Acid-suppressive medication and incidence of chronic childhood immune-mediated diseases: A scoping review.

BACKGROUND: Use of acid-suppressive medications (ASMs), for example, proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs), has been rising along with the incidence of pediatric immune-mediated diseases (IMDs). We conducted a scoping review to characterize the literature about prenatal or pediatric exposure to ASMs in relation to incident pediatric IMDs. METHODS: Electronic searches were conducted to identify studies from 2001 to 2023 on (a) prenatal or pediatric exposure to PPIs and/or H2RAs and (b) the risk of developing chronic IMDs during childhood. Eligible studies after title/abstract and full-text screening underwent data abstraction. RESULTS: Of 26 eligible studies, 11 focused on prenatal ASM exposure and 16 on pediatric exposure. Asthma was the most commonly investigated outcome (16 studies), followed by other allergic diseases (8), eosinophilic esophagitis (3), inflammatory bowel disease (2), and other autoimmune diseases (2). Positive associations between ASM exposure and pediatric IMD outcomes emerged in all but two recent studies, which reported null or negative associations with allergic diseases. The strength of associations was similar across exposure times (prenatal/pediatric), medications (PPIs/H2RAs), and outcomes. Dose-response relationships were often present (7/11 studies). Reported effects by trimester and age of exposure varied. Commonly reported limitations were residual confounding, exposure misclassification, and outcome misclassification. CONCLUSION: In summary, prenatal or pediatric exposure to PPIs and/or H2RAs has frequently, but not exclusively, been associated with the development of asthma, other allergic diseases, and chronic gastrointestinal IMDs. However, concerns remain about confounding and other sources of bias. Prescribers and families should be aware of these possible risks of ASMs.

Optimizing photoswitchable MEK.

Optogenetic approaches are transforming quantitative studies of cell-signaling systems. A recently developed photoswitchable mitogen-activated protein kinase kinase 1 (MEK1) enzyme (psMEK) short-circuits the highly conserved Extracellular Signal-Regulated Kinase (ERK)-signaling cascade at the most proximal step of effector kinase activation. However, since this optogenetic tool relies on phosphorylation-mimicking substitutions in the activation loop of MEK, its catalytic activity is predicted to be substantially lower than that of wild-type MEK that has been phosphorylated at these residues. Here, we present evidence that psMEK indeed has suboptimal functionality in vivo and propose a strategy to circumvent this limitation by harnessing gain-of-function, destabilizing mutations in MEK. Specifically, we demonstrate that combining phosphomimetic mutations with additional mutations in MEK, chosen for their activating potential, restores maximal kinase activity in vitro. We establish that this modification can be tuned by the choice of the destabilizing mutation and does not interfere with reversible activation of psMEK in vivo in both Drosophila and zebrafish. To illustrate the types of perturbations enabled by optimized psMEK, we use it to deliver pulses of ERK activation during zebrafish embryogenesis, revealing rheostat-like responses of an ERK-dependent morphogenetic event.

Imaging Glycosylation In Vivo by Metabolic Labeling and Magnetic Resonance Imaging.

Glycosylation is a ubiquitous post-translational modification, present in over 50% of the proteins in the human genome, with important roles in cell-cell communication and migration. Interest in glycome profiling has increased with the realization that glycans can be used as biomarkers of many diseases, including cancer. We report here the first tomographic imaging of glycosylated tissues in live mice by using metabolic labeling and a gadolinium-based bioorthogonal MRI probe. Significant N-azidoacetylgalactosamine dependent T1  contrast was observed in vivo two hours after probe administration. Tumor, kidney, and liver showed significant contrast, and several other tissues, including the pancreas, spleen, heart, and intestines, showed a very high contrast (>10-fold). This approach has the potential to enable the rapid and non-invasive magnetic resonance imaging of glycosylated tissues in vivo in preclinical models of disease.

Detection of transgene expression using hyperpolarized 13C urea and diffusion-weighted magnetic resonance spectroscopy.

