether these findings are applicable to epidermal growth factor receptor (EGFR). CPZ dose-dependently inhibited the growth/survival of the non-small cell lung cancer (NSCLC) cell line, PC9 harboring an EGFR-activating (EGFR exon 19 deletion). In addition, CPZ not only suppressed the growth/survival of gefitinib (GEF)-resistant PC9ZD cells harboring T790 M, but also restored their sensitivities to GEF. Furthermore, CPZ overcame GEF resistance caused by Met amplification in HCC827GR cells. As for the mechanism of CPZ-induced growth suppression, we found that although CPZ hardly influenced the phosphorylation of EGFR, it effectively reduced the phosphorylation of ERK and AKT. When utilized in combination with trametinib (a MEK inhibitor), dabrafenib (an RAF inhibitor), and everolimus (an mTOR inhibitor), CPZ suppressed the growth of PC9ZD cells cooperatively with everolimus but not with trametinib or dabrafenib. Immunofluorescent staining revealed that EGFR shows a perinuclear pattern and was intensely colocalized with the late endosome marker, Rab11. However, after CPZ treatment, EGFR was unevenly distributed in the cells, and colocalization with the early endosome marker Rab5 and EEA1 became more apparent, indicating that CPZ disrupted the intracellular transport of EGFR. These results suggest that CPZ has therapeutic potential for NSCLC with mutated EGFR by a novel mechanism different from conventional TKIs alone or in combination with other agents.

Efficacy of long-term indomethacin therapy in prolonging pregnancy after fetoscopic laser surgery for twin-to-twin transfusion syndrome: a collaborative cohort study.

OBJECTIVE: To evaluate the efficacy of long-term indomethacin therapy (LIT) in prolonging pregnancy and reducing spontaneous preterm birth (PTB) in patients undergoing fetoscopic laser surgery (FLS) for the management of twin-to-twin transfusion syndrome (TTTS). DESIGN: Retrospective cohort study of prospectively collected data. SETTING: Collaborative multicentre study. POPULATION: Five hundred and fifty-seven consecutive TTTS cases that underwent FLS. METHODS: Long-term indomethacin therapy was defined as indomethacin use for at least 48 hours. Log-binomial regression was used to estimate the relative risk of PTB in the LIT group compared with a non-LIT group. Cox regression was used to evaluate the association between LIT use and FLS-to-delivery survival. MAIN OUTCOME MEASURES: Gestational age (GA) at delivery. RESULTS: Among the 411 pregnancies included, a total of 180 patients (43.8%) received LIT after FLS and 231 patients (56.2%) did not. Median GA at fetal intervention did not differ between groups (20.4 weeks). Median GA at delivery was significantly higher in the LIT group (33.6 weeks) compared with the non-LIT group (31.1 weeks; P < 0.001). FLS-to-delivery interval was significantly longer in the LIT group (P < 0.001). The risks of PTB before 34, 32, 28 and 26 weeks of gestation were all significantly lower in the LIT group compared with the non-LIT group (relative risks 0.69, 0.51, 0.37 and 0.18, respectively). The number needed to treat with LIT to prevent one PTB before 32 weeks of gestation was four, and to prevent one PTB before 34 weeks was five. CONCLUSION: Long-term indomethacin after FLS for TTTS was found to be associated with prolongation of pregnancy and reduced risk for PTB. TWEETABLE ABSTRACT: Long-term indomethacin used after fetoscopic laser surgery for twin-to-twin transfusion syndrome is effective in prolonging pregnancy and reducing the risk for preterm birth; especially extreme preterm birth.

Perinatal outcomes of fetoscopic laser surgery for twin-twin transfusion syndrome in triplet pregnancy: cohort study, systematic review and meta-analysis.

