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To establish the incidence, risk factors and prognostic effect of anemia in children living with HIV (CLWH).Retrospective nested case-control study of patients 0-18 years in five centers in sub-Saharan Africa, 2004-2014.Incident cases of anemia were identified from electronic records and matched with CLWH without anemia. We calculated the incidence density of anemia and used conditional logistic regression to evaluate its association with risk factors, stratified by severity and type of anemia. We used a Cox proportional hazards model to evaluate the impact of anemia on survival.Two thousand, one hundred and thirty-seven children were sampled. The incidence density of anemia was 1 per 6.6 CLWH-years. Anemia was moderate in 31.8% and severe in 17.3% of anemia cases, which had 10-year mortality hazards of 3.4 and 4.5, respectively. Microcytic anemia (36% cases) was associated with 2.3-fold hazard of 10-year mortality, and with malnutrition and CD4 + suppression. Normocytic anemia (50.5% cases) was associated with 2.6-fold hazards of 10-year mortality, and with more severe malnutrition, CD4 + suppression, and WHO stage, but inversely associated with lamivudine and nevirapine therapy. Macrocytic anemia (13.5% cases) was neither associated with higher 10-year mortality nor with severe malnutrition or CD4 + suppression but was associated with WHO stage II/III and negatively associated with lamivudine therapy.This large multicountry study of CLWH found a high incidence density of anemia. Higher severity, normocytic and microcytic types of anemia were independently associated with long-term mortality. Laboratory studies are needed to decipher the mechanisms of anemia and how it impacts mortality in CLWH.

Compare maternal and perinatal outcomes between emergency and electively scheduled cesarean-hysterectomy for placenta accreta spectrum (PAS) disorders.Single-center retrospective cohort study including 125 cases of antenatally suspected and pathologically confirmed PAS disorders. Maternal and perinatal outcomes were analyzed. Multivariate logistic regression was used to test associations. Survival curves exploring risk factors for emergency birth were sought.25 (20%) and 100 (80%) patients had emergency and electively scheduled birth, respectively. Emergency birth had a higher estimated blood loss (2772 [2256.75] vs. 1561.19 [1152.95], P 0.001), with a higher rate of coagulopathy (40% vs. 6%; P 0.001) and bladder injury (44% vs. 13%; P 0.001); and was associated with increased rates of blood transfusion (aOR 4.9, CI95% 1.3-17.5, P = 0.01), coagulopathy (aOR 16.4, CI95% 2.6-101.4, P = 0.002) and urinary tract injury (aOR 6.96, CI95% 1.5-30.7, P = 0.01). Gestational age at birth was lower in the emergency group (31.55 [4.75] vs. 35.19 [2.77], P = 0.001), no difference in perinatal mortality was found. A sonographically short cervix and/or history of APH had an increased cumulative risk of emergency birth with advancing gestational age.Patients with PAS disorders managed in a tertiary center by a multidisciplinary team requiring emergency birth have increased maternal morbidity and poorer perinatal outcomes than those with electively scheduled birth.

The spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) facilitates viral entry into host cells and is the key target for neutralizing antibodies. The SARS-CoV-2 lineage B.1.620 carries fifteen mutations in the S protein and is spread in Africa, the US and Europe, while lineage R.1 harbors four mutations in S and infections were observed in several countries, particularly Japan and the US. However, the impact of the mutations in B.1.620 and R.1 S proteins on antibody-mediated neutralization and host cell entry are largely unknown. Here, we report that these mutations are compatible with robust ACE2 binding and entry into cell lines, and they markedly reduce neutralization by vaccine-induced antibodies. Our results reveal evasion of neutralizing antibodies by B.1.620 and R.1, which might have contributed to the spread of these lineages.

Early screening for placenta accreta spectrum (PAS) is not established in Canada, yet has been demonstrated with a 2-stage strategy in patients classified as at risk at the nuchal translucency examination. We performed a retrospective analysis of women with singleton pregnancies who had first-trimester screening and subsequently had a pathology-confirmed PAS. We sought those who met high-risk clinical criteria for PAS: previous uterine surgeries and an anterior low-lying placenta. Over 80% of women met both high-risk criteria at the nuchal translucency examination. Lack of early recognition and risk stratification resulted in a late median gestational age at suspicion and diagnosis of PAS.

To monitor infection by the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and successful vaccination against coronavirus disease 2019 (COVID‐19), the kinetics of neutralizing or blocking anti‐SARS‐CoV‐2 antibody titers need to be assessed. Here, we report the development of a quick and inexpensive surrogate SARS‐CoV‐2 blocking assay (SUBA) using immobilized recombinant human angiotensin‐converting enzyme 2 (hACE2) and human cells expressing the native form of surface SARS‐CoV‐2 spike protein. Spike protein‐expressing cells bound to hACE2 in the absence or presence of blocking antibodies were quantified by measuring the optical density of cell‐associated crystal violet in a spectrophotometer. The advantages are that SUBA is a fast and inexpensive assay, which does not require biosafety level 2‐ or 3‐approved laboratories. Most importantly, SUBA detects blocking antibodies against the native trimeric cell‐bound SARS‐CoV‐2 spike protein and can be rapidly adjusted to quickly pre‐screen already approved therapeutic antibodies or sera from vaccinated individuals for their ACE2 blocking activities against any emerging SARS‐CoV‐2 variants., A simple, inexpensive surrogate SARS‐CoV‐2 neutralization assay is introduced. Ectopic expression of the SARS‐CoV‐2 spike protein confers binding of Ramos‐Ig ‐ or HEK293 cells to plate‐bound recombinant human angiotensin‐converting‐enzyme‐2. This interaction can be blocked with reconvalescent or immune serum or with anti‐receptor‐binding domain antibodies. Bound spike‐expressing cells are quantitated with crystal violet.

There is little evidence evaluating angiogenic growth factor testing in real-world obstetric settings. This investigation evaluated maternal and perinatal pregnancy outcomes associated with maternal PlGF (placental growth factor) levels in real-world clinical care of high-risk pregnancies. From March 2017 to December 2019, 979 pregnant women with suspected risk of placental dysfunction, hypertensive disorders of pregnancy, or fetal growth restriction completed PlGF testing between 20+0 and 35+6 weeks of gestation. Maternal, fetal, and delivery characteristics were extracted through the electronic medical record system. The primary outcome of preterm birth was assessed using Royston-Parmar survival models and summarized with Kaplan-Meier methods. Of the 979 pregnant women, 289 had low PlGF levels (29.5%), and 690 had normal PlGF levels (70.5%). The survival probability of ongoing pregnancy free from preterm birth within 2- and 4-weeks following PlGF testing was significantly reduced in women with low PlGF levels, relative to women with normal PlGF levels (0.57 versus 0.99, standardized survival difference, −0.43 [95% CI, −0.76 to −0.09], and 0.37 versus 0.99, standardized survival difference, −0.62 [95% CI −0.87 to −0.38], respectively). Women with low PlGF levels were more likely to develop early-onset preeclampsia (adjusted odds ratio, 58.2 [95% CI, 32.1–105.4]) and have a stillbirth (adjusted odds ratio, 15.9 [95% CI, 7.6–33.3]). PlGF status distinguished placental from fetal causes of stillbirth. Low PlGF levels in high-risk pregnant women are strongly associated with increased rates of imminent preterm birth, as well as related adverse outcomes, including early-onset preeclampsia and stillbirth.

BackgroundThere is growing evidence of sex differences in placental vascular development. The objective of this study was to investigate the effect of fetal sex on uterine artery pulsatility index (PI) throughout gestation in a cohort of normal and complicated pregnancies.MethodsA prospective longitudinal study was conducted in 240 pregnant women. Pulsed wave Doppler ultrasound of the proximal uterine arteries was performed at a 4-weekly interval between 14 and 40 weeks of gestation. The patients were classified retrospectively as normal or complicated (one or more of maternal preeclampsia, preterm birth, or small for gestational age). To assess if the change in uterine artery PI during gestation differed between normal and complicated pregnancies and between fetal sexes, the uterine artery PI was modeled using a linear function of gestational age and the rate of change was estimated from the slope.ResultsWhile the uterine artery PI did not differ over gestation between females and males for normal pregnancies, the trajectory of this index differed by fetal sex for pregnancies complicated by either preeclampsia, preterm birth, or fetal growth restriction (p< 0.0001). The male fetuses in the complicated pregnancy group had an elevated slope compared to the other groups (p< 0.0001), suggesting a more progressive deterioration in uteroplacental perfusion over gestation.ConclusionsThe uterine artery PI is widely used to assess uteroplacental function in clinical settings. The observation that this metric changes more rapidly in complicated pregnancies where the fetus was male highlights the importance of sex when interpreting hemodynamic markers of placental maturation.

