Evaluation of a Low-Fat Low-Calorie Meal on the Relative Bioavailability of Trametinib and Dabrafenib: Results From a Randomized, Open-Label, 2-Part Study in Healthy Participants.

In this randomized, open-label, 2-part, 2 × 2 crossover, phase 1 study, the effect of a low-fat low-calorie (LFLC) meal on the relative bioavailability of a trametinib 2-mg tablet or dabrafenib 150-mg capsule was evaluated in healthy participants. Trametinib adjusted geometric mean ratios (90%CI) of fed : fasted for area under the concentration-time curve (AUC) from time 0 to the last quantifiable concentration and AUC from time 0 extrapolated to infinity were 0.76 (0.71-0.82) and 0.82 (0.77-0.88), respectively. For dabrafenib, the adjusted geometric mean ratios of AUC from time 0 to the last quantifiable concentration and AUC from time 0 extrapolated to infinity (90%CI) for fed:fasted were 0.85 (0.79-0.91) and 0.86 (0.80-0.92), respectively. Consumption of an LFLC meal delayed trametinib and dabrafenib absorption, with an increase in time to maximum concentration of ≈15 and ≈30 minutes, respectively, compared to the fasted state. These findings indicate that consumption of an LFLC meal reduced the bioavailability and delayed the absorption of trametinib and dabrafenib, supporting current recommendations to administer both drugs in the fasting state; however, an occasional LFLC meal is unlikely to affect the pharmacokinetics of the drugs once steady state is reached and, by consequence, not likely to alter the overall intended efficacy.

Intersection of food insecurity and moral experiences of those involved in paediatric healthcare: A scoping review of child, caregiver and healthcare provider perspectives.

Food insecurity is a significant social and health issue for children in high-income countries and contributes to sub-optimal child outcomes. This scoping review examines how food insecurity intersects with the moral experiences of those involved in providing and receiving paediatric health care. Multiple databases were searched using a priori inclusion criteria, papers were screened by multiple reviewers. Searches yielded nine papers. Descriptive data was summarised and qualitative results extracted from included papers were analysed using inductive and deductive thematic analysis. Four main themes emerged: Food insecurity threatens caregiver and healthcare provider identity; is food insecurity the business of health? is screening for food insecurity surveillance or facilitating assistance? and the lived experience of navigating the tension of managing food insecurity and a child's health condition. The moral experiences lens has magnified the countless everyday encounters in which values and beliefs about what is 'right' or 'just' can be realised or thwarted in the context of the intersection between healthcare and food insecurity. Review findings have implications relating to the inclusion of children's voices in healthcare settings, healthcare practice and policy design, and the development and use of FI screening tools.

Characterization of the blood oxygen level dependent hemodynamic response function in human subcortical regions with high spatiotemporal resolution.

Subcortical brain regions are absolutely essential for normal human function. These phylogenetically early brain regions play critical roles in human behaviors such as the orientation of attention, arousal, and the modulation of sensory signals to cerebral cortex. Despite the critical health importance of subcortical brain regions, there has been a dearth of research on their neurovascular responses. Blood oxygen level dependent (BOLD) functional MRI (fMRI) experiments can help fill this gap in our understanding. The BOLD hemodynamic response function (HRF) evoked by brief (<4 s) neural activation is crucial for the interpretation of fMRI results because linear analysis between neural activity and the BOLD response relies on the HRF. Moreover, the HRF is a consequence of underlying local blood flow and oxygen metabolism, so characterization of the HRF enables understanding of neurovascular and neurometabolic coupling. We measured the subcortical HRF at 9.4T and 3T with high spatiotemporal resolution using protocols that enabled reliable delineation of HRFs in individual subjects. These results were compared with the HRF in visual cortex. The HRF was faster in subcortical regions than cortical regions at both field strengths. There was no significant undershoot in subcortical areas while there was a significant post-stimulus undershoot that was tightly coupled with its peak amplitude in cortex. The different BOLD temporal dynamics indicate different vascular dynamics and neurometabolic responses between cortex and subcortical nuclei.

Temporal stability of the hemodynamic response function across the majority of human cerebral cortex.

