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

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

Venous thromboembolism in Cushing syndrome: results from an EuRRECa and Endo-ERN survey.

Background: Patients with Cushing syndrome (CS) are at increased risk of venous thromboembolism (VTE). Objective: The aim was to evaluate the current management of new cases of CS with a focus on VTE and thromboprophylaxis. Design and methods: A survey was conducted within those that report in the electronic reporting tool (e-REC) of the European Registries for Rare Endocrine Conditions (EuRRECa) and the involved main thematic groups (MTG's) of the European Reference Networks for Rare Endocrine Disorders (Endo-ERN) on new patients with CS from January 2021 to July 2022. Results: Of 222 patients (mean age 44 years, 165 females), 141 patients had Cushing disease (64%), 69 adrenal CS (31%), and 12 patients with ectopic CS (5.4%). The mean follow-up period post-CS diagnosis was 15 months (range 3-30). Cortisol-lowering medications were initiated in 38% of patients. One hundred fifty-four patients (69%) received thromboprophylaxis (including patients on chronic anticoagulant treatment), of which low-molecular-weight heparins were used in 96% of cases. VTE was reported in six patients (2.7%), of which one was fatal: two long before CS diagnosis, two between diagnosis and surgery, and two postoperatively. Three patients were using thromboprophylaxis at time of the VTE diagnosis. The incidence rate of VTE in patients after Cushing syndrome diagnosis in our study cohort was 14.6 (95% CI 5.5; 38.6) per 1000 person-years. Conclusion: Thirty percent of patients with CS did not receive preoperative thromboprophylaxis during their active disease stage, and half of the VTE cases even occurred during this stage despite thromboprophylaxis. Prospective trials to establish the optimal thromboprophylaxis strategy in CS patients are highly needed. Significance statement: The incidence rate of venous thromboembolism in our study cohort was 14.6 (95% CI 5.5; 38.6) per 1000 person-years. Notably, this survey showed that there is great heterogeneity regarding time of initiation and duration of thromboprophylaxis in expert centers throughout Europe.

A stochastic model for topographically influenced cell migration.

Migrating cells traverse a range of topographic configurations presented by the native extracellular environment to conduct their physiologic functions. It is well documented cells can modulate their behaviour in response to different topographic features, finding promising applications in biomaterial and bioimplant design. It is useful, in these areas of research, to be able to predict which topographic arrangements could be used to promote certain patterns of migration prior to laboratory experimentation. Despite a profusion of study and interest shown in these fields by experimentalists, the related modelling literature is as yet relatively sparse and tend to focus more on either cell-matrix interaction or morphological responses of cells. We propose a mathematical model for individual cell migration based on an Ornstein-Uhlenbeck process, and set out to see if the model can be used to predict migration patterns on 2-d isotropic and anisotropic topographies, whose characteristics can be broadly described as either uniform flat, uniform linear with variable ridge density or non-uniform disordered with variable feature density. Results suggest the model is capable of producing realistic patterns of migration for flat and linear topographic patterns, with calibrated output closely approximating NIH3T3 fibroblast migration behaviour derived from an experimental dataset, in which migration linearity increased with ridge density and average speed was highest at intermediate ridge densities. Exploratory results for non-uniform disordered topographies suggest cell migration patterns may adopt disorderedness present in the topography and that 'distortion' introduced to linear topographic patterns may not impede linear guidance of migration, given its magnitude is bounded within certain limits. We conclude that an Ornstein-Uhlenbeck based model for topographically influenced migration may be useful to predict patterns of migration behaviour for certain isotropic (flat) and anisotropic (linear) topographies in the NIH3T3 fibroblast cell line, but additional investigation is required to predict with confidence migration patterns for non-uniform disordered topographic arrangements.

Female squirrel monkeys' (Saimiri boliviensis) responses to inequity in a group context; testing a link between cooperation and inequity responses.