PURPOSE: To assess the potential of a gene reporter system, based on a urea transporter (UTB) and hyperpolarized [(13) C]urea. METHODS: Mice were implanted subcutaneously with either unmodified control cells or otherwise identical cells expressing UTB. After injection of hyperpolarized [(13) C]urea, a spin echo sequence was used to measure urea concentration, T1 , and diffusion in control and UTB-expressing tissue. RESULTS: The apparent diffusion coefficient of hyperpolarized urea was 21% lower in tissue expressing UTB, in comparison with control tissue (P < 0.05, 1-tailed t-test, n = 6 in each group). No difference in water apparent diffusion coefficient or cellularity between these tissues was found, indicating that they were otherwise similar in composition. CONCLUSION: Expression of UTB, by mediating cell uptake of urea, lowers the apparent diffusion coefficient of hyperpolarized (13) C urea in tissue and thus the transporter has the potential to be used as a magnetic resonance-based gene reporter in vivo. Magn Reson Med 73:1401-1406, 2015. © 2014 Wiley Periodicals, Inc.

A new likelihood ratio metric for the psychomotor vigilance test and its sensitivity to sleep loss.

The Psychomotor Vigilance Test (PVT) is a widely used assay of behavioural alertness sensitive to the effects of sleep loss and circadian misalignment. However, there is currently no accepted PVT composite outcome metric that captures response slowing, attentional lapses and compensatory premature reactions observed typically in sleep-deprived subjects. We developed a novel likelihood ratio metric (LRM) based on relative frequency distributions in 50 categories of reaction times (RT) and false starts in alert and sleep-deprived subjects (acute total sleep deprivation: n = 31 subjects). The LRM had the largest effect size both in a 33-h total sleep deprivation protocol [1.96; 95% confidence interval (CI): 1.61-2.44; followed by response speed 1/RT, effect size 1.93, 95% CI: 1.55-2.65] and in a chronic partial sleep restriction protocol (1.22; 95% CI: 0.96-1.59; followed by response speed 1/RT, effect size 1.21, 95% CI: 0.94-1.59; 5 nights at 4 h sleep per night; n = 43 subjects). LRM scores correlated highly with response speed (R(2 ) = 0.986), and less well with five other common PVT outcome metrics (R(2 ) = 0.111-0.886). In conclusion, the new LRM is a sensitive PVT outcome metric with high statistical power that takes subtle sleep loss-related changes in the distribution of reaction times (including false starts) into account, is not prone to outliers, does not require baseline data and can be calculated and interpreted easily. Congruence between LRM and PVT response speed and their similar effect size rankings support the use of response speed as the primary, most sensitive and most parsimonious standard PVT outcome metric for determining neurobehavioural deficits from sleep loss.

Spatial mapping of functional pelvic bone marrow using FLT PET.

The purpose of this study was to determine the ability of regions identified with bony landmarks on CT imaging to accurately represent active bone marrow when compared to FLT PET imaging. These surrogate regions could then be used to create a bone marrow sparing radiation therapy plan when FLT PET imaging is not available. Whole body (WB) FLT PET images were obtained of 18 subjects prior to chemoradiation therapy. The FLT image of each subject was registered to a CT image acquired for that subject to obtain anatomic information of the pelvis. Seventeen regions were identified based on features of the pelvic bones, sacrum, and femoral heads. The probability of FLT uptake being located in each of 17 different CT-based regions of the bony pelvis was calculated using Tukey's multiple comparison test. Statistical analysis of FLT uptake in the pelvis indicated four distinct groups within the 17 regions that had similar levels of activity. Regions located in the central part of the pelvis, including the superior part of the sacrum, the inner halves of the iliac crests, and the L5 vertebral body, had greater FLT uptake than those in the peripheral regions (p-value < 0.05). We have developed a method to use CT-defined pelvic bone regions to represent FLT PET-identified functional bone marrow. Individual regions that have a statistically significant probability of containing functional bone marrow can be used as avoidance regions to reduce radiation dose to functional bone marrow in radiation therapy planning. However, because likely active bone marrow regions and pelvic targets typically overlap, patient-specific spatial detail may be advantageous in IMRT planning scenarios and may best be provided using FLT PET imaging.

