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.

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.

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.

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.

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.

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.

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.

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.

Evaluation of trace mineral source and preharvest deletion of trace minerals from finishing diets on tissue mineral status in pigs.

OBJECTIVE: An experiment was conducted to evaluate dietary supplemental trace mineral source and deletion on mineral content in tissues. METHODS: Weanling crossbred pigs (n = 144; 72 barrows and 72 gilts; body weight [BW] = 7.4±1.05 kg) were used. A basal diet was prepared, and trace mineral premix containing either inorganic (ITM) or organic (OTM) trace minerals (Cu, Fe, Mn, and Zn) was added to the basal diet. Pigs were blocked by sex and BW and randomly allotted to 24 pens for a total of 6 pigs per pen, and fed a diet containing either ITM or OTM supplemented at the 1998 NRC requirement estimates for each of 5 BW phases (Phase I to V) from 7 to 120 kg. The trace mineral supplementation was deleted for 6, 4, 2, and 0 wk of Phase V; regarding nutrient adequacy during this phase, the indigenous dietary Fe and Mn was sufficient, Cu was marginal and Zn was deficient. RESULTS: At the end of Phase IV, Mn content (mg/kg on the dry matter basis) was greater (p<0.05) in heart (0.77 vs 0.68), kidney (6.32 vs 5.87), liver (9.46 vs 8.30), and longissimus dorsi (LD; 0.30 vs 0.23) of pigs fed OTM. The pigs fed OTM were greater (p<0.05) in LD Cu (2.12 vs 1.89) and Fe (21.75 vs 19.40) and metacarpal bone Zn (141.86 vs 130.05). At the end of Phase V, increased length of deletion period (from 0 to 6 wk) resulted in a decrease (linear, p<0.01) in liver Zn (196.5 to 121.8), metacarpal bone Zn (146.6 to 86.2) and an increase (linear, p<0.01) in heart Mn (0.70 to 1.08), liver Mn (7.74 to 12.96), and kidney Mn (5.58 to 7.56). The only mineral source by deletion period interaction (p<0.05) was observed in LD Zn. CONCLUSION: The results demonstrated differential effects of mineral deletion on tissue mineral content depending on both mineral assessed and source of the mineral.

Maternal experience raising girls with autism spectrum disorder: a qualitative study.

BACKGROUND: A growing line of research has sought to characterize the different presentations of autism spectrum disorder (ASD) among boys and girls. Much less is known about maternal experience and mother-child relationship in children with ASD based on child gender. The present qualitative study aimed to investigate the mother-daughter relationship from the perspective of mothers who are raising girls with ASD with normal intelligence and functional verbal communication. METHODS: Eleven in-depth interviews were conducted with mothers of girls with ASD, ages 10-19 years. Data were analysed in an interactive process commonly used in naturalistic inquiry. Results provide insight into the unique maternal experience of raising a daughter with ASD. RESULTS: Mothers reported a sense of exclusion from the neurotypical population and male-dominant ASD population and transformation in relationship. Themes identified were skepticism and delayed diagnosis, disbelief from others, lack of information about girls with ASD, higher social demands in adolescence, puberty challenges around hygiene, disappointment about physical appearance, vulnerability in relationships and worries about future functioning. The mother-daughter relationship started with an early expectation of a close and intimate relationship that then underwent a transformation, which challenged maternal competence, reshaped expectations and created a different bond between mother and daughter. CONCLUSIONS: The findings in this qualitative study highlight the impact of gender on the maternal experience of raising a daughter with ASD and contribute to a better understanding of the needs of both mothers and daughters. These results can help providers support the mother-daughter dyad by recognizing gender-specific challenges.

No more time to stay 'single' in the detection of Anisakis pegreffii, A. simplex (s. s.) and hybridization events between them: a multi-marker nuclear genotyping approach.

A multi-marker nuclear genotyping approach was performed on larval and adult specimens of Anisakis spp. (N = 689) collected from fish and cetaceans in allopatric and sympatric areas of the two species Anisakis pegreffii and Anisakis simplex (s. s.), in order to: (1) identify specimens belonging to the parental taxa by using nuclear markers (allozymes loci) and sequence analysis of a new diagnostic nuclear DNA locus (i.e. partial sequence of the EF1 α-1 nDNA region) and (2) recognize hybrid categories. According to the Bayesian clustering algorithms, based on those markers, most of the individuals (N = 678) were identified as the parental species [i.e. A. pegreffii or A. simplex (s. s.)], whereas a smaller portion (N = 11) were recognized as F1 hybrids. Discordant results were obtained when using the polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLPs) of the internal transcribed spacer (ITS) ribosomal DNA (rDNA) on the same specimens, which indicated the occurrence of a large number of 'hybrids' both in sympatry and allopatry. These findings raise the question of possible misidentification of specimens belonging to the two parental Anisakis and their hybrid categories derived from the application of that single marker (i.e. PCR-RFLPs analysis of the ITS of rDNA). Finally, Bayesian clustering, using allozymes and EF1 α-1 nDNA markers, has demonstrated that hybridization between A. pegreffii and A. simplex (s. s.) is a contemporary phenomenon in sympatric areas, while no introgressive hybridization takes place between the two species.