Primates of several species respond negatively to receiving less preferred rewards than a partner for completing the same task (inequity responses), either rejecting rewards or refusing to participate in the task when disadvantaged. This has been linked to cooperation, with species that cooperate frequently refusing to participate in inequity tasks (the 'cooperation hypothesis'). However, inequity is a social response, and previous research has involved dyads, precluding studying the effects of additional social partners. While dyads allow for tighter control in experimental settings, dyadic interactions in nature do not take place in a social vacuum, so understanding the role of the social context is needed to verify that the pattern of results supports the cooperation hypothesis. Here we focus on Bolivian squirrel monkeys, Saimiri boliviensis, a highly social species that does not generally cooperate and has not responded to inequity in previous dyadic research, although they do respond to receiving a lower reward than they expected. In the current study, we provide a more nuanced test by studying female Bolivian squirrel monkeys, the demographic most likely to cooperate in both field and laboratory contexts, in a more socially relevant group setting. For some reward values, females responded in both the inequity condition, rejecting less preferred rewards when they were disadvantaged relative to their social group, and a contrast condition, wherein all animals received a lower reward than they expected, making it difficult to disentangle contrast from inequity. As in capuchin monkeys, refusals increased when monkeys were to receive low-value rewards compared to medium-value rewards. These results suggest that the relationship between cooperation and inequity responses may be more nuanced than previously suggested, with demographic, social context and reward value potentially influencing outcomes even within species.

Instantaneous 4D micro-particle image velocimetry (µPIV) via multifocal microscopy (MUM).

Multifocal microscopy (MUM), a technique to capture multiple fields of view (FOVs) from distinct axial planes simultaneously and on one camera, was used to perform micro-particle image velocimetry (µPIV) to reconstruct velocity and shear stress fields imposed by a liquid flowing around a cell. A diffraction based multifocal relay was used to capture images from three different planes with 630 nm axial spacing from which the axial positions of the flow-tracing particles were calculated using the image sharpness metric. It was shown that MUM can achieve an accuracy on the calculated velocity of around (0.52 ± 0.19) µm/s. Using fixed cells, MUM imaged the flow perturbations at sub-cellular level, which showed characteristics similar to those observed in the literature. Using live cells as an exemplar, MUM observed the effect of changing cell morphology on the local flow during perfusion. Compared to standard confocal laser scanning microscope, MUM offers a clear advantage in acquisition speed for µPIV (over 300 times faster). This is an important characteristic for rapidly evolving biological systems where there is the necessity to monitor in real time entire volumes to correlate the sample responses to the external forces.

Antenatal preventative pelvic floor muscle exercise intervention led by midwives to reduce postnatal urinary incontinence (APPEAL): protocol for a feasibility and pilot cluster randomised controlled trial.

BACKGROUND: Antenatal pelvic floor muscle exercises (PFME) in women without prior urinary incontinence (UI) are effective in reducing postnatal UI; however, UK midwives often do not provide advice and information to women on undertaking PFME, with evidence that among women who do receive advice, many do not perform PFME. METHODS: The primary aim of this feasibility and pilot cluster randomised controlled trial is to provide a potential assessment of the feasibility of undertaking a future definitive trial of a midwifery-led antenatal intervention to support women to perform PFME in pregnancy and reduce UI postnatally. Community midwifery teams in participating NHS sites comprise trial clusters (n = 17). Midwives in teams randomised to the intervention will be trained on how to teach PFME to women and how to support them in undertaking PFME in pregnancy. Women whose community midwifery teams are allocated to control will receive standard antenatal care only. All pregnant women who give birth over a pre-selected sample month who receive antenatal care from participating community midwifery teams (clusters) will be sent a questionnaire at 10-12 weeks postpartum (around 1400-1500 women). Process evaluation data will include interviews with midwives to assess if the intervention could be implemented as planned. Interviews with women in both trial arms will explore their experiences of support from midwives to perform PFME during pregnancy. Data will be stored securely at the Universities of Birmingham and Exeter. Results will be disseminated through publications aimed at maternity service users, clinicians, and academics and inform a potential definitive trial of effectiveness. The West Midlands-Edgbaston Research Ethics Committee approved the study protocol. DISCUSSION: Trial outcomes will determine if criteria to progress to a definitive cluster trial are met. These include women's questionnaire return rates, prevalence of UI, and other health outcomes as reported by women at 10-12 weeks postpartum. Progress to a definitive trial however is likely to be prevented in the UK context by new perinatal pelvic health service, although this may be possible elsewhere. TRIAL REGISTRATION: https://doi.org/10.1186/ISRCTN10833250 . Registered 09/03/2020.

