Perinatal and neonatal outcomes of high-risk asymptomatic women from a specialist preterm birth surveillance clinic.

OBJECTIVES: To report the perinatal outcomes of high-risk asymptomatic women who attended a specialist preterm surveillance clinic (PSC) to undergo screening for spontaneous preterm birth (PTB) in Ireland. METHODS: Single center, retrospective cohort study of asymptomatic high risk women who attended the PSC between January 2019 and December 2022. A comprehensive database of all patients who attended the clinic during the study period was constructed and analyzed. Overall outcomes were reported, and stratified per the occurrence of preterm or term birth. Iatrogenic PTBs were included in the outcome data. RESULTS: Following exclusions for loss-to-follow-up, 762 cases were analyzed, constituting 2262 PSC visits. Of those, 183 women were prescribed progesterone (24.0 %), and 100 women underwent cervical cerclage (13.1 %) to prevent spontaneous PTB. Overall, 2.4 %, 6.2 % and 18.6 % of participants gave birth prior to 30 weeks, 34 weeks, and 37 weeks, respectively. The median gestational age at birth for the entire cohort was 38.6 weeks (inter-quartile range (IQR) 37.2-39.6 weeks). Women who delivered < 37 weeks were significantly more likely to be smokers (p = 0.030), have a previous spontaneous PTB (p = 0.016), have multiple pregnancies (p < 0.001), type 1 or 2 diabetes (p = 0.044), or have a previous full dilatation caesarean section birth (p = 0.024). Infants born prior to 37 weeks were more likely to have a lower median birthweight (2270 vs 3300 g, p < 0.001), be admitted to a neonatal intensive care unit (53.8 % vs 2.3 %, p < 0.001) or experience short-term morbidity, including respiratory support (38.0 % vs 1.6 %, p < 0.001). CONCLUSIONS: Over 80% of women deemed to be at high risk of PTB gave birth at term gestations following attendance at a PSC during pregnancy. Most women can be successfully managed without interventions, instead employing a policy of serial cervical surveillance, to identify those at greatest risk of PTB.

Performance of QUiPP App v.2 tool for prediction of preterm birth in asymptomatic high-risk women attending preterm specialist clinic: external validation study.

OBJECTIVE: To validate externally the QUiPP App v.2 algorithms in an independent cohort of high-risk asymptomatic women attending a preterm birth (PTB) surveillance clinic in Ireland. METHODS: This was a retrospective, single-center, observational study assessing discrimination and calibration of the QUiPP App v.2 at six predetermined clinical timepoints (PTB at < 30, < 34 and < 37 weeks of pregnancy and PTB within 1, 2 and 4 weeks of testing). Discrimination was assessed by estimating the area under the receiver-operating-characteristics curve (AUC) and sensitivity at fixed false-positive rates of 5%, 10% and 20%. Model calibration was assessed to evaluate the concordance between expected and observed outcomes. P-values < 0.05 were considered statistically significant. No adjustments for treatment effects were made. RESULTS: Overall, 762 women with 1660 PTB surveillance clinic visits using the QUiPP App v.2 between 2019 and 2022 were analyzed. The study population included 142 (18.6%) patients who later experienced PTB. The QuiPP App's performance in the prediction of short-term outcomes, such as birth within 1 week (AUC, 0.866 (95% CI, 0.755-0.955)), 2 weeks (AUC, 0.721 (95% CI, 0.569-0.854)) and 4 weeks (AUC, 0.775 (95% CI, 0.699-0.842)), and delivery at < 30 weeks (AUC, 0.747 (95% CI, 0.613-0.865)), was superior to its ability to predict longer-term outcomes (PTB at < 37 weeks: AUC, 0.631 (95% CI, 0.596-0.668)). Calibration was generally good for low-risk results, as the predicted risk in these patients tended to match the observed incidence. However, in women deemed to be at greater risk of PTB, the predicted probability superseded the observed incidence of PTB. CONCLUSIONS: The QUiPP App v.2 accurately discriminates women who are at short-term risk of PTB. A 'treatment paradox' may influence calibration in high-risk women. Further research is needed to ascertain if QuiPP treatment thresholds can be safely adjusted in women receiving prophylactic treatment to prevent PTB, and whether this improves the outcome. © 2024 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

A cross-sectional survey of women's views and preferences for preterm birth screening and treatment.

