GDF15 linked to maternal risk of nausea and vomiting during pregnancy.

GDF15, a hormone acting on the brainstem, has been implicated in the nausea and vomiting of pregnancy, including its most severe form, hyperemesis gravidarum (HG), but a full mechanistic understanding is lacking1-4. Here we report that fetal production of GDF15 and maternal sensitivity to it both contribute substantially to the risk of HG. We confirmed that higher GDF15 levels in maternal blood are associated with vomiting in pregnancy and HG. Using mass spectrometry to detect a naturally labelled GDF15 variant, we demonstrate that the vast majority of GDF15 in the maternal plasma is derived from the feto-placental unit. By studying carriers of rare and common genetic variants, we found that low levels of GDF15 in the non-pregnant state increase the risk of developing HG. Conversely, women with ß-thalassaemia, a condition in which GDF15 levels are chronically high5, report very low levels of nausea and vomiting of pregnancy. In mice, the acute food intake response to a bolus of GDF15 is influenced bi-directionally by prior levels of circulating GDF15 in a manner suggesting that this system is susceptible to desensitization. Our findings support a putative causal role for fetally derived GDF15 in the nausea and vomiting of human pregnancy, with maternal sensitivity, at least partly determined by prepregnancy exposure to the hormone, being a major influence on its severity. They also suggest mechanism-based approaches to the treatment and prevention of HG.

Prenatal cortisol exposure impairs adrenal function but not glucose metabolism in adult sheep.

Adverse environmental conditions before birth are known to programme adult metabolic and endocrine phenotypes in several species. However, whether increments in fetal cortisol concentrations of the magnitude commonly seen in these conditions can cause developmental programming remains unknown. Thus, this study investigated the outcome of physiological increases in fetal cortisol concentrations on glucose-insulin dynamics and pituitary-adrenal function in adult sheep. Compared with saline treatment, intravenous fetal cortisol infusion for 5 days in late gestation did not affect birthweight but increased lamb body weight at 1-2 weeks after birth. Adult glucose dynamics, insulin sensitivity and insulin secretion were unaffected by prenatal cortisol overexposure, assessed by glucose tolerance tests, hyperinsulinaemic-euglycaemic clamps and acute insulin administration. In contrast, prenatal cortisol infusion induced adrenal hypo-responsiveness in adulthood with significantly reduced cortisol responses to insulin-induced hypoglycaemia and exogenous adrenocorticotropic hormone (ACTH) administration relative to saline treatment. The area of adrenal cortex expressed as a percentage of the total cross-sectional area of the adult adrenal gland was also lower after prenatal cortisol than saline infusion. In adulthood, basal circulating ACTH but not cortisol concentrations were significantly higher in the cortisol than saline-treated group. The results show that cortisol overexposure before birth programmes pituitary-adrenal development with consequences for adult stress responses. Physiological variations in cortisol concentrations before birth may, therefore, have an important role in determining adult phenotypical diversity and adaptability to environmental challenges.

Fetally-encoded GDF15 and maternal GDF15 sensitivity are major determinants of nausea and vomiting in human pregnancy.

Human pregnancy is frequently accompanied by nausea and vomiting that may become severe and life-threatening, as in hyperemesis gravidarum (HG), the cause of which is unknown. Growth Differentiation Factor-15 (GDF15), a hormone known to act on the hindbrain to cause emesis, is highly expressed in the placenta and its levels in maternal blood rise rapidly in pregnancy. Variants in the maternal GDF15 gene are associated with HG. Here we report that fetal production of GDF15, and maternal sensitivity to it, both contribute substantially to the risk of HG. We found that the great majority of GDF15 in maternal circulation is derived from the feto-placental unit and that higher GDF15 levels in maternal blood are associated with vomiting and are further elevated in patients with HG. Conversely, we found that lower levels of GDF15 in the non-pregnant state predispose women to HG. A rare C211G variant in GDF15 which strongly predisposes mothers to HG, particularly when the fetus is wild-type, was found to markedly impair cellular secretion of GDF15 and associate with low circulating levels of GDF15 in the non-pregnant state. Consistent with this, two common GDF15 haplotypes which predispose to HG were associated with lower circulating levels outside pregnancy. The administration of a long-acting form of GDF15 to wild-type mice markedly reduced subsequent responses to an acute dose, establishing that desensitisation is a feature of this system. GDF15 levels are known to be highly and chronically elevated in patients with beta thalassemia. In women with this disorder, reports of symptoms of nausea or vomiting in pregnancy were strikingly diminished. Our findings support a causal role for fetal derived GDF15 in the nausea and vomiting of human pregnancy, with maternal sensitivity, at least partly determined by pre-pregnancy exposure to GDF15, being a major influence on its severity. They also suggest mechanism-based approaches to the treatment and prevention of HG.