The basement membrane (BM) is a special type of extracellular matrix and presents the major barrier cancer cells have to overcome multiple times to form metastases. Here we show that BM stiffness is a major determinant of metastases formation in several tissues and identify netrin-4 (Net4) as a key regulator of BM stiffness. Mechanistically, our biophysical and functional analyses in combination with mathematical simulations show that Net4 softens the mechanical properties of native BMs by opening laminin node complexes, decreasing cancer cell potential to transmigrate this barrier despite creating bigger pores. Our results therefore reveal that BM stiffness is dominant over pore size, and that the mechanical properties of 'normal' BMs determine metastases formation and patient survival independent of cancer-mediated alterations. Thus, identifying individual Net4 protein levels within native BMs in major metastatic organs may have the potential to define patient survival even before tumour formation. The ratio of Net4 to laminin molecules determines BM stiffness, such that the more Net4, the softer the BM, thereby decreasing cancer cell invasion activity. The manuscript has been formally accepted for publication by Nature Materials. The manuscript needs shortening of the body, wherefore, final acceptance will be given upon re-submission of the shortened manuscript body. ispartof: Nature Materials vol:20 issue:6 ispartof: location:England status: Published online

OBJECTIVES: To evaluate the feasibility of using umbilical artery (UA) Doppler waveforms to measure fetal heart rate short term variation (STV) across gestation. METHODS: A prospective longitudinal study was conducted at two study sites in 195 women with pregnancies considered low risk. Pulsed wave Doppler of the UAs was performed at a 4-weekly interval between 14–40 weeks of gestation using a standardized imaging protocol. Up to 12 consecutive UA Doppler waveforms were analyzed using an off-line processing software. Fetal heart rate STV was calculated using average R-to-R intervals extracted from the waveforms and baseline corrected for fetal heart rate. RESULTS: Baseline corrected short term fetal heart rate variation increased significantly with gestational age (conditional R(2) = 0.37, p < 0.0001) and was inversely correlated with fetal heart rate (conditional R(2) = 0.54, p < 0.0001). The short term variation ranged (median (interquartile range)) from 3.5 (2.9–4.1) ms at 14–20 weeks’ gestation to 6.3 (4.8–7.7) ms at 34–40 weeks’ gestation. The change in short term heart rate variation did not differ between study sites, different models of ultrasound machine or individual sonographers. CONCLUSIONS: Umbilical artery Doppler waveforms offer a robust and feasible method to derive short term variation of the fetal heart rate. It needs to be emphasized that the umbilical-Doppler derived short term variation is not interchangeable with measurements derived with computerized cardiotocography. Accordingly, further investigations need to validate associations with outcome to determine the value of concurrent fetal cardiovascular and heart rate evaluation that are possible with the technique described here.

Objectives: The WHO recommends that children and adolescents living with HIV (CALHIV) complete TB symptom screening at every clinical encounter but evidence supporting this recommendation is limited. We evaluated the performance of the recommended TB symptom screening in six high-burden TB/HIV countries. Design: Retrospective longitudinal cohort. Methods: We extracted data from electronic medical records of CALHIV receiving care from clinics in Botswana, Eswatini, Lesotho, Malawi, Tanzania, and Uganda from January 2014 to June 2017. We defined incident TB cases as those prescribed TB treatment within 30 days of TB diagnosis. We analyzed the most recent symptom screen preceding a TB diagnosis. In accordance with WHO guidelines, positive screens were defined as current fever, cough, poor weight gain, or recent TB contact. Odds of TB disease was modeled by screen result and age at which screening was conducted. Results: Twenty thousand seven hundred and six patients collectively had 316 740 clinic visits, of which 240 161 (75.8%) had documented TB symptom screens. There were 35 701 (14.9%) positive TB symptom screens, and 1212 incident TB diagnoses. Sensitivity and specificity of the TB symptom screen to diagnose TB were 61.2% (95% CI 58.4--64.0) and 88.8% (95% CI 88.7--88.9), respectively. Log odds of documented TB for positive or negative screens was statistically different only for screens conducted at ages 7--17. Conclusion: Although specificity was high, the sensitivity of the TB symptom screen to detect TB in CALHIV was low. More accurate screening approaches are needed to optimally identify TB disease in CALHIV.

The evolution of multidisciplinary team-based care for women with placenta accreta spectrum disorder has delivered stepwise improvements in clinical outcomes. Central to this overall goal is the ability to limit blood loss at surgery. Placement of inflatable balloons within the pelvic arteries, most commonly in the anterior divisions of the internal iliac arteries, became popular in many centers, at the expense of prolonging surgical care and with attendant risks of vascular injury. In tandem, the need to expose pelvic sidewall anatomy to safely identify the course of the ureters re-popularized the alternative strategy of ligating the same anterior divisions of the internal iliac arteries. With incremental gains in surgical expertise, described in 5 steps in this review, our teams have witnessed a steady decline in surgical blood loss. Nevertheless, a subset of women has the most severe form of placenta accreta spectrum, namely placenta previa-percreta. Such women are at risk of major hemorrhage during surgery from vessels arising outside the territories of the internal iliac arteries. These additional blood supplies, mostly from the external iliac arteries, pose significant risks of major blood loss even in experienced hands. To address this risk, some centers, principally in China, have adopted an approach of routinely placing an infrarenal aortic balloon, with both impressively low rates of blood loss and an ability to conserve the uterus by resecting the placenta with the affected portion of the uterine wall. We review these literature developments in the context of safely performing elective cesarean hysterectomy for placenta previa-percreta, the most severe placenta accreta spectrum disorder.

Effective vaccines and monoclonal antibodies have been developed against coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the appearance of virus variants with higher transmissibility and pathogenicity is a major concern because of their potential to escape vaccines and clinically approved SARS-CoV-2- antibodies. Here, we use flow cytometry-based binding and pseudotyped SARS-CoV-2 neutralization assays to determine the efficacy of boost immunization and therapeutic antibodies to neutralize the dominant Omicron variant. We provide compelling evidence that the third vaccination with BNT162b2 increases the amount of neutralizing serum antibodies against Delta and Omicron variants, albeit to a lower degree when compared to the parental Wuhan strain. Therefore, a third vaccination is warranted to increase titers of protective serum antibodies, especially in the case of the Omicron variant. We also found that most clinically approved and otherwise potent therapeutic antibodies against the Delta variant failed to recognize and neutralize the Omicron variant. In contrast, some antibodies under preclinical development potentially neutralized the Omicron variant. Our studies also support using a flow cytometry-based antibody binding assay to rapidly monitor therapeutic candidates and serum titers against emerging SARS-CoV-2 variants.

BACKGROUND: Patients at high risk of severe preeclampsia and fetal growth restriction have low circulating levels of placental growth factor and features of maternal vascular malperfusion placental pathology at delivery. Multimodal screening and commencement of aspirin prophylaxis at 11 to 13 weeks' gestation markedly reduces the risk of preterm delivery with preeclampsia. However, the additional role of low-molecular-weight heparin and mechanisms of action remain uncertain. Because low-molecular-weight heparin augments the production and release of placental growth factor in vitro by both placental villi and vascular endothelium, it may be effective to suppress the risk of severe preeclampsia in a niche group of high-risk patients with low circulating placental growth factor in the early second trimester. OBJECTIVE: This study aimed to define a gestational age-specific reference range for placental growth factor and to test the hypothesis that prophylactic low-molecular-weight heparin administered in the early second trimester may restore deficient circulating placental growth factor levels and thereby prolong pregnancy. STUDY DESIGN: Centile curves for circulating placental growth factor levels from 12 to 36 weeks' gestation were derived using quantile regression of combined data from a published cohort of 4207 unselected nulliparous patients in Cambridge, United Kingdom, at 4 sampling time points (12, 20, 28, and 36 weeks' gestation) and the White majority (n=531) of a healthy nulliparous cohort in Toronto, Canada, at 16 weeks' gestation using the same test platform. Within a specialty high-risk clinic in Toronto, a niche group of 7 patients with a circulating placental growth factor at the

TRIANNI mice carry an entire set of human immunoglobulin V region gene segments and are a powerful tool to rapidly isolate human monoclonal antibodies. After immunizing these mice with DNA encoding the spike protein of SARS‐CoV‐2 and boosting with spike protein, we identified 29 hybridoma antibodies that reacted with the SARS‐CoV‐2 spike protein. Nine antibodies neutralize SARS‐CoV‐2 infection at IC50 values in the subnanomolar range. ELISA‐binding studies and DNA sequence analyses revealed one cluster of three clonally related neutralizing antibodies that target the receptor‐binding domain and compete with the cellular receptor hACE2. A second cluster of six clonally related neutralizing antibodies bind to the N‐terminal domain of the spike protein without competing with the binding of hACE2 or cluster 1 antibodies. SARS‐CoV‐2 mutants selected for resistance to an antibody from one cluster are still neutralized by an antibody from the other cluster. Antibodies from both clusters markedly reduced viral spread in mice transgenic for human ACE2 and protected the animals from SARS‐CoV‐2‐induced weight loss. The two clusters of potent non‐competing SARS‐CoV‐2 neutralizing antibodies provide potential candidates for therapy and prophylaxis of COVID‐19. The study further supports transgenic animals with a human immunoglobulin gene repertoire as a powerful platform in pandemic preparedness initiatives. This article is protected by copyright. All rights reserved