ESE Clinical Practice Guideline on functioning and nonfunctioning pituitary adenomas in pregnancy.

Pregnancies are rare in women with pituitary adenomas, which may relate to hormone excess from secretory subtypes such as prolactinomas or corticotroph adenomas. Decreased fertility may also result from pituitary hormone deficiencies due to compression of the gland by large tumours and/or surgical or radiation treatment of the lesion. Counselling premenopausal women with pituitary adenomas about their chance of conceiving spontaneously or with assisted reproductive technology, and the optimal pre-conception treatment, should start at the time of initial diagnosis. The normal physiological changes during pregnancy need to be considered when interpreting endocrine tests in women with pituitary adenomas. Dose adjustments in hormone substitution therapies may be needed across the trimesters. When medical therapy is used for pituitary hormone excess, consideration should be given to the known efficacy and safety data specific to pregnant women for each therapeutic option. In healthy women, pituitary gland size increases during pregnancy. Since some pituitary adenomas also enlarge during pregnancy, there is a risk of visual impairment, especially in women with macroadenomas or tumours near the optic chiasm. Pituitary apoplexy represents a rare acute complication of adenomas requiring surveillance, with surgical intervention needed in some cases. This guideline describes the choice and timing of diagnostic tests and treatments from the pre-conception stage until after delivery, taking into account adenoma size, location and endocrine activity. In most cases, pregnant women with pituitary adenomas should be managed by a multidisciplinary team in a centre specialised in the treatment of such tumours.

Quantifying the frequency and volume of urine deposition by grazing sheep using tri-axial accelerometers.

Urine patches deposited in pasture by grazing animals are sites of reactive nitrogen (N) loss to the environment due to high concentrations of N exceeding pasture uptake requirements. In order to upscale N losses from the urine patch, several urination parameters are required, including where, when and how often urination events occur as well as the volume and chemical composition. There are limited data available in this respect, especially for sheep. Here, we seek to address this knowledge gap by using non-invasive sensor-based technology (accelerometers) on ewes grazing in situ, using a Boolean algorithm to detect urination events in the accelerometer signal. We conducted an initial study with penned Welsh Mountain ewes (n = 5), with accelerometers attached to the hind, to derive urine flow rate and to determine whether urine volume could be estimated from ewe squat time. Then accelerometers attached to the hind of Welsh Mountain ewes (n = 30 at each site) were used to investigate the frequency of sheep urination events (n = 35 946) whilst grazing two extensively managed upland pastures (semi-improved and unimproved) across two seasons (spring and autumn) at each site (35-40 days each). Sheep urinated at a frequency of 10.2 ± 0.2 and 8.1 ± 0.3 times per day in the spring and autumn, respectively, while grazing the semi-improved pasture. Urination frequency was greater (19.0 ± 0.4 and 15.3 ± 0.3 times per day in the spring and autumn, respectively) in the unimproved pasture. Ewe squat duration could be reliably used to predict the volume of urine deposited per event and was thus used to estimate mean daily urine production volumes. Sheep urinated at a rate of 16.6 mL/s and, across the entire dataset, sheep squatted for an average of 9.62 ± 0.03 s per squatting event, producing an estimated average individual urine event volume of 159 ± 1 mL (n = 35 946 events), ranging between 17 and 745 mL (for squat durations of 1 to 45 s). The estimated mean daily urine volume was 2.15 ± 0.04 L (n = 2 669 days) across the entire dataset. The data will be useful for modelling studies estimating N losses (e.g. ammonia (NH3) volatilisation, nitrous oxide (N2O) emission via nitrification and denitrification and nitrate (NO3-) leaching) from urine patches.