Age and the anaesthetist: considerations for the individual anaesthetist and workforce planning: Guidelines about the ageing anaesthetic workforce from the Association of Anaesthetists: Guidelines for the ageing anaesthetic workforce from the Association of Anaesthetists.

There is clear evidence of a growing workforce gap and this is compounded by demographic data that show the current workforce is ageing. Within the current workforce, more doctors are taking voluntary early retirement and the loss of these experienced clinicians from departments can have wide-ranging effects. Older doctors are at risk of age-related health problems (e.g. sight, musculoskeletal, menopause) and are more susceptible to the effects of fatigue, which may increase the risk of error and or complaint. The purpose of this working party and advocacy campaign was to address concerns over the number of consultants retiring at the earliest opportunity and whether a different approach could extend the working career of consultant anaesthetists and SAS doctors. This could be viewed as 'pacing your career'. The earlier this is considered in a clinician's career the greater the potential mitigation on individuals.

Imaging-based feedback cooling of a levitated nanoparticle.

Imaging-based detection of the motion of levitated nanoparticles complements a widely used interferometric detection method, providing a precise and robust way to estimate the position of the particle. Here, we demonstrate a camera-based feedback cooling scheme for a charged nanoparticle levitated in a linear Paul trap. The nanoparticle levitated in vacuum was imaged using a complementary metal-oxide semiconductor (CMOS) camera system. The images were processed in real-time with a microcontroller integrated with a CMOS image sensor. The phase-delayed position signal was fed back to one of the trap electrodes, resulting in cooling by velocity damping. Our study provides a simple and versatile approach applicable for the control of low-frequency mechanical oscillators.

Realizing Einstein's Mirror: Optomechanical Damping with a Thermal Photon Gas.

Einstein described the damping and thermalization of the center-of-mass motion of a mirror placed inside a blackbody cavity by collisions with thermal photons. While the time for damping even a microscale or nanoscale object is so long that it is not experimentally viable, we show that this damping is feasible using the high-intensity light from an amplified thermal light source with a well-defined chemical potential. We predict this damping of the center-of-mass motion will occur on timescales of tens of seconds for small optomechanical systems.

MTT and Blood-Brain Barrier Disruption within Asymptomatic Vascular WM Lesions.

BACKGROUND AND PURPOSE: White matter lesions of presumed ischemic origin are associated with progressive cognitive impairment and impaired BBB function. Studying the longitudinal effects of white matter lesion biomarkers that measure changes in perfusion and BBB patency within white matter lesions is required for long-term studies of lesion progression. We studied perfusion and BBB disruption within white matter lesions in asymptomatic subjects. MATERIALS AND METHODS: Anatomic imaging was followed by consecutive dynamic contrast-enhanced and DSC imaging. White matter lesions in 21 asymptomatic individuals were determined using a Subject-Specific Sparse Dictionary Learning algorithm with manual correction. Perfusion-related parameters including CBF, MTT, the BBB leakage parameter, and volume transfer constant were determined. RESULTS: MTT was significantly prolonged (7.88 [SD, 1.03] seconds) within white matter lesions compared with normal-appearing white (7.29 [SD, 1.14] seconds) and gray matter (6.67 [SD, 1.35] seconds). The volume transfer constant, measured by dynamic contrast-enhanced imaging, was significantly elevated (0.013 [SD, 0.017] minutes-1) in white matter lesions compared with normal-appearing white matter (0.007 [SD, 0.011] minutes-1). BBB disruption within white matter lesions was detected relative to normal white and gray matter using the DSC-BBB leakage parameter method so that increasing BBB disruption correlated with increasing white matter lesion volume (Spearman correlation coefficient = 0.44; P < .046). CONCLUSIONS: A dual-contrast-injection MR imaging protocol combined with a 3D automated segmentation analysis pipeline was used to assess BBB disruption in white matter lesions on the basis of quantitative perfusion measures including the volume transfer constant (dynamic contrast-enhanced imaging), the BBB leakage parameter (DSC), and MTT (DSC). This protocol was able to detect early pathologic changes in otherwise healthy individuals.