SARS-CoV-2 recombinant spike ferritin nanoparticle vaccine adjuvanted with Army Liposome Formulation containing monophosphoryl lipid A and QS-21: a phase 1, randomised, double-blind, placebo-controlled, first-in-human clinical trial.

BACKGROUND: A self-assembling SARS-CoV-2 WA-1 recombinant spike ferritin nanoparticle (SpFN) vaccine co-formulated with Army Liposomal Formulation (ALFQ) adjuvant containing monophosphoryl lipid A and QS-21 (SpFN/ALFQ) has shown protective efficacy in animal challenge models. This trial aims to assess the safety and immunogenicity of SpFN/ALFQ in a first-in-human clinical trial. METHODS: In this phase 1, randomised, double-blind, placebo-controlled, first-in-human clinical trial, adults were randomly assigned (5:5:2) to receive 25 µg or 50 µg of SpFN/ALFQ or saline placebo intramuscularly at day 1 and day 29, with an optional open-label third vaccination at day 181. Enrolment and randomisation occurred sequentially by group; randomisation was done by an interactive web-based randomisation system and only designated unmasked study personnel had access to the randomisation code. Adults were required to be seronegative and unvaccinated for inclusion. Local and systemic reactogenicity, adverse events, binding and neutralising antibodies, and antigen-specific T-cell responses were quantified. For safety analyses, exact 95% Clopper-Pearson CIs for the probability of any incidence of an unsolicited adverse event was computed for each group. For immunogenicity results, CIs for binary variables were computed using the exact Clopper-Pearson methodology, while CIs for geometric mean titres were based on 10 000 empirical bootstrap samples. Post-hoc, paired one-sample t tests were used to assess the increase in mean log-10 neutralising antibody titres between day 29 and day 43 (after the second vaccination) for the primary SARS-CoV-2 targets of interest. This trial is registered at ClinicalTrials.gov, NCT04784767, and is closed to new participants. FINDINGS: Between April 7, and June 29, 2021, 29 participants were enrolled in the study. 20 individuals were assigned to receive 25 µg SpFN/ALFQ, four to 50 µg SpFN/ALFQ, and five to placebo. Neutralising antibody responses peaked at day 43, 2 weeks after the second dose. Neutralisation activity against multiple omicron subvariants decayed more slowly than against the D614G or beta variants until 5 months after second vaccination for both dose groups. CD4+ T-cell responses were elicited 4 weeks after the first dose and were boosted after a second dose of SpFN/ALFQ for both dose groups. Neutralising antibody titres against early omicron subvariants and clade 1 sarbecoviruses were detectable after two immunisations and peaked after the third immunisation for both dose groups. Neutralising antibody titres against XBB.1.5 were detected after three vaccinations. Passive IgG transfer from vaccinated volunteers into Syrian golden hamsters controlled replication of SARS-CoV-1 after challenge. INTERPRETATION: SpFN/ALFQ was well tolerated and elicited robust and durable binding antibody and neutralising antibody titres against a broad panel of SARS-CoV-2 variants and other sarbecoviruses. FUNDING: US Department of Defense, Defense Health Agency.

Changes in Eye Tracking Features Across Periods of Overpressure Exposure.