OBJECTIVES: Primary outcomes were to determine; 1) the desire for more patient information from healthcare professionals on preterm birth (PTB) prevention 2) the desire for PTB screening surveillance or participation in research or 3) the acceptability of transvaginal ultrasound (TVUS) or vaginal examinations to predict spontaneous PTB. METHODS: A 19-question, piloted, self-administered survey was completed by unselected pregnant women in a tertiary maternity hospital in Dublin, Ireland. Data was collected to include maternal socio-demographics, past obstetric history, and current pregnancy details, in addition to views and preferences on PTB screening and preventative treatments. Statistical analysis to include binary and multinomial regression was performed by IBM SPSS Statistics for Windows (Version 29.0). RESULTS: 277 women completed the study survey. 9.4% of women had attended the preterm birth surveillance clinic (PSC). 75.1% of respondents indicated a preference for more information from healthcare professionals about PTB. 65% reported that TVUS and vaginal examinations were acceptable in pregnancy. The acceptability of antenatal examinations was significantly influenced by ethnicity; white European (OR 2.58, CI 1.12-5.95, p = 0.003) and Asian (OR 3.39, CI 1.18-9.67, p = 0.02). Discomfort (25.3%) and vaginal bleeding (11.9%) were the most frequently reported concerns about TVUS. 95.7% of unselected women indicated that they would accept treatment to prevent PTB. Vaginal progesterone (53.8%) was preferred treatment compared to cervical cerclage (15.9%) or cervical pessary (16.6%). 55.6% of respondents stated they attend or wish to attend for additional appointments or research opportunities for PTB screening. Women with a previous PTB or second trimester miscarriage were more likely to attend or wish to attend for PTB screening (OR 3.23, CI 1.34-7.79, p = 0.009). CONCLUSION: PTB is an important healthcare priority for pregnant women in Ireland. However, women require more information, counselling and reassurance about the utility and safety of TVUS in PSCs.

In Silico Discovery and Validation of Neuropeptide-Y-Binding Peptides for Sensors.

Wearable sensors for human health, performance, and state monitoring, which have a linear response to the binding of biomarkers found in sweat, saliva, or urine, are of current interest for many applications. A critical part of any device is a biological recognition element (BRE) that is able to bind a biomarker at the surface of a sensor with a high affinity and selectivity to produce a measurable signal response. In this study, we discover and compare 12-mer peptides that bind to neuropeptide Y (NPY), a stress and human health biomarker, using independent and complimentary experimental and computational approaches. The affinities of the NPY-binding peptides discovered by both methods are equivalent and below the micromolar level, which makes them suitable for application in sensors. The in silico design protocol for peptide-based BREs is low cost, highly efficient, and simple, suggesting its utility for discovering peptide binders to a variety of biomarker targets.

Proton beam behavior in a parallel configured MRI-proton therapy hybrid: Effects of time-varying gradient magnetic fields.