OBJECTIVES: The aims of this study were to investigate the perinatal outcome of dichorionic triamniotic (DCTA) and monochorionic triamniotic (MCTA) triplet pregnancies complicated by twin-twin transfusion syndrome (TTTS) treated with fetoscopic laser photocoagulation (FLP) in two academic fetal centers, and to conduct a systematic review of previously published data to investigate perinatal survival in this targeted population. METHODS: The first part of the study was a retrospective cohort study of prospectively collected data of consecutive triplet pregnancies with TTTS that underwent FLP at two fetal treatment centers between 2012 and 2020. Demographic, preoperative and operative variables and postoperative outcome were collected. Perinatal outcomes were investigated. The second part of the study was a systematic review and meta-analysis of studies evaluating the outcome of DCTA and/or MCTA triplet pregnancies, including our cohort study. PubMed, Web of Science and Scopus were searched from inception to September 2020. Primary outcomes were fetal survival (survival to birth), neonatal survival (survival to 28 days of age) and gestational age (GA) at birth. RESULTS: A total of 31 sets of triplets with TTTS managed with FLP were included in the cohort study. Of these, 24 were DCTA and seven were MCTA. There were no significant differences in preoperative and operative variables between the two groups. There were also no significant differences between groups in GA at delivery or perinatal survival rate, including fetal and neonatal survival of at least one triplet, at least two triplets and all three triplets. Nine studies, including our cohort study, were included in the systematic review (156 DCTA and 37 MCTA triplet pregnancies treated with FLP). The overall fetal and neonatal survival was 79% (95% CI, 75-83%) and 75% (95% CI, 71-79%), respectively, in DCTA cases and 74% (95% CI, 52-92%) and 71% (95% CI, 49-89%), respectively, in MCTA cases. The rate of preterm birth before 28 weeks and before 32 weeks' gestation was 14% (95% CI, 4-29%) and 61% (95% CI, 50-72%), respectively, in DCTA triplets and 21% (95% CI, 3-45%) and 82% (95% CI, 62-96%), respectively, in MCTA triplets. CONCLUSIONS: Triplet pregnancies with TTTS are at high risk of adverse perinatal outcome and preterm birth, regardless of chorionicity. The rate of survival after FLP in MCTA triplets was higher in our study than that reported in previous studies and is currently comparable with survival in DCTA triplets, which could be due to improved surgical skills. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Iatrogenic chorioamniotic separation and septostomy following fetoscopic laser photocoagulation for twin-twin transfusion syndrome.

OBJECTIVE: To compare the perinatal outcomes of pregnancies complicated by chorioamniotic separation (CAS) vs septostomy following fetoscopic laser photocoagulation (FLP) for twin-twin transfusion syndrome (TTTS). METHODS: This was a retrospective cohort analysis of monochorionic diamniotic twin pregnancies with TTTS that underwent FLP at one of two university-affiliated tertiary medical centers between January 2012 and December 2020. CAS and septostomy were diagnosed either during the procedure or by ultrasonography within 24-48 h after FLP. Data on procedure and postprocedure parameters, pregnancy outcomes and survival were collected from the patients' electronic medical records. Pregnancies were stratified according to the presence of CAS, septostomy or neither. Patients diagnosed with both CAS and septostomy were analyzed separately. RESULTS: Of the 522 women included in the cohort, 38 (7.3%) were diagnosed with CAS, 68 (13.0%) with septostomy and 23 (4.4%) with both CAS and septostomy. The remaining 393 (75.3%) women comprised the control group. Groups did not differ in demographic characteristics. The septostomy group had a lower rate of selective fetal growth restriction than did the CAS and control groups (24.2% vs 36.8% vs 42.7%, respectively; P = 0.017). Moreover, intertwin size discordance was lower in the septostomy group (15.1% vs 23.4% in the CAS group and 25.5% in the control group; P = 0.001). Median gestational age at FLP was significantly lower in the CAS group (19.3 weeks vs 20.4 weeks in controls and 20.9 weeks in the septostomy group; P = 0.049). The rate of delivery prior to 34 weeks was significantly higher in the CAS group (89.2%), followed by the septostomy group (80.9%), compared with the control group (69.0%) (P = 0.006). A secondary analysis demonstrated that patients with both CAS and septostomy presented the highest rates of delivery prior to 34 weeks (100%) and 32 weeks (68.2%). CONCLUSIONS: CAS and septostomy following laser surgery for TTTS are independently associated with higher rates of preterm delivery. The presence of these two findings in the same patient enhances the risk of prematurity. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Donor UNC-93 Homolog B1 genetic polymorphism predicts survival outcomes after unrelated bone marrow transplantation.

UNC-93 homolog B1 (UNC93B1) is a key regulator of toll-like receptors (TLRs), pattern recognition receptors that sense invading pathogens and manage the innate immune response and deliver them from the endoplasmic reticulum to their respective endosomal signaling compartments. Several types of TLRs are known to contribute to the inflammatory process after allogeneic hematopoietic stem cell transplantation (SCT), so UNC93B1 might play integral roles there. We investigated the influence of the UNC93B1 single-nucleotide polymorphism (SNP) rs308328 (T>C) on transplant outcomes in a cohort of 237 patients undergoing unrelated HLA-matched bone marrow transplantation (BMT) for hematologic malignancies through the Japan Marrow Donor Program. The donor UNC93B1 C/C genotype was associated with a better 3-year overall survival than the donor UNC93B1 C/T or T/T genotype. An analysis of the UNC93B1 rs308328 genotype may therefore be useful for selecting the donor, estimating the prognosis, and creating therapeutic strategies after allogeneic SCT.

