The willingness of UK adults with intellectual disabilities to take COVID-19 vaccines.

BACKGROUND: Given the much greater COVID-19 mortality risk experienced by people with intellectual disabilities (ID), understanding the willingness of people with ID to take a COVID-19 vaccine is a major public health issue. METHOD: In December 2020 to February 2021, across the United Kingdom, 621 adults with ID were interviewed remotely and 348 family carers or support workers of adults with ID with greater needs completed an online survey, including a question on willingness to take a COVID-19 vaccine if offered. RESULTS: Eighty-seven per cent of interviewees with ID were willing to take a COVID-19 vaccine, with willingness associated with white ethnicity, having already had a flu vaccine, gaining information about COVID-19 from television but not from social media, and knowing COVID-19 social restrictions rules. A percentage of 81.7% of surveyed carers of adults with ID with greater needs reported that the person would be willing to take a COVID-19 vaccine, with willingness associated with white ethnicity, having a health condition of concern in the context of COVID-19, having had a flu vaccine, being close to someone who had died due to COVID-19, and having shielded at some point during the pandemic. CONCLUSIONS: Reported willingness to take the COVID-19 vaccine is high among adults with ID in the United Kingdom, with factors associated with willingness having clear implications for public health policy and practice.

Understanding burden in caregivers of colorectal cancer survivors: what role do patient and caregiver factors play?

This study investigated how both caregiver and patient factors predict different aspects of burden in colorectal cancer caregivers. One hundred and fifty-three caregiver-survivor dyads separately provided information on patient disease and treatment-related factors, and perceived global health status (EORTC QLQ30), along with caregiver socio-demographic factors, health and care-related activities. Four multiple regression analyses were conducted to assess the influence of caregiver characteristics, patient characteristics and care-related activities on four dimensions of burden from the Caregiver Reaction Assessment scale. Caregiver characteristics significantly predicted health and financial burden (11%-13% of explained variance) with comorbidity and younger age increasing this risk. Patient health, in particular global health status and the presence of a stoma, predicted all burden scores, explaining 14%-22% of variance. Care-related activities was also a significant predictor of all burden scores, explaining an additional 5%-11% of variance, with time involved in caring the most consistent predictor. Results highlight that a combination of factors influence caregiver burden. These results may be used to identify those most at risk, allowing practitioners to deliver tailored effective support. In particular, efforts to alleviate the burden of caring on caregiver schedule may be merited, given that this was the domain in which the burden was greatest.

A qualitative study exploring the views, attitudes and beliefs of patients and health professionals towards exercise intervention for people who are surgically treated for lung cancer.

Surgical removal remains the best curative option for patients diagnosed with early-stage lung cancer. However, it is also associated with significant morbidity and reduced quality of life. Interventions to improve patient outcomes are required. This study aimed to explore the views, attitudes and beliefs of key stakeholders on exercise intervention for people who are surgically treated for lung cancer to inform the development of future interventions. Focus groups and individual interviews were carried out at two Scottish sites. The study was guided by the Health Action Process Approach behaviour change model. A total of 23 (12 patients and 11 health professionals) participated in the study. The data analysis resulted in three main themes: attitudes and beliefs, external factors and intervention design. The results highlighted certain key elements that should be included in an exercise intervention, such as the need for supervised sessions, an element of individualisation and the perceived social benefits of exercising with others. This study emphasises the importance of including key stakeholders in the development of complex interventions such as exercise and provides important information for the development of future exercise intervention trials for people who are surgically treated for lung cancer.

The symptom phenotype of oncology outpatients remains relatively stable from prior to through 1 week following chemotherapy.