Guidelines for the management of glucocorticoids during the peri-operative period for patients with adrenal insufficiency: Guidelines from the Association of Anaesthetists, the Royal College of Physicians and the Society for Endocrinology UK.

These guidelines aim to ensure that patients with adrenal insufficiency are identified and adequately supplemented with glucocorticoids during the peri-operative period. There are two major categories of adrenal insufficiency. Primary adrenal insufficiency is due to diseases of the adrenal gland (failure of the hormone-producing gland), and secondary adrenal insufficiency is due to deficient adrenocorticotropin hormone secretion by the pituitary gland, or deficient corticotropin-releasing hormone secretion by the hypothalamus (failure of the regulatory centres). Patients taking physiological replacement doses of corticosteroids for either primary or secondary adrenal insufficiency are at significant risk of adrenal crisis and must be given stress doses of hydrocortisone during the peri-operative period. Many more patients other than those with adrenal and hypothalamic-pituitary causes of adrenal failure are receiving glucocorticoids as treatment for other medical conditions. Daily doses of prednisolone of 5 mg or greater in adults and 10-15 mg.m-2 hydrocortisone equivalent or greater in children may result in hypothalamo-pituitary-adrenal axis suppression if administered for 1 month or more by oral, inhaled, intranasal, intra-articular or topical routes; this chronic administration of glucocorticoids is the most common cause of secondary adrenal suppression, sometimes referred to as tertiary adrenal insufficiency. A pragmatic approach to adrenal replacement during major stress is required; considering the evidence available, blanket recommendations would not be appropriate, and it is essential for the clinician to remember that adrenal replacement dosing following surgical stress or illness is in addition to usual steroid treatment. Patients with previously undiagnosed adrenal insufficiency sometimes present for the first time following the stress of surgery. Anaesthetists must be familiar with the symptoms and signs of acute adrenal insufficiency so that inadequate supplementation or undiagnosed adrenal insufficiency can be detected and treated promptly. Delays may prove fatal.

Quantum Spectrometry for Arbitrary Noise.

We present a technique for recovering the spectrum of a non-Markovian bosonic bath and/or non-Markovian noises coupled to a harmonic oscillator. The treatment is valid under the conditions that the environment is large and hot compared to the oscillator, and that its temporal autocorrelation functions are symmetric with respect to time translation and reflection-criteria which we consider fairly minimal. We model a demonstration of the technique as deployed in the experimental scenario of a nanosphere levitated in a Paul trap, and show that it would effectively probe the spectrum of an electric field noise source from 10^{2} to 10^{6} Hz with a resolution inversely proportional to the measurement time. This technique may be deployed in quantum sensing, metrology, computing, and in experimental probes of foundational questions.

Cerebral Ketones Detected by 3T MR Spectroscopy in Patients with High-Grade Glioma on an Atkins-Based Diet.