The apolipoprotein E4 (APOE4) allele is associated with an increased risk of Alzheimer disease and a decreased risk of glaucoma, but the underlying mechanisms remain poorly understood. Here, we found that in two mouse glaucoma models, microglia transitioned to a neurodegenerative phenotype characterized by upregulation of Apoe and Lgals3 (Galectin-3), which were also upregulated in human glaucomatous retinas. Mice with targeted deletion of Apoe in microglia or carrying the human APOE4 allele were protected from retinal ganglion cell (RGC) loss, despite elevated intraocular pressure (IOP). Similarly to Apoe

With the increasing size of datasets used in medical imaging research, the need for automated data curation is arising. One important data curation task is the structured organization of a dataset for preserving integrity and ensuring reusability. Therefore, we investigated whether this data organization step can be automated. To this end, we designed a convolutional neural network (CNN) that automatically recognizes eight different brain magnetic resonance imaging (MRI) scan types based on visual appearance. Thus, our method is unaffected by inconsistent or missing scan metadata. It can recognize pre-contrast T1-weighted (T1w),post-contrast T1-weighted (T1wC), T2-weighted (T2w), proton density-weighted (PDw) and derived maps (e.g. apparent diffusion coefficient and cerebral blood flow). In a first experiment,we used scans of subjects with brain tumors: 11065 scans of 719 subjects for training, and 2369 scans of 192 subjects for testing. The CNN achieved an overall accuracy of 98.7%. In a second experiment, we trained the CNN on all 13434 scans from the first experiment and tested it on 7227 scans of 1318 Alzheimer’s subjects. Here, the CNN achieved an overall accuracy of 98.5%. In conclusion, our method can accurately predict scan type, and can quickly and automatically sort a brain MRI dataset virtually without the need for manual verification. In this way, our method can assist with properly organizing a dataset, which maximizes the shareability and integrity of the data.

Viral mutations are an emerging concern in reducing SARS-CoV-2 vaccination efficacy. Second generation vaccines will need to elicit neutralizing antibodies against sites that are evolutionarily conserved across the sarbecovirus subgenus. Here, we immunized mice containing a human antibody repertoire with diverse sarbecovirus receptor binding domains (RBDs) to identify antibodies targeting conserved sites of vulnerability. Antibodies with broad reactivity against diverse clade B RBDs targeting the conserved class 4 epitope, with recurring IGHV/IGKV pairs, were readily elicited but were non-neutralizing. However, rare class 4 antibodies binding this conserved RBD supersite showed potent neutralization of SARS-CoV-2 and all variants of concern. Structural analysis revealed that neutralizing ability of cross-reactive antibodies was reserved only for those with an elongated CDRH3 that extends the antiparallel beta-sheet RBD core and orients the antibody light chain to obstruct ACE2-RBD interactions. These results identify a structurally defined pathway for vaccine strategies eliciting escape-resistant SARS-CoV-2 neutralizing antibodies., Graphical Abstract, Viral mutations are an emerging concern in reducing SARS-CoV-2 vaccination efficacy. Burnett et al. immunized humanized mice with different diverse sarbecovirus RBDs to elicit antibodies targeting conserved sites. Non-neutralizing cross-reactive antibodies targeting the conserved class 4 epitope were readily elicited. Neutralizing ability was reserved only for antibodies binding this conserved supersite through an elongated CDRH3 that obstructed ACE2-RBD interactions.

The present study aimed to evaluate the effectiveness of a school-based multi-activity HIIT on aerobic fitness (AF) and hemodynamic parameters in children. 46 students were randomized into an intervention group (INT) (N=22) and a control group (CON) (N=24). Throughout a 3-month intervention period, both INT and CON participated in the regular physical education classes (PE) twice a week. Only INT received an instructed HIIT during the first 20 min of the PE. In addition to an AF-test, peripheral (pBP) and central (cBP) blood pressure, augmentation pressure (AP), and aortic pulse wave velocity (aPWV) were assessed. Significant differences in intervention effects in favor of INT were detected for AF (7.73, P=0.007), peripheral systolic BP (−6.13 mmHg, P=0.038), central systolic BP (−5.19 mmHg, P = 0.041), AP (−2.02 mmHg, P=0.013), and aPWV (−0.19 m/sec, P=0.031). The regular HITT intervention showed beneficial effects on AF, BP, and parameters of vascular stiffness already in children.

Purpose: Patients with 1p/19q codeleted low-grade glioma (LGG) have longer overall survival and better treatment response than patients with 1p/19q intact tumors. Therefore, it is relevant to know the 1p/19q status. To investigate whether the 1p/19q status can be assessed prior to tumor resection, we developed a machine learning algorithm to predict the 1p/19q status of presumed LGG based on preoperative MRI. Experimental Design: Preoperative brain MR images from 284 patients who had undergone biopsy or resection of presumed LGG were used to train a support vector machine algorithm. The algorithm was trained on the basis of features extracted from post-contrast T1-weighted and T2-weighted MR images and on patients' age and sex. The performance of the algorithm compared with tissue diagnosis was assessed on an external validation dataset of MR images from 129 patients with LGG from The Cancer Imaging Archive (TCIA). Four clinical experts also predicted the 1p/19q status of the TCIA MR images. Results: The algorithm achieved an AUC of 0.72 in the external validation dataset. The algorithm had a higher predictive performance than the average of the neurosurgeons (AUC 0.52) but lower than that of the neuroradiologists (AUC of 0.81). There was a wide variability between clinical experts (AUC 0.45–0.83). Conclusions: Our results suggest that our algorithm can noninvasively predict the 1p/19q status of presumed LGG with a performance that on average outperformed the oncological neurosurgeons. Evaluation on an independent dataset indicates that our algorithm is robust and generalizable.

Background Placenta accreta spectrum (PAS) disorders are a potentially life-threatening complication of pregnancy that demand coordinated interdisciplinary care to achieve safer outcomes. The rising incidence of this disease is due to a growing number of uterine surgical procedures, including the rising incidence of pregnancy following Caesarean section. Objective To provide current evidence-based guidelines on the optimal methods used to effectively screen, diagnose, and manage PAS disorders. Methods Members of the guideline committee were selected on the basis of their ongoing expertise in managing this condition across Canada and by practice setting. The committee reviewed all available evidence in the English medical literature, including published guidelines, and evaluated diagnostic tests, surgical procedures, and clinical outcomes. Evidence Published literature, including clinical practice guidelines, was retrieved through searches of Medline and The Cochrane Library to March 2018 using appropriate controlled vocabulary and key words. Results were restricted to systematic reviews, randomized controlled trials, and observational studies written in English. Searches were updated on a regular basis and incorporated in the guideline to July 2018. Values The quality of evidence in this document was graded using the criteria described in the Report of the Canadian Task Force on Preventive Health Care. Results This document reviews the evidence regarding the available diagnostic and surgical techniques used for optimal management of women with suspected PAS disorders, including anaesthesia and practical considerations for interdisciplinary care. Benefits, Harms, and Costs Implementation of the guideline recommendations will improve awareness of this disease and increase the proportion of affected women receiving interdisciplinary care in regional centres. Conclusions Interdisciplinary team-based care providing accurate diagnostic services, coordinated planning, and safer surgery deliver effective care with improved clinical outcomes in comparison with alternative management. Summary Statements 1The incidence of placenta accreta spectrum disorders is steadily rising in many countries, likely due to the increasing proportion of women becoming pregnant following a variety of surgical procedures to the uterus, including multiple Caesarean sections. 2Placenta accreta spectrum disorders in the setting of prior Caesarean section deliveries arises from pregnancy implantation within the niche created by this surgery near the cervicoisthmic junction of the uterus. This early presentation as a "Caesarean section scar pregnancy" may be diagnosed by ultrasound methods. 3Ultrasound may be used to screen for, and to diagnose, pregnancies with anterior placenta previa that are complicated by placenta accreta spectrum disorders. The effectiveness of ultrasound in this context depends upon awareness of clinical risk factors, imaging quality, operator experience, gestational age, imaging modalities, and adequate bladder filling. 4Magnetic resonance imaging may complement multimodal ultrasound in the diagnosis and staging of placenta accreta spectrum disorders, though its effectiveness is currently limited by the relative contraindication to the use of a gadolinium contrast enhancing agent. 5Placenta accreta spectrum disorders are potentially life-threatening and demand regional interdisciplinary team-based care to deliver the safest outcomes for mothers and infants. Recommendations 1Pregnant women with clinical risk factors for placenta accreta spectrum disorders and anterior placenta previa at the 18–20-week fetal anatomical ultrasound should be referred for specialist imaging to diagnose or exclude this disorder (II-2A). 2Women with a diagnosis of placenta accreta spectrum disorder should be referred to a regional centre dedicated to the interdisciplinary management of this condition (II-3A). 3Protocol-based interdisciplinary care from diagnosis to surgery will optimize both intraoperative and postoperative outcomes (II-3A). 4Antenatal admission to a designated regional management centre may be indicated, especially following an antepartum hemorrhage, or based on considerations of geography or transport conditions (III-B). 5For otherwise healthy women with no history of vaginal bleeding, the optimal timing of elective Caesarean section delivery is around 34–36 weeks gestation (II-3B). Surgery should be considered earlier for repeated episodes of antepartum hemorrhage or contractions to reduce the risks of emergent unplanned surgery and should ideally be preceded by a course of corticosteroids to enhance fetal lung maturation if prior to 35+0 weeks gestation (II-2A). 6Regional anaesthesia may be safer than general anaesthesia as it is associated with reduced blood loss and is preferred by patients and their partners (II-2A). A massive transfusion protocol should be in place to respond to significant blood loss (III-B). 7Intravenous tranexamic acid should be administered at the commencement of surgery because it reduces intraoperative blood loss (I-A). 8Surgery should be performed in the modified lithotomy position, using midline access, sufficiently high so as to deliver the fetus without incising through the placenta; preoperative or intraoperative ultrasound can be used to guide the optimal uterine incision (III-B). No attempt should be made to remove the placenta if it shows no signs of separation as this may cause substantial hemorrhage (III-B). 9Presently there is insufficient evidence to recommend giving or withholding uterotonic drugs after delivery of the fetus (III-C). 10Presently there is insufficient evidence to recommend either approach (preoperative balloon placement or intraoperative ligation) designed to arrest blood flow from the internal iliac arteries prior to hysterectomy (II-1C). 11Focal central disease may be amenable to wedge resection, with complete removal of the placenta and repair of the uterus (the triple-P procedure) (II-3B). 12Classical Caesarean section and non-removal of the invasive placenta is an acceptable method of delivery but is associated with a protracted course of recovery and a persistent risk of hysterectomy (II-3B). 13Women who retain their fertility following a diagnosis of placenta accreta spectrum disorder should be instructed to access specialist ultrasound early in any future pregnancy so that all management options are available should a Caesarean section scar pregnancy be found (III-B). 14Prenatal diagnosis of the more severe forms of placenta accreta spectrum disorder, expressed as a Caesarean section scar pregnancy, may permit management using minimally invasive surgical techniques (II-3B). 15Though many women with placenta accreta spectrum disorder in well-resourced countries receive safe care, more research and knowledge translation are needed to effectively deliver all management options at the population-based level (III-B).

