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.

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.

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.

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.

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.

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.

A Comparative Study of in†vitro Assays for Predicting the Nonspecific Binding of PET Imaging Agents in†vivo.

Nonspecific binding (NSB) is a key parameter in optimizing PET imaging tracers. We compared the ability to predict NSB of three available methods: LIMBA, rat fu,brain , and CHI(IAM). Even though NSB is often associated with lipophilicity, we observed that logD does not correlate with any of these assays, clearly indicating that lipophilicity, while influencing NSB, is insufficient to predict it. A cross-comparison of the methods showed that all three correlate and are useful predictors of NSB. The three assays, however, rank the molecules slightly differently, illustrating the challenge of comparing molecules within a narrow chemical space. We also noted that CHI(IAM) values more effectively predict VNS , a measure of in vivo NSB in the human brain. CHI(IAM) measurements might be a closer model of the actual physicochemical interaction between PET tracer candidates and cell membranes, and seems to be the method of choice for the optimization of in vivo NSB.

Assessment of a white matter reference region for 11C-UCB-J PET quantification.

11C-UCB-J is a positron emission tomography (PET) radioligand that has been used in humans for synaptic vesicle glycoprotein 2A (SV2A) imaging and as a potential synaptic density marker. The centrum semiovale (CS) is a proposed reference region for noninvasive quantification of 11C-UCB-J, due to negligible concentrations of SV2A in this region in baboon brain assessed by in vitro methods. However, in displacement scans with SV2A-specific drug levetiracetam in humans, a decrease in 11C-UCB-J concentration was observed in the CS, consistent with some degree of specific binding. The current study aims to validate the CS as a reference region by (1) optimizing CS region of interest (ROI) to minimize spill-in from gray matter with high radioactivity concentrations; (2) investigating convergence of CS ROI values using ordered subset expectation maximization (OS-EM) reconstruction, and (3) comparing baseline CS volume of distribution (VT) to nondisplaceable uptake in gray matter, VND. Improving ROI definition and increasing OS-EM iterations during reconstruction decreased the difference between CS VT and VND. However, even with these corrections, CS VT overestimated VND by ∼35-40%. These measures showed significant correlation, suggesting that, though biased, the CS may be a useful estimate of nondisplaceable uptake, allowing for noninvasive quantification for SV2A PET.

Associations between imprinted gene differentially methylated regions, appetitive traits and body mass index in children.

BACKGROUND: Knowledge regarding genetic influences on eating behaviours is expanding; yet less is known regarding contributions of epigenetic variation to appetitive traits and body mass index (BMI) in children. OBJECTIVE: The purpose of this study was to explore relationships between methylation at differentially methylated regions (DMRs) of imprinted genes (insulin-like growth factor 2/H19 and Delta-like, Drosophila, homolog 1/maternally expressed gene 3) using DNA extracted from umbilical cord blood leucocytes, two genetically influenced appetitive traits (food responsiveness and satiety responsiveness) and BMI. METHODS: Data were obtained from participants (N = 317; mean age = 3.6 years; SD = 1.8 years) from the Newborn Epigenetic STudy. Conditional process models were implemented to investigate the associations between DMRs of imprinted genes and BMI, and test whether this association was mediated by appetitive traits and birthweight and moderated by sex. RESULTS: Appetitive traits and birthweight did not mediate the relationship between methylation at DMRs. Increased insulin-like growth factor 2 DMR methylation was associated with higher satiety responsiveness. Higher satiety responsiveness was associated with lower BMI. Associations between methylation at DMRs, appetitive traits and BMI differed by sex. CONCLUSIONS: This is one of the first studies to demonstrate associations between epigenetic variation established prior to birth with appetitive traits and BMI in children, providing support for the need to uncover genetic and epigenetic mechanisms for appetitive traits predisposing some individuals to obesity.

Elevated metabolites of acetaminophen in cord blood of children with obesity.

BACKGROUND: High-throughput metabolomics has been used cross-sectionally to evaluate differential metabolic profiles associated with human obesity. OBJECTIVES: This study longitudinally assessed the cord blood metabolome to explore if metabolic signatures of obesity at age 3-5 are apparent at birth. METHODS: In a nested case-control design, metabolomics analysis was performed on umbilical cord blood of 25 children who developed obesity by age 3-5 years, compared with 25 sex-matched non-obese children enrolled as part of an ongoing birth cohort. Logistic regression models were used to identify significant metabolites, adjusting for maternal pre-pregnancy obesity. RESULTS: Children who had obesity by age 3-5 years had elevated levels of medium and long chain fatty acids including stearate, oleate and palmitate at birth. Children with obesity were also more likely to have elevated levels of acetaminophen metabolites at birth, specifically: 3-(N-acetyl-L-cystein-S-yl) acetaminophen, 2-hydroxyacetaminophen sulfate, 2-methoxyacetaminophen glucuronide and p-acetamidophenyl glucuronide. CONCLUSION: Although the observed increases in lipids are consistent with previous metabolomic studies of obesity, this study is the first to report associations between acetaminophen metabolites and obesity in children; however, we lack mechanistic insights for this link. Larger human studies with longer follow-up and laboratory-controlled animal experiments are needed to clarify associations.