Some oncology outpatients experience a higher number of and more severe symptoms during chemotherapy (CTX). However, little is known about whether this high risk phenotype persists over time. Latent transition analysis (LTA) was used to examine the probability that patients remained in the same symptom class when assessed prior to the administration of and following their next dose of CTX. For the patients whose class membership remained consistent, differences in demographic and clinical characteristics, and quality of life (QOL) were evaluated. The Memorial Symptom Assessment Scale (MSAS) was used to evaluate symptom burden. LTA was used to identify subgroups of patients with distinct symptom experiences based on the occurrence of the MSAS symptoms. Of the 906 patients evaluated, 83.9% were classified in the same symptom occurrence class at both assessments. Of these 760 patients, 25.0% were classified as Low-Low, 44.1% as Moderate-Moderate and 30.9% as High-High. Compared to the Low-Low class, the other two classes were younger, more likely to be women and to report child care responsibilities, and had a lower functional status and a higher comorbidity scores. The two higher classes reported lower QOL scores. The use of LTA could assist clinicians to identify higher risk patients and initiate more aggressive interventions.

A phase II/III randomized study to compare the efficacy and safety of rigosertib plus gemcitabine versus gemcitabine alone in patients with previously untreated metastatic pancreatic cancer.

BACKGROUND: Rigosertib (ON 01910.Na), a first-in-class Ras mimetic and small-molecule inhibitor of multiple signaling pathways including polo-like kinase 1 (PLK1) and phosphoinositide 3-kinase (PI3K), has shown efficacy in preclinical pancreatic cancer models. In this study, rigosertib was assessed in combination with gemcitabine in patients with treatment-naïve metastatic pancreatic adenocarcinoma. MATERIALS AND METHODS: Patients with metastatic pancreatic adenocarcinoma were randomized in a 2:1 fashion to gemcitabine 1000 mg/m(2) weekly for 3 weeks of a 4-week cycle plus rigosertib 1800 mg/m(2) via 2-h continuous IV infusions given twice weekly for 3 weeks of a 4-week cycle (RIG + GEM) versus gemcitabine 1000 mg/m(2) weekly for 3 weeks in a 4-week cycle (GEM). RESULTS: A total of 160 patients were enrolled globally and randomly assigned to RIG + GEM (106 patients) or GEM (54). The most common grade 3 or higher adverse events were neutropenia (8% in the RIG + GEM group versus 6% in the GEM group), hyponatremia (17% versus 4%), and anemia (8% versus 4%). The median overall survival was 6.1 months for RIG + GEM versus 6.4 months for GEM [hazard ratio (HR), 1.24; 95% confidence interval (CI) 0.85-1.81]. The median progression-free survival was 3.4 months for both groups (HR = 0.96; 95% CI 0.68-1.36). The partial response rate was 19% versus 13% for RIG + GEM versus GEM, respectively. Of 64 tumor samples sent for molecular analysis, 47 were adequate for multiplex genetic testing and 41 were positive for mutations. The majority of cases had KRAS gene mutations (40 cases). Other mutations detected included TP53 (13 cases) and PIK3CA (1 case). No correlation between mutational status and efficacy was detected. CONCLUSIONS: The combination of RIG + GEM failed to demonstrate an improvement in survival or response compared with GEM in patients with metastatic pancreatic adenocarcinoma. Rigosertib showed a similar safety profile to that seen in previous trials using the IV formulation.

Empowering drug development: Leveraging insights from imaging technologies to enable the advancement of digital health technologies.

The US Food and Drug Administration (FDA) has publicly recognized the importance of improving drug development efficiency, deeming translational biomarkers a top priority. The use of imaging biomarkers has been associated with increased rates of drug approvals. An appropriate level of validation provides a pragmatic way to choose and implement these biomarkers. Standardizing imaging modality selection, data acquisition protocols, and image analysis (in ways that are agnostic to equipment and algorithms) have been key to imaging biomarker deployment. The best known examples come from studies done via precompetitive collaboration efforts, which enable input from multiple stakeholders and data sharing. Digital health technologies (DHTs) provide an opportunity to measure meaningful aspects of patient health, including patient function, for extended periods of time outside of the hospital walls, with objective, sensor-based measures. We identified the areas where learnings from the imaging biomarker field can accelerate the adoption and widespread use of DHTs to develop novel treatments. As with imaging, technical validation parameters and performance acceptance thresholds need to be established. Approaches amenable to multiple hardware options and data processing algorithms can be enabled by sharing DHT data and by cross-validating algorithms. Data standardization and creation of shared databases will be vital. Pre-competitive consortia (public-private partnerships and professional societies that bring together all stakeholders, including patient organizations, industry, academic experts, and regulators) will advance the regulatory maturity of DHTs in clinical trials.