INTRODUCTION: Repetitive exposure to blast overpressure waves can be a part of routine military and law enforcement training. However, our understanding of the effects of that repetitive exposure on human neurophysiology remains limited. To link an individual's cumulative exposure with their neurophysiological effects, overpressure dosimetry needs to be concurrently collected with relevant physiological signals. Eye tracking has shown promise for providing insight into neurophysiological change because of neural injury, but video-based technology limits usage to a laboratory or clinic. In the present work, we show capability for using electrooculography-based eye tracking to enable physiological assessment in the field during activities involved repetitive blast exposures. MATERIALS AND METHODS: Overpressure dosimetry was accomplished by using a body-worn measurement system that captures continuous sound pressure levels as well as pressure waveforms of blast event in the range of 135-185 dB peak (0.1-36 kPa). Electrooculography eye tracking was performed using a commercial Shimmer Sensing system, which captured horizontal eye movements of both the left and right eyes, as well as vertical eye movements of the right eye, from which blinks can also be extracted. Data were collected during breaching activities that included repetitive use of explosives. Participants in the study were U.S. Army Special Operators and Federal Bureau of Investigations special agents. Approval for research was received by the Massachucetts Institute of Technology Committee on the Use of Humans as Experimental Subjects, the Air Force Human Research Protections Office, and the Federal Bureau of Investigations Institutional Review Board. RESULTS: The energy from overpressure events was accumulated and summarized into an 8-hour equivalent of sound pressure level (i.e., LZeq8hr). The total exposure in a single day, i.e., the LZeq8hr, ranged from 110 to 160 dB. Oculomotor features, such as blink and saccade rate, as well as variance in blink waveforms, show changes across the period of overpressure exposure. However, the features that showed significant change across the population were not necessarily the ones that showed significant correlation with the levels of overpressure exposure. A regression model built to predict overpressure levels from oculomotor features alone showed a significant association (R = 0.51, P < .01). Investigation of the model indicates that changes in the saccade rate and blink waveforms are driving the relationship. CONCLUSIONS: This study successfully demonstrated that eye tracking can be performed during training activities, such as explosive breaching, and that the modality may provide insight into neurophysiological change across periods of overpressure exposure. The results presented herein show that electrooculography-based eye tracking may be a useful method of assessing individualized physiological effects of overpressure exposure in the field. Future work is focused on time-dependent modeling to assess continuous changes in eye movements as this will enable building dose-response curves.

Improving interstitial transport of macromolecules through reduction in cell volume fraction in tumor tissues.

Interstitial transport of large molecules and nanoparticles is an important concern in nanomedicine-mediated cancer treatment. To that end, the current study was proposed to improve the transport through enlargement of extracellular space by treating tumors with hypertonic solution of mannitol and cytotoxic agents (e.g., ethacrynic acid [ECA]), which could effectively shrink and kill cells, respectively. In the study, the improvement in interstitial penetration of dextran was investigated ex vivo using rat fibrosarcoma tissues sectioned into 600 µm slices. Experimental data showed that the hypertonic solution was more effective than ECA for improving interstitial penetration of dextran with molecular weights ranging from 4000 to 2,000,000. The extent of improvement depended on the size of dextran molecules and the time when the treatment was applied. Results from the study suggested that increases in both size and connectedness of interstitial pathways were important for improvement of interstitial transport of large molecules and nanoparticles. FROM THE CLINICAL EDITOR: This study reports on the optimization of interstitial transport both for large molecules and nanoparticles in nanomedicine-mediated cancer treatment. The study demonstrates that hypertonic solutions could efficiently lead to cancer cell shrinkage and more so than the applied cytotoxic agent thereby improving transport of chemotherapeutic entities.

Parental experiences of psychological interventions for recurrent abdominal pain in childhood.

Active components of psychological intervention for RAP remain unclear. This study involved completing interviews about parental experience of psychological intervention for RAP to ascertain how and why psychological intervention can be effective. Difficulty making sense of RAP and barriers to treatment were identified as struggles. Acceptance and containment were key overlapping mechanisms, which allowed families to develop a changed relationship with the pain and manage the impact of pain. To further develop interventions, the role of containment should be considered and acceptance-based interventions explored, given the growing evidence base in this area. Practical implications of this research are also discussed.

Aircraft Noise Effects on Sleep-Results of a Pilot Study Near Philadelphia International Airport.