The hemodynamic response function (HRF) measured with functional magnetic resonance imaging is generated by vascular and metabolic responses evoked by brief (<4 s) stimuli. It is known that the human HRF varies across cortex, between subjects, with stimulus paradigms, and even between different measurements in the same cortical location. However, our results demonstrate that strong HRFs are remarkably repeatable across sessions separated by time intervals up to 3 months. In this study, a multisensory stimulus was used to activate and measure the HRF across the majority of cortex (>70%, with lesser reliability observed in some areas of prefrontal cortex). HRFs were measured with high spatial resolution (2-mm voxels) in central gray matter to minimize variations caused by partial-volume effects. HRF amplitudes and temporal dynamics were highly repeatable across four sessions in 20 subjects. Positive and negative HRFs were consistently observed across sessions and subjects. Negative HRFs were generally weaker and, thus, more variable than positive HRFs. Statistical measurements showed that across-session variability is highly correlated to the variability across events within a session; these measurements also indicated a normal distribution of variability across cortex. The overall repeatability of the HRFs over long time scales generally supports the long-term use of event-related functional magnetic resonance imaging protocols.

Retinotopic variations of the negative blood-oxygen-level dependent hemodynamic response function in human primary visual cortex.

Functional magnetic resonance imaging (fMRI) measures blood-oxygen-level-dependent (BOLD) contrast that is generally assumed to be linearly related to excitatory neural activity. The positive hemodynamic response function (pHRF) is the positive BOLD response (PBR) evoked by a brief neural stimulation; the pHRF is often used as the impulse response for linear analysis of neural excitation. Many fMRI studies have observed a negative BOLD response (NBR) that is often associated with neural suppression. However, the temporal dynamics of the NBR evoked by a brief stimulus, the negative HRF (nHRF), remains unclear. Here, a unilateral visual stimulus was presented in a slow event-related design to elicit both pHRFs in the stimulus representation (SR), and nHRFs elsewhere. The observed nHRFs were not inverted versions of the pHRF previously reported. They were characterized by a stronger initial negative response followed by a significantly later positive peak. In contralateral primary visual cortex (V1), these differences varied with eccentricity from the SR. Similar nHRFs were observed in ipsilateral V1 with less eccentricity variation. Experiments with the blocked version of the same stimulus confirmed that brain regions presenting the unexpected nHRF dynamics correspond to those presenting a strong NBR. These data demonstrated that shift-invariant temporal linearity did not hold for the NBR while confirming that the PBR maintained rough linearity. Modeling indicated that the observed nHRFs can be created by suppression of both blood flow and oxygen metabolism. Critically, the nHRF can be misinterpreted as a pHRF due to their similarity, which could confound linear analysis for event-related fMRI experiments.NEW & NOTEWORTHY We investigate dynamics of the negative hemodynamic response function (nHRF), the negative blood-oxygen-level-dependent (BOLD) response (NBR) evoked by a brief stimulus, in human early visual cortex. Here, we show that the nHRFs are not inverted versions of the corresponding pHRFs. The nHRF has complex dynamics that varied significantly with eccentricity. The results also show shift-invariant temporal linearity does not hold for the NBR.

More than BOLD: Dual-spin populations create functional contrast.

PURPOSE: Functional MRI contrast has generally been associated with changes in transverse relaxivity caused by blood oxygen concentration, the so-called blood oxygen level dependent contrast. However, this interpretation of fMRI contrast has been called into question by several recent experiments at high spatial resolution. Experiments were conducted to examine contrast dependencies that cannot be explained only by differences in relaxivity in a single-spin population. METHODS: Measurements of functional signal and contrast were obtained in human early visual cortex during a high-contrast visual stimulation over a large range of TEs and for several flip angles. Small voxels (1.5 mm) were used to restrict the measurements to cortical gray matter in early visual areas identified using retinotopic mapping procedures. RESULTS: Measurements were consistent with models that include 2 spin populations. The dominant population has a relatively short transverse lifetime that is strongly modulated by activation. However, functional contrast is also affected by volume changes between this short-lived population and the longer-lived population. CONCLUSION: Some of the previously observed "nonclassical" behaviors of functional contrast can be explained by these interacting dual-spin populations.

Dynamics of the cerebral blood flow response to brief neural activity in human visual cortex.

