The key component of a microstructural diffusion MRI ‘super-scanner’ is a dedicated high-strength gradient system that enables stronger diffusion weightings per unit time compared to conventional ...gradient designs. This can, in turn, drastically shorten the time needed for diffusion encoding, increase the signal-to-noise ratio, and facilitate measurements at shorter diffusion times. This review, written from the perspective of the UK National Facility for In Vivo MR Imaging of Human Tissue Microstructure, an initiative to establish a shared 300 mT/m-gradient facility amongst the microstructural imaging community, describes ten advantages of ultra-strong gradients for microstructural imaging. Specifically, we will discuss how the increase of the accessible measurement space compared to a lower-gradient systems (in terms of Δ, b-value, and TE) can accelerate developments in the areas of 1) axon diameter distribution mapping; 2) microstructural parameter estimation; 3) mapping micro-vs macroscopic anisotropy features with gradient waveforms beyond a single pair of pulsed-gradients; 4) multi-contrast experiments, e.g. diffusion-relaxometry; 5) tractography and high-resolution imaging in vivo and 6) post mortem; 7) diffusion-weighted spectroscopy of metabolites other than water; 8) tumour characterisation; 9) functional diffusion MRI; and 10) quality enhancement of images acquired on lower-gradient systems. We finally discuss practical barriers in the use of ultra-strong gradients, and provide an outlook on the next generation of ‘super-scanners’.
•Improved estimation of axon diameter in vivo.•Better fitting of complex microstructure models.•Improved characterisation of tumours.•Facilitation of multi-contrast MRI experiments.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Background
Pharmacological ascorbate (intravenous delivery reaching plasma concentrations ≈ 20 mM; P-AscH
−
) has emerged as a promising therapeutic strategy for glioblastoma. Recently, a single-arm ...phase 2 clinical trial demonstrated a significant increase in overall survival when P-AscH
−
was combined with temozolomide and radiotherapy. As P-AscH
−
relies on iron-dependent mechanisms, this study aimed to assess the predictive potential of both molecular and imaging-based iron-related markers to enhance the personalization of P-AscH
−
therapy in glioblastoma participants.
Methods
Participants (
n
= 55) with newly diagnosed glioblastoma were enrolled in a phase 2 clinical trial conducted at the University of Iowa (NCT02344355). Tumor samples obtained during surgical resection were processed and stained for transferrin receptor and ferritin heavy chain expression. A blinded pathologist performed pathological assessment. Quantitative susceptibility mapping (QSM) measures were obtained from pre-radiotherapy MRI scans following maximal safe surgical resection. Circulating blood iron panels were evaluated prior to therapy through the University of Iowa Diagnostic Laboratory.
Results
Through univariate analysis, a significant inverse association was observed between tumor transferrin receptor expression and overall and progression-free survival. QSM measures exhibited a significant, positive association with progression-free survival. Subjects were actively followed until disease progression and then were followed through chart review or clinical visits for overall survival.
Conclusions
This study analyzes iron-related biomarkers in the context of P-AscH
−
therapy for glioblastoma. Integrating molecular, systemic, and imaging-based markers offers a multifaceted approach to tailoring treatment strategies, thereby contributing to improved patient outcomes and advancing the field of glioblastoma therapy.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background
No study has performed an exercise intervention that included high-intensity, free-weight, functional resistance training, and assessed frailty status as an inclusion criteria and outcome ...measure via original, standardized tools, in pre-frail females.
Objectives
Determine if the intervention strategy is not only feasible and safe, but can also improve frailty status, functional task performance, and muscle strength.
Design
Pilot, quasi-experimental.
Setting
Community.
Participants 20 older-adults with pre-frailty characteristics
Intervention
12-weeks (3 days/week, 45–60 minutes/session) of multi-component exercise, inclusive of aerobic, resistance, balance and flexibility exercises. The crux of the program was balance and resistance exercises, the latter utilized high-intensity, free-weight, functional resistance training. The control group maintained their usual care.
Measurements
Feasibility and safety (dropout, adherence, and adverse event)
Frailty (Frailty Phenotype, Clinical Frailty Scale, and gait speed)
Functional task performance (grip strength and sit-to-stand time); and
Isometric and isotonic strength of the knee extensors and elbow flexors.
Results
No participants dropped out of the intervention or experienced an adverse event, and adherence averaged 88.3%. The exercise group became less frail, whereas the control group became more frail. There was a significant within-group improvement in exercise participants gait speed (p ≤ 0.01, +0.24 m/sec), grip strength (p ≤ 0.01, +3.9 kg), and sit-to-stand time (p ≤ 0.01, -5.0 sec). There was a significant within-group improvement in exercise participants knee extension isometric torque (p ≤ 0.05, +7.4 Nm) and isotonic velocity (p = ≤ 0.01, +37.5 °/sec). Elbow flexion isotonic velocity significantly declined within the control group (p ≤ 0.01, -20.2 °/sec) and demonstrated a significant between-group difference (p ≤ 0.05, 40.73 °/sec) post-intervention.