BACKGROUND AND PURPOSE: Ketogenic diets are being explored as a possible treatment for several neurological diseases, but the physiologic impact on the brain is unknown. The objective of this study was to evaluate the feasibility of 3T MR spectroscopy to monitor brain ketone levels in patients with high-grade gliomas who were on a ketogenic diet (a modified Atkins diet) for 8 weeks. MATERIALS AND METHODS: Paired pre- and post-ketogenic diet MR spectroscopy data from both the lesion and contralateral hemisphere were analyzed using LCModel software in 10 patients. RESULTS: At baseline, the ketone bodies acetone and ß-hydroxybutyrate were nearly undetectable, but by week 8, they increased in the lesion for both acetone (0.06 ± 0.03 ≥ 0.27 ± 0.06 IU, P = .005) and ß-hydroxybutyrate (0.07 ± 0.07 ≥ 0.79 ± 0.32 IU, P = .046). In the contralateral brain, acetone was also significantly increased (0.041 ± 0.01 ≥ 0.16 ± 0.04 IU, P = .004), but not ß-hydroxybutyrate. Acetone was detected in 9/10 patients at week 8, and ß-hydroxybutyrate, in 5/10. Acetone concentrations in the contralateral brain correlated strongly with higher urine ketones (r = 0.87, P = .001) and lower fasting glucose (r = -0.67, P = .03). Acetoacetate was largely undetectable. Small-but-statistically significant decreases in NAA were also observed in the contralateral hemisphere at 8 weeks. CONCLUSIONS: This study suggests that 3T MR spectroscopy is feasible for detecting small cerebral metabolic changes associated with a ketogenic diet, provided that appropriate methodology is used.

Super-resolution imaging of a low frequency levitated oscillator.

We describe the measurement of the secular motion of a levitated nanoparticle in a Paul trap with a CMOS camera. This simple method enables us to reach signal-to-noise ratios as good as 106 with a displacement sensitivity better than 10-16 m2/Hz. This method can be used to extract trap parameters as well as the properties of the levitated particles. We demonstrate continuous monitoring of the particle dynamics on time scales of the order of weeks. We show that by using the improvement given by super-resolution imaging, a significant reduction in the noise floor can be attained, with an increase in the bandwidth of the force sensitivity. This approach represents a competitive alternative to standard optical detection for a range of low frequency oscillators where low optical powers are required.

Strong and recurring seasonality revealed within stream diatom assemblages.

Improving stream water quality in agricultural landscapes is an ecological priority and a legislative duty for many governments. Ecosystem health can be effectively characterised by organisms sensitive to water quality changes such as diatoms, single-celled algae that are a ubiquitous component of stream benthos. Diatoms respond within daily timescales to variables including light, temperature, nutrient availability and flow conditions that result from weather and land use characteristics. However, little consideration has been given to the ecological dynamics of diatoms through repeated seasonal cycles when assessing trajectories of stream function, even in catchments actively managed to reduce human pressures. Here, six years of monthly diatom samples from three independent streams, each receiving differing levels of diffuse agricultural pollution, reveal robust and repeated seasonal variation. Predicted seasonal changes in climate-related variables and anticipated ecological impacts must be fully captured in future ecological and water quality assessments, if the apparent resistance of stream ecosystems to pollution mitigation measures is to be better understood.

Field Evaluation of a Portable Whispering Gallery Mode Accelerometer.

An accelerometer utilising the optomechanical coupling between an optical whispering gallery mode (WGM) resonance and the motion of the WGM cavity itself was prototyped and field-tested on a vehicle. We describe the assembly of this portable, battery operated sensor and the field-programmable gate array automation. Pre-trial testing using an electrodynamic shaker demonstrated linear scale-factors with <0.3% standard deviation ( ± 6 g range where g = 9.81 ms - 2 ), and a strong normalised cross-correlation coefficient (NCCC) of r ICP / WGM = 0.997 when compared with an integrated circuit piezoelectric (ICP) accelerometer. A noise density of 40 µ g Hz - 1 / 2 was obtained for frequencies of 2⁻7 kHz, increasing to 130 µ g Hz - 1 / 2 at 200 Hz, and 250 µ g Hz - 1 / 2 at 100 Hz. A reduction in the cross-correlation was found during the trial, r ICP / WGM = 0.36, which we attribute to thermal fluctuations, mounting differences, and the noisy vehicle environment. The deployment of this hand-fabricated sensor, shown to operate and survive during ±60 g shocks, demonstrates important steps towards the development of a chip-scale device.