Microbial sulfate reduction and organic sulfur formation in sinking marine particles.

Climate change is driving an expansion of marine oxygen-deficient zones, which may alter the global cycles of carbon, sulfur, nitrogen, and trace metals. Currently, however, we lack a full mechanistic understanding of how oxygen deficiency affects organic carbon cycling and burial. Here, we show that cryptic microbial sulfate reduction occurs in sinking particles from the eastern tropical North Pacific oxygen-deficient zone and that some microbially produced sulfide reacts rapidly to form organic sulfur that is resistant to acid hydrolysis. Particle-hosted sulfurization could enhance carbon preservation in sediments underlying oxygen-deficient water columns and serve as a stabilizing feedback between expanding anoxic zones and atmospheric carbon dioxide. A similar mechanism may help explain more-extreme instances of organic carbon preservation associated with marine anoxia in Earth history.

Infant EEG theta modulation predicts childhood intelligence.

Intellectual functioning is a critical determinant of economic and personal productivity. Identifying early neural predictors of cognitive function in infancy will allow us to map the neurodevelopmental pathways that underpin individual differences in intellect. Here, in three different cohorts we investigate the association between a putative neurophysiological indicator of information encoding (change in frontal theta during a novel video) in infancy and later general cognitive outcome. In a discovery cohort of 12-month-old typically developing infants, we recorded EEG during presentation of dynamic movies of people and objects. Frontal theta power (3-6 Hz) significantly increased during the course of viewing each video. Critically, increase in frontal theta during viewing of a video was associated with a differential response to repetition of that specific video, confirming relation to learning. Further, individual differences in the magnitude of change in frontal theta power were related to concurrent nonverbal cognitive level. We then sought to extend this association in two independent samples enriched for variation in cognitive outcome due to the inclusion of infants at familial risk for autism. We observed similar patterns of theta EEG change at 12 months, and found a predictive relation to verbal and nonverbal cognitive skills measured at 2, 3 and 7 years of age. For the subset of high-risk infants later diagnosed with autism, infant theta EEG explained over 80% of the variance in nonverbal skills at age 3 years. We suggest that EEG theta change in infancy is an excellent candidate predictive biomarker that could yield substantial insight into the mechanisms that underlie individual differences in childhood intelligence, particularly in high risk populations.

Biomarker responses in New Zealand green-lipped mussels Perna canaliculus exposed to microplastics and triclosan.

Microplastics (MPs) are of increasing concern for filter feeding marine and freshwater species. Additionally MPs can sorb hydrophobic contaminants from the water, potentially providing an additional pathway of exposure of aquatic species to contaminants. An acute 48 h laboratory study was conducted to investigate the effects of microplastics and triclosan, both individually and combined, on New Zealand's green-lipped mussel, Perna canaliculus. Biomarkers included clearance rate, oxygen uptake, byssus production; and superoxide dismutase (SOD) activity, glutathione-S-transferase (GST) activity and lipid peroxidation in the gill tissue. Microplastics and triclosan, both individually and combined significantly decreased oxygen uptake and byssus production. These physiological responses were not observed when the microplastics were spiked with triclosan. Triclosan, both alone and spiked to microplastics, increased mussel oxidative stress markers including SOD activity and lipid peroxidation. An enhanced effect was observed on the SOD enzyme activity when mussels were exposed to microplastics spiked with triclosan. No effects on the biochemical biomarkers were observed for mussels exposed to microplastic only. Microplastics enhanced the uptake of triclosan in mussel tissue compared with triclosan only treatments indicating that microplastics potentially provide an additional pathway of exposure to hydrophobic contaminants.

Diagnosis of death using neurological criteria in adult patients on extracorporeal membrane oxygenation: Development of UK guidance.