Current objective data on aircraft noise effects on sleep are needed in the US to inform policy. In this pilot field study, heart rate and body movements were continuously measured during sleep of residents living in the vicinity of Philadelphia International Airport (PHL) and in a control region without aircraft noise with sociodemographic characteristics similar to the exposed region (N = 40 subjects each). The primary objective was to establish the feasibility of unattended field measurements. A secondary objective was to compare objective and subjective measures of sleep and health between control and aircraft noise exposed groups. For all measurements, there was less than 10% of data loss, demonstrating the feasibility of unattended home measurements. Based on 2375 recorded aircraft noise events, we found a significant (unadjusted p = 0.0136) exposure-response function between the maximum sound pressure level of aircraft noise events and awakening probability inferred from heart rate increases and body movements, which was similar to previous studies. Those living near the airport reported poorer sleep quality and poorer health than the control group in general, but when asked in the morning about their last night's sleep, no significant difference was found between groups. Neither systolic nor diastolic morning blood pressures differed between study regions. While this study demonstrates the feasibility of unattended field study measurements, for a national study around multiple US airports refinements of the study design are necessary to further lower methodological expense and increase participation rates.

MRI-only brain radiotherapy: Assessing the dosimetric accuracy of synthetic CT images generated using a deep learning approach.

PURPOSE: This study assessed the dosimetric accuracy of synthetic CT images generated from magnetic resonance imaging (MRI) data for focal brain radiation therapy, using a deep learning approach. MATERIAL AND METHODS: We conducted a study in 77 patients with brain tumors who had undergone both MRI and computed tomography (CT) imaging as part of their simulation for external beam treatment planning. We designed a generative adversarial network (GAN) to generate synthetic CT images from MRI images. We used Mutual Information (MI) as the loss function in the generator to overcome the misalignment between MRI and CT images (unregistered data). The model was trained using all MRI slices with corresponding CT slices from each training subject's MRI/CT pair. RESULTS: The proposed GAN method produced an average mean absolute error (MAE) of 47.2 ±â€¯11.0 HU over 5-fold cross validation. The overall mean Dice similarity coefficient between CT and synthetic CT images was 80% ±â€¯6% in bone for all test data. Though training a GAN model may take several hours, the model only needs to be trained once. Generating a complete synthetic CT volume for each new patient MRI volume using a trained GAN model took only one second. CONCLUSIONS: The GAN model we developed produced highly accurate synthetic CT images from conventional, single-sequence MRI images in seconds. Our proposed method has strong potential to perform well in a clinical workflow for MRI-only brain treatment planning.

WHO Environmental Noise Guidelines for the European Region: A Systematic Review on Environmental Noise and Effects on Sleep.

To evaluate the quality of available evidence on the effects of environmental noise exposure on sleep a systematic review was conducted. The databases PSYCINFO, PubMed, Science Direct, Scopus, Web of Science and the TNO Repository were searched for non-laboratory studies on the effects of environmental noise on sleep with measured or predicted noise levels and published in or after the year 2000. The quality of the evidence was assessed using GRADE criteria. Seventy four studies predominately conducted between 2000 and 2015 were included in the review. A meta-analysis of surveys linking road, rail, and aircraft noise exposure to self-reports of sleep disturbance was conducted. The odds ratio for the percent highly sleep disturbed for a 10 dB increase in Lnight was significant for aircraft (1.94; 95% CI 1.61-2.3), road (2.13; 95% CI 1.82-2.48), and rail (3.06; 95% CI 2.38-3.93) noise when the question referred to noise, but non-significant for aircraft (1.17; 95% CI 0.54-2.53), road (1.09; 95% CI 0.94-1.27), and rail (1.27; 95% CI 0.89-1.81) noise when the question did not refer to noise. A pooled analysis of polysomnographic studies on the acute effects of transportation noise on sleep was also conducted and the unadjusted odds ratio for the probability of awakening for a 10 dBA increase in the indoor Lmax was significant for aircraft (1.35; 95% CI 1.22-1.50), road (1.36; 95% CI 1.19-1.55), and rail (1.35; 95% CI 1.21-1.52) noise. Due to a limited number of studies and the use of different outcome measures, a narrative review only was conducted for motility, cardiac and blood pressure outcomes, and for children's sleep. The effect of wind turbine and hospital noise on sleep was also assessed. Based on the available evidence, transportation noise affects objectively measured sleep physiology and subjectively assessed sleep disturbance in adults. For other outcome measures and noise sources the examined evidence was conflicting or only emerging. According to GRADE criteria, the quality of the evidence was moderate for cortical awakenings and self-reported sleep disturbance (for questions that referred to noise) induced by traffic noise, low for motility measures of traffic noise induced sleep disturbance, and very low for all other noise sources and investigated sleep outcomes.