Seismicity on tidally active solid-surface worlds.

Tidal interactions between planets or stars and the bodies that orbit them dissipate energy in their interiors. The dissipated energy heats the interior and a fraction of that energy will be released as seismic energy. Here we formalize a model to describe the tidally-driven seismic activity on planetary bodies based on tidal dissipation. To constrain the parameters of our model we use the seismic activity of the Moon, driven by tidal dissipation from the Earth-Moon interactions. We then apply this model to predict the amount of seismic energy release and largest seismic events on other moons in our Solar System and exoplanetary bodies. We find that many moons in the Solar System should be more seismically active than the Earth's Moon and many exoplanets should exhibit more seismic activity than the Earth. Finally, we examine how temporal-spatial variations in tidal dissipation manifest as variations in the locations and timing of seismic events on these bodies.

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.

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.

Active Aß immunotherapy CAD106 in Alzheimer's disease: A phase 2b study.

INTRODUCTION: This randomized, double-blind, placebo-controlled, 90-week study assessed safety, tolerability, and immunogenicity of CAD106 with/without adjuvant in patients with mild Alzheimer's disease. METHODS: One hundred twenty-one patients received up to seven intramuscular injections of CAD106 (150 µg or 450 µg) or placebo ± adjuvant over 60 weeks. An amyloid positron emission tomography (PET) substudy was also conducted. RESULTS: CAD106 induced strong serological responses (amyloid-beta [Aß]-Immunoglobuline G[IgG]) in 55.1% (150 µg) and 81.1% (450 µg) of patients (strong serological responders [SSRs]). Serious adverse events (SAEs) were reported in 24.5% (95% confidence interval [CI] 16.7-33.8) of the patients in the active treatment group and in 6.7% (95% CI 0.2-31.9) in the placebo group. Three of the SAEs were classified as possibly related to study drug by the investigators. No evidence of central nervous system inflammation was found. Amyloid-related imaging abnormalities (ARIAs) occurred in six cases, all of them were strong serological responders. None of the ARIAs were symptomatic. Serum Aß-IgG titer area under the curves correlated negatively with amyloid PET standardized uptake value ratio percentage change from baseline to week 78 within the CAD106-treated patients (r = -0.84, P = .0004). Decrease in cortical gray-matter volume from baseline to week 78 was larger in SSRs than in controls (P = .0077). DISCUSSION: Repeated CAD106 administration was generally well tolerated. CAD106 450 µg with alum adjuvant demonstrated the best balance between antibody response and tolerability.

An atmospheric pressure chemical ionisation liquid chromatographic-tandem mass spectrometry method for the analysis of benzodiazepines in urine.

The objective of this work was to establish an analytical method for the analysis of 7 Benzodiazepines (diazepam, oxazepam, temazepam, nordiazepam, desalkylflurazepam, alprazolam and α-hydroxyalprazolam) in urine specimens taken from drivers suspected of driving under the influence of drugs. The specimen, calibrator and control preparation involved hydrolysis of conjugated benzodiazepines using ß-glucuronidase in sodium acetate buffer, with incubation at 60°C for 2h. Specimens were then centrifuged, before being diluted 1 in 5 (total dilution 1 in 10), with 10% acetonitrile in water. Specimens were analysed using a Shimadzu Prominence UPLC coupled to an AB Sciex 4000 QTrap LC-MS-MS. The chromatographic column was a Shim-pack XR ODS 2.2µm. 3.0×50mm column and the mobile phase was a binary gradient system comprising of mobile phase A which was an ammonium formate/formic acid buffer dissolved in water and mobile phase B which was an ammonium formate/formic acid buffer dissolved in Acetonitrile. APCI was selected as the ionisation technique and the MS was operated in MRM mode, monitoring 2 transitions per analyte. The validation of the method is described. The method was found to be linear, accurate and precise (within day and between day) for diazepam, oxazepam, temazepam, nordiazepam, desalkylflurazepam, alprazolam and α-hydroxyalprazolam. The results of 480 cases are reviewed and show that alprazolam use was found in 35% of cases. Use of benzodiazepines resulting in oxazepam, nordiazepam or temazepam were found ca. 70% of cases analysed.

Disparities in Cervical Cancer Incidence and Mortality: Can Epigenetics Contribute to Eliminating Disparities?

Screening for uterine cervical intraepithelial neoplasia (CIN) followed by aggressive treatment has reduced invasive cervical cancer (ICC) incidence and mortality. However, ICC cases and carcinoma in situ (CIS) continue to be diagnosed annually in the United States, with minorities bearing the brunt of this burden. Because ICC peak incidence and mortality are 10-15 years earlier than other solid cancers, the number of potential years of life lost to this cancer is substantial. Screening for early signs of CIN is still the mainstay of many cervical cancer control programs. However, the accuracy of existing screening tests remains suboptimal. Changes in epigenetic patterns that occur as a result of human papillomavirus infection contribute to CIN progression to cancer, and can be harnessed to improve existing screening tests. However, this requires a concerted effort to identify the epigenomic landscape that is reliably altered by HPV infection specific to ICC, distinct from transient changes.

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.