Can Anti-Müllerian Hormone levels predict future pregnancy outcomes in recurrent pregnancy loss?

OBJECTIVE: Serum Anti-Müllerian Hormone (AMH) levels have been shown to be lower among women who have experienced recurrent pregnancy loss (RPL) compared with the general population. However, it is unclear whether it can predict livebirth. This study aims to determine whether AMH can predict the likelihood of a livebirth in women with RPL. STUDY DESIGN: Prospective analysis of a consecutive cohort of women undergoing investigation for RPL in a tertiary referral centre over a seven year period (August 2014 -December 2021). Analysis was performed using descriptive statistics, chi-square models and logistic regression models adjusting for maternal age and previous livebirth. Exclusion criteria for the regression analysis included abnormal parental karyotype and abnormal pelvic ultrasound scan. Pregnancy outcome was defined as livebirth or further pregnancy loss. RESULTS: There were 488 women who underwent investigation of RPL during the study period. Of these, 65.2% (n = 318) conceived following attendance at the clinic. The majority of these women (69.4%, n = 221) proceeded to have a livebirth. There were no differences in median AMH levels between the livebirth group and the further pregnancy loss group (11 pmol/L vs 9 pmol/L respectively (p = 0.083). AMH did not affect clinical pregnancy rates (p = 0.77, 95% CI = 0.99 [0.98, 1.01]) or pregnancy outcome (p = 0.30, 95% CI = 1.01 [0.99, 1.04]). Abnormal pelvic ultrasonography (p = 0.04) and an abnormal parental karyotype (p = 0.04) were associated with an increased likelihood of a subsequent pregnancy loss. CONCLUSION: Although AMH levels may have some utility in counselling of some couples with RPL, these contemporaneous data indicate that low AMH does not negatively influence subsequent pregnancy outcome in women with recurrent pregnancy loss.

Stopping targeted therapy for complete responders in advanced BRAF mutant melanoma.

BRAF inhibitors revolutionised the management of melanoma patients and although resistance occurs, there is a subgroup of patients who maintain durable disease control. For those cases with durable complete response (CR) it is not clear whether it is safe to cease therapy. Here we identified 13 patients treated with BRAF +/- MEK inhibitors, who cease therapy after prolonged CR (median = 34 months, range 20-74). Recurrence was observed in 3/13 (23%) patients. In the remaining 10 patients with sustained CR off therapy, the median follow up after discontinuation was 19 months (range 8-36). We retrospectively measured ctDNA levels using droplet digital PCR (ddPCR) in longitudinal plasma samples. CtDNA levels were undetectable in 11/13 cases after cessation and remained undetectable in patients in CR (10/13). CtDNA eventually became detectable in 2/3 cases with disease recurrence, but remained undetectable in 1 patient with brain only progression. Our study suggests that consideration could be given to ceasing targeted therapy in the context of prolonged treatment, durable response and no evidence of residual disease as measured by ctDNA.

Improved calibration of the OMEGA gas Cherenkov detector.

Inertial fusion implosions are diagnosed using γ rays to characterize the implosion physics or measure basic nuclear properties, including cross sections. For the latter, previously reported measurements at laser facilities using gas Cherenkov detectors are limited by a large systematic uncertainty in the detector response. We present a novel in situ calibration technique using neutron inelastic scattering, which we apply to the new GCD-3 detector. The calibration accuracy is improved by ∼3× over the previous method.

Simultaneous measurement of the HT and DT fusion burn histories in inertial fusion implosions.

Measuring the thermonuclear burn history is an important way to diagnose inertial fusion implosions. Using the gas Cherenkov detectors at the OMEGA laser facility, we measure the HT fusion burn in a H2+T2 gas-fueled implosion for the first time. Using multiple detectors with varied Cherenkov thresholds, we demonstrate a technique for simultaneously measuring both the HT and DT burn histories from an implosion where the total reaction yields are comparable. This new technique will be used to study material mixing and kinetic phenomena in implosions.

Next generation gamma-ray Cherenkov detectors for the National Ignition Facility.

