Angular momentum generation in nuclear fission.

When a heavy atomic nucleus splits (fission), the resulting fragments are observed to emerge spinning1; this phenomenon has been a mystery in nuclear physics for over 40 years2,3. The internal generation of typically six or seven units of angular momentum in each fragment is particularly puzzling for systems that start with zero, or almost zero, spin. There are currently no experimental observations that enable decisive discrimination between the many competing theories for the mechanism that generates the angular momentum4-12. Nevertheless, the consensus is that excitation of collective vibrational modes generates the intrinsic spin before the nucleus splits (pre-scission). Here we show that there is no significant correlation between the spins of the fragment partners, which leads us to conclude that angular momentum in fission is actually generated after the nucleus splits (post-scission). We present comprehensive data showing that the average spin is strongly mass-dependent, varying in saw-tooth distributions. We observe no notable dependence of fragment spin on the mass or charge of the partner nucleus, confirming the uncorrelated post-scission nature of the spin mechanism. To explain these observations, we propose that the collective motion of nucleons in the ruptured neck of the fissioning system generates two independent torques, analogous to the snapping of an elastic band. A parameterization based on occupation of angular momentum states according to statistical theory describes the full range of experimental data well. This insight into the role of spin in nuclear fission is not only important for the fundamental understanding and theoretical description of fission, but also has consequences for the γ-ray heating problem in nuclear reactors13,14, for the study of the structure of neutron-rich isotopes15,16, and for the synthesis and stability of super-heavy elements17,18.

Autologous patient-derived exhausted nano T-cells exploit tumor immune evasion to engage an effective cancer therapy.

BACKGROUND: Active targeting by surface-modified nanoplatforms enables a more precise and elevated accumulation of nanoparticles within the tumor, thereby enhancing drug delivery and efficacy for a successful cancer treatment. However, surface functionalization involves complex procedures that increase costs and timelines, presenting challenges for clinical implementation. Biomimetic nanoparticles (BNPs) have emerged as unique drug delivery platforms that overcome the limitations of actively targeted nanoparticles. Nevertheless, BNPs coated with unmodified cells show reduced functionalities such as specific tumor targeting, decreasing the therapeutic efficacy. Those challenges can be overcome by engineering non-patient-derived cells for BNP coating, but these are complex and cost-effective approaches that hinder their wider clinical application. Here we present an immune-driven strategy to improve nanotherapeutic delivery to tumors. Our unique perspective harnesses T-cell exhaustion and tumor immune evasion to develop a groundbreaking new class of BNPs crafted from exhausted T-cells (NExT) of triple-negative breast cancer (TNBC) patients by specific culture methods without sophisticated engineering. METHODS: NExT were generated by coating PLGA (poly(lactic-co-glycolic acid)) nanoparticles with TNBC-derived T-cells exhausted in vitro by acute activation. Physicochemical characterization of NExT was made by dynamic light scattering, electrophoretic light scattering and transmission electron microscopy, and preservation and orientation of immune checkpoint receptors by flow cytometry. The efficacy of chemotherapy-loaded NExT was assessed in TNBC cell lines in vitro. In vivo toxicity was made in CD1 mice. Biodistribution and therapeutic activity of NExT were determined in cell-line- and autologous patient-derived xenografts in immunodeficient mice. RESULTS: We report a cost-effective approach with a good performance that provides NExT naturally endowed with immune checkpoint receptors (PD1, LAG3, TIM3), augmenting specific tumor targeting by engaging cognate ligands, enhancing the therapeutic efficacy of chemotherapy, and disrupting the PD1/PDL1 axis in an immunotherapy-like way. Autologous patient-derived NExT revealed exceptional intratumor accumulation, heightened chemotherapeutic index and efficiency, and targeted the tumor stroma in a PDL1+ patient-derived xenograft model of triple-negative breast cancer. CONCLUSIONS: These advantages underline the potential of autologous patient-derived NExT to revolutionize tailored adoptive cancer nanotherapy and chemoimmunotherapy, which endorses their widespread clinical application of autologous patient-derived NExT.

Rechallenge in idiosyncratic drug-induced liver injury: An analysis of cases in two large prospective registries according to existing definitions.