Trapped Ion Quantum Computing Using Optical Tweezers and Electric Fields.

We propose a new scalable architecture for trapped ion quantum computing that combines optical tweezers delivering qubit state-dependent local potentials with oscillating electric fields. Since the electric field allows for long-range qubit-qubit interactions mediated by the center-of-mass motion of the ion crystal alone, it is inherently scalable to large ion crystals. Furthermore, our proposed scheme does not rely on either ground-state cooling or the Lamb-Dicke approximation. We study the effects of imperfect cooling of the ion crystal, as well as the role of unwanted qubit-motion entanglement, and discuss the prospects of implementing the state-dependent tweezers in the laboratory.

Prenatal predictors of motor function in children with open spina bifida: a retrospective cohort study.

OBJECTIVE: To identify predictors for intact motor function (MF) at birth and at 12 months of life in babies with prenatally versus postnatally repaired open spina bifida (OSB). DESIGN: Retrospective cohort study. SETTING: Texas Children's Hospital, 2011-2018. POPULATION: Patients who underwent either prenatal or postnatal OSB repair. METHODS: Prenatal MF of the lower extremities was evaluated by ultrasound following a metameric distribution at the time of diagnosis (US1), 6 weeks postoperatively (or 6 weeks after initial evaluation in postnatally repaired cases) (US2) and at the last ultrasound before delivery (US3). At birth and at 12 months, MF was assessed clinically. Intact MF (S1) was defined as the observation of plantar flexion of the ankle. Results from logistic regression analysis are expressed as odds ratios (95% confidence intervals, P values). RESULTS: A total of 127 patients were included: 93 with prenatal repair (51 fetoscopic; 42 open hysterotomy repair) and 34 with postnatal repair. In the prenatal repair group, predictors for intact MF at birth and at 12 months included: absence of clubfeet (OR 11.3, 95% CI 3.2-39.1, P < 0.01; OR 10.8 95% CI 2.4-47.6, P < 0.01); intact MF at US1 (OR 19.7, 95% CI 5.0-76.9, P < 0.01; OR 8.7, 95% CI 2.0-38.7, P < 0.01); intact MF at US2 (OR 22, 95% CI 6.5-74.2, P < 0.01; OR 13.5, 95% 3.0-61.4, P < 0.01); intact MF at US3 (OR 13.7, 95% CI 3.4-55.9, P < 0.01; OR 12.6, 95% CI 2.5-64.3, P < 0.01); and having a flat lesion (OR 11.2, 95% CI 2.4-51.1, P < 0.01; OR 4.1, 95% CI 1.1-16.5, P = 0.04). In the postnatal repair group, the only predictor of intact MF at 12 months was having intact MF at birth (OR 15.2, 95% CI 2.0-113.3, P = 0.03). CONCLUSIONS: The detection of intact MF in utero from mid-gestation to delivery predicts intact MF at birth and at 12 months in babies who undergo prenatal OSB repair. TWEETABLE ABSTRACT: Detection of intact motor function in utero predicts intact motor function at birth and at 1 year in fetuses who undergo prenatal OSB repair.

Impact of the size of the lesion in prenatal neural tube defect repair on imaging, neurosurgical and motor outcomes: a retrospective cohort study.

OBJECTIVES: (1) To compare brain findings between large and non-large neural tube defect (NTD); (2) to evaluate the impact of large lesion on the surgical parameters; (3) to study any associations between the size of the lesions and brain findings 6 weeks postoperatively and neurological short-term outcomes. DESIGN: Retrospective cohort study. SETTING: Texas Children's Hospital, between 2011 and 2018. POPULATION: Patients who underwent prenatal NTD repair. METHODS: Large lesion was defined when the lesion's surface was >75th centile of our cohorts' lesions. MAIN OUTCOME MEASURES: Time of referral: ventriculomegaly and anatomical level of the lesion; surgery: duration and need for relaxing incisions. 6 weeks postoperative: hindbrain herniation (HBH) and ventriculomegaly. After delivery: dehiscence, need for hydrocephalus treatment and motor function. RESULTS: A total of 99 patients were included, 25 of whom presented with large lesions. Type of lesion and ventriculomegaly were comparable between individuals with large and non-large lesions. Individuals with large lesions were associated with increased need for relaxing incisions by 5.4 times (95% CI 1.3-23.2, P = 0.02). Six weeks postoperatively, having a large lesion decreased by ten times the likelihood of having a postoperative reversal of HBH (odds ratio = 0.1, 95% CI 0.1-0.4, P < 0.01). At birth, larger lesions increased the risk for repair dehiscence by 6.1 times (95% CI 1.6-22.5, P < 0.01) and the risk of dehiscence or leakage of cerebrospinal fluid at birth by 5.5 times (95% CI 1.6-18.9, P < 0.01). CONCLUSION: Prenatal repair of patients with large NTD presents a lower proportion of HBH reversal 6 weeks after the surgery, a higher risk of dehiscence and a higher need for postnatal repair. TWEETABLE ABSTRACT: Evaluation of the size of fetal NTD can predict adverse neurological outcomes after prenatal NTD repair.