PURPOSE: Real-time magnetic resonance (MR) guidance is of interest to various groups globally because the superior soft tissue contrast MR images offer over other x-ray-based imaging modalities. Because of the precision required in proton therapy, proton therapy treatments rely heavily on image guidance. Integrating a magnetic resonance imaging (MRI) into a proton therapy treatment is a challenge. The charged particles (protons) used in proton therapy experience magnetic forces when travelling through the MRI magnetic fields. Given that it is desired that proton beams can be delivered with submillimeter accuracy, it is important that all potential sources of beam displacement are well modeled and understood. This study investigated the behavior of monoenergetic proton beams in the presence of a simulated set of realistic three-dimensional (3D) vector magnetic gradient fields required for spatial localization during imaging. This deflecting source has not been previously investigated. METHODS: Three-dimensional magnetic vector fields from a superconducting 0.5 T open bore MRI magnet model (previously developed in-house) and 3D magnetic fields from an in-house gradient coil model were applied to two types of computer simulations. In all simulations, monoenergetic proton pencil beams (from 80 to 250 MeV) were used. The initial directions of proton beams were varied. In all simulations, the orientation of the B0 field coincided with the positive z-axis in the simulation geometry. The first type of simulation is based on an analytic magnetic force equation (analytic simulations) while the second type is a full Monte Carlo (MC) simulation. The analytic simulations were limited to propagating the proton beams in vacuum but could be rapidly calculated in a desktop computer while the MC simulations were calculated in a cluster computer. The proton beam locations and dose profiles at the central plane (z = 0 cm) with or without magnetic fields were extracted and used to quantify the effect of the presence of the different magnetic fields on the proton beam. RESULTS: The analytic simulations agree with MC results within 0.025 mm, thus acting as the verification of MC calculations. The presence of the B0 field caused the beam to follow a helical trajectory which resulted in angular offsets of 4.9o , 3.6o , and 2.8o for the 80, 150, and 250 MeV, respectively. Magnetic field deflections caused by a rapid MRI sequence (bSSFP, with maximum gradient strength of 40 mT/m) show a pattern of distortion which remained spatially invariant in the MR's field of view. For the 80 MeV beam, this pattern shows a maximum ranged in the y direction of 1.5 mm. The presence of the B0 field during the bSSFP simulations adds the same beam rotation to the observed during the B0 only simulations. CONCLUSION: This investigation reveals that time-varying gradient magnetic fields required for image generation can cause a small spread in the proton beams used in the study which are independent of the effects arising from the B0 field. Further, studies where clinical beam kernels were convolved with this spread show that these magnetic fields are expected to have an insignificant impact on the beam's entrance dose.

Minimal skin dose increase in longitudinal rotating biplanar linac-MR systems: examination of radiation energy and flattening filter design.

The magnetic fields of linac-MR systems modify the path of contaminant electrons in photon beams, which alters patient entrance skin dose. Also, the increased SSD of linac-MR systems reduces the maximum achievable dose rate. To accurately quantify the changes in entrance skin dose, the authors use EGSnrc Monte Carlo calculations that incorporate 3D magnetic field of the Alberta 0.5 T longitudinal linac-MR system. The Varian 600C linac head geometry assembled on the MRI components is used in the BEAMnrc simulations for 6 MV and 10 MV beam models and skin doses are calculated at an average depth of 70 µm using DOSXYZnrc. 3D modeling shows that magnetic fringe fields decay rapidly and are small at the linac head. SSDs between 100 and 120 cm result in skin-dose increases of between ~6%-19% and ~1%-9% for the 6 and 10 MV beams, respectively. For 6 MV, skin dose increases from ~10.5% to ~1.5% for field-size increases of 5 × 5 cm(2) to 20 × 20 cm(2). For 10 MV, skin dose increases by ~6% for a 5 × 5 cm(2) field, and decreases by ~1.5% for a 20 × 20 cm(2) field. Furthermore, the proposed reshaped flattening filter increases the dose rate from the current 355 MU min(-1) to 529 MU min(-1) (6 MV) or 604 MU min(-1) (10 MV), while the skin-dose increases by only an additional ~2.6% (all percent increases in skin dose are relative to D max). This study suggests that there is minimal increase in the entrance skin dose and minimal/no decrease in the dose rate of the Alberta longitudinal linac-MR system. The even lower skin dose increase at 10 MV offers further advantages in future designs of linac-MR prototypes.

Heritability of naevus patterns in an adult twin cohort from the Brisbane Twin Registry: a cross-sectional study.