The newest generation of Gas Cherenkov Detector (GCD-3) employed in Inertial Confinement Fusion experiments at the Omega Laser Facility has provided improved performance over previous generations. Comparison of reaction histories measured using two different deuterium-tritium fusion products, namely gamma rays using GCD and neutrons using Neutron Temporal Diagnostic (NTD), have provided added credibility to both techniques. GCD-3 is now being brought to the National Ignition Facility (NIF) to supplement the existing Gamma Reaction History (GRH-6m) located 6 m from target chamber center (TCC). Initially it will be located in a reentrant well located 3.9 m from TCC. Data from GCD-3 will inform the design of a heavily-shielded "Super" GCD to be located as close as 20 cm from TCC. It will also provide a test-bed for faster optical detectors, potentially lowering the temporal resolution from the current ∼100 ps state-of-the-art photomultiplier tubes (PMT) to ∼10 ps Pulse Dilation PMT technology currently under development.

Aerogel Cherenkov detector for characterizing the intense flash x-ray source, Cygnus, spectrum.

An aerogel Cherenkov detector is proposed to measure the X-ray energy spectrum from the Cygnus-intense flash X-ray source operated at the Nevada National Security Site. An array of aerogels set at a variety of thresholds between 1 and 3 MeV will be adequate to map out the bremsstrahlung X-ray production of the Cygnus, where the maximum energy of the spectrum is normally around 2.5 MeV. In addition to the Cherenkov radiation from aerogels, one possible competing light-production mechanism is optical transition radiation (OTR), which may be significant in aerogels due to the large number of transitions from SiO2 clusters to vacuum voids. To examine whether OTR is a problem, four aerogel samples were tested using a mono-energetic electron beam (varied in the range of 1-3 MeV) at NSTec Los Alamos Operations. It was demonstrated that aerogels can be used as a Cherenkov medium, where the rate of the light production is about two orders magnitude higher when the electron beam energy is above threshold.

Cognitive outcomes of temporal lobe epilepsy surgery in older patients.

PURPOSE: To examine the cognitive risks of temporal lobe surgery in patients aged 50 years and older. METHODS: We analysed data from 55 patients who underwent temporal lobe surgery (26 left-sided:29 right sided) from 1988 to 2012 at our centre. Pre-surgical and one year post-operative memory and naming capacity were compared to data obtained from two younger cohorts; 185 aged 18-30 and 220 aged 31-49. RESULTS: Pre-operative memory impairments were most marked for the oldest cohort and were associated with a longer duration of epilepsy. Naming capacity improved with age and better performance was associated with a later age at epilepsy onset. Post-operative declines were largest in older patients, achieving statistical significance for verbal memory, naming and subjective ratings. Left temporal lobe resections carried the greatest risk of memory and naming decline. Cognitive outcomes were unrelated to seizure outcome, VIQ or mood. CONCLUSION: Our findings indicate the cognitive risks of TLE surgery are greater for older patients. Cognitive outcomes need to be considered when assessing the efficacy of epilepsy surgery in older cohorts and pre-operative performance levels need to be taken into account.

Neural stimulators: a guide to imaging and postoperative appearances.

Implantable neural stimulators have been developed to aid patients with debilitating neurological conditions that are not amenable to other therapies. The aim of this article is to improve understanding of correct anatomical placement as well as the relevant imaging methods used to assess these devices. Potential complications following their insertion and an overview of the current indications and potential mechanism of action of these devices is provided.

Monte Carlo validation experiments for the gas Cherenkov detectors at the National Ignition Facility and Omega.

The gas Cherenkov detectors at NIF and Omega measure several ICF burn characteristics by detecting multi-MeV nuclear γ emissions from the implosion. Of primary interest are γ bang-time (GBT) and burn width defined as the time between initial laser-plasma interaction and peak in the fusion reaction history and the FWHM of the reaction history respectively. To accurately calculate such parameters the collaboration relies on Monte Carlo codes, such as GEANT4 and ACCEPT, for diagnostic properties that cannot be measured directly. This paper describes a series of experiments performed at the High Intensity γ Source (HIγS) facility at Duke University to validate the geometries and material data used in the Monte Carlo simulations. Results published here show that model-driven parameters such as intensity and temporal response can be used with less than 50% uncertainty for all diagnostics and facilities.

The autophagy-associated factors DRAM1 and p62 regulate cell migration and invasion in glioblastoma stem cells.