Prediction of post-laser fetal death in selective growth restriction complicating twin-twin transfusion syndrome using standardized definitions.

OBJECTIVE: Selective fetal growth restriction (sFGR) complicating twin-twin transfusion syndrome (TTTS) is associated with a 3-6-fold increased risk of fetal demise after fetoscopic laser surgery (FLS). Identifying these patients is challenging due to varying definitions of sFGR used in the literature. The objective of this study was to determine the association of three currently used definitions for sFGR with demise of the smaller twin, typically the donor, following FLS for TTTS. METHODS: This was a retrospective cohort study of monochorionic diamniotic twin pregnancies undergoing FLS for TTTS between January 2015 and December 2018. Classification of the cohort as sFGR or non-sFGR was performed using three different definitions: (1) estimated fetal weight (EFW) of one twin < 10th centile and intertwin EFW discordance > 25%, according to the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) (Definition A); (2) EFW of one twin < 3rd centile, according to the solitary criterion for sFGR reported in a Delphi consensus (Definition B); and (3) presence of at least two of four of the following criteria: EFW of one twin < 10th centile, abdominal circumference of one twin < 10th centile, intertwin EFW discordance of ≥ 25% and umbilical artery pulsatility index of the smaller twin > 95th centile, according to the contributory criteria for sFGR in monochorionic diamniotic twin pregnancies reported in the Delphi consensus (Definition C). Pearson's χ2 and univariate and multivariate logistic regression analyses were performed to assess the association of classification as sFGR according to the different definitions with fetal demise within 48 h after FLS. RESULTS: A total of 124 pregnancies underwent FLS for TTTS during the study period. Of these, 46/124 (37.1%) were identified as having sFGR according to the ISUOG criteria (Definition A), 57/124 (46.0%) based on EFW < 3rd centile (Definition B) and 70/124 (56.5%) according to the Delphi contributory criteria (Definition C). There were no differences in maternal body mass index, recipient twin amniotic fluid volume, gestational age (GA) at intervention or GA at delivery between sFGR and non-sFGR cases for any of the three definitions. There were also no differences in the rates of postprocedure recipient demise or Doppler abnormalities in the recipient. Regardless of the definition used, sFGR cases showed a significantly higher rate of postprocedure donor twin demise compared with that in non-sFGR cases (Definition A: 28.3% vs 3.8%, P < 0.01; Definition B: 22.8% vs 4.5%, P = 0.02; Definition C: 22.9% vs 0%, P < 0.01). For all of the sFGR definitions, the rate of Stage-III TTTS was increased in sFGR compared to non-sFGR cases (Definition A: 65.2% vs 35.9%, P ≤ 0.01; Definition B: 59.6% vs 35.8%, P = 0.04; Definition C: 62.9% vs 25.9%, P < 0.01). All cases of donor demise met the criteria for sFGR according to Definition C. Classification as sFGR according to Definition C was associated with a significantly higher rate of post-FLS donor demise compared to Definitions A and B (χ2 , 15.32; P < 0.01). Logistic regression analysis demonstrated that sFGR cases had an increased risk of donor demise (Definition A: odds ratio (OR), 4.97 (95% CI, 1.77-13.94), P < 0.01; Definition B: OR, 4.39 (95% CI, 1.36-14.15), P = 0.01) and that staging of TTTS was also predictive of demise (OR, 2.26 (95% CI, 1.14-4.47), P = 0.02). After adjusting for GA at intervention and stage of TTTS, the results were similar (Definition A: OR, 6.48 (95% CI, 2.11-24.56), P = 0.002; Definition B: OR, 4.16 (95% CI, 1.35-15.74), P = 0.02). CONCLUSIONS: The rate of fetal demise following FLS for TTTS is increased in the presence of sFGR. Improving diagnosis of sFGR should improve counseling and may affect management. The Delphi method of defining sFGR based on the presence of at least two of four contributory criteria had the highest predictive value for donor demise following FLS for TTTS. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.