Direct isotopic evidence of biogenic methane production and efflux from beneath a temperate glacier.

The base of glaciers and ice sheets provide environments suitable for the production of methane. High pressure conditions beneath the impermeable 'cap' of overlying ice promote entrapment of methane reserves that can be released to the atmosphere during ice thinning and meltwater evacuation. However, contemporary glaciers and ice sheets are rarely accounted for as methane contributors through field measurements. Here, we present direct field-based evidence of methane production and release from beneath the Icelandic glacier Sólheimajökull, where geothermal activity creates sub-oxic conditions suited to methane production and preservation along the meltwater flow path. Methane production at the glacier bed (48 tonnes per day, or 39 mM CH4 m-2 day-1), and evasion to the atmosphere from the proglacial stream (41 tonnes per day, or 32 M CH4 m-2 day-1) indicates considerable production and release to the atmosphere during the summer melt season. Isotopic signatures (-60.2‰ to -7.6‰ for δ13CCH4 and -324.3‰ to +161.1‰ for DCH4), support a biogenic signature within waters emerging from the subglacial environment. Temperate glacial methane production and release may thus be a significant and hitherto unresolved contributor of a potent greenhouse gas to the atmosphere.

Fertility in classical galactosaemia, a study of N-glycan, hormonal and inflammatory gene interactions.

BACKGROUND: Classical Galactosaemia (CG) (OMIM #230400) is a rare inborn error of galactose metabolism caused by deficiency of the enzyme galactose-1-phosphate uridylyltransferase (GALT). Long-term complications persist in treated patients despite dietary galactose restriction with significant variations in outcomes suggesting epigenetic glycosylation influences. Primary Ovarian Insufficiency (POI) is a very significant complication affecting females with follicular depletion noted in early life. We studied specific glycan synthesis, leptin system and inflammatory gene expression in white blood cells as potential biomarkers of infertility in 54 adults with CG adults (27 females and 27 males) (age range 17-51 yr) on a galactose-restricted diet in a multi-site Irish and Dutch study. Gene expression profiles were tested for correlation with a serum Ultra-high Performance Liquid Chromatography (UPLC)-Immunoglobulin (IgG)-N-glycan galactose incorporation assay and endocrine measurements. RESULTS: Twenty five CG females (93%) had clinical and biochemical evidence of POI. As expected, the CG female patients, influenced by hormone replacement therapy, and the healthy controls of both genders showed a positive correlation between log leptin and BMI but this correlation was not apparent in CG males. The strongest correlations between serum leptin levels, hormones, G-ratio (galactose incorporation assay) and gene expression data were observed between leptin, its gene and G-Ratios data (rs = - 0.68) and (rs = - 0.94) respectively with lower circulating leptin in CG patients with reduced IgG galactosylation. In CG patients (males and females analysed as one group), the key glycan synthesis modifier genes MGAT3 and FUT8, which influence glycan chain bisecting and fucosylation and subsequent cell signalling and adhesion, were found to be significantly upregulated (p < 0.01 and p < 0.05) and also the glycan synthesis gene ALG9 (p < 0.01). Both leptin signalling genes LEP and LEPR were found to be upregulated (p < 0.01) as was the inflammatory genes ANXA1 and ICAM1 and the apoptosis gene SEPT4 (p < 0.01). CONCLUSIONS: These results validate our previous findings and provide novel experimental evidence for dysregulation of genes LEP, LEPR, ANXA1, ICAM1 and SEPT4 for CG patients and combined with our findings of abnormalities of IgG glycosylation, hormonal and leptin analyses elaborate on the systemic glycosylation and cell signalling abnormalities evident in CG which likely influence the pathophysiology of POI.

Gravimetry through non-linear optomechanics.