Dissociable effects of methylphenidate, atomoxetine and placebo on regional cerebral blood flow in healthy volunteers at rest: a multi-class pattern recognition approach.

The stimulant drug methylphenidate (MPH) and the non-stimulant drug atomoxetine (ATX) are both widely used for the treatment of attention deficit/hyperactivity disorder (ADHD), but their differential effects on human brain function are poorly understood. PET and blood oxygen level dependent (BOLD) fMRI have been used to study the effects of MPH and BOLD fMRI is beginning to be used to delineate the effects of MPH and ATX in the context of cognitive tasks. The BOLD signal is a proxy for neuronal activity and is dependent on three physiological parameters: regional cerebral blood flow (rCBF), cerebral metabolic rate of oxygen and cerebral blood volume. To identify areas sensitive to MPH and ATX and assist interpretation of BOLD studies in healthy volunteers and ADHD patients, it is therefore of interest to characterize the effects of these drugs on rCBF. In this study, we used arterial spin labeling (ASL) MRI to measure rCBF non-invasively in healthy volunteers after administration of MPH, ATX or placebo. We employed multi-class pattern recognition (PR) to discriminate the neuronal effects of the drugs, which accurately discriminated all drug conditions from one another and provided activity patterns that precisely localized discriminating brain regions. We showed common and differential effects in cortical and subcortical brain regions. The clearest differential effects were observed in four regions: (i) in the caudate body where MPH but not ATX increased rCBF, (ii) in the midbrain/substantia nigra and (iii) thalamus where MPH increased and ATX decreased rCBF plus (iv) a large region of cerebellar cortex where ATX increased rCBF relative to MPH. Our results demonstrate that combining ASL and PR yields a sensitive method for detecting the effects of these drugs and provides insights into the regional distribution of brain networks potentially modulated by these compounds.

Quantifying phytate in dairy digesta and feces: alkaline extraction and high-performance ion chromatography.

Development of an analytical method with appropriate combination of extraction and quantification approaches for undigested phytate in ruminant feces and digesta will advance knowledge of phytate degradation in ruminants and help to reduce phosphorus excretion. Established quantification methods give satisfactory results for feedstuffs and nonruminant manure but recovery of phytate is incomplete for ruminant feces and digesta because of their complex sample matrix and low ratio of phytate to inorganic P. The objective was to develop a robust, accurate, sensitive, and inexpensive method to extract and quantify phytate in feeds, ruminant feces, and digesta. Diets varying in phytate content were fed to dairy heifers, dry cows, and lactating cows to generate digesta and fecal samples of varying composition to challenge extraction and quantification methods. Samples were extracted with 0.5 M HCl or 0.25 M NaOH + 0.05 M EDTA. Acid extracts were mixed with 20% NaCl, alkaline extracts were acidified to final pH < 2, and then both extracts were clarified with C18 cartridges and 0.2-µm filters. High-performance ion chromatography (HPIC) was used to quantify phytate. In feed samples, the measured phytate was comparable in alkaline and acid extracts (2,965 vs. 3,085 µg/g of DM). In digesta and fecal samples, alkaline extraction yielded greater estimates of phytate content than did acid extraction (40.7 vs. 33.6 and 202.9 vs. 144.4 µg/g of DM for digesta and fecal samples, respectively). Analysis of alkaline extracts by HPIC is usually not possible because of sample matrix interferences; acidification and C(18)-cartridge elution of alkaline extracts prevented this interference. Pure phytate added to dry samples before extraction was almost completely recovered (88 to 105%), indicating high extraction efficiency, no adverse effect of extract clean-up procedures, and accurate quantification of phytate. The proposed method is rapid, inexpensive, robust, and combines the extraction power of NaOH-EDTA with the precision and sensitivity of HPIC quantification, allowing accurate quantification of phytate in feeds, ruminant digesta, and fecal samples.