The aggressiveness of glioblastoma multiforme (GBM) is defined by local invasion and resistance to therapy. Within established GBM, a subpopulation of tumor-initiating cells with stem-like properties (GBM stem cells, GSCs) is believed to underlie resistance to therapy. The metabolic pathway autophagy has been implicated in the regulation of survival in GBM. However, the status of autophagy in GBM and its role in the cancer stem cell fraction is currently unclear. We found that a number of autophagy regulators are highly expressed in GBM tumors carrying a mesenchymal signature, which defines aggressiveness and invasion, and are associated with components of the MAPK pathway. This autophagy signature included the autophagy-associated genes DRAM1 and SQSTM1, which encode a key regulator of selective autophagy, p62. High levels of DRAM1 were associated with shorter overall survival in GBM patients. In GSCs, DRAM1 and SQSTM1 expression correlated with activation of MAPK and expression of the mesenchymal marker c-MET. DRAM1 knockdown decreased p62 localization to autophagosomes and its autophagy-mediated degradation, thus suggesting a role for DRAM1 in p62-mediated autophagy. In contrast, autophagy induced by starvation or inhibition of mTOR/PI-3K was not affected by either DRAM1 or p62 downregulation. Functionally, DRAM1 and p62 regulate cell motility and invasion in GSCs. This was associated with alterations of energy metabolism, in particular reduced ATP and lactate levels. Taken together, these findings shed new light on the role of autophagy in GBM and reveal a novel function of the autophagy regulators DRAM1 and p62 in control of migration/invasion in cancer stem cells.

Simultaneous intracranial EEG-fMRI in humans: protocol considerations and data quality.

We have recently performed simultaneous intracranial EEG and fMRI recordings (icEEG-fMRI) in patients with epilepsy. In this technical note, we examine limited thermometric data for potential electrode heating during our protocol and found that heating was ≤0.1 °C in-vitro at least 10 fold less than in-vivo limits. We quantify EEG quality, which can be degraded by MRI scanner-induced artefacts, and fMRI image (gradient echo echo-planar imaging: GE-EPI) signal quality around the electrodes, which can be degraded by electrode interactions with B1 (radiofrequency) and B0 (static) magnetic fields. We recorded EEG outside and within the MRI scanner with and without scanning. EEG quality was largely preserved during scanning and in particular heartbeat-related artefacts were small compared to epileptic events. To assess the GE-EPI signal reduction around the electrodes, we compared image signal intensity along paths into the brain normal to its surface originating from the individual platinum-iridium electrode contacts. GE-EPI images were obtained at 1.5 T with an echo time (TE) of 40 ms and repetition time (TR) of 3000 ms and a slice thickness of 2.5 mm. We found that GE-EPI signal intensity reduction was confined to a 10 mm radius and that it was reduced on average by less than 50% at 5mm from the electrode contacts. The GE-EPI image signal reduction also varied with electrode orientation relative to the MRI scanner axes; in particular, cortical grid contacts with a normal along the scanner's main magnetic field (B(0)) axis have higher artefact levels relative to those with a normal perpendicular to the z-axis. This suggests that the artefacts were predominantly susceptibility-related rather than due to B1 interactions. This information can be used to guide interpretation of results of icEEG-fMRI experiments proximal to the electrodes, and to optimise artefact reduction strategies.

Development and characterization of sub-100 ps photomultiplier tubes.

We describe the evaluation of a microchannel plate (MCP) photomultiplier tube (PMT), incorporating a 3 µm pore MCP and constant voltage anode and cathode gaps. The use of the small pore size results in PMTs with response functions of the order of 85 ps full-width-half-maximum, while the constant electric field across the anode and cathode gaps produces a uniform response function over the entire operating range of the device. The PMT was characterized on a number of facilities and employed on gas Cherenkov detectors fielded on various deuterium tritium fuel (DT) implosions on the Omega Laser Facility at the University of Rochester. The Cherenkov detectors are part of diagnostic development to measure Gamma ray reaction history for DT implosions on the National Ignition Facility.

Gamma bang time analysis at OMEGA.

Absolute bang time measurements with the gas Cherenkov detector (GCD) and gamma reaction history (GRH) diagnostic have been performed to high precision at the OMEGA laser facility at the University of Rochester with bang time values for the two diagnostics agreeing to within 5 ps on average. X-ray timing measurements of laser-target coupling were used to calibrate a facility-generated laser timing fiducial with rms spreads in the measured coupling times of 9 ps for both GCD and GRH. Increased fusion yields at the National Ignition Facility (NIF) will allow for improved measurement precision with the GRH easily exceeding NIF system design requirements.

GEANT4 simulations of Cherenkov reaction history diagnostics.