INTRODUCTION: Data on positive rechallenge in idiosyncratic drug-induced liver injury (DILI) are scarce. We aim to analyse the clinical presentation, outcome and drugs associated with positive rechallenge in two DILI registries. METHODS: Cases from the Spanish and Latin American DILI registries were included. Demographics, clinical characteristics and outcome of cases with positive rechallenge according to CIOMS/RUCAM and current definitions were analysed. RESULTS: Of 1418 patients with idiosyncratic DILI, 58 cases had positive rechallenge (4.1%). Patients with positive rechallenge had shorter duration of therapy (p=0.001) and latency (p=0.003). In patients with rechallenge, aspartate transaminase levels were increased (p=0.026) and showed a prolonged time to recovery (p=0.020), albeit no differences were seen in terms of fatal outcomes. The main drug implicated in rechallenge was amoxicillin-clavulanate (17%). The majority of re-exposure events were unintentional (71%). Using both existing definitions of positive rechallenge, there were four cases which exclusively fulfilled the current criteria and five which only meet the historical definition. All cases of positive rechallenge, irrespective of the pattern of damage, fulfilled the criteria of either alanine transaminase (ALT) ≥3 times the upper limit of normal (ULN) and/or alkaline phosphatase (ALP) ≥2 times ULN. CONCLUSIONS: Episodes of rechallenge were characterised by shorter duration of therapy and latency, and longer time to resolution, but did not show an increased incidence of fatal outcome. Based on our findings, ALT ≥3 times ULN and/or ALP ≥2 times ULN, regardless of the pattern of damage, is proposed as a new definition of rechallenge in DILI.

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.

Perforation of cavum septi pellucidi in open spina bifida and need for hydrocephalus treatment by 1 year of age.

OBJECTIVE: In-utero repair of an open neural tube defect (ONTD) reduces the risk of developing severe hydrocephalus postnatally. Perforation of the cavum septi pellucidi (CSP) may reflect increased intraventricular pressure in the fetal brain. We sought to evaluate the association of perforated CSP visualized on fetal imaging before and/or after in-utero ONTD repair with the eventual need for hydrocephalus treatment by 1 year of age. METHODS: This was a retrospective cohort study of consecutive patients who underwent laparotomy-assisted fetoscopic ONTD repair between 2014 and 2021 at a single center. Eligibility criteria for surgery were based on those of the Management of Myelomeningocele Study (MOMS), although a maternal prepregnancy body mass index of up to 40 kg/m2 was allowed. Fetal brain imaging was performed with ultrasound and magnetic resonance imaging (MRI) at referral and 6 weeks postoperatively. Stored ultrasound and MRI scans were reviewed retrospectively to assess CSP integrity. Medical records were reviewed to determine whether hydrocephalus treatment was needed within 1 year of age. Parametric and non-parametric tests were used as appropriate to compare outcomes between cases with perforated CSP and those with intact CSP as determined on ultrasound at referral. Logistic regression analysis was performed to assess the predictive performance of various imaging markers for the need for hydrocephalus treatment. RESULTS: A total of 110 patients were included. Perforated CSP was identified in 20.6% and 22.6% of cases on preoperative ultrasound and MRI, respectively, and in 26.6% and 24.2% on postoperative ultrasound and MRI, respectively. Ventricular size increased between referral and after surgery (median, 11.00 (range, 5.89-21.45) mm vs 16.00 (range, 7.00-43.5) mm; P < 0.01), as did the proportion of cases with severe ventriculomegaly (ventricular width ≥ 15 mm) (12.7% vs 57.8%; P < 0.01). Complete CSP evaluation was achieved on preoperative ultrasound in 107 cases, of which 22 had a perforated CSP and 85 had an intact CSP. The perforated-CSP group presented with larger ventricles (mean, 14.32 ± 3.45 mm vs 10.37 ± 2.37 mm; P < 0.01) and a higher rate of severe ventriculomegaly (40.9% vs 5.9%; P < 0.01) compared to those with an intact CSP. The same trends were observed at 6 weeks postoperatively for mean ventricular size (median, 21.0 (range, 13.0-43.5) mm vs 14.3 (range, 7.0-29.0) mm; P < 0.01) and severe ventriculomegaly (95.0% vs 46.8%; P < 0.01). Cases with a perforated CSP at referral had a lower rate of hindbrain herniation (HBH) reversal postoperatively (65.0% vs 88.6%; P = 0.01) and were more likely to require treatment for hydrocephalus (89.5% vs 22.7%; P < 0.01). The strongest predictor of the need for hydrocephalus treatment within 1 year of age was lack of HBH reversal on MRI (odds ratio (OR), 36.20 (95% CI, 5.96-219.12); P < 0.01) followed by perforated CSP on ultrasound at referral (OR, 23.40 (95% CI, 5.42-100.98); P < 0.01) and by perforated CSP at 6-week postoperative ultrasound (OR, 19.48 (95% CI, 5.68-66.68); P < 0.01). CONCLUSIONS: The detection of a perforated CSP in fetuses with ONTD can reliably identify those cases at highest risk for needing hydrocephalus treatment by 1 year of age. Evaluation of this brain structure can improve counseling of families considering fetal surgery for ONTD, in order to set appropriate expectations about postnatal outcome. © 2023 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.