Surface waves and crustal structure on Mars.

We detected surface waves from two meteorite impacts on Mars. By measuring group velocity dispersion along the impact-lander path, we obtained a direct constraint on crustal structure away from the InSight lander. The crust north of the equatorial dichotomy had a shear wave velocity of approximately 3.2 kilometers per second in the 5- to 30-kilometer depth range, with little depth variation. This implies a higher crustal density than inferred beneath the lander, suggesting either compositional differences or reduced porosity in the volcanic areas traversed by the surface waves. The lower velocities and the crustal layering observed beneath the landing site down to a 10-kilometer depth are not a global feature. Structural variations revealed by surface waves hold implications for models of the formation and thickness of the martian crust.

Evaluation of [(11)C]MRB for assessment of occupancy of norepinephrine transporters: Studies with atomoxetine in non-human primates.

[(11)C]MRB is one of the most promising radioligands used to measure brain norepinephrine transporters (NET) with positron emission tomography (PET). The objective of this study was to evaluate the suitability of [(11)C]MRB for drug occupancy studies of NET using atomoxetine (ATX), a NET uptake inhibitor used in the treatment of depression and attention-deficit hyperactivity disorder (ADHD). A second goal of the study was identification of a suitable reference region. Ten PET studies were performed in three anesthetized rhesus monkeys following an infusion of ATX or placebo. [(11)C]MRB arterial input functions and ATX plasma levels were also measured. A dose-dependent reduction of [(11)C]MRB volume of distribution was observed after correction for [(11)C]MRB plasma free fraction. ATX IC(50) was estimated to be 31 ± 10ng/mL plasma. This corresponds to an effective dose (ED(50)) of 0.13mg/kg, which is much lower than the therapeutic dose of ATX in ADHD (1.0-1.5mg/kg). [(11)C]MRB binding potential BP(ND) in the thalamus was estimated to be 1.8 ± 0.3. Defining a reference region for a NET radiotracer is challenging due to the widespread and relatively uniform distribution of NET in the brain. Three regions were evaluated for use as reference region: caudate, putamen and occipital cortex. Caudate was found to be the most suitable for preclinical drug occupancy studies in rhesus monkeys. The IC(50) estimate obtained using MRTM2 BP(ND) without arterial blood sampling was 21 ± 3ng/mL (using caudate as the reference region). This study demonstrated that [(11)C]MRB is suitable for drug occupancy studies of NET.

Broiler breeder manure phosphorus forms are affected by diet, location, and period of accumulation.

Phosphorus (P) modifications of poultry diets have successfully decreased the total P (TP) in manures, but the effects on manure water-soluble P (WSP(M)) remain unclear. Our objectives were to characterize P forms in broiler breeder manures as affected by dietary P modification, location within the pen, and manure accumulation period. Two diets were formulated with and without phytase to attain 0.40% available P (AvP) during the breeder laying phase (22-64 wk of age). Manure was collected after accumulation periods of 48 h, 3 wk, and 39 wk in locations under the feeder and drinker and under the common area (between the feeder and drinker) of the pen. The TP, WSP(M), orthophosphate, and phytate in manure were measured. Broiler breeders that were fed phytase with a simultaneous reduction in nonphytate P (NPP) produced manures with 15% lower TP than those fed a traditional diet, but did not change WSP(M) when averaged over manure accumulation periods and locations within the pen. Regardless of diet, location within the pen, or accumulation period (r(2) = 0.76), the WSP(M) increased linearly as the manure moisture increased. As manure accumulation periods increased (48 h, 3 wk, and 39 wk), TP manure concentrations increased (11.9, 13.2, and 17.3 g/kg, respectively), orthophosphate proportions increased (73.2, 80.1, and 91.0%, respectively), and phytate proportions decreased (23.1, 17.0, and 6.7%, respectively). The mineralization of phytate and other organic complexes, which drive off carbon dioxide, presumably contributed to the increased orthophosphate and TP concentrations. Keeping breeder manures dry helps to avoid the mineralization of phytate to orthophosphate; this mineralization increased WSP(M) in our study, and thus increased the potential for elevated P loss in runoff when surface applied.