This paper compares the results from a GEANT4 simulation of the gas Cherenkov detector 1 (GCD1) with previous simulations and experimental data from the Omega laser facility. The GCD1 collects gammas emitted during a deuterium-tritium capsule implosion and converts them, through several processes, to Cherenkov light. Photon signals are recorded using subnanosecond photomultiplier tubes, producing burn reaction histories. The GEANT4 GCD1 simulation is first benchmarked against ACCEPT, an integrated tiger series code, with good agreement. The simulation is subsequently compared with data from the Omega laser facility, where experiments have been performed to measure the effects of Hohlraum materials on reaction history signals, in preparation for experiments at the National Ignition Facility.

Diagnosing inertial confinement fusion gamma ray physics (invited).

The gamma reaction history (GRH) diagnostic is a multichannel, time-resolved, energy-thresholded γ-ray spectrometer that provides a high-bandwidth, direct-measurement of fusion reaction history in inertial confinement fusion implosion experiments. 16.75 MeV deuterium+tritium (DT) fusion γ-rays, with a branching ratio of the order of 10(-5)γ/(14 MeV n), are detected to determine fundamental burn parameters, such as nuclear bang time and burn width, critical to achieving ignition at the National Ignition Facility. During the tritium/hydrogen/deuterium ignition tuning campaign, an additional γ-ray line at 19.8 MeV, produced by hydrogen+tritium fusion with a branching ratio of unity, will increase the available γ-ray signal and may allow measurement of reacting fuel composition or ion temperature. Ablator areal density measurements with the GRH are also made possible by detection of 4.43 MeV γ-rays produced by inelastic scatter of DT fusion neutrons on (12)C nuclei in the ablating plastic capsule material.

Imaging haemodynamic changes related to seizures: comparison of EEG-based general linear model, independent component analysis of fMRI and intracranial EEG.

BACKGROUND: Simultaneous EEG-fMRI can reveal haemodynamic changes associated with epileptic activity which may contribute to understanding seizure onset and propagation. METHODS: Nine of 83 patients with focal epilepsy undergoing pre-surgical evaluation had seizures during EEG-fMRI and analysed using three approaches, two based on the general linear model (GLM) and one using independent component analysis (ICA): The results were compared with intracranial EEG. RESULTS: The canonical GLM analysis revealed significant BOLD signal changes associated with seizures on EEG in 7/9 patients, concordant with the seizure onset zone in 4/7. The Fourier GLM analysis revealed changes in BOLD signal corresponding with the results of the canonical analysis in two patients. ICA revealed components spatially concordant with the seizure onset zone in all patients (8/9 confirmed by intracranial EEG). CONCLUSION: Ictal EEG-fMRI visualises plausible seizure related haemodynamic changes. The GLM approach to analysing EEG-fMRI data reveals localised BOLD changes concordant with the ictal onset zone when scalp EEG reflects seizure onset. ICA provides additional information when scalp EEG does not accurately reflect seizures and may give insight into ictal haemodynamics.

Premature mortality in refractory partial epilepsy: does surgical treatment make a difference?

BACKGROUND: Epilepsy carries an increased risk of premature death. For some people with intractable focal epilepsy, surgery offers hope for a seizure-free life. The authors aimed to see whether epilepsy surgery influenced mortality in people with intractable epilepsy. METHODS: The authors audited survival status in two cohorts (those who had surgery and those who had presurgical assessment but did not have surgery). RESULTS: There were 40 known deaths in the non-surgical group (3365 person years of follow-up) and 19 in the surgical group (3905 person-years of follow-up). Non-operated patients were 2.4 times (95% CI 1.4 to 4.2) as likely to die as those who had surgery. They were 4.5 times (95% CI 1.9 to 10.9) as likely to die a probable epilepsy-related death. In the surgical group, those with ongoing seizures 1 year after surgery were 4.0 (95% CI 1.2 to 13.7) times as likely to die as those who were seizure-free or who had only simple partial seizures. Time-dependent Cox analysis showed that the yearly outcome group did not significantly affect mortality (HR 1.3, 95% CI 0.9 to 1.8). CONCLUSION: Successful epilepsy surgery was associated with a reduced risk of premature mortality, compared with those with refractory focal epilepsy who did not have surgical treatment. To some extent, the reduced mortality is likely to be conferred by inducing freedom from seizures. It is not certain whether better survival is attributable only to surgery, as treatment decisions were not randomised, and there may be inherent differences between the groups.