Nutrient and pollutant metals within earthworm residues are immobilized in soil during decomposition.

Earthworms are known to bioaccumulate metals, making them a potential vector for metal transport in soils. However, the fate of metals within soil upon death of earthworms has not been characterized. We compared the fate of nutrient (Ca, Mg, Mn) and potentially toxic (Cu, Zn, Pb) metals during decomposition of Amynthas agrestis and Lumbricus rubellus in soil columns. Cumulative leachate pools, exchangeable pools (0.1 M KCl + 0.01 M acetic acid extracted), and stable pools (16 M HNO3 + 12 M HCl extracted) were quantified in the soil columns after 7, 21, and 60 days of decomposition. Soil columns containing A. agrestis and L. rubellus had significantly higher cumulative leachate pools of Ca, Mn, Cu, and Pb than Control soil columns. Exchangeable and stable pools of Cu, Pb, and Zn were greater for A. agrestis and L. rubellus soil columns than Control soil columns. However, we estimated that > 98 % of metals from earthworm residues were immobilized in the soil in an exchangeable or stable form over the 60 days using a mass balance approach. Micro-XRF images of longitudinal thin sections of soil columns after 60 days containing A. agrestis confirm metals immobilization in earthworm residues. Our research demonstrates that nutrient and toxic metals are stabilized in soil within earthworm residues.

The Assessment of Risk in Cardiothoracic Intensive Care (ARCtIC): prediction of hospital mortality after admission to cardiothoracic critical care.

The models used to predict outcome after adult general critical care may not be applicable to cardiothoracic critical care. Therefore, we analysed data from the Case Mix Programme to identify variables associated with hospital mortality after admission to cardiothoracic critical care units and to develop a risk-prediction model. We derived predictive models for hospital mortality from variables measured in 17,002 patients within 24 h of admission to five cardiothoracic critical care units. The final model included 10 variables: creatinine; white blood count; mean arterial blood pressure; functional dependency; platelet count; arterial pH; age; Glasgow Coma Score; arterial lactate; and route of admission. We included additional interaction terms between creatinine, lactate, platelet count and cardiac surgery as the admitting diagnosis. We validated this model against 10,238 other admissions, for which the c index (95% CI) was 0.904 (0.89-0.92) and the Brier score was 0.055, while the slope and intercept of the calibration plot were 0.961 and -0.183, respectively. The discrimination and calibration of our model suggest that it might be used to predict hospital mortality after admission to cardiothoracic critical care units.

Atypical pituitary adenomas: 10 years of experience in a reference centre in Portugal.

INTRODUCTION: Primary pituitary tumours are classified by the World Health Organization as typical adenoma, atypical adenoma, or carcinoma. Information on the incidence and prevalence of these pituitary tumours is limited, and these data in Portugal are scarce, obsolete, or non-existent. Our study evaluates pituitary adenomas (PA) in the population of Lisbon, and it aims to describe the prevalence of all subgroups in order to revise the incidence of the 'atypical' histological type and its correlation to tumour subtype, invasion, and recurrence. PATIENTS AND METHODS: A retrospective, descriptive analysis of patients with PA diagnosed between 2004 and 2013 was performed at Santa Maria University Hospital, a national reference centre. RESULTS: Of the 220 PA cases diagnosed, 28 (12.7%) fulfilled criteria for atypical lesions, and within that group, 23 were macroadenomas (82.1%) and 13 showed radiological evidence of invasion (46.4%). Ages ranged from 29 and 81 years (mean, 53.4 years). Eleven patients (39.3%) had functional tumours. Sixteen of the 28 patients (57.1%) experienced tumour recurrences; in the 100 adenomas monitored for more than 5 years, the recurrence rate in atypical PA was 7 times higher than in typical PA. Immunohistochemically, 28.6% of the tumours stained positively for ACTH, 25% for gonadotrophins, and 17.9% for prolactin. The proliferation index (Ki67) ranged from 3% and 25% (mean, 6.4%). CONCLUSIONS: Atypical PAs make up 12.7% of all surgically treated PA cases, and they tend to be invasive and recurrent macroadenomas. We found no differences in metastatic potential between typical and atypical PA.

Association between fetal position at onset of labor and mode of delivery: a prospective cohort study.