Repeated Administration Effects on Psychomotor Vigilance Test Performance.

Study Objectives: The Psychomotor Vigilance Test (PVT) is reported to be free of practice effects that can otherwise confound the effects of sleep loss and circadian misalignment on performance. This differentiates the PVT from more complex cognitive tests. To the best of our knowledge, no study has systematically investigated practice effects on the PVT across multiple outcome domains, depending on administration interval, and in ecologically more valid settings. Methods: We administered a validated 3-minute PVT (PVT-B) 16 times in 45 participants (23 male, mean ± SD age 32.6 ± 7.3 years, range 25-54 years) with administration intervals of ≥10 days, ≤5 days, or 4 times per day. We investigated linear and logarithmic trends across repeated administrations in 10 PVT-B outcome variables. Results: The fastest 10% of response times (RT; plin = .0002), minimum RT (plog = .0010), and the slowest 10% of reciprocal RT (plog = .0124) increased while false starts (plog = 0.0050) decreased with repeated administration, collectively decreasing RT variability (plog = .0010) across administrations. However, the observed absolute changes were small (e.g., -0.03 false starts per administration, linear fit) and are probably irrelevant in practice. Test administration interval did not modify the effects of repeated administration on PVT-B performance (all p > .13 for interaction). Importantly, mean and median RT, response speed, and lapses, which are among the most frequently used PVT outcomes, did not change systematically with repeated administration. Conclusions: PVT-B showed stable performance across repeated administrations. Combined with its high sensitivity, this corroborates the status of the PVT as the de facto gold standard measure of the neurobehavioral effects of sleep loss and circadian misalignment.

Effects of -12° head-down tilt with and without elevated levels of CO2 on cognitive performance: the SPACECOT study.

Microgravity and elevated levels of CO2 are two common environmental stressors in spaceflight that may affect cognitive performance of astronauts. In this randomized, double-blind, crossover trial (SPACECOT), 6 healthy males (mean ± SD age: 41 ± 5 yr) were exposed to 0.04% (ambient air) and 0.5% CO2 concentrations during 26.5-h periods of -12° head-down tilt (HDT) bed rest with a 1-wk washout period between exposures. Subjects performed the 10 tests of the Cognition Test Battery before and on average 0.1, 5.2, and 21.0 h after the initiation of HDT bed rest. HDT in ambient air induced a change in response strategy, with increased response speed (+0.19 SD; P = 0.0254) at the expense of accuracy (-0.19 SD; P = 0.2867), resulting in comparable cognitive efficiency. The observed effects were small and statistically significant for cognitive speed only. However, even small declines in accuracy can potentially cause errors during mission-critical tasks in spaceflight. Unexpectedly, exposure to 0.5% CO2 reversed the response strategy changes observed under HDT in ambient air. This was possibly related to hypercapnia-induced cerebrovascular reactivity that favors cortical regions in general and the frontal cortex in particular, or to the CNS arousing properties of mildly to moderately increased CO2 levels. There were no statistically significant time-in-CO2 effects for any cognitive outcome. The small sample size and the small effect sizes are major limitations of this study and its findings. The results should not be generalized beyond the group of investigated subjects until they are confirmed by adequately powered follow-up studies. NEW & NOTEWORTHY Simulating microgravity with exposure to 21 h of -12° head-down tilt bed rest caused a change in response strategy on a range of cognitive tests, with a statistically significant increase in response speed at the expense of accuracy. Cognitive efficiency was not affected. The observed speed-accuracy tradeoff was small but may nevertheless be important for mission-critical tasks in spaceflight. Importantly, the change in response strategy was reversed by increasing CO2 concentrations to 0.5%.

Body mass index differences in pseudohypoparathyroidism type 1a versus pseudopseudohypoparathyroidism may implicate paternal imprinting of Galpha(s) in the development of human obesity.