BACKGROUND: Heritability of naevi counts is widely acknowledged as a potential surveillance parameter for prevention purposes. The contribution of heritability to the changes seen in naevus number and morphology over time and their corresponding dermoscopic characteristics is unknown, but is important to understand in order to account for adequate prevention measures. OBJECTIVES: To identify naevus characteristics that are strongly influenced by heritability. METHODS: This cross-sectional study included 220 individuals [76 monozygotic (MZ), 144 dizygotic (DZ)], recruited from the Brisbane Twin Naevus Study. Participants received full body imaging and dermoscopy of naevi ≥ 5 mm in diameter. Dermoscopic type, total naevus count (TNC), change in TNC with age, and naevus distribution, size, colour and profile were compared between MZ and DZ twins. Heritability of these traits was assessed via Falconer's estimate. RESULTS: Significant differences were found in comparing MZ and DZ twins for TNC, numbers of naevi 5·0-7·9 mm in diameter, counts of light-brown naevi, naevi on the back and sun-protected sites, and naevi with the 'nonspecific' dermoscopic pattern. CONCLUSIONS: This study strongly supports a heritable component to TNC, as well as changes in TNC, and the number of medium-sized naevi, light-brown naevi, specific sites and certain dermoscopic features in adults. These characteristics should be taken into account by naevus surveillance programmes and further studied to identify candidate gene associations for clinical and dermoscopic patterns in conjunction with melanoma risk stratification.

Skin dose in longitudinal and transverse linac-MRIs using Monte Carlo and realistic 3D MRI field models.

PURPOSE: The magnetic fields of linac-MR systems modify the path of contaminant electrons in photon beams, which alters patient skin dose. To accurately quantify the magnitude of changes in skin dose, the authors use Monte Carlo calculations that incorporate realistic 3D magnetic field models of longitudinal and transverse linac-MR systems. METHODS: Finite element method (FEM) is used to generate complete 3D magnetic field maps for 0.56 T longitudinal and transverse linac-MR magnet assemblies, as well as for representative 0.5 and 1.0 T Helmholtz MRI systems. EGSnrc simulations implementing these 3D magnetic fields are performed. The geometry for the BEAMnrc simulations incorporates the Varian 600C 6 MV linac, magnet poles, the yoke, and the magnetic shields of the linac-MRIs. Resulting phase-space files are used to calculate the central axis percent depth-doses in a water phantom and 2D skin dose distributions for 70 µm entrance and exit layers using DOSXYZnrc. For comparison, skin doses are also calculated in the absence of magnetic field, and using a 1D magnetic field with an unrealistically large fringe field. The effects of photon field size, air gap (longitudinal configuration), and angle of obliquity (transverse configuration) are also investigated. RESULTS: Realistic modeling of the 3D magnetic fields shows that fringe fields decay rapidly and have a very small magnitude at the linac head. As a result, longitudinal linac-MR systems mostly confine contaminant electrons that are generated in the air gap and have an insignificant effect on electrons produced further upstream. The increase in the skin dose for the longitudinal configuration compared to the zero B-field case varies from ∼1% to ∼14% for air gaps of 5-31 cm, respectively. (All dose changes are reported as a % of D(max).) The increase is also field-size dependent, ranging from ∼3% at 20 × 20 cm(2) to ∼11% at 5 × 5 cm(2). The small changes in skin dose are in contrast to significant increases that are calculated for the unrealistic 1D magnetic field. For the transverse configuration, the entrance skin dose is equal or smaller than that of the zero B-field case for perpendicular beams. For a 10 × 10 cm(2) oblique beam the transverse magnetic field decreases the entry skin dose for oblique angles less than ±20° and increases it by no more than 10% for larger angles up to ±45°. The exit skin dose is increased by 42% for a 10 × 10 cm(2) perpendicular beam, but appreciably drops and approaches the zero B-field case for large oblique angles of incidence. CONCLUSIONS: For longitudinal linac-MR systems only a small increase in the entrance skin dose is predicted, due to the rapid decay of the realistic magnetic fringe fields. For transverse linac-MR systems, changes to the entrance skin dose are small for most scenarios. For the same geometry, on the exit side a fairly large increase is observed for perpendicular beams, but significantly drops for large oblique angles of incidence. The observed effects on skin dose are not expected to limit the application of linac-MR systems in either the longitudinal or transverse configuration.