The diagnosis of death using neurological criteria is an important legal method of establishing death in the UK. The safety of the diagnosis lies in the exclusion of conditions which may mask the diagnosis and the testing of the fundamental reflexes of the brainstem including the apnoea reflex. Extracorporeal membrane oxygenation for cardiac or respiratory support can impact upon these tests, both through drug sequestration in the circuit and also through the ability to undertake the apnoea test. Until recently, there has been no nationally accepted guidance regarding the conduct of the tests to undertake the diagnosis of death using neurological criteria for a patient on extracorporeal membrane oxygenation. This article considers both the background to and the process of guideline development.

Psychiatric and neurocognitive consequences of endogenous hypercortisolism.

Psychiatric and neurocognitive symptoms due to hypercortisolism were already described by Harvey Cushing in his original paper on patients with Cushing's syndrome (CS). Nowadays, it is well known that psychiatric and cognitive complaints are two of the most common, and most distressing, symptoms in patients with CS. Psychiatric symptoms are indeed a major clinical manifestation of CS. The most commonly observed psychiatric conditions are depression and anxiety, whilst mania and psychosis are less common. Several domains of cognitive function are impaired at diagnosis, including episodic and working memory, executive function and attention. Following treatment, one-fourth of the patients still experience depressed mood, and the cognitive impairments are only partially restored. Consequently, quality of life in patients with CS is severely and persistently affected. Neuroimaging studies have also illustrated the deleterious effects of hypercortisolism on the brain by demonstrating reduced grey matter volumes and cortical thickness, altered resting-state functional responses and during cognitive tasks, as well as widespread reduced white matter integrity, especially in structures important for cognitive function and emotional processing, both before and after successful abrogation of hypercortisolism. In this paper, we summarize the current knowledge on the psychiatric and neurocognitive consequences of hypercortisolism in patients with CS, both before, and after successful treatment. In addition, we review the structural and functional brain abnormalities associated with hypercortisolism and discuss the influence of these factors on quality of life.

Sample preparation with sucrose cryoprotection dramatically alters Zn distribution in the rodent hippocampus, as revealed by elemental mapping.

Transition metal ions (Fe, Mn, Cu, Zn) are essential for healthy brain function, but altered concentration, distribution, or chemical form of the metal ions has been implicated in numerous brain pathologies. Currently, it is not possible to image the cellular or sub-cellular distribution of metal ions in vivo and therefore, studying brain-metal homeostasis largely relies on ex vivo in situ elemental mapping. Sample preparation methods that accurately preserve the in vivo elemental distribution are essential if one wishes to translate the knowledge of elemental distributions measured ex vivo toward increased understanding of chemical and physiological pathways of brain disease. The choice of sample preparation is particularly important for metal ions that exist in a labile or mobile form, for which the in vivo distribution could be easily distorted by inappropriate sample preparation. One of the most widely studied brain structures, the hippocampus, contains a large pool of labile and mobile Zn. Herein, we describe how sucrose cryoprotection, the gold standard method of preparing tissues for immuno-histochemistry or immuno-fluorescence, which is also often used as a sample preparation method for elemental mapping studies, drastically alters hippocampal Zn distribution. Based on the results of this study, in combination with a comparison against the strong body of published literature that has used either rapid plunge freezing of brain tissue, or sucrose cryo-protection, we strongly urge investigators in the future to cease using sucrose cryoprotection as a method of sample preparation for elemental mapping, especially if Zn is an analyte of interest.

What the public think about participation in medical research during an influenza pandemic: an international cross-sectional survey.