CONTEXT: Obesity is a prominent feature of Albright hereditary osteodystrophy (AHO), a disorder caused by heterozygous GNAS mutations that disrupt the stimulatory G protein alpha-subunit Galpha(s). Because Galpha(s) is paternally imprinted in certain hormone target tissues, maternal inheritance of AHO leads to multihormone resistance [pseudohypoparathyroidism type 1a (PHP1a)], whereas paternal inheritance leads to AHO alone [pseudopseudohypoparathyroidism (pseudoPHP)]. Classically, the obesity in AHO is described as occurring similarly in both conditions. SETTING: This observational study was conducted at the General Clinical Research Center, Johns Hopkins University School of Medicine; National Institutes of Health. PATIENTS: Fifty-three patients with AHO (40 with PHP1a and 13 with pseudoPHP) and two with progressive osseous heteroplasia were studied. MAIN OUTCOME MEASURES: Main outcome measures were weight and height sd score (SDS), body mass index (BMI) percentiles, and BMI z-scores. RESULTS: Patients with PHP1a had significantly greater mean weight SDS, BMI percentages, and BMI z-scores compared with patients with pseudoPHP. These differences in BMI were secondary to adipose content based on dual energy x-ray absorptiometry analysis. The mean BMI z-score +/- sem for PHP1a was 2.31 +/- 0.18 compared with 0.65 +/- 0.31 in pseudoPHP (P = 0.000032). Twenty-five of 40 (62.5%) patients with PHP1a had mean BMI z-scores greater than two SDS above the mean, whereas no patients with pseudoPHP had BMI z-scores in this range. CONCLUSIONS: Although the AHO phenotype for PHP1a and pseudoPHP has been thought to be similar, we have found that obesity is a more prominent feature in PHP1a than in pseudoPHP and that severe obesity is characteristic of PHP1a specifically. These findings may implicate paternal imprinting of Galpha(s) in the development of human obesity.

MRI measurements of reporter-mediated increases in transmembrane water exchange enable detection of a gene reporter.

Non-invasive imaging of gene expression can be used to track implanted cells in vivo but often requires the addition of an exogenous contrast agent that may have limited tissue access. We show that the urea transporter (UT-B) can be used as a gene reporter, where reporter expression is detected using 1H MRI measurements of UT-B-mediated increases in plasma membrane water exchange. HEK cells transfected with the reporter showed an increased apparent water exchange rate (AXR), which increased in line with UT-B expression. AXR values measured in vivo, in UT-B-expressing HEK cell xenografts, were significantly higher (about twofold, P < 0.0001), compared with non-expressing controls. Fluorescence imaging of a red fluorescent protein (mStrawberry), co-expressed with UT-B showed that UT-B expression correlated in a linear fashion with AXR. Transduction of rat brain cells in situ with a lentiviral vector expressing UT-B resulted in about a twofold increase in AXR at the site of virus injection.

Optoacoustic Detection of Early Therapy-Induced Tumor Cell Death Using a Targeted Imaging Agent.

Purpose: The development of new treatments and their deployment in the clinic may be assisted by imaging methods that allow an early assessment of treatment response in individual patients. The C2A domain of Synaptotagmin-I (C2Am), which binds to the phosphatidylserine (PS) exposed by apoptotic and necrotic cells, has been developed as an imaging probe for detecting cell death. Multispectral optoacoustic tomography (MSOT) is a real-time and clinically applicable imaging modality that was used here with a near infrared (NIR) fluorophore-labeled C2Am to image tumor cell death in mice treated with a TNF-related apoptosis-inducing ligand receptor 2 (TRAILR2) agonist and with 5-fluorouracil (5-FU).Experimental Design: C2Am was labeled with a NIR fluorophore and injected intravenously into mice bearing human colorectal TRAIL-sensitive Colo205 and TRAIL-resistant HT-29 xenografts that had been treated with a potent agonist of TRAILR2 and in Colo205 tumors treated with 5-FU.Results: Three-dimensional (3D) MSOT images of probe distribution showed development of tumor contrast within 3 hours of probe administration and a signal-to-background ratio in regions containing dead cells of >10 after 24 hours. A site-directed mutant of C2Am that is inactive in PS binding showed negligible binding. Tumor retention of the active probe was strongly correlated (R2 = 0.97, P value < 0.01) with a marker of apoptotic cell death measured in histologic sections obtained post mortem.Conclusions: The rapid development of relatively high levels of contrast suggests that NIR fluorophore-labeled C2Am could be a useful optoacoustic imaging probe for detecting early therapy-induced tumor cell death in the clinic. Clin Cancer Res; 23(22); 6893-903. ©2017 AACR.