Placental pathology assessment following delivery in pregnancies complicated by preeclampsia, fetal growth restriction, abruption, and stillbirth reveals a range of underlying diseases. The most common pathology is maternal vascular malperfusion, characterized by high-resistance uterine artery Doppler waveforms and abnormal expression of circulating maternal angiogenic growth factors. Rare placental diseases (massive perivillous fibrinoid deposition and chronic histiocytic intervillositis) are reported to have high recurrence risks, but their associations with uterine artery Doppler waveforms and angiogenic growth factors are presently ill-defined.To characterize the patterns of serial placental growth factor measurements and uterine artery Doppler waveform assessments in pregnancies that develop specific types of placental pathology to gain insight into their relationships with the timing of disease onset and pregnancy outcomes.A retrospective cohort study conducted between January 2017 and November 2021 included all singleton pregnancies with at least 1 measurement of maternal circulating placental growth factor between 16 and 36 weeks' gestation, delivery at our institution, and placental pathology analysis demonstrating diagnostic features of maternal vascular malperfusion, fetal vascular malperfusion, villitis of unknown etiology, chronic histiocytic intervillositis, or massive perivillous fibrinoid deposition. Profiles of circulating placental growth factor as gestational age advanced were compared between these placental pathologies. Maternal and perinatal outcomes were recorded.A total of 337 pregnancies from 329 individuals met our inclusion criteria. These comprised placental pathology diagnoses of maternal vascular malperfusion (n=109), fetal vascular malperfusion (n=87), villitis of unknown etiology (n=96), chronic histiocytic intervillositis (n=16), and massive perivillous fibrinoid deposition (n=29). Among patients who developed maternal vascular malperfusion, placental growth factor levels gradually declined as pregnancy progressed (placental growth factor10th percentile at 16-20 weeks' gestation in 42.9%; 20-24 weeks in 61.9%; 24-28 weeks in 77%; and 28-32 weeks in 81.4%) accompanied by mean uterine artery Doppler pulsatility index95th percentile in 71.6% cases. Patients who developed either fetal vascular malperfusion or villitis of unknown etiology mostly exhibited normal circulating placental growth factor values in association with normal uterine artery Doppler waveforms (mean [standard deviation] pulsatility index values: fetal vascular malperfusion, 1.14 [0.49]; villitis of unknown etiology, 1.13 [0.45]). Patients who developed either chronic histiocytic intervillositis or massive perivillous fibrinoid deposition exhibited persistently low placental growth factor levels from the early second trimester (placental growth factor10th centile at 16-20 weeks' gestation in 80% and 77.8%, respectively; 20-24 weeks in 88.9% and 63.6%; 24-28 weeks in 85.7% and 75%), all in combination with normal uterine artery Doppler waveforms (mean pulsatility index95th centile: chronic histiocytic intervillositis, 25%; massive perivillous fibrinoid deposition, 37.9%). Preeclampsia developed in 83 of 337 (24.6%) patients and was most common in those developing maternal vascular malperfusion (54/109, 49.5%) followed by chronic histiocytic intervillositis (7/16, 43.8%). There were 29 stillbirths in the cohort (maternal vascular malperfusion, n=10 [9.2%]; fetal vascular malperfusion, n=5 [5.7%]; villitis of unknown etiology, n=1 [1.0%]; chronic histiocytic intervillositis, n=7 [43.8%]; massive perivillous fibrinoid deposition, n=6 [20.7%]). Most patients experiencing stillbirth exhibited normal uterine artery Doppler waveforms (21/29, 72.4%) and had nonmaternal vascular malperfusion pathologies (19/29, 65.5%). By contrast, 28 of 29 (96.5%) patients experiencing stillbirth had ≥1 low placental growth factor values before fetal death.Serial circulating maternal placental growth factor tests, in combination with uterine artery Doppler waveform assessments in the second trimester, may indicate the likely underlying type of placental pathology mediating severe adverse perinatal events. This approach has the potential to test disease-specific therapeutic strategies to improve clinical outcomes. Serial placental growth factor testing, compared with uterine artery Doppler studies, identifies a greater proportion of patients destined to have a poor perinatal outcome because diseases other than maternal vascular malperfusion are characterized by normal uteroplacental circulation.

OBJECTIVES—: To determine the relationship between blood flow in the fetal descending aorta and discordant umbilical arteries (UAs). METHODS—: Pulsed wave Doppler of both UAs and the descending aorta was performed at 4-weekly intervals between 14 and 40 weeks of gestation in 209 pregnant women. In datasets with discordant UAs, a linear mixed effects model was used to determine the categorical relationship between the UA pulsatility index (PI) (high, low and average) and the descending aorta PI. RESULTS—: Of the 209 cases, 81 had a discordance of greater than 25% in UA PI during one of their visits. There were no differences in birth outcomes between the groups with concordant and discordant UA PIs. In the cases with discordant UA PIs, the descending aorta PI was most strongly associated with both the average UA PI (P = .008), and with the UA with the lower PI (P = .008). CONCLUSIONS—: The relationship between blood flow in the descending aorta and UAs is consistent with the law for combining resistances in parallel. Measurements of the descending aorta PI, particularly in a scenario with discordant UAs, may inform the stability of the feto-placental circulation where discordant UA PIs are found.

The Delta variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), B.1.617.2, emerged in India and has spread to over 80 countries. B.1.617.2 replaced B.1.1.7 as the dominant virus in the United Kingdom, resulting in a steep increase in new infections, and a similar development is expected for other countries. Effective countermeasures require information on susceptibility of B.1.617.2 to control by antibodies elicited by vaccines and used for coronavirus disease 2019 (COVID-19) therapy. We show, using pseudotyping, that B.1.617.2 evades control by antibodies induced upon infection and BNT162b2 vaccination, although to a lesser extent as compared to B.1.351. We find that B.1.617.2 is resistant against bamlanivimab, a monoclonal antibody with emergency use authorization for COVID-19 therapy. Finally, we show increased Calu-3 lung cell entry and enhanced cell-to-cell fusion of B.1.617.2, which may contribute to augmented transmissibility and pathogenicity of this variant. These results identify B.1.617.2 as an immune evasion variant with increased capacity to enter and fuse lung cells., Graphical abstract, The B.1.617.2 (Delta) variant challenges efforts to control the COVID-19 pandemic. Arora et al. provide evidence that B.1.617.2 may enter human lung cells and fuse neighboring cells more efficiently than the initially circulating virus. Further, the study suggests that B.1.617.2 may evade neutralization by antibodies elicited upon infection and vaccination.