Conclusions
The intervention strategy appears to be feasible and safe, and may also improve frailty status, functional task performance, and muscle strength. These results help calculate effect size for a future randomized controlled trial.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Frailty is a state of vulnerability to poor resolution of homeostasis after a stressor event and is strongly associated with adverse outcomes. Therefore, the assessment of frailty may be an essential ...part of evaluation in any healthcare encounter that might result in an escalation of care. The purpose of the study was to assess the frequency and association of frailty with clinical outcomes in patients subject to rapid response team (RRT) review.
In this multi-national prospective observational cohort study, centres with existing RRTs collected data over a 7-day period, with follow up of all patients at 24 h following their RRT call and at hospital discharge or 30 days following the event trigger (whichever came sooner). Investigators also collected data on the triggers and interventions provided and a bedside assessment on the level of patients' frailty using a clinical frailty scale.
Amongst 1133 patients, 40% were screened as frail, which was associated with older age (p < 0.001), admission under a medical speciality (p < 0.001), increased severity of illness at the time of the RRT review (p = 0.0047), and substantially higher frequency of limitations of care (p < 0.001). Importantly, 72% of patients screened as frail were either dead or dependent on hospital care by 30 days (p < 0.001). In the multivariable analysis, the significant risk factors for the composite endpoint "poor recovery" (died or were hospital-dependent by 30 days) were age (odds ratio (OR), 1.04; 95% confidence interval (CI), 1.03-1.05; p < 0.001), frailty level (p < 0.001), existing limitation of care (OR, 2.0; 95% CI, 1.3-3.0; p < 0.001), and the quick sequential organ failure assessment (qSOFA) score (p < 0.001).
Higher frailty scores were associated with increased mortality and dependence on health care at 30 days. Our results indicate that frailty has an influence on the clinical trajectory of deteriorating patients and that such assessment should be included in discussion of goals and expectations of care.
Netherlands Trial Registry, NTR5535 . Registered on 23 December 2015.
Chromothripsis and chromoanasynthesis are catastrophic events leading to clustered genomic rearrangements. Whole-genome sequencing revealed frequent complex genomic rearrangements (n = 16/26) in ...brain tumors developing in mice deficient for factors involved in homologous-recombination-repair or non-homologous-end-joining. Catastrophic events were tightly linked to Myc/Mycn amplification, with increased DNA damage and inefficient apoptotic response already observable at early postnatal stages. Inhibition of repair processes and comparison of the mouse tumors with human medulloblastomas (n = 68) and glioblastomas (n = 32) identified chromothripsis as associated with MYC/MYCN gains and with DNA repair deficiencies, pointing towards therapeutic opportunities to target DNA repair defects in tumors with complex genomic rearrangements.
Recent advances are enabling delivery of precision genomic medicine to cancer clinics. While the majority of approaches profile panels of selected genes or hotspot regions, comprehensive data ...provided by whole genome and transcriptome sequencing and analysis (WGTA) presents an opportunity to align a much larger proportion of patients to therapies.
Samples from 570 patients with advanced or metastatic cancer of diverse types enrolled in the Personalized OncoGenomics (POG) program underwent WGTA. DNA-based data, including mutations, copy number, and mutation signatures, were combined with RNA-based data, including gene expression and fusions, to generate comprehensive WGTA profiles. A multidisciplinary molecular tumour board used WGTA profiles to identify and prioritize clinically actionable alterations and inform therapy. Patient responses to WGTA-informed therapies were collected.
Clinically actionable targets were identified for 83% of patients, 37% of whom received WGTA-informed treatments. RNA expression data were particularly informative, contributing to 67% of WGTA-informed treatments; 25% of treatments were informed by RNA expression alone. Of a total 248 WGTA-informed treatments, 46% resulted in clinical benefit. RNA expression data were comparable to DNA-based mutation and copy number data in aligning to clinically beneficial treatments. Genome signatures also guided therapeutics including platinum, PARP inhibitors, and immunotherapies. Patients accessed WGTA-informed treatments through clinical trials (19%), off-label use (35%), and as standard therapies (46%) including those which would not otherwise have been the next choice of therapy, demonstrating the utility of genomic information to direct use of chemotherapies as well as targeted therapies.
Integrating RNA expression and genome data illuminated treatment options that resulted in 46% of treated patients experiencing positive clinical benefit, supporting the use of comprehensive WGTA profiling in clinical cancer care.