OBJECTIVES: To determine the association between fetal position at onset of labor and mode of delivery, specifically left occipito-anterior (LOA) fetal position and spontaneous vaginal delivery (SVD). METHODS: All nulliparous women who were booked at the Birmingham Women's NHS Foundation Trust over an 18-month period from April 2007 to September 2008 with a singleton live fetus without structural anomalies at term gestation were invited to take part in the study. Women recruited to the study underwent a transabdominal ultrasound scan to determine fetal occiput position at the onset of labor. They were then followed up until birth to determine outcome. The primary outcome measure was mode of delivery, categorized into SVD, instrumental delivery and Cesarean section. RESULTS: Of 1647 eligible women, 1250 had valid scans at onset of labor; 155 of the 1250 (12.4%) had fetuses in the LOA position. Analysis showed no evidence of difference in odds ratio (OR) of SVD for fetuses in the LOA position compared with all other positions (OR 0.864 (95% CI, 0.617-1.209); P = 0.394). No difference remained with adjustment for confounding effects of variables known to influence mode of delivery (OR 0.837 (95% CI, 0.551-1.272); P = 0.405). No other occipital position showed significant association with SVD. There was no evidence of the LOA position being associated with Cesarean section, ventouse or forceps delivery. CONCLUSION: There is no evidence of an association between the fetal LOA position at onset of labor and SVD. This finding challenges the conventional theory that LOA is the optimum fetal position at onset of labor, and suggests that antenatal practices encouraging adoption of the LOA position through maternal posturing are unnecessary.

Disease-specific quality of life evaluation and its determinants in Cushing's syndrome: what have we learnt?

Cushing's syndrome (CS) has a considerable negative impact on patient health-related quality of life (HRQoL). Two disease-specific instruments (the CushingQoL and the Tuebingen CD-25 questionnaire) are now available to assess the impact of the disease and its treatment on HRQoL. The purpose of this review was to summarize the characteristics of the studies which have used these two instruments to date and summarize their findings regarding (a) the determinants of disease-specific HRQoL in patients with CS and (b) the impact of treatment for CS on disease-specific HRQoL. A total of 7 studies were identified, 5 with the CushingQoL and 2 with the Tuebingen CD-25. Most were observational studies, though the CushingQoL had been used in one randomized clinical trial. In terms of clinical factors, there was some evidence for an association between UFC levels and disease-specific HRQoL, though the presence and strength of the association varied between studies. There was also some evidence that a more recent diagnosis of CS could lead to poorer HRQoL, and that length of time with adrenal insufficiency may also affect HRQoL. There was no evidence for an impact on disease-specific HRQoL of etiology or of the clinical signs and symptoms associated with CS, such as bruising, rubor, and fat deposits. One factor which did have a significant negative effect on HRQoL was the presence of depression. No clear picture emerged as to the effect of demographic variables such as age and gender on HRQoL scores, though there was some evidence for poorer HRQoL in female patients. As regards treatment, the two interventions studied to date (transsphenoidal surgery and pasireotide) both showed significant gains in HRQoL, with moderate to large effect sizes. This type of review is useful in summarizing knowledge to date and suggesting future research directions.

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 'pocket guide' to total internal reflection fluorescence.

The phenomenon of total internal reflection fluorescence (TIRF) was placed in the context of optical microscopy by Daniel Axelrod over three decades ago. TIRF microscopy exploits the properties of an evanescent electromagnetic field to optically section sample regions in the close vicinity of the substrate where the field is induced. The first applications in cell biology targeted investigation of phenomena at the basolateral plasma membrane. The most notable application of TIRF is single-molecule experiments, which can provide information on fluctuation distributions and rare events, yielding novel insights on the mechanisms governing the molecular interactions that underpin many fundamental processes within the cell. This short review intends to provide a 'one stop shop' explanation of the electromagnetic theory behind the remarkable properties of the evanescent field, guide the reader through the principles behind building or choosing your own TIRF system and consider how the most popular applications of the method exploit the evanescent field properties.

(Micro)spectroscopic analyses of particle size dependence on arsenic distribution and speciation in mine wastes.

The chemical speciation and distribution of potentially toxic metal(loid)s in mine wastes is critical to assessing the risks posed by these wastes and predicting the potential bioavailability of the metal(loid)s present. Of additional potential importance is the role of particle size in the fate, transport, and toxicity of contaminated mining materials. Spectroscopic analyses of size-separated mine tailings and adjacent background samples from the Randsburg Historic Mining District, California were conducted to quantify the speciation and distribution of arsenic (As) as a function of particle size. Micro-X-ray fluorescence (µXRF) mapping of separate size fractions was used to identify multiple populations of particles with different As:Fe ratios, indicating a variety of distinct arsenic-bearing species. Bulk extended X-ray absorption fine structure (EXAFS) spectroscopy identified phases including arseniosiderite, Ca2Fe3(3+)(AsO4)3O3·3H2O, and As(V) sorbed to iron hydroxides (ferrihydrite, goethite), confirming a strong statistical correlation between arsenic and iron observed in both µXRF studies and bulk chemical analyses. Differences in As speciation between the mine tailings and background samples also suggest that weathering of crystalline As-bearing phases in tailings leads to sorption of dissolved arsenic to iron hydroxides in nontailings background material.