Patients at high risk of severe preeclampsia and fetal growth restriction have low circulating levels of placental growth factor and features of maternal vascular malperfusion placental pathology at delivery. Multimodal screening and commencement of aspirin prophylaxis at 11 to 13 weeks' gestation markedly reduces the risk of preterm delivery with preeclampsia. However, the additional role of low-molecular-weight heparin and mechanisms of action remain uncertain. Because low-molecular-weight heparin augments the production and release of placental growth factor in vitro by both placental villi and vascular endothelium, it may be effective to suppress the risk of severe preeclampsia in a niche group of high-risk patients with low circulating placental growth factor in the early second trimester.This study aimed to define a gestational age-specific reference range for placental growth factor and to test the hypothesis that prophylactic low-molecular-weight heparin administered in the early second trimester may restore deficient circulating placental growth factor levels and thereby prolong pregnancy.Centile curves for circulating placental growth factor levels from 12 to 36 weeks' gestation were derived using quantile regression of combined data from a published cohort of 4207 unselected nulliparous patients in Cambridge, United Kingdom, at 4 sampling time points (12, 20, 28, and 36 weeks' gestation) and the White majority (n=531) of a healthy nulliparous cohort in Toronto, Canada, at 16 weeks' gestation using the same test platform. Within a specialty high-risk clinic in Toronto, a niche group of 7 patients with a circulating placental growth factor at the10th centile in the early second trimester received daily prophylactic low-molecular-weight heparin (enoxaparin; 40 mg subcutaneously) and were followed up until delivery (group 1). Their baseline characteristics, delivery details, and placental pathologies were compared with 5 similar patients who did not receive low-molecular-weight heparin during the observation period (group 2) and further with 21 patients who delivered with severe preeclampsia (group 3) in the same institution.A gestational age-specific reference range for placental growth factor levels at weekly intervals between 12 and 36 weeks was established for White women with singleton pregnancies. Within group 1, 5 of 7 patients demonstrated a sustained increase in circulating placental growth factor levels, whereas placental growth factor levels did not increase in group 2 or group 3 patients who did not receive low-molecular-weight heparin. Group 1 patients receiving low-molecular-weight heparin therapy exhibited a later gestation at delivery, relative to groups 2 and 3 (36 weeks [33-37] vs 23 weeks [22-26] and 28 weeks [27-31], respectively), and consequently had higher birthweights (1.93 kg [1.1-2.7] vs 0.32 kg [0.19-0.39] and 0.73 kg [0.52-1.03], respectively). The incidence of stillbirth was lowest in group 1 (14% [1 of 7]), relative to groups 2 and 3 (80% [4 of 5] and 29% [6 of 21], respectively). Maternal vascular malperfusion was the most common placental pathology found in association with abnormal uterine artery Doppler.In patients at high risk of a serious adverse pregnancy outcome owing to placental disease, the addition of low-molecular-weight heparin to aspirin prophylaxis in the early second trimester may restore deficient circulating placental growth factor to mediate an improved perinatal outcome. These data support the implementation of a multicenter pilot randomized control trial where patients are recruited primarily based on the assessment of placental function in the early second trimester.

Transmission of SARS-CoV-2 from humans to farmed mink was observed in Europe and the US. In the infected animals viral variants arose that harbored mutations in the spike (S) protein, the target of neutralizing antibodies, and these variants were transmitted back to humans. This raised concerns that mink might become a constant source of human infection with SARS-CoV-2 variants associated with an increased threat to human health and resulted in mass culling of mink. Here, we report that mutations frequently found in the S proteins of SARS-CoV-2 from mink were mostly compatible with efficient entry into human cells and its inhibition by soluble ACE2. In contrast, mutation Y453F reduced neutralization by an antibody with emergency use authorization for COVID-19 therapy and by sera/plasma from COVID-19 patients. These results suggest that antibody responses induced upon infection or certain antibodies used for treatment might offer insufficient protection against SARS-CoV-2 variants from mink., Graphical Abstract, Transmission of SARS-CoV-2 between humans and farmed mink has caused concerns since viruses from mink have acquired mutations in the spike protein. Hoffmann et al. show that these mink-specific mutations do not increase entry into human cells but cause partial evasion from neutralization by a therapeutic antibody and convalescent plasma/sera.

Objective To describe the evolution and evaluation of protocol-based multidisciplinary quality improvement (QI) in women undergoing cesarean hysterectomy for radiologically suspected and pathologically confirmed placenta accreta spectrum (PAS) disorders. Methods A single-center, retrospective cohort study was conducted of all patients undergoing cesarean hysterectomy for PAS disorders between March 2009 and June 2018. Two distinct periods were defined to compare outcomes: 2009-2011 (initial period) and 2017-2018 (current period). Primary outcomes included blood loss and administration of blood products. Secondary outcomes included perioperative levels of hemoglobin, adverse events and complications, time to mobilization, and length of hospitalization. Results Among the 105 consecutive patients identified, there were 26 in the initial period and 32 in the current period. With the implementation of all QI care bundles, median estimated surgical blood loss halved from 2000 mL in the initial period to 1000 mL in the current period, and fewer patients required allogenic blood transfusion (61.5% vs 25%). Patients in the current period demonstrated improved postoperative levels of hemoglobin compared to those in the initial period (101 g/L vs 89 g/L) and had a shorter median postoperative hospital stay (3 days vs 5 days). Conclusion These results support the implementation of a multifaceted QI and patient care initiative for women with PAS disorders.

Background Fetal sex is known to affect pregnancy outcomes. In current clinical practice, monitoring of fetal well-being is based on Doppler ultrasound measurements of major placental and fetal vessels. The objective of this study was to investigate the effect of fetal sex on Doppler parameters throughout gestation in healthy pregnancy. Methods A prospective study was conducted in 240 pregnant women with ultrasound examinations at a 4-weekly interval between 12 and 38 weeks of gestation. Pulsed Doppler spectra were collected for the umbilical arteries (UAs), middle cerebral artery (MCA), descending abdominal aorta (DAo), and ductus venosus (DV). Linear mixed effects models were used to determine if the pulsatility indices (PIs) of these vessels depended on gestational age and fetal sex. Results While there were no differences in the MCA PI and DV PIV over gestation between female and male fetuses, the trajectory of the UA and DAo PIs differed by fetal sex (p = 0.02 and p = 0.01, respectively). Conclusions Doppler ultrasound parameters were found to be dependent on fetal sex for some vessels and not for others in healthy pregnancies. Further investigations are needed to understand the physiological mechanisms for these sex differences and the relevance for disease processes in pregnancy.

Introduction A growing number of Liaison Committee on Medical Education–accredited allopathic medical schools offer formal bilingual (English and Spanish) medical education, and numerous other schools offer medical Spanish through elective workshops as part of their curricula. One significant health disparity in the Hispanic community is the incidence of HIV among Spanish-speaking men who have sex with men (MSM). Pre-exposure prophylaxis (PrEP) has emerged as an effective strategy to reduce the risk of HIV transmission. Methods We developed an education module to train clinicians to discuss PrEP with Spanish-speaking MSM. Our module is adapted from an English module on PrEP education. It includes a Spanish-language PowerPoint slide deck with information about PrEP as well as a Spanish-language videotaped scripted clinical encounter. Results The module was implemented on three occasions with 18 participants, and learners reported increased comfort in discussing and confidence in prescribing PrEP with Spanish-speaking patients. Discussion This workshop can be incorporated within medical Spanish curriculums offered at health professional schools and community-based organizations dedicated to reducing the HIV burden in the Spanish-speaking Hispanic community.

Objective To review the most effective clinical approaches to disengage an impacted fetal head during cesarean delivery. Target Population Women who undergo cesarean delivery of an infant with a deeply impacted head. Options The "push" technique (from below) or the "pull" technique (reverse breech extraction). Outcomes Proper management of this clinical scenario can reduce maternal and perinatal morbidity and mortality. Benefits, Harms, and Costs Using an evidence-informed approach when an impacted fetal head is anticipated has the potential to reduce maternal and fetal complications and short- and long-term harm and their associated costs. Research into the value of simulation learning, regular labour assessments, and team preparedness for possible interventions will help inform quality care. Evidence The following search terms were entered into PubMed/Medline, Google Scholar, and Cochrane for the publication period 2012–2019: • ‘Guidelines' ‘manual' • ‘Caesarean Section' • ‘full dilation' • ‘operative delivery' • ‘impacted head' • ‘Caesarean' AND ‘full dilation' AND ‘impacted head' • ‘Caesarean' AND ‘second stage of labour' OR ‘second stage' AND ‘impacted head' • ‘Caesarean' OR ‘operative delivery' AND ‘impacted head' A total of 32 articles were retrieved and 24 were deemed appropriate to include as references. Many of these articles represented expert opinion. Randomized controlled trials had small sample sizes and were conducted in settings that limit the generalizability of their findings to the Canadian population.20 Intended Users Intrapartum health care providers.