Precision gravimetry is key to a number of scientific and industrial applications, including climate change research, space exploration, geological surveys and fundamental investigations into the nature of gravity.  A variety of quantum systems, such as atom interferometry and on-chip-Bose-Einstein condensates have thus far been investigated to this aim. Here, we propose a new method which involves using a quantum optomechanical system for measurements of gravitational acceleration. As a proof-of-concept, we investigate the fundamental sensitivity for gravitational accelerometry of a cavity optomechanical system with a trilinear radiation pressure light-matter interaction. The phase of the optical output encodes the gravitational acceleration g and is the only component which needs to be measured. We prove analytically that homodyne detection is the optimal readout method and we predict an ideal fundamental sensitivity of Δg = 10-15 ms-2 for state-of-the-art parameters of optomechanical systems, showing that they could, in principle, surpass the best atomic interferometers even for low optical intensities. Further, we show that the scheme is strikingly robust to the initial thermal state of the oscillator.

An analytical model for the detection of levitated nanoparticles in optomechanics.

Interferometric position detection of levitated particles is crucial for the centre-of-mass (CM) motion cooling and manipulation of levitated particles. In combination with balanced detection and feedback cooling, this system has provided picometer scale position sensitivity, zeptonewton force detection, and sub-millikelvin CM temperatures. In this article, we develop an analytical model of this detection system and compare its performance with experimental results allowing us to explain the presence of spurious frequencies in the spectra.

7T Brain MRS in HIV Infection: Correlation with Cognitive Impairment and Performance on Neuropsychological Tests.

BACKGROUND AND PURPOSE: Validated neuroimaging markers of HIV-associated neurocognitive disorder in patients on antiretroviral therapy are urgently needed for clinical trials. The purpose of this study was to explore the relationship between cognitive impairment and brain metabolism in older subjects with HIV infection. It was hypothesized that MR spectroscopy measurements related to neuronal health and function (particularly N-acetylaspartate and glutamate) would be lower in HIV-positive subjects with worse cognitive performance. MATERIALS AND METHODS: Forty-five HIV-positive patients (mean age, 58.9 ± 5.3 years; 33 men) underwent detailed neuropsychological testing and brain MR spectroscopy at 7T. Twenty-four subjects were classified as having asymptomatic cognitive impairment, and 21 were classified as having symptomatic cognitive impairment. Single-voxel proton MR spectra were acquired from 5 brain regions and quantified using LCModel software. Brain metabolites and neuropsychological test results were compared using nonparametric statistics and Pearson correlation coefficients. RESULTS: Differences in brain metabolites were found between symptomatic and asymptomatic subjects, with the main findings being lower measures of N-acetylaspartate in the frontal white matter, posterior cingulate cortex, and precuneus. In the precuneus, glutamate was also lower in the symptomatic group. In the frontal white matter, precuneus, and posterior cingulate cortex, NAA and glutamate measurements showed significant positive correlation with better performance on neuropsychological tests. CONCLUSIONS: Compared with asymptomatic subjects, symptomatic HIV-positive subjects had lower levels of NAA and glutamate, most notably in the frontal white matter, which also correlated with performance on neuropsychological tests. High-field MR spectroscopy offers insight into the pathophysiology associated with cognitive impairment in HIV and may be useful as a quantitative outcome measure in future treatment trials.

Major agricultural changes required to mitigate phosphorus losses under climate change.

Phosphorus losses from land to water will be impacted by climate change and land management for food production, with detrimental impacts on aquatic ecosystems. Here we use a unique combination of methods to evaluate the impact of projected climate change on future phosphorus transfers, and to assess what scale of agricultural change would be needed to mitigate these transfers. We combine novel high-frequency phosphorus flux data from three representative catchments across the UK, a new high-spatial resolution climate model, uncertainty estimates from an ensemble of future climate simulations, two phosphorus transfer models of contrasting complexity and a simplified representation of the potential intensification of agriculture based on expert elicitation from land managers. We show that the effect of climate change on average winter phosphorus loads (predicted increase up to 30% by 2050s) will be limited only by large-scale agricultural changes (e.g., 20-80% reduction in phosphorus inputs).The impact of climate change on phosphorus (P) loss from land to water is unclear. Here, the authors use P flux data, climate simulations and P transfer models to show that only large scale agricultural change will limit the effect of climate change on average winter P loads in three catchments across the UK.