OBJECTIVES: The public and patients are primary contributors and beneficiaries of pandemic-relevant clinical research. However, their views on research participation during a pandemic have not been systematically studied. We aimed to understand public views regarding participation in clinical research during a hypothetical influenza pandemic. STUDY DESIGN: This is an international cross-sectional survey. METHODS: We surveyed the views of nationally representative samples of people in Belgium, Poland, Spain, Ireland, the United Kingdom, Canada, Australia and New Zealand, using a scenario-based instrument during the 2017 regional influenza season. Descriptive and regression analyses were conducted. RESULTS: Of the 6804 respondents, 5572 (81.8%) thought pandemic-relevant research was important, and 5089 (74.8%) thought 'special rules' should be applied to make this research feasible. The respondents indicated willingness to take part in lower risk (4715, 69.3%) and higher risk (3585, 52.7%) primary care and lower risk (4780, 70.3%) and higher risk (4113, 60.4%) intensive care unit (ICU) study scenarios. For primary care studies, most (3972, 58.4%) participants preferred standard enrolment procedures such as prospective written informed consent, but 2327 (34.2%) thought simplified procedures would be acceptable. For ICU studies, 2800 (41.2%) preferred deferred consent, and 2623 (38.6%) preferred prospective third-party consent. Greater knowledge about pandemics, trust in a health professional, trust in the government, therapeutic misconception and having had ICU experience as a patient or carer predicted increased willingness to participate in pandemic-relevant research. CONCLUSIONS: Our study indicates current public support for pandemic-relevant clinical research. Tailored information and initiatives to advance research literacy and maintain trust are required to support pandemic-relevant research participation and engagement.

Corrosion threshold data of metallic materials in various operating environment of offshore wind turbine parts (tower, foundation, and nacelle/gearbox).

This paper outlines corrosion thresholds for different environmental conditions of metallic materials commonly used in the tower, foundation, and nacelle/gearbox of an offshore wind turbine. These threshold values were derived from laboratory corrosion testing employing electrochemical analysis techniques, using the media/solvents that are representative to the operating environment of those wind turbine parts, such as seawater, grease, oils/lubricants, or their combination, at room temperature and at 328K. These values can provide an indication when general/local corrosion or protective film/surface damages have occurred. They can thus be utilised for detecting and monitoring corrosion at certain locations in the wind turbine structure. The presented data have been verified and validated to ensure their repeatability and reliability by means of numerous laboratory tests in accordance to the relevant engineering test standards and an extensive literature/published data review.

Why don't corticotroph tumors always produce Cushing's disease?

OBJECTIVE: Silent corticotroph tumors are a pituitary neuroendocrine tumor subtype of corticotroph lineage that do not clinically express Cushing's disease. The silencing of this type of tumor is not fully understood. The aim of the present study was to delve into the lack of secretory activity, studying the post-transcriptional and post-translational regulation of POMC/ACTH in a series of molecularly identified functioning and silent corticotroph tumors. DESIGN: We analyzed 24 silent corticotroph, 23 functioning corticotroph and 25 silent gonadotroph tumors. METHODS: We used Sanger sequencing, quantitative real-time PCR and Western blot to analyze genetic alterations in POMC, gene expression of TBX19, NEUROD1, POMC, PCSK1, PCSK2, CPE and PAM and protein expression of POMC, PC1/3, PC2, CPE and PAM. RESULTS: We found different polymorphisms in the POMC gene of corticotroph tumors, some of them related to deficiency of proopiomelanocortin. Silent corticotroph tumors showed lower PC1/3 gene and protein expression than functioning ones, especially compared to micro-functioning corticotroph tumors (all P < 0.05). Moreover, we found a positive correlation between PC2 and CPE gene and protein expression (rho ≥ 0.670, P < 0.009) in silent corticotroph tumors compared with functioning ones. CONCLUSIONS: By studying the post-transcriptional and post-translational processing of POMC and ACTH, respectively, in a large series of silent and functioning corticotroph tumors, we found that the lack of secretory activity of these tumors is related to an impaired processing of POMC and a high degradation of ACTH, with the macro-functioning corticotroph tumor behaving as an intermediate state between micro-functioning and silent corticotroph tumors.

The cell wall regulates dynamics and size of plasma-membrane nanodomains in Arabidopsis.