The global spread of SARS-CoV-2/COVID-19 is devastating health systems and economies worldwide. Recombinant or vaccine-induced neutralizing antibodies are used to combat the COVID-19 pandemic. However, the recently emerged SARS-CoV-2 variants B.1.1.7 (UK), B.1.351 (South Africa), and P.1 (Brazil) harbor mutations in the viral spike (S) protein that may alter virus-host cell interactions and confer resistance to inhibitors and antibodies. Here, using pseudoparticles, we show that entry of all variants into human cells is susceptible to blockade by the entry inhibitors soluble ACE2, Camostat, EK-1, and EK-1-C4. In contrast, entry of the B.1.351 and P.1 variant was partially (Casirivimab) or fully (Bamlanivimab) resistant to antibodies used for COVID-19 treatment. Moreover, entry of these variants was less efficiently inhibited by plasma from convalescent COVID-19 patients and sera from BNT162b2-vaccinated individuals. These results suggest that SARS-CoV-2 may escape neutralizing antibody responses, which has important implications for efforts to contain the pandemic., Graphical abstract, Comparison of the SARS-CoV-2 variants B.1.1.7, B.1.351, and P.1 shows that inhibitors under clinical evaluation are still effective in blocking entry, though the B.1.351 and P.1 variants evade antibody responses induced upon infection as well as vaccination and evade certain therapeutic antibodies.

Bilateral ligation of the anterior division of the internal iliac arteries can be a lifesaving intervention for severe pelvic hemorrhage. The procedure results in decreased pelvic perfusion and promotes coagulation. The classical method of internal iliac artery ligation involved extensive retroperitoneal dissection with complete circumferential isolation of the vessel to allow the passage of a suture around the artery. This can be surgically challenging and fraught with risks of inadvertent injury to the surrounding iliac veins. We propose a contemporary technique that requires limited dissection of the anterior division of the internal iliac artery. A few millimeters of space is created on either side of the artery by spreading right-angle forceps parallel to the vessel. The artery is occluded by 2 large vascular clips. Because circumferential vessel dissection is not necessary with this technique, there is limited disruption of the delicate underlying internal iliac vein. In addition, this approach may decrease the risk of inadvertent injury to the adjacent external iliac vein. By showcasing the ease of our approach to internal iliac artery ligation, we hope to empower surgeons with an alternative approach to this lifesaving procedure.

Aberrant neural oscillations hallmark numerous brain disorders. Here, we first report a method to track the phase of neural oscillations in real-time via endpoint-corrected Hilbert transform (ecHT) that mitigates the characteristic Gibbs distortion. We then used ecHT to show that the aberrant neural oscillation that hallmarks essential tremor (ET) syndrome, the most common adult movement disorder, can be transiently suppressed via transcranial electrical stimulation of the cerebellum phase-locked to the tremor. The tremor suppression is sustained shortly after the end of the stimulation and can be phenomenologically predicted. Finally, we use feature-based statistical-learning and neurophysiological-modelling to show that the suppression of ET is mechanistically attributed to a disruption of the temporal coherence of the aberrant oscillations in the olivocerebellar loop, thus establishing its causal role. The suppression of aberrant neural oscillation via phase-locked driven disruption of temporal coherence may in the future represent a powerful neuromodulatory strategy to treat brain disorders., Aberrant synchronous oscillations have been associated with numerous brain disorders, including essential tremor. The authors show that synchronous cerebellar activity can casually affect essential tremor and that its underlying mechanism may be related to the temporal coherence of the tremulous movement.

Histopathological growth patterns (HGPs) are independent prognosticators for colorectal liver metastases (CRLM). Currently, HGPs are determined postoperatively. In this study, we evaluated radiomics for preoperative prediction of HGPs on computed tomography (CT), and its robustness to segmentation and acquisition variations. Patients with pure HGPs [i.e. 100% desmoplastic (dHGP) or 100% replacement (rHGP)] and a CT-scan who were surgically treated at the Erasmus MC between 2003–2015 were included retrospectively. Each lesion was segmented by three clinicians and a convolutional neural network (CNN). A prediction model was created using 564 radiomics features and a combination of machine learning approaches by training on the clinician’s and testing on the unseen CNN segmentations. The intra-class correlation coefficient (ICC) was used to select features robust to segmentation variations; ComBat was used to harmonize for acquisition variations. Evaluation was performed through a 100 × random-split cross-validation. The study included 93 CRLM in 76 patients (48% dHGP; 52% rHGP). Despite substantial differences between the segmentations of the three clinicians and the CNN, the radiomics model had a mean area under the curve of 0.69. ICC-based feature selection or ComBat yielded no improvement. Concluding, the combination of a CNN for segmentation and radiomics for classification has potential for automatically distinguishing dHGPs from rHGP, and is robust to segmentation and acquisition variations. Pending further optimization, including extension to mixed HGPs, our model may serve as a preoperative addition to postoperative HGP assessment, enabling further exploitation of HGPs as a biomarker. Supplementary Information The online version contains supplementary material available at 10.1007/s10585-021-10119-6.

Methods: In an effort to study sex-specific genetic factors associated with PD, we explored 2 large genetic datasets from the International Parkinson?s Disease Genomics Consortium and the UK Biobank consisting of 13,020male PD cases, 7,936 paternal proxy cases, 89,660 male controls, 7,947 female PD cases, 5,473 maternal proxy cases, and 90,662 female controls. We performed GWASmeta-analyses to identify distinct patterns of genetic risk contributing to disease inmale versus female PD cases. Results: In total, 19 genomewide significant regions were identified and no sex-specific effects were observed. A high genetic correlation between the male and female PD GWAS were identified (rg = 0.877) and heritability estimates were identical between male and female PD cases (~ 20%). Interpretation: We did not detect any significant genetic differences between male or female PD cases. Our study does not support the notion that common genetic variation on the autosomes could explain the difference in prevalence of PD between males and females cases at least when considering the current sample size under study. Further studies are warranted to investigate the genetic architecture of PD explained by X and Y chromosomes and further evaluate environmental effects that could potentially contribute to PD etiology in male versus female patients. FUNDING: This work was supported in part by the Intramural Research Programs of the National Institute of Neurological Disorders and Stroke (NINDS), the National Institute on Aging (NIA), and the National Institute of Environmental Health Sciences both part of the National Institutes of Health, Department of Health and Human Services; Project numbers 1ZIA-NS003154, Z01-AG000949-02, and Z01-ES101986. In addition, this work was supported by the Department of Defense (award W81XWH-09-2-0128), and The Michael J. Fox Foundation for Parkinson’s Research. This work was supported by National Institutes of Health grants R01NS037167, R01CA141668, and P50NS071674, American Parkinson Disease Association (APDA); Barnes Jewish Hospital Foundation; Greater St Louis Chapter of the APDA. The KORA (Cooperative Research in the Region of Augsburg) research platform was started and financed by the Forschungszentrum für Umwelt und Gesundheit, which is funded by the German Federal Ministry of Education, Science, Research, and Technology and by the State of Bavaria. This study was also funded by the German Federal Ministry of Education and Research (BMBF) under the funding code 031A430A, the EU Joint Programme - Neurodegenerative Diseases Research (JPND) project under the aegis of JPND -www.jpnd.eu – through Germany, BMBF, funding code 01ED1406 and iMed – the Helmholtz Initiative on Personalized Medicine. This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD, USA (http://biowulf.nih.gov), and DNA panels, samples, and clinical data from the National Institute of Neurological Disorders and Stroke Human Genetics Resource Center DNA and Cell Line Repository. People who contributed samples are acknowledged in descriptions of every panel on the repository website. We thank P. Tienari (Molecular Neurology Programme, Biomedicum, University of Helsinki), T. Peuralinna (Department of Neurology, Helsinki University Central Hospital), L. Myllykangas (Folkhalsan Institute of Genetics and Department of Pathology, University of Helsinki), and R. Sulkava (Department of Public Health and General Practice Division of Geriatrics, University of Eastern Finland) for the Finnish controls (Vantaa85+ GWAS data). This study was also funded by the Sigrid Juselius Foundation (KM). We used genomewide association data generated by the Wellcome Trust Case–Control Consortium 2 (WTCCC2) from UK patients with Parkinson’s disease and UK control individuals from the 1958 Birth Cohort and National Blood Service. UK population control data was made available through WTCCC1. As with previous IPDGC efforts, this study makes use of data generated by the Wellcome Trust Case-Control Consortium. A full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under awards 076113, 085475, and 090355. This study was also supported by Parkinson’s UK (grants 8047 and J-0804) and the Medical Research Council (G0700943 and G1100643). Sequencing and genotyping done in McGill University was supported by grants from the Michael J. Fox Foundation, the Canadian Consortium on Neurodegeneration in Aging (CCNA), the Canada First Research Excellence Fund (CFREF), awarded to McGill University for the Healthy Brains for Healthy Lives (HBHL) program and Parkinson’s Society Canada. The access to part of the participants at McGill has been made possible thanks to the Quebec Parkinson’s Network (http://rpq-qpn.ca/en). We thank the Quebec Parkinson’s Network (http://rpq-qpn.org) and its members. Harvard NeuroDiscovery Biomarker Study (HBS) is a collaboration of HBS investigators and funded through philanthropy and NIH and Non-NIH funding sources. The HBS Investigators have not participated in reviewing the data analysis or content of the manuscript. PPMI – a public-private partnership – is funded by the Michael J. Fox Foundation for Parkinson’s Research and funding partners, the full names of all of the PPMI funding partners can be found at www.ppmi-info.org/ fundingpartners. The PPMI Investigators have not participated in reviewing the data analysis or content of the manuscript. For up-to-date information on the study, visit www.ppmi-info.org. Parkinson’s Disease Biomarker Program (PDBP) consortium is supported by the National Institute of Neurological Disorders and Stroke (NINDS) at the National Institutes of Health. A full list of PDBP investigators can be found at https://pdbp.ninds.nih.gov/ policy. The PDBP Investigators have not participated in reviewing the data analysis or content of the manuscript