Expansion of Sidman's theory: The inclusion of prompt stimuli in equivalence classes.

Stimulus equivalence is defined as the ability to relate stimuli in novel ways after training in which not all of the stimuli had been directly linked to one another. Sidman (2000) suggested all elements of conditional discrimination training contingencies that result in equivalence potentially become class members. Research has demonstrated the inclusion of samples, comparisons, responses, and reinforcers in equivalence classes. Given the evidence that all elements of a conditional discrimination become part of the class, the purpose of this study was to determine if class-specific prompts would also enter into their relevant equivalence classes. Experiment 1 investigated the inclusion of prompts in an equivalence class using abstract stimuli with neurotypical students enrolled in higher education courses. Experiment 2 systematically replicated Experiment 1 using meaningful stimuli and individuals diagnosed with autism spectrum disorder. The results of both experiments demonstrated that class-specific prompts became part of equivalence classes with the other positive elements of the contingency. The results are discussed in terms of class expansion and the potential impact on equivalence-based instruction.

Improving Constraints on Planetary Interiors With PPs Receiver Functions.

Seismological constraints obtained from receiver function (RF) analysis provide important information about the crust and mantle structure. Here, we explore the utility of the free-surface multiple of the P-wave (PP) and the corresponding conversions in RF analysis. Using earthquake records, we demonstrate the efficacy of PPs-RFs before illustrating how they become especially useful when limited data is available in typical planetary missions. Using a transdimensional hierarchical Bayesian deconvolution approach, we compute robust P-to-S (Ps)- and PPs-RFs with InSight recordings of five marsquakes. Our Ps-RF results verify the direct Ps converted phases reported by previous RF analyses with increased coherence and reveal other phases including the primary multiple reverberating within the uppermost layer of the Martian crust. Unlike the Ps-RFs, our PPs-RFs lack an arrival at 7.2 s lag time. Whereas Ps-RFs on Mars could be equally well fit by a two- or three-layer crust, synthetic modeling shows that the disappearance of the 7.2 s phase requires a three-layer crust, and is highly sensitive to velocity and thickness of intra-crustal layers. We show that a three-layer crust is also preferred by S-to-P (Sp)-RFs. While the deepest interface of the three-layer crust represents the crust-mantle interface beneath the InSight landing site, the other two interfaces at shallower depths could represent a sharp transition between either fractured and unfractured materials or thick basaltic flows and pre-existing crustal materials. PPs-RFs can provide complementary constraints and maximize the extraction of information about crustal structure in data-constrained circumstances such as planetary missions.

Potential Pitfalls in the Analysis and Structural Interpretation of Seismic Data from the Mars InSight Mission.

The Seismic Experiment for Interior Structure (SEIS) of the InSight mission to Mars, has been providing direct information on Martian interior structure and dynamics of that planet since it landed. Compared to seismic recordings on Earth, ground motion measurements acquired by SEIS on Mars are made under dramatically different ambient noise conditions, but include idiosyncratic signals that arise from coupling between different InSight sensors and spacecraft components. This work is to synthesize what is known about these signal types, illustrate how they can manifest in waveforms and noise correlations, and present pitfalls in structural interpretations based on standard seismic analysis methods. We show that glitches, a type of prominent transient signal, can produce artifacts in ambient noise correlations. Sustained signals that vary in frequency, such as lander modes which are affected by variations in temperature and wind conditions over the course of the Martian Sol, can also contaminate ambient noise results. Therefore, both types of signals have the potential to bias interpretation in terms of subsurface layering. We illustrate that signal processing in the presence of identified nonseismic signals must be informed by an understanding of the underlying physical processes in order for high fidelity waveforms of ground motion to be extracted. While the origins of most idiosyncratic signals are well understood, the 2.4 Hz resonance remains debated and the literature does not contain an explanation of its fine spectral structure. Even though the selection of idiosyncratic signal types discussed in this paper may not be exhaustive, we provide guidance on best practices for enhancing the robustness of structural interpretations.