The blood oxygen-level dependent (BOLD) functional magnetic resonance imaging (fMRI) signal depends on an interplay of cerebral blood flow (CBF), oxygen metabolism, and cerebral blood volume. Despite wide usage of BOLD fMRI, it is not clear how these physiological components create the BOLD signal. Here, baseline CBF and its dynamics evoked by a brief stimulus (2 s) in human visual cortex were measured at 3T. We found a stereotypical CBF response: immediate increase, rising to a peak a few second after the stimulus, followed by a significant undershoot. The BOLD hemodynamic response function (HRF) was also measured in the same session. Strong correlations between HRF and CBF peak responses indicate that the flow responses evoked by neural activation in nearby gray matter drive the early HRF. Remarkably, peak CBF and HRF were also strongly modulated by baseline perfusion. The CBF undershoot was reliable and significantly correlated with the HRF undershoot. However, late-time dynamics of the HRF and CBF suggest that oxygen metabolism can also contribute to the HRF undershoot. Combined measurement of the CBF and HRF for brief neural activation is a useful tool to understand the temporal dynamics of neurovascular and neurometabolic coupling.

Characterization of the hemodynamic response function across the majority of human cerebral cortex.

A brief (<4 s) period of neural activation evokes a stereotypical sequence of vascular and metabolic events to create the hemodynamic response function (HRF) measured using functional magnetic resonance imaging (fMRI). Linear analysis of fMRI data requires that the HRF be treated as an impulse response, so the character and temporal stability of the HRF are critical issues. Here, a simple audiovisual stimulus combined with a fast-paced task was used to evoke a strong HRF across a majority, ∼77%, of cortex during a single scanning session. High spatiotemporal resolution (2-mm voxels, 1.25-s acquisition time) was used to focus HRF measurements specifically on the gray matter for whole brain. The majority of activated cortex responds with positive HRFs, while ∼27% responds with negative (inverted) HRFs. Spatial patterns of the HRF response amplitudes were found to be similar across subjects. Timing of the initial positive lobe of the HRF was relatively stable across the cortical surface with a mean of 6.1 ±â€¯0.6 s across subjects, yet small but significant timing variations were also evident in specific regions of cortex. The results provide guidance for linear analysis of fMRI data. More importantly, this method provides a means to quantify neurovascular function across most of the brain, with potential clinical utility for the diagnosis of brain pathologies such as traumatic brain injury.

Analyses of mineral specific surface area and hydroxyl substitution for intact bone.

Bone minerals possess two primary hydrogen sources: hydroxide ions in the nanocrystalline core and structural water in the amorphous surface layer. In order to accurately measure their concentrations using hydrogen to phosphorus cross polarization NMR spectroscopy, it is necessary to analyze the dependence of signal intensities on serial contact times, namely, cross polarization kinetics. A reliable protocol is developed to iteratively decompose the severely overlapped spectra and to analyze the cross-polarization kinetics, leading to measurement of hydroxyl and structural water concentrations. Structural water concentration is used to estimate mineral specific surface area and nanocrystal thickness for intact bone.

Process mapping: enhancing the implementation of the Liverpool Care Pathway.

Arohanui Hospice is a 12-bed specialist palliative care service based in Palmerston North, New Zealand. It serves a population of 180 000 people spread over a wide geographical area, both urban and rural. The Liverpool Care Pathway (LCP) was initially implemented at the hospice inpatient unit in January 2005. Following this, the 'LCP Pilot Project' was developed. This project involved the implementation of the LCP within three aged residential care facilities and two wards within the regional hospital. Included in the project was a research component to enable evaluation of the effectiveness of the LCP in each setting. This article will consider and demonstrate the use of process mapping (Buckman, 2003) as a quality improvement tool to enhance the effective implementation and sustained use of the LCP for the dying patient within aged residential care. Measures are considered that support the implementation of the LCP at an organisational level rather than at a purely clinical level. While this work has been completed within the New Zealand context, it is believed that the principles are transferable to similar settings internationally.

Effects of experimentally induced plantar insensitivity on forces and pressures under the foot during normal walking.

Pressures under the foot during level walking were measured in 15 healthy young adults (8 females, 7 males, mean age 25.7, S.D. 5.3) before and after immersing the feet in ice-cold water (2 degrees C) for 30 min to evaluate the role of plantar insensitivity on gait patterns. Following ice water immersion, there was a significant decrease in walking speed. Maximum forces and peak pressures under the foot decreased, with the exception of an increase in loading under the third to fifth metatarsal heads. Contact times increased under all regions of the foot, and force-time and pressure-time integrals increased under the second and third to fifth metatarsal head regions. It is concluded that plantar insensitivity significantly alters the distribution, duration, and to a lesser extent, the magnitude of forces and pressures under the foot when walking. These results suggest that in the neuropathic foot, gait changes caused by plantar insensitivity may be partly responsible for the redistribution and altered duration of loading, whereas the increase in the magnitude of forces and pressures are primarily due to other disease-related factors.