Background Maternally administered corticosteroids are routinely used to accelerate fetal lung maturation in pregnancies at risk of early preterm delivery. Although, among the subgroup with growth restriction, a majority show a temporary improvement in umbilical artery Doppler waveforms that may be sustained up to 7 days, a minority will acutely decompensate in response to corticosteroids in association with deteriorating umbilical and fetal Doppler waveforms. The basis for such acute Doppler changes is presently unknown. Our group has developed a noninvasive ultrasound methodology to measure wave reflections in the umbilical artery and have established that wave reflection metrics are sensitive to structural changes in the placental vasculature and to acute changes in vascular tone. Using this approach, we demonstrated in healthy pregnant mice that fetoplacental vascular resistance decreased in betamethasone-treated mice compared with saline-treated controls. Objective This study aimed to investigate the effects of betamethasone administration on the wave reflection metrics in a mouse model of fetal growth restriction and to compare these findings with equivalent measurements in human fetuses. Study Design Pregnant CD-1 mice were housed from embryonic day 14.5 to embryonic day 17.5 in either a normoxic (21% O2, n=24) or hypoxic environment (11% O2, n=22), the latter being an established mouse model of fetal growth restriction. To investigate the effect of maternally administered betamethasone on the fetoplacental vasculature, ultrasound imaging was performed at baseline and 4 hours after treatment (either betamethasone or sterile saline). Umbilical artery wave reflection metrics were compared between the groups and for the effect of fetal sex. In addition, a cohort of 10 pregnant women with elevated umbilical artery pulsatility index and evidence of fetal growth restriction and 6 controls were imaged before and after corticosteroid administration. Results In the mouse model, after betamethasone administration, the female fetuses from the hypoxia group showed a 15% increase in umbilical artery diameter, a 98% increase in umbilical artery blood flow, and a 27% decrease in umbilical artery reflection coefficient, whereas the males from the hypoxia group showed no substantial changes. In agreement with our mouse findings, umbilical artery reflections were found to be larger in human growth-restricted fetuses than controls in women at risk of preterm birth. Conclusion Our studies provide insight into the mechanism whereby the human growth-restricted fetus may exhibit a temporary favorable fetoplacental vascular response to maternally administered corticosteroids. Further investigations are needed to understand why the male growth-restricted fetus seems unable to mount this favorable vascular response.

To assess patient satisfaction with the use of portable video media (PVM) for the purpose of taking informed consent for common urological outpatient procedures performed under local anaesthesia.Patients undergoing the following procedures were approached for recruitment: flexible cystoscopy with or without biopsy, transrectal ultrasound-guided prostate biopsy or flexible cystoscopy with insertion or removal of a ureteric stent. Audio-visual media were developed for each procedure, with each script translated from English into isiXhosa and Afrikaans. The study involved a cross-over for each patient between standard verbal consent (SVC) and PVM consent, with each patient randomised to start with SVC or PVM consent. Each of these consent arms was assessed via a questionnaire.Sixty patients completed participation, with PVM as the first exposure for 28 patients and 32 patients receiving SVC as their first arm of the study. When comparing the overall satisfaction between SVC and PVM consent (the total scores out of 18 for the questionnaire), patients scored significantly higher for PVM consent (M = 16.3 ± 2.4) compared to SVC (M = 15.4 ± 2.9) (p = 0.002). 92% of the total patient sample preferred PVM consent.Portable video media proved superior to SVC in improving satisfaction in the consent process for common outpatient urological procedures performed under local anaesthesia.

Objectives: The purpose of this article was to further elucidate the pathophysiology of Mirror (Ballantyne) syndrome within the context of known biomarkers for preeclampsia.Methods: This novel insight from clinical practice involved a case of post-twin-to-twin transfusion syndrome-laser hydrops in an ex-donor twin, corroborated by histopathologic placental territory edema and maternal sequelae of Mirror syndrome. We serially measured the levels of activin A, follistatin, endothelin-1 (ET-1), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), soluble fms-like tyrosine kinase 1 (sFlt), and von Willebrand factor (vWF) in the maternal serum from disease evolution through to recovery.Results: The paired finding of hydropic ex-donor twin and placenta, supports the theory of placental injury as the source of potential molecular mediators, leading to local placental edema, associated fetal hydrops and the maternal preeclamptic picture. Notably, we elucidated a temporal spectrum of maternal serum mediators (soluble Flt-1, endothelin-1, 8-isoprostane, activin-A, ICAM-1, and vWF) involved in the pathogenesis of Mirror syndrome.Conclusion: Better understanding of the pathogenesis of Mirror syndrome has important implications for clinical management.