Nematodes associated with terrestrial gastropod molluscs in Belgium and additional characterisation of Pellioditis californica and P. hermaphrodita.

A survey for slug- and snail-associated nematodes was conducted in forests, parks, botanical gardens, and nature reserves at 13 localities in Belgium to uncover more diversity of gastropod mollusc-associated nematodes and to characterise Pellioditis populations found in the country. A total of 319 slugs and snails belonging to nine species were examined. Arion vulgaris was the most commonly found mollusc species in this study (eight locations), and 19.4% of the examined mollusc specimens were found infected by nematodes. The highest prevalence of nematodes was observed in Cornu aspersum (60%) followed by A. vulgaris (34.8%), Limax maximus (28.6%), and Cepaea sp. (20%). Eleven nematode species belonging to eight families were isolated and identified from the mollusc hosts including Alloionema appendiculatum, Angiostoma dentiferum, A. gandavense, Angiostrongylus vasorum, Cosmocerca longicauda, Panagrolaimus cf. subelongatus, Pellioditis californica, P. hermaphrodita, Rhabditis sp., Tetrameres cf. fissispina, and Troglostrongylus cf. brevior.Pellioditis was the most commonly found nematode genus (at nine localities) and C. longicauda and P. californica were reported in Belgium for the first time. Co-infections of more than one nematode species were observed in eight (2.5%) molluscs specimens. Most co-infections consisted of two nematode species. In one A. vulgaris specimen, a co-infection of three nematode species (A. vasorum, P. hermaphrodita, and Tetrameres cf. fissispina) was observed. Four ex vivo cultures of P. californica and six ex vivo cultures of P. hermaphrodita were established from single hermaphrodites, and both species were described based on light microscopy, scanning electron microscopy, and morphometric, morphological, and molecular data.

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.

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.

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.

A differential therapeutic consideration for use of corticosteroids according to established COVID-19 clinical phenotypes in critically ill patients.

Objective: To determine if the use of corticosteroids was associated with Intensive Care Unit (ICU) mortality among whole population and pre-specified clinical phenotypes. Design: A secondary analysis derived from multicenter, observational study. Setting: Critical Care Units. Patients: Adult critically ill patients with confirmed COVID-19 disease admitted to 63 ICUs in Spain. Interventions: Corticosteroids vs. no corticosteroids. Main variables of interest: Three phenotypes were derived by non-supervised clustering analysis from whole population and classified as (A: severe, B: critical and C: life-threatening). We performed a multivariate analysis after propensity optimal full matching (PS) for whole population and weighted Cox regression (HR) and Fine-Gray analysis (sHR) to assess the impact of corticosteroids on ICU mortality according to the whole population and distinctive patient clinical phenotypes. Results: A total of 2017 patients were analyzed, 1171 (58%) with corticosteroids. After PS, corticosteroids were shown not to be associated with ICU mortality (OR: 1.0; 95% CI: 0.98-1.15). Corticosteroids were administered in 298/537 (55.5%) patients of "A" phenotype and their use was not associated with ICU mortality (HR = 0.85 [0.55-1.33]). A total of 338/623 (54.2%) patients in "B" phenotype received corticosteroids. No effect of corticosteroids on ICU mortality was observed when HR was performed (0.72 [0.49-1.05]). Finally, 535/857 (62.4%) patients in "C" phenotype received corticosteroids. In this phenotype HR (0.75 [0.58-0.98]) and sHR (0.79 [0.63-0.98]) suggest a protective effect of corticosteroids on ICU mortality. Conclusion: Our finding warns against the widespread use of corticosteroids in all critically ill patients with COVID-19 at moderate dose. Only patients with the highest inflammatory levels could benefit from steroid treatment.