Validation of the Cognition Test Battery for Spaceflight in a Sample of Highly Educated Adults.

BACKGROUND: Neuropsychological changes that may occur due to the environmental and psychological stressors of prolonged spaceflight motivated the development of the Cognition Test Battery. The battery was designed to assess multiple domains of neurocognitive functions linked to specific brain systems. Tests included in Cognition have been validated, but not in high-performing samples comparable to astronauts, which is an essential step toward ensuring their usefulness in long-duration space missions. METHODS: We administered Cognition (on laptop and iPad) and the WinSCAT, counterbalanced for order and version, in a sample of 96 subjects (50% women; ages 25-56 yr) with at least a Master's degree in science, technology, engineering, or mathematics (STEM). We assessed the associations of age, sex, and administration device with neurocognitive performance, and compared the scores on the Cognition battery with those of WinSCAT. Confirmatory factor analysis compared the structure of the iPad and laptop administration methods using Wald tests. RESULTS: Age was associated with longer response times (mean ß = 0.12) and less accurate (mean ß = -0.12) performance, women had longer response times on psychomotor (ß = 0.62), emotion recognition (ß = 0.30), and visuo-spatial (ß = 0.48) tasks, men outperformed women on matrix reasoning (ß = -0.34), and performance on an iPad was generally faster (mean ß = -0.55). The WinSCAT appeared heavily loaded with tasks requiring executive control, whereas Cognition assessed a larger variety of neurocognitive domains. DISCUSSION: Overall results supported the interpretation of Cognition scores as measuring their intended constructs in high performing astronaut analog samples.Moore TM, Basner M, Nasrini J, Hermosillo E, Kabadi S, Roalf DR, McGuire S, Ecker AJ, Ruparel K, Port AM, Jackson CT, Dinges DF, Gur RC. Validation of the Cognition Test Battery for spaceflight in a sample of highly educated adults. Aerosp Med Hum Perform. 2017; 88(10):937-946.

Rapid Imaging of Tumor Cell Death In Vivo Using the C2A Domain of Synaptotagmin-I.

Cell death is an important target for imaging the early response of tumors to treatment. We describe here the validation of a phosphatidylserine-binding agent for detecting tumor cell death in vivo based on the C2A domain of synaptotagmin-I. Methods: The capability of near-infrared fluorophore-labeled and 99mTc- and 111In-labeled derivatives of C2Am for imaging tumor cell death, using planar near-infrared fluorescence imaging and SPECT, respectively, was evaluated in implanted and genetically engineered mouse models of lymphoma and in a human colorectal xenograft. Results: The fluorophore-labeled C2Am derivative showed predominantly renal clearance and high specificity and sensitivity for detecting low levels of tumor cell death (2%-5%). There was a significant correlation (R > 0.9, P < 0.05) between fluorescently labeled C2Am binding and histologic markers of cell death, including cleaved caspase-3, whereas there was no such correlation with a site-directed mutant of C2Am (iC2Am) that does not bind phosphatidylserine. 99mTc-C2Am and 111In-C2Am also showed favorable biodistribution profiles, with predominantly renal clearance and low nonspecific retention in the liver and spleen at 24 h after probe administration. 99mTc-C2Am and 111In-C2Am generated tumor-to-muscle ratios in drug-treated tumors of 4.3× and 2.2×, respectively, at 2 h and 7.3× and 4.1×, respectively, at 24 h after administration. Conclusion: Given the favorable biodistribution profile of 99mTc- and 111In-labeled C2Am, and their ability to produce rapid and cell death-specific image contrast, these agents have potential for clinical translation.