All authors: Andrea Cossarizza Hyun‐Dong Chang Andreas Radbruch Andreas Acs Dieter Adam Sabine Adam‐Klages William W. Agace Nima Aghaeepour Mübeccel Akdis Matthieu Allez Larissa Nogueira Almeida Giorgia Alvisi Graham Anderson Immanuel Andrä Francesco Annunziato Achille Anselmo Petra Bacher Cosima T. Baldari Sudipto Bari Vincenzo Barnaba Joana Barros‐Martins Luca Battistini Wolfgang Bauer Sabine Baumgart Nicole Baumgarth Dirk Baumjohann Bianka Baying Mary Bebawy Burkhard Becher Wolfgang Beisker Vladimir Benes Rudi Beyaert Alfonso Blanco Dominic A. Boardman Christian Bogdan Jessica G. Borger Giovanna Borsellino Philip E. Boulais Jolene A. Bradford Dirk Brenner Ryan R. Brinkman Anna E. S. Brooks Dirk H. Busch Martin Büscher Timothy P. Bushnell Federica Calzetti Garth Cameron Ilenia Cammarata Xuetao Cao Susanna L. Cardell Stefano Casola Marco A. Cassatella Andrea Cavani Antonio Celada Lucienne Chatenoud Pratip K. Chattopadhyay Sue Chow Eleni Christakou Luka Čičin‐Šain Mario Clerici Federico S. Colombo Laura Cook Anne Cooke Andrea M. Cooper Alexandra J. Corbett Antonio Cosma Lorenzo Cosmi Pierre G. Coulie Ana Cumano Ljiljana Cvetkovic Van Duc Dang Chantip Dang‐Heine Martin S. Davey Derek Davies Sara De Biasi Genny Del Zotto Gelo Victoriano Dela Cruz Michael Delacher Silvia Della Bella Paolo Dellabona Günnur Deniz Mark Dessing James P. Di Santo Andreas Diefenbach Francesco Dieli Andreas Dolf Thomas Dörner Regine J. Dress Diana Dudziak Michael Dustin Charles‐Antoine Dutertre Friederike Ebner Sidonia B. G. Eckle Matthias Edinger Pascale Eede Götz R.A. Ehrhardt Marcus Eich Pablo Engel Britta Engelhardt Anna Erdei Charlotte Esser Bart Everts Maximilien Evrard Christine S. Falk Todd A. Fehniger Mar Felipo‐Benavent Helen Ferry Markus Feuerer Andrew Filby Kata Filkor Simon Fillatreau Marie Follo Irmgard Förster John Foster Gemma A. Foulds Britta Frehse Paul S. Frenette Stefan Frischbutter Wolfgang Fritzsche David W. Galbraith Anastasia Gangaev Natalio Garbi Brice Gaudilliere Ricardo T. Gazzinelli Jens Geginat Wilhelm Gerner Nicholas A. Gherardin Kamran Ghoreschi Lara Gibellini Florent Ginhoux Keisuke Goda Dale I. Godfrey Christoph Goettlinger Jose M. González‐Navajas Carl S. Goodyear Andrea Gori Jane L. Grogan Daryl Grummitt Andreas Grützkau Claudia Haftmann Jonas Hahn Hamida Hammad Günter Hämmerling Leo Hansmann Goran Hansson Christopher M. Harpur Susanne Hartmann Andrea Hauser Anja E. Hauser David L. Haviland David Hedley Daniela C. Hernández Guadalupe Herrera Martin Herrmann Christoph Hess Thomas Höfer Petra Hoffmann Kristin Hogquist Tristan Holland Thomas Höllt Rikard Holmdahl Pleun Hombrink Jessica P. Houston Bimba F. Hoyer Bo Huang Fang‐Ping Huang Johanna E. Huber Jochen Huehn Michael Hundemer Christopher A. Hunter William Y. K. Hwang Anna Iannone Florian Ingelfinger Sabine M Ivison Hans‐Martin Jäck Peter K. Jani Beatriz Jávega Stipan Jonjic Toralf Kaiser Tomas Kalina Thomas Kamradt Stefan H. E. Kaufmann Baerbel Keller Steven L. C. Ketelaars Ahad Khalilnezhad Srijit Khan Jan Kisielow Paul Klenerman Jasmin Knopf Hui‐Fern Koay Katja Kobow Jay K. Kolls Wan Ting Kong Manfred Kopf Thomas Korn Katharina Kriegsmann Hendy Kristyanto Thomas Kroneis Andreas Krueger Jenny Kühne Christian Kukat Désirée Kunkel Heike Kunze‐Schumacher Tomohiro Kurosaki Christian Kurts Pia Kvistborg Immanuel Kwok Jonathan Landry Olivier Lantz Paola Lanuti Francesca LaRosa Agnès Lehuen Salomé LeibundGut‐Landmann Michael D. Leipold Leslie Y.T. Leung Megan K. Levings Andreia C. Lino Francesco Liotta Virginia Litwin Yanling Liu Hans‐Gustaf Ljunggren Michael Lohoff Giovanna Lombardi Lilly Lopez Miguel López‐Botet Amy E. Lovett‐Racke Erik Lubberts Herve Luche Burkhard Ludewig Enrico Lugli Sebastian Lunemann Holden T. Maecker Laura Maggi Orla Maguire Florian Mair Kerstin H. Mair Alberto Mantovani Rudolf A. Manz Aaron J. Marshall Alicia Martínez‐Romero Glòria Martrus Ivana Marventano Wlodzimierz Maslinski Giuseppe Matarese Anna Vittoria Mattioli Christian Maueröder Alessio Mazzoni James McCluskey Mairi McGrath Helen M. McGuire Iain B. McInnes Henrik E. Mei Fritz Melchers Susanne Melzer Dirk Mielenz Stephen D. Miller Kingston H.G. Mills Hans Minderman Jenny Mjösberg Jonni Moore Barry Moran Lorenzo Moretta Tim R. Mosmann Susann Müller Gabriele Multhoff Luis Enrique Muñoz Christian Münz Toshinori Nakayama Milena Nasi Katrin Neumann Lai Guan Ng Antonia Niedobitek Sussan Nourshargh Gabriel Núñez José‐Enrique O'Connor Aaron Ochel Anna Oja Diana Ordonez Alberto Orfao Eva Orlowski‐Oliver Wenjun Ouyang Annette Oxenius Raghavendra Palankar Isabel Panse Kovit Pattanapanyasat Malte Paulsen Dinko Pavlinic Livius Penter Pärt Peterson Christian Peth Jordi Petriz Federica Piancone Winfried F. Pickl Silvia Piconese Marcello Pinti A. Graham Pockley Malgorzata Justyna Podolska Zhiyong Poon Katharina Pracht Immo Prinz Carlo E. M. Pucillo Sally A. Quataert Linda Quatrini Kylie M. Quinn Helena Radbruch Tim R. D. J. Radstake Susann Rahmig Hans‐Peter Rahn Bartek Rajwa Gevitha Ravichandran Yotam Raz Jonathan A. Rebhahn Diether Recktenwald Dorothea Reimer Caetano Reis e Sousa Ester B.M. Remmerswaal Lisa Richter Laura G. Rico Andy Riddell Aja M. Rieger J. Paul Robinson Chiara Romagnani Anna Rubartelli Jürgen Ruland Armin Saalmüller Yvan Saeys Takashi Saito Shimon Sakaguchi Francisco Sala‐de‐Oyanguren Yvonne Samstag Sharon Sanderson Inga Sandrock Angela Santoni Ramon Bellmàs Sanz Marina Saresella Catherine Sautes‐Fridman Birgit Sawitzki Linda Schadt Alexander Scheffold Hans U. Scherer Matthias Schiemann Frank A. Schildberg Esther Schimisky Andreas Schlitzer Josephine Schlosser Stephan Schmid Steffen Schmitt Kilian Schober Daniel Schraivogel Wolfgang Schuh Thomas Schüler Reiner Schulte Axel Ronald Schulz Sebastian R. Schulz Cristiano Scottá Daniel Scott‐Algara David P. Sester T. Vincent Shankey Bruno Silva‐Santos Anna Katharina Simon Katarzyna M. Sitnik Silvano Sozzani Daniel E. Speiser Josef Spidlen Anders Stahlberg Alan M. Stall Natalie Stanley Regina Stark Christina Stehle Tobit Steinmetz Hannes Stockinger Yousuke Takahama Kiyoshi Takeda Leonard Tan Attila Tárnok Gisa Tiegs Gergely Toldi Julia Tornack Elisabetta Traggiai Mohamed Trebak Timothy I.M. Tree Joe Trotter John Trowsdale Maria Tsoumakidou Henning Ulrich Sophia Urbanczyk Willem van de Veen Maries van den Broek Edwin van der Pol Sofie Van Gassen Gert Van Isterdael René A.W. van Lier Marc Veldhoen Salvador Vento‐Asturias Paulo Vieira David Voehringer Hans‐Dieter Volk Anouk von Borstel Konrad von Volkmann Ari Waisman Rachael V. Walker Paul K. Wallace Sa A. Wang Xin M. Wang Michael D. Ward Kirsten A Ward‐Hartstonge Klaus Warnatz Gary Warnes Sarah Warth Claudia Waskow James V. Watson Carsten Watzl Leonie Wegener Thomas Weisenburger Annika Wiedemann Jürgen Wienands Anneke Wilharm Robert John Wilkinson Gerald Willimsky James B. Wing Rieke Winkelmann Thomas H. Winkler Oliver F. Wirz Alicia Wong Peter Wurst Jennie H. M. Yang Juhao Yang Maria Yazdanbakhsh Liping Yu Alice Yue Hanlin Zhang Yi Zhao Susanne Maria Ziegler Christina Zielinski Jakob Zimmermann Arturo Zychlinsky., These guidelines are a consensus work of a considerable number of members of the immunology and flow cytometry community. They provide the theory and key practical aspects of flow cytometry enabling immunologists to avoid the common errors that often undermine immunological data. Notably, there are comprehensive sections of all major immune cell types with helpful Tables detailing phenotypes in murine and human cells. The latest flow cytometry techniques and applications are also described, featuring examples of the data that can be generated and, importantly, how the data can be analysed. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid, all written and peer‐reviewed by leading experts in the field, making this an essential research companion., This work was supported by the Netherlands Organisation for Scientific Research – Domain Applied and Engineering Sciences (NWO-TTW), research program VENI 15924. This work was funded by the Deutsche Forschungsgemeinschaft. European Union Innovative Medicines Initiative - Joint Undertaking - RTCure Grant Agreement 777357 and innovation program (Grant Agreement 695551).

Placental dysfunction is a major contributing factor to fetal growth restriction. Placenta-mediated fetal growth restriction occurs through chronic fetal hypoxia owing to poor placental perfusion through a variety of mechanisms. Maternal vascular malperfusion is the most common placental disease contributing to fetal growth restriction; however, the role of rare placental diseases should not be overlooked. Although the features of maternal vascular malperfusion are identifiable on placental pathology, antepartum diagnostic methods are evolving. Placental imaging and uterine artery Doppler, used in conjunction with angiogenic growth factors (specifically placenta growth factor and soluble fms-like tyrosine kinase-1), play an increasingly important role.

While CRISPR screens are helping uncover genes regulating many cell-intrinsic processes, existing approaches are suboptimal for identifying extracellular gene functions, particularly in the tissue context. Here, we developed an approach for spatial functional genomics called Perturb-map. We applied Perturb-map to knock out dozens of genes in parallel in a mouse model of lung cancer and simultaneously assessed how each knockout influenced tumor growth, histopathology, and immune composition. Moreover, we paired Perturb-map and spatial transcriptomics for unbiased analysis of CRISPR-edited tumors. We found that in Tgfbr2 knockout tumors, the tumor microenvironment (TME) was converted to a fibro-mucinous state, and T cells excluded, concomitant with upregulated TGFβ and TGFβ-mediated fibroblast activation, indicating that TGFβ-receptor loss on cancer cells increased TGFβ bioavailability and its immunosuppressive effects on the TME. These studies establish Perturb-map for functional genomics within the tissue at single-cell resolution with spatial architecture preserved and provide insight into how TGFβ responsiveness of cancer cells can affect the TME.

Uterine tachysystole (TS) is a potentially significant intrapartum complication seen most commonly in induced or augmented labors but may also occur in women with spontaneous labor. When it occurs, maternal and perinatal complications can arise if not identified and managed promptly by obstetric care providers. Over recent years, new definitions of the condition have facilitated further research into the field, which has been synthesized to inform clinical management guidelines and protocols. We propose a set of recommendations pertaining to TS in line with contemporary evidence and obstetric practice.