Defining Meyer's loop-temporal lobe resections, visual field deficits and diffusion tensor tractography.

Anterior temporal lobe resection is often complicated by superior quadrantic visual field deficits (VFDs). In some cases this can be severe enough to prohibit driving, even if a patient is free of seizures. These deficits are caused by damage to Meyer's loop of the optic radiation, which shows considerable heterogeneity in its anterior extent. This structure cannot be distinguished using clinical magnetic resonance imaging sequences. Diffusion tensor tractography is an advanced magnetic resonance imaging technique that enables the parcellation of white matter. Using seed voxels antero-lateral to the lateral geniculate nucleus, we applied this technique to 20 control subjects, and 21 postoperative patients. All patients had visual fields assessed with Goldmann perimetry at least three months after surgery. We measured the distance from the tip of Meyer's loop to the temporal pole and horn in all subjects. In addition, we measured the size of temporal lobe resection using postoperative T(1)-weighted images, and quantified VFDs. Nine patients suffered VFDs ranging from 22% to 87% of the contralateral superior quadrant. In patients, the range of distance from the tip of Meyer's loop to the temporal pole was 24-43 mm (mean 34 mm), and the range of distance from the tip of Meyer's loop to the temporal horn was -15 to +9 mm (mean 0 mm). In controls the range of distance from the tip of Meyer's loop to the temporal pole was 24-47 mm (mean 35 mm), and the range of distance from the tip of Meyer's loop to the temporal horn was -11 to +9 mm (mean 0 mm). Both quantitative and qualitative results were in accord with recent dissections of cadaveric brains, and analysis of postoperative VFDs and resection volumes. By applying a linear regression analysis we showed that both distance from the tip of Meyer's loop to the temporal pole and the size of resection were significant predictors of the postoperative VFDs. We conclude that there is considerable variation in the anterior extent of Meyer's loop. In view of this, diffusion tensor tractography of the optic radiation is a potentially useful method to assess an individual patient's risk of postoperative VFDs following anterior temporal lobe resection.

The spatio-temporal mapping of epileptic networks: combination of EEG-fMRI and EEG source imaging.

Simultaneous EEG-fMRI acquisitions in patients with epilepsy often reveal distributed patterns of Blood Oxygen Level Dependant (BOLD) change correlated with epileptiform discharges. We investigated if electrical source imaging (ESI) performed on the interictal epileptiform discharges (IED) acquired during fMRI acquisition could be used to study the dynamics of the networks identified by the BOLD effect, thereby avoiding the limitations of combining results from separate recordings. Nine selected patients (13 IED types identified) with focal epilepsy underwent EEG-fMRI. Statistical analysis was performed using SPM5 to create BOLD maps. ESI was performed on the IED recorded during fMRI acquisition using a realistic head model (SMAC) and a distributed linear inverse solution (LAURA). ESI could not be performed in one case. In 10/12 remaining studies, ESI at IED onset (ESIo) was anatomically close to one BOLD cluster. Interestingly, ESIo was closest to the positive BOLD cluster with maximal statistical significance in only 4/12 cases and closest to negative BOLD responses in 4/12 cases. Very small BOLD clusters could also have clinical relevance in some cases. ESI at later time frame (ESIp) showed propagation to remote sources co-localised with other BOLD clusters in half of cases. In concordant cases, the distance between maxima of ESI and the closest EEG-fMRI cluster was less than 33 mm, in agreement with previous studies. We conclude that simultaneous ESI and EEG-fMRI analysis may be able to distinguish areas of BOLD response related to initiation of IED from propagation areas. This combination provides new opportunities for investigating epileptic networks.

Balloon cells associated with granule cell dispersion in the dentate gyrus in hippocampal sclerosis.

Granule cell dispersion (GCD) is a common finding in hippocampal sclerosis in patients with intractable focal epilepsy. It is considered to be an acquired, post-developmental rather than a pre-existing abnormality, involving dispersion of either mature or newborn neurones, but the precise factors regulating it and its relationship to seizures are unknown. We present two cases of GCD with associated CD34-immunopositive balloon cells, a cell phenotype associated with focal cortical dysplasia type IIB, considered to be a developmental cortical lesion promoting epilepsy. This observation opens up the debate regarding the origin of balloon cells and CD34 expression and their temporal relationship to seizures.