WE-E-BRB-06: Monte Carlo Calculations of the Skin Dose for Longitudinal Linac-MR System Using Realistic Three-Dimensional Magnetic Field Modeling.

PURPOSE: This study quantifies the effects of the magnetic field of a longitudinal linac-MR system (B-field parallel to beam direction) on skin dose due to the confinement of contaminant electrons, using Monte Carlo calculations and realistic 3-D models of the magnetic field. METHODS: The complete realistic 3-D magnetic fields generated by the bi-planar Linac-MR magnet assembly are calculated with the finite element method using Opera- 3D. EGSnrc simulations are performed in the presence of ∼0.6T and IT MRI fields that have realistic rapid fall-off of the fringe field. The simulation geometry includes a Varian 600C 6MV linac, the yoke and magnetic shields of the MRIs, and features an isocentre distance of 126 cm. Phase spaces at the surface of a water phantom are scored using BEAMnrc; DOSXYZnrc is used to score the resulting CAX percent depth-doses in the phantom and the 2D skin dose distributions in the first 70 urn layer. For comparison, skin doses are also calculated in the absence of magnetic field and using a 1-D magnetic field with an unrealistic fringe field. The effects of field size and air gap (between phantom surface and magnet pole) are also examined. RESULTS: Analysis of the phase-space and dose distributions reveals that significant containment of electrons occurs primarily close to the uniform magnetic field region. The increase in skin dose due to the magnetic field depends on the air gap, varying from 1% to 13% for air gaps of 5 to 31 cm, respectively. The increase is also field-size dependent, varying from 3% at 20×20 cm2 to 11% at 5×5 cm2. CONCLUSIONS: Calculations based on various realistic MRI 3D magnetic-field maps that appropriately account for the rapid decay of the fringe field show that the increase in the patient skin dose of a longitudinal Linac-MR system is clinically insignificant.

Using albumin to improve the therapeutic properties of diabetes treatments.

Achieving tight glycaemic control remains an unmet need for many patients with type 2 diabetes, despite improved treatments. To meet glycaemic targets, attempts have been made to improve existing drugs and to develop new classes of drugs. Recent advances include insulin analogues that more closely mimic physiologic insulin levels, and incretin-based therapies, which capitalize on the glucoregulatory properties of native glucagon-like peptide-1 (GLP-1). Although promising, these agents are associated with limitations, including hypoglycaemia with insulin, gastrointestinal adverse events with GLP-1 receptor agonists and frequent dosing with both classes. Albumin is an abundant natural drug carrier that has been used to improve the half-life, tolerability and efficacy of a number of bioactive agents. Here, we review the physiologic roles of albumin and how albumin technologies are being used to prolong duration of action of therapies for diabetes, including insulin and incretin-based therapies.

Maternal gene expression profiling during pregnancy and preeclampsia in human peripheral blood mononuclear cells.