Arterial transit time effects in pulsed arterial spin labeling CBF mapping: insight from a PET and MR study in normal human subjects.

Arterial transit time (ATT), a key parameter required to calculate absolute cerebral blood flow in arterial spin labeling (ASL), is subject to much uncertainty. In this study, ASL ATTs were estimated on a per-voxel basis using data measured by both ASL and positron emission tomography in the same subjects. The mean ATT increased by 260 +/- 20 (standard error of the mean) ms when the imaging slab shifted downwards by 54 mm, and increased from 630 +/- 30 to 1220 +/- 30 ms for the first slice, with an increase of 610 +/- 20 ms over a four-slice slab when the gap between the imaging and labeling slab increased from 20 to 74 mm. When the per-slice ATTs were employed in ASL cerebral blood flow quantification and the in-slice ATT variations ignored, regional cerebral blood flow could be significantly different from the positron emission tomography measures. ATT also decreased with focal activation by the same amount for both visual and motor tasks (approximately 80 ms). These results provide a quantitative relationship between ATT and the ASL imaging geometry and yield an assessment of the assumptions commonly used in ASL imaging. These findings should be considered in the interpretation of, and comparisons between, different ASL-based cerebral blood flow studies. The results also provide spatially specific ATT data that may aid in optimizing the ASL imaging parameters.

Dynamic synergy of graphitic nanoplatelets and multi-walled carbon nanotubes in polyetherimide nanocomposites.

Hybridizing graphitic nanoplatelets (GNP) with commercially functionalized multi-walled carbon nanotubes (MWCNTs) in a polyetherimide (PEI) composite at a total loading of 0.5 wt% resulted in considerable improvements in electrical conductivity, thermal conductivity and dynamic mechanical properties, compared to solely GNP or solely MWCNT composites at the same total loading. The results reveal a synergistic interaction between the GNPs and MWCNTs based on GNP protection against fragmentation of the MWCNTs during high power sonication, while still allowing full dispersion of both fillers, by providing a shielding mechanism against MWCNT damage during dispersion processing. A new process for molecular level dispersion of exfoliated GNPs in PEI is also reported. Field emission scanning electron microscopy revealed strong interactions between PEI and the flat surfaces of GNPs and effectively intercalated GNP morphology within the matrix. GNPs alone can also produce excellent electrical conductivity improvements: at 1.0 wt% of GNP, electrical conductivity of the composite increased by 11 orders of magnitude and the percolation threshold was determined to be between 0.5 and 1.0 wt% of GNP.

Changes in cortical grey matter density associated with long-standing retinal visual field defects.

Retinal lesions caused by eye diseases such as glaucoma and age-related macular degeneration can, over time, eliminate stimulation of parts of the visual cortex. This could lead to degeneration of inactive cortical neuronal tissue, but this has not been established in humans. Here, we used magnetic resonance imaging to assess the effects of prolonged sensory deprivation in human visual cortex. High-resolution anatomical magnetic resonance images were obtained in subjects with foveal (age-related macular degeneration) and peripheral (glaucoma) retinal lesions as well as age-matched controls. Comparison of grey matter between patient and control groups revealed density reductions in the approximate retinal lesion projection zones in visual cortex. This indicates that long-term cortical deprivation, due to retinal lesions acquired later in life, is associated with retinotopic-specific neuronal degeneration of visual cortex. Such degeneration could interfere with therapeutic strategies such as the future application of artificial retinal implants to overcome lesion-induced visual impairment.