Objetivo: Evaluar si el uso de corticoesteroides (CC) se asocia con la mortalidad en la unidad de cuidados intensivos (UCI) en la población global y dentro de los fenotipos clínicos predeterminados. Diseño: Análisis secundario de estudio multicéntrico observacional. Ámbito: UCI. Pacientes: Pacientes adultos con COVID-19 confirmado ingresados en 63 UCI de España. Intervención: Corticoides vs. no corticoides. Variables de interés principales: A partir del análisis no supervisado de grupos, 3 fenotipos clínicos fueron derivados y clasificados como: A grave, B crítico y C potencialmente mortal. Se efectuó un análisis multivariado después de un propensity optimal full matching (PS) y una regresión ponderada de Cox (HR) y análisis de Fine-Gray (sHR) para evaluar el impacto del tratamiento con CC sobre la mortalidad en la población general y en cada fenotipo clínico. Resultados: Un total de 2.017 pacientes fueron analizados, 1.171 (58%) con CC. Después del PS, el uso de CC no se relacionó significativamente con la mortalidad en UCI (OR: 1,0; IC 95%: 0,98-1,15). Los CC fueron administrados en 298/537 (55,5%) pacientes del fenotipo A y no se observó asociación significativa con la mortalidad (HR = 0,85; 0,55-1,33). Un total de 338/623 (54,2%) pacientes del fenotipo B recibieron CC sin efecto significativo sobre la mortalidad (HR = 0,72; 0,49-1,05). Por último, 535/857 (62,4%) pacientes del fenotipo C recibieron CC. En este fenotipo, se evidenció un efecto protector de los CC sobre la mortalidad HR (0,75; 0,58-0,98). Conclusión: Nuestros hallazgos alertan sobre el uso indiscriminado de CC a dosis moderadas en todos los pacientes críticos con COVID-19. Solamente pacientes con elevado estado de inflamación podrían beneficiarse con el tratamiento con CC.

Hybrid Fluorescent Mass-Tag Nanotrackers as Universal Reagents for Long-Term Live-Cell Barcoding.

Barcoding and pooling cells for processing as a composite sample are critical to minimize technical variability in multiplex technologies. Fluorescent cell barcoding has been established as a standard method for multiplexing in flow cytometry analysis. In parallel, mass-tag barcoding is routinely used to label cells for mass cytometry. Barcode reagents currently used label intracellular proteins in fixed and permeabilized cells and, therefore, are not suitable for studies with live cells in long-term culture prior to analysis. In this study, we report the development of fluorescent palladium-based hybrid-tag nanotrackers to barcode live cells for flow and mass cytometry dual-modal readout. We describe the preparation, physicochemical characterization, efficiency of cell internalization, and durability of these nanotrackers in live cells cultured over time. In addition, we demonstrate their compatibility with standardized cytometry reagents and protocols. Finally, we validated these nanotrackers for drug response assays during a long-term coculture experiment with two barcoded cell lines. This method represents a new and widely applicable advance for fluorescent and mass-tag barcoding that is independent of protein expression levels and can be used to label cells before long-term drug studies.

Extended p_{3/2} Neutron Orbital and the N=32 Shell Closure in

The one-neutron knockout from ^{52}Ca in inverse kinematics onto a proton target was performed at ∼230 MeV/nucleon combined with prompt γ spectroscopy. Exclusive quasifree scattering cross sections to bound states in ^{51}Ca and the momentum distributions corresponding to the removal of 1f_{7/2} and 2p_{3/2} neutrons were measured. The cross sections, interpreted within the distorted-wave impulse approximation reaction framework, are consistent with a shell closure at the neutron number N=32, found as strong as at N=28 and N=34 in Ca isotopes from the same observables. The analysis of the momentum distributions leads to a difference of the root-mean-square radii of the neutron 1f_{7/2} and 2p_{3/2} orbitals of 0.61(23) fm, in agreement with the modified-shell-model prediction of 0.7 fm suggesting that the large root-mean-square radius of the 2p_{3/2} orbital in neutron-rich Ca isotopes is responsible for the unexpected linear increase of the charge radius with the neutron number.

Real-life analysis on safety and efficacy of asciminib for ponatinib pretreated patients with chronic myeloid leukemia.

Failure of second-generation tyrosine kinase inhibitors (2GTKI) is a challenging situation in patients with chronic myeloid leukemia (CML). Asciminib, recently approved by the US Federal Drug Administration, has demonstrated in clinical trials a good efficacy and safety profile after failure of 2GTKI. However, no study has specifically addressed response rates to asciminib in ponatinib pretreated patients (PPT). Here, we present data on responses to asciminib from 52 patients in clinical practice, 20 of them (38%) with prior ponatinib exposure. We analyzed retrospectively responses and toxicities under asciminib and compared results between PPT and non-PPT patients.After a median follow-up of 30 months, 34 patients (65%) switched to asciminib due to intolerance and 18 (35%) due to resistance to prior TKIs. Forty-six patients (88%) had received at least 3 prior TKIs. Regarding responses, complete cytogenetic response was achieved or maintained in 74% and 53% for non-PPT and PPT patients, respectively. Deeper responses such as major molecular response and molecular response 4.5 were achieved in 65% and 19% in non-PPT versus 32% and 11% in PPT, respectively. Two patients (4%) harbored the T315I mutation, both PPT.In terms of toxicities, non-PPT displayed 22% grade 3-4 TEAE versus 20% in PPT. Four patients (20% of PPT) suffered from cross-intolerance with asciminib as they did under ponatinib.Our data supports asciminib as a promising alternative in resistant and intolerant non-PPT patients, as well as in intolerant PPT patients; the resistant PPT subset remains as a challenging group in need of further therapeutic options.