UNLABELLED: Preeclampsia is a major obstetrical complication affecting maternal and fetal health. While it is clear that there is a substantial placental contribution to preeclampsia pathogenesis, the maternal contribution is less well characterized. We therefore performed a genome-wide transcriptome analysis to explore disease-associated changes in maternal gene expression patterns in peripheral blood mononuclear cells (PBMCs). METHODS: Preeclampsia was defined as gestational hypertension, proteinuria and hyperurecimia. Total RNA was isolated from PBMCs obtained from women with uncomplicated pregnancies (n = 5) and women with preeclamptic pregnancies (n = 5). Gene expression analysis was carried out using Agilent oligonucleotide microarrays. Biological pathway analysis was undertaken using Ingenuity Pathway Analysis software. Quantitative real-time PCR (QRTPCR) was performed to validate the gene expression changes of selected genes in normotensive and preeclamptic patients (n = 12 each). RESULTS: We identified a total of 368 genes that were differentially expressed in women with preeclampsia compared to normal controls with false discovery rate (FDR) controlled at 10%. In follow up experiments we further analyzed the expression levels of a number of genes that were identified as altered by the microarray data including survivin (BIRC5), caveolin (CAV1), GATA binding protein-1 (GATA1), signal tranducer and activator of transcription 1 (STAT1), E2F transcription factor-1 (E2F1), fibronectin-1 (FN1), interleukin-4 (IL-4), matrix metalloprotease-9 (MMP-9) and WAP four disulfide domain protein (WFDC-1) by QRTPCR. Additionally we performed immuno blot analysis and zymography to verify some of these candidate genes at the protein level. Computational analysis of gene function identified an anti-proliferative and altered immune function cellular phenotype in severe preeclamptic samples. CONCLUSIONS: We have characterized the genome-wide mRNA expression changes associated with preeclampsia-specific genes in circulating maternal blood cells at the time of delivery. In addition to providing information relating to the biological basis of the preeclampsia phenotype, our data provide a number of potential biomarkers for use in the further characterization of this disease.

Altered expression and coregulation of dopamine signalling genes in schizophrenia and bipolar disorder.

INTRODUCTION: signalling through dopamine receptors is of critical importance in the brain and is implicated in schizophrenia and bipolar disorder, but its underlying molecular mechanisms remain poorly understood. MATERIALS AND METHODS: using a yeast two-hybrid approach, we previously identified 11 novel dopamine receptor-interacting proteins. Here we compare gene expression levels for 17 genes [including all 11 dopamine receptor interacting proteins, all 5 dopamine receptors (DRD1-DRD5) and DARPP-32] by real-time polymerase chain reaction, using prefrontal cortex post mortem brain samples from 33 schizophrenic, 32 bipolar disorder and 34 control subjects. RESULTS: the expression of C14ORF28, GNB2L1, MLLT3, DRD2 and DARPP-32 genes was altered in schizophrenia and/or bipolar disorder samples relative to controls (P < 0.05). Hierarchical clustering analysis revealed the expression of these five genes (C14ORF28, GNB2L1, MLLT3, DARPP-32, DRD2) is closely correlated in patients. However, in controls, DRD2 expression in relation to the other genes appears to be very different, suggesting abnormal DRD2 activity is an important trigger in the pathophysiology of schizophrenia and bipolar disorder. CONCLUSIONS: our data suggest: (i) C14ORF28, GNB2L1, MLLT3, DRD2 and DARPP-32 are important in the pathogenesis of schizophrenia and bipolar disorder; (ii) these two disorders share common disease-related mechanisms linked to dopamine signalling; (iii) the expression of these genes is closely correlated; and (iv) DRD2 provides the initial trigger in the pathogenesis of these disorders.

BCR-ABL: a multi-faceted promoter of DNA mutation in chronic myelogeneous leukemia.

The role of the BCR-ABL oncogene in the progression of chronic myeloid leukemia (CML) to blast crisis (BC) is unknown. The appearance of chromosomal aberrations in patients with CML BC has led to many attempts to elucidate a mechanism whereby BCR-ABL affects DNA damage and repair. BCR-ABL-expressing cells have been found to accumulate genetic abnormalities, but the mechanism leading to this genomic instability is controversial. In this study, we review the effects of BCR-ABL on DNA repair mechanisms, centrosomes, checkpoint activation and apoptosis. BCR-ABL has diverse effects on these mechanisms, but which of these effects are necessary for the progression of CML to BC is still unresolved.

Radiation induced currents in MRI RF coils: application to linac/MRI integration.