Plant plasma-membrane (PM) proteins are involved in several vital processes, such as detection of pathogens, solute transport, and cellular signaling. For these proteins to function effectively there needs to be structure within the PM allowing, for example, proteins in the same signaling cascade to be spatially organized. Here we demonstrate that several proteins with divergent functions are located in clusters of differing size in the membrane using subdiffraction-limited Airyscan confocal microscopy. Single particle tracking reveals that these proteins move at different rates within the membrane. Actin and microtubule cytoskeletons appear to significantly regulate the mobility of one of these proteins (the pathogen receptor FLS2) and we further demonstrate that the cell wall is critical for the regulation of cluster size by quantifying single particle dynamics of proteins with key roles in morphogenesis (PIN3) and pathogen perception (FLS2). We propose a model in which the cell wall and cytoskeleton are pivotal for regulation of protein cluster size and dynamics, thereby contributing to the formation and functionality of membrane nanodomains.

Dynamic discriminant model for predicting respiratory distress at birth based on mass volume ratio in fetuses with congenital lung malformation.

OBJECTIVES: The congenital lung malformation volume ratio (CVR) is a prenatal ultrasound measurement that parameterizes congenital lung malformation (CLM) size. The aims of this study were to use serial measurements to create estimated growth curves of fetal CVR for asymptomatic and symptomatic neonates with CLM and to investigate whether a discriminant prognostic model based on these measurements could predict accurately which fetuses with CLM will require invasive respiratory support at delivery and should therefore be delivered at a tertiary-care facility. METHODS: This was a retrospective study of fetuses diagnosed prenatally with CLM at three tertiary-care children's hospitals between 2009 and 2016. Those with two or more sonographic measurements of CVR were included. Serial fetal CVR measurements were used to create estimated growth curves for neonates with and those without respiratory symptoms at delivery, defined as requiring invasive respiratory support for the first 24 h after delivery. A discriminant model based on serial CVR measurements was used to calculate the dynamic probability of the need for invasive respiratory support. The performance of this model overall and in preterm and term neonates was compared with those using maximum CVR thresholds of 1.0 and 1.6. RESULTS: Of the 147 neonates meeting the inclusion criteria, 16 (10.9%) required postnatal invasive respiratory support. The estimated CVR growth curve models showed different growth trajectories for asymptomatic and symptomatic neonates, with significantly higher CVR in symptomatic neonates, and values peaking late in the second trimester at around 25 weeks' gestation in asymptomatic neonates. All prognostic methods had high accuracy for the prediction of the need for invasive respiratory support in term neonates, but the discriminant model had the best performance overall (area under the receiver-operating characteristics curve (AUC) = 0.88) and in the preterm population (AUC = 0.85). CONCLUSIONS: The estimated CVR growth curves showed different growth patterns in asymptomatic and symptomatic neonates with CLM. The dynamic discriminant model performed well overall and particularly in neonates that were carried to term. Development of an externally validated clinical tool based on this analysis could be useful in determining the site of delivery for fetuses with CLM. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Replication of a rare risk haplotype on 1p36.33 for autism spectrum disorder.

Hundreds of genes have been implicated in autism spectrum disorders (ASDs). In genetically heterogeneous conditions, large families with multiple affected individuals provide strong evidence implicating a rare variant, and replication of the same variant in multiple families is unusual. We previously published linkage analyses and follow-up exome sequencing in seven large families with ASDs, implicating 14 rare exome variants. These included rs200195897, which was transmitted to four affected individuals in one family. We attempted replication of those variants in the MSSNG database. MSSNG is a unique resource for replication of ASD risk loci, containing whole genome sequence (WGS) on thousands of individuals diagnosed with ASDs and family members. For each exome variant, we obtained all carriers and their relatives in MSSNG, using a TDT test to quantify evidence for transmission and association. We replicated the transmission of rs200195897 to four affected individuals in three additional families. rs200195897 was also present in three singleton affected individuals, and no unaffected individuals other than transmitting parents. We identified two additional rare variants (rs566472488 and rs185038034) transmitted with rs200195897 on 1p36.33. Sanger sequencing confirmed the presence of these variants in the original family segregating rs200195897. To our knowledge, this is the first example of a rare haplotype being transmitted with ASD in multiple families. The candidate risk variants include a missense mutation in SAMD11, an intronic variant in NOC2L, and a regulatory region variant close to both genes. NOC2L is a transcription repressor, and several genes involved in transcription regulation have been previously associated with ASDs.