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.

Association between ambulatory skills and diffusion tensor imaging of corpus callosal white matter in infants with spina bifida.

OBJECTIVES: To assess brain white matter using diffusion tensor imaging (DTI) at 1 year of age in infants diagnosed with open neural tube defect (ONTD) and explore the association of DTI parameters with ambulatory skills at 30 months of age. METHODS: Magnetic resonance imaging (MRI) was performed at an average of 12 months of age and included an echo planar axial DTI sequence with diffusion gradients along 20 non-collinear directions. TORTOISE software was used to correct DTI raw data for motion artifacts, and DtiStudio, DiffeoMap and RoiEditor were used for further postprocessing. DTI data were analyzed in terms of fractional anisotropy (FA), trace, radial diffusivity and axial diffusivity. These parameters reflect the integrity and maturation of white-matter motor pathways. At 30 months of age, ambulation status was evaluated by a developmental pediatrician, and infants were classified as ambulatory if they were able to walk independently with or without orthoses or as non-ambulatory if they could not. Linear mixed-effects method was used to examine the association between study outcomes and study group. Possible confounders were sought, and analyses were adjusted for age at MRI scan and ventricular size by including them in the regression model as covariates. RESULTS: Twenty patients with ONTD were included in this study, including three cases that underwent postnatal repair and 17 cases that underwent prenatal repair. There were five ambulatory and 15 non-ambulatory infants evaluated at a mean age of 31.5 ± 5.7 months. MRI was performed at 50.3 (2-132.4) weeks postpartum. When DTI analysis results were compared between ambulatory and non-ambulatory infants, significant differences were observed in the corpus callosum (CC). Compared with non-ambulatory infants, ambulatory infants had increased FA in the splenium (0.62 (0.48-0.75) vs 0.41 (0.34-0.49); P = 0.01, adjusted P = 0.02), genu (0.64 (0.47-0.80) vs 0.47 (0.35-0.61); P = 0.03, adjusted P = 0.004) and body (0.55 (0.45-0.65) vs 0.40 (0.35-0.46), P = 0.01, adjusted P = 0.01). Reduced trace was observed in the CC of ambulatory children at the level of the splenium (0.0027 (0.0018-0.0037) vs 0.0039 (0.0034-0.0044) mm2 /s; P = 0.04, adjusted P = 0.03) and genu (0.0029 (0.0020-0.0038) vs 0.0039 (0.0033-0.0045) mm2 /s; P = 0.04, adjusted P = 0.01). In addition, radial diffusivity was reduced in the CC of the ambulatory children at the level of the splenium (0.00057 (0.00025-0.00089) vs 0.0010 (0.00084-0.00120) mm2 /s; P = 0.02, adjusted P = 0.02) and the genu (0.00058 (0.00028-0.00088) vs 0.0010 (0.00085-0.00118) mm2 /s; P = 0.02, adjusted P = 0.02). There were no differences in axial diffusivity between ambulatory and non-ambulatory children. CONCLUSION: This study demonstrates a significant association between white matter integrity of connecting fibers of the corpus callosum, as assessed by DTI, and ambulatory skills at 30 months of age in infants with ONTD. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

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.

Pairing Forces Govern Population of Doubly Magic

Direct proton-knockout reactions of ^{55}Sc at ∼220 MeV/nucleon were studied at the RIKEN Radioactive Isotope Beam Factory. Populated states of ^{54}Ca were investigated through γ-ray and invariant-mass spectroscopy. Level energies were calculated from the nuclear shell model employing a phenomenological internucleon interaction. Theoretical cross sections to states were calculated from distorted-wave impulse approximation estimates multiplied by the shell model spectroscopic factors, which describe the wave function overlap of the ^{55}Sc ground state with states in ^{54}Ca. Despite the calculations showing a significant amplitude of excited neutron configurations in the ground-state of ^{55}Sc, valence proton removals populated predominantly the ground state of ^{54}Ca. This counterintuitive result is attributed to pairing effects leading to a dominance of the ground-state spectroscopic factor. Owing to the ubiquity of the pairing interaction, this argument should be generally applicable to direct knockout reactions from odd-even to even-even nuclei.