NCT02155621
•A prospective study of 570 patients used whole genome and transcriptome analysis (WGTA) for real-time treatment options•Of 248 WGTA-informed treatments, 46% resulted in clinical benefit to the patient•RNA expression information was as valuable as DNA-based information for selecting treatments with clinical benefit•Integrated data informs selection of standard-of-care therapies, clinical trial enrollment and off-label use•This study supports the use of whole genome and transcriptome analysis in clinical cancer care
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Infant habitual sleep has been proposed as an important moderator of development in domains such as attention, memory or temperament. To test such hypotheses, we need to know how to accurately and ...consistently assess habitual sleep in infancy. Common assessment methods include easy to deploy but subjective parent-report measures (diary/sleep questionnaire); or more labour-intensive but objective motor movement measures (actigraphy). Understanding the degree to which these methods provide converging insights is important, but cross-method agreement has yet to be investigated longitudinally. Moreover, it is unclear whether concordance systematically varies with infant or maternal characteristics that could represent confounders in observational studies. This longitudinal study (up to 4 study visits/participant) investigated cross-method concordance on one objective (7-day actigraphy) and three commonly used subjective (7-day sleep diary, Brief Infant Sleep Questionnaire, Sleep & Settle Questionnaire) sleep measures in 76 typically developing infants (age: 4–14 months) and assessed the impact of maternal characteristics (stress, age, education) and infant characteristics (age) on cross-method concordance. In addition, associations between objective and subjective sleep measures and a measure of general developmental status (Ages & Stages Questionnaire) were investigated. A range of equivalence analyses (tests of equivalence, correlational analyses, Bland-Altman plots) showed mixed agreement between sleep measures. Most importantly, cross-method agreement was associated with maternal stress levels and infant age. Specifically, agreement between different measures of night waking was better for mothers experiencing higher stress levels and was higher for younger than older infants; the reverse pattern was true for day sleep duration. Interestingly, objective and subjective measures did not yield the same patterns of association with developmental domains, indicating that sleep method choice can influence which associations are found between sleep and cognitive development. However, results converged across day sleep and problem-solving skills, highlighting the importance of studying day sleep in future studies. We discuss implications of sleep method choice for investigating sleep in the context of studying infant development and behaviour.
•A range of equivalence analyses showed mixed agreement between subjective and objective sleep measures.•Cross-method agreement was associated with maternal stress levels and infant age.•Objective and subjective measures did not yield the same patterns of association with developmental domains except for day sleep duration.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The reproducible radio outbursts of SS Cygni Russell, T. D; Miller-Jones, J. C. A; Sivakoff, G. R ...
Monthly Notices of the Royal Astronomical Society,
08/2016, Volume:
460, Issue:
4
Journal Article
Peer reviewed
Open access
We present the results of our intensive radio observing campaign of the dwarf nova SS Cyg during its 2010 April outburst. We argue that the observed radio emission was produced by synchrotron ...emission from a transient radio jet. Comparing the radio light curves from previous and subsequent outbursts of this system (including high-resolution observations from outbursts in 2011 and 2012) shows that the typical long and short outbursts of this system exhibit reproducible radio outbursts that do not vary significantly between outbursts, which is consistent with the similarity of the observed optical, ultraviolet and X-ray light curves. Contemporaneous optical and X-ray observations show that the radio emission appears to have been triggered at the same time as the initial X-ray flare, which occurs as disc material first reaches the boundary layer. This raises the possibility that the boundary region may be involved in jet production in accreting white dwarf systems. Our high spatial resolution monitoring shows that the compact jet remained active throughout the outburst with no radio quenching.
RAFT-mediated polymerisation-induced self-assembly (PISA) is used to prepare six types of amphiphilic block copolymer nanoparticles which were subsequently evaluated as putative Pickering emulsifiers ...for the stabilisation of n-dodecane-in-water emulsions. It was found that linear poly(glycerol monomethacrylate)-poly(2-hydroxypropyl methacrylate) (PGMA-PHPMA) diblock copolymer spheres and worms do not survive the high shear homogenisation conditions used for emulsification. Stable emulsions are obtained, but the copolymer acts as a polymeric surfactant; individual chains rather than particles are adsorbed at the oil-water interface. Particle dissociation during emulsification is attributed to the weakly hydrophobic character of the PHPMA block. Covalent stabilisation of these copolymer spheres or worms can be readily achieved by addition of ethylene glycol dimethacrylate (EGDMA) during the PISA synthesis. TEM studies confirm that the resulting cross-linked spherical or worm-like nanoparticles survive emulsification and produce genuine Pickering emulsions. Alternatively, stabilisation can be achieved by either replacing or supplementing the PHPMA block with the more hydrophobic poly(benzyl methacrylate) (PBzMA). The resulting linear spheres or worms also survive emulsification and produce stable n-dodecane-in-water Pickering emulsions. The intrinsic advantages of anisotropic worms over isotropic spheres for the preparation of Pickering emulsions are highlighted. The former particles are more strongly adsorbed at similar efficiencies compared to spheres and also enable smaller oil droplets to be produced for a given copolymer concentration. The scalable nature of PISA formulations augurs well for potential applications of anisotropic block copolymer nanoparticles as Pickering emulsifiers.
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