The integration of medical linear accelerators (linac) with magnetic resonance imaging (MRI) systems is advancing the current state of image-guided radiotherapy. The MRI in these integrated units will provide real-time, accurate tumor locations for radiotherapy treatment, thus decreasing geometric margins around tumors and reducing normal tissue damage. In the real-time operation of these integrated systems, the radiofrequency (RF) coils of MRI will be irradiated with radiation pulses from the linac. The effect of pulsed radiation on MRI radio frequency (RF) coils is not known and must be studied. The instantaneous radiation induced current (RIC) in two different MRI RF coils were measured and presented. The frequency spectra of the induced currents were calculated. Some basic characterization of the RIC was also done: isolation of the RF coil component responsible for RIC, dependence of RIC on dose rate, and effect of wax buildup placed on coil on RIC. Both the time and frequency characteristics of the RIC were seen to vary with the MRI RF coil used. The copper windings of the RF coils were isolated as the main source of RIC. A linear dependence on dose rate was seen. The RIC was decreased with wax buildup, suggesting an electronic disequilibrium as the cause of RIC. This study shows a measurable RIC present in MRI RF coils. This unwanted current could be possibly detrimental to the signal to noise ratio in MRI and produce image artifacts.

Radio frequency shielding for a linac-MRI system.

The real-time operation of a linac-MRI system will require proper radio frequency (RF) shielding such that the MRI images can be acquired without extraneous RF noise from the linac. We report on the steps taken to successfully shield the linac from the MRI such that the two devices can operate independently of one another. RF power density levels are reported internally and externally to the RF cage which houses the linac and MRI. The shielding effectiveness of the RF cage has been measured in the frequency range 1-50 MHz and is presented. Lastly MRI images of two phantoms are presented during linac operation. This work illustrates that the accelerating structure of a linac and an MRI can be housed within the same RF cage. The 6 MV linac can be operated to produce radiation with no measurable degradation in image quality due to RF effects.

Radio frequency noise from an MLC: a feasibility study of the use of an MLC for linac-MR systems.

Currently several groups are actively researching the integration of a megavoltage teletherapy unit with magnetic resonance (MR) imaging for real-time image-guided radiotherapy. The use of a multileaf collimator (MLC) for intensity-modulated radiotherapy for linac-MR units must be investigated. The MLC itself will likely reside in the fringe field of the MR and the motors will produce radio frequency (RF) noise. The RF noise power spectral density from a Varian 52-leaf MLC motor, a Varian Millennium MLC motor and a brushless fan motor has been measured as a function of the applied magnetic field using a near field probe set. For the Varian 52-leaf MLC system, the RF noise produced by 13 of 52 motors is studied as a function of distance from the MLC. Data are reported in the frequency range suitable for 0.2-1.5 T linac-MR systems. Below 40 MHz the Millennium MLC motor tested showed more noise than the Varian 52-leaf motor or the brushless fan motor. The brushless motor showed a small dependence on the applied magnetic field. Images of a phantom were taken by the prototype linac-MR system with the MLC placed in close proximity to the magnet. Several orientations of the MLC in both shielded and non-shielded configurations were studied. For the case of a non-shielded MLC and associated cables, the signal-to-noise ratio (SNR) was reduced when 13 of 52 MLC leaves were moved during imaging. When the MLC and associated cables were shielded, the measured SNR of the images with 13 MLC leaves moving was experimentally the same as the SNR of the stationary MLC image. When the MLC and cables are shielded, subtraction images acquired with and without MLC motion contains no systematic signal. This study illustrates that the small RF noise produced by functioning MLC motors can be effectively shielded to avoid SNR degradation. A functioning MLC can be incorporated into a linac-MR unit.

Radio frequency noise from clinical linear accelerators.

There is a great deal of interest in image-guided radiotherapy (IGRT), and to advance the state of IGRT, an integrated linear accelerator-magnetic resonance (linac-MR) system has been proposed. Knowledge of the radiofrequency (RF) emissions near a linac is important for the design of appropriate RF shielding to facilitate the successful integration of these two devices. The frequency spectra of both electric and magnetic fields of RF emission are measured using commercially available measurement probes near the treatment couch in three clinical linac vaults with distinct physical layouts. The magnitude spectrum of the RF power emitted from these three linacs is then estimated. The electric field spectrum was also measured at several distances from the linac modulator in order to assess the effects of variations in spatial location in the treatment vault. A large fraction of RF power is emitted at frequencies below 5 MHz. However, the measured RF power at the Larmor frequency (8.5 MHz) of the proposed 0.2 T MR in the linac-MR (0.4-14.6 microW m(-2)) is still large enough to cause artifacts in MR images. Magnetron-based linacs generally emit much larger RF power than klystron-based linacs. In the frequency range of 1-50 MHz, only slight variation in the measured electric field is observed as a function of measurement position. This study suggests that the RF emissions are strong enough to cause image artifacts in MRI systems.

BCR/ABL induces chromosomal instability after genotoxic stress and alters the cell death threshold.

Earlier reports have suggested that the BCR/ABL oncogene, associated with chronic myeloid leukemia, induces a mutator phenotype; however, it is unclear whether this leads to long-term changes in chromosomes and whether the phenotype is found in primary chronic myelogeneous leukemia (CML) cells. We have addressed both these issues. BCR/ABL-expressing cell lines show an increase in DNA breaks after treatment with etoposide as compared to control cells. However, although BCR/ABL-expressing cell lines have an equivalent cell survival, they have an increase in chromosomal translocations after DNA repair as compared to control cells. This demonstrates that BCR/ABL expression decreases the fidelity of DNA repair. To see whether this is true in primary CML samples, normal CD34+ progenitor cells and CML progenitor cells were treated with etoposide. CML progenitor cells have equivalent survival but have an increase in DNA double-strand breaks (DSBs). Spectral karyotyping demonstrates new chromosomal translocations in CML cells, but not normal progenitor cells, consistent with error-prone DNA repair. Taken together, these data demonstrate that BCR/ABL enhances the accumulation of DSBs and alters the apoptotic threshold in CML leading to error-prone DNA repair.

Seven genomic subtypes of chronic fatigue syndrome/myalgic encephalomyelitis: a detailed analysis of gene networks and clinical phenotypes.

AIM: Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a multisystem disease, the pathogenesis of which remains undetermined. The authors have recently reported a study of gene expression that identified differential expression of 88 human genes in patients with CFS/ME. Clustering of quantitative PCR (qPCR) data from patients with CFS/ME revealed seven distinct subtypes with distinct differences in Medical Outcomes Survey Short Form-36 scores, clinical phenotypes and severity. METHODS: In this study, for each CFS/ME subtype, those genes whose expression differed significantly from that of normal blood donors were identified, and then gene interactions, disease associations and molecular and cellular functions of those gene sets were determined. Genomic analysis was then related to clinical data for each CFS/ME subtype. RESULTS: Genomic analysis revealed some common (neurological, haematological, cancer) and some distinct (metabolic, endocrine, cardiovascular, immunological, inflammatory) disease associations among the subtypes. Subtypes 1, 2 and 7 were the most severe, and subtype 3 was the mildest. Clinical features of each subtype were as follows: subtype 1 (cognitive, musculoskeletal, sleep, anxiety/depression); subtype 2 (musculoskeletal, pain, anxiety/depression); subtype 3 (mild); subtype 4 (cognitive); subtype 5 (musculoskeletal, gastrointestinal); subtype 6 (postexertional); subtype 7 (pain, infectious, musculoskeletal, sleep, neurological, gastrointestinal, neurocognitive, anxiety/depression). CONCLUSION: It was particularly interesting that in the seven genomically derived subtypes there were distinct clinical syndromes, and that those which were most severe were also those with anxiety/depression, as would be expected in a disease with a biological basis.