Blood-based gene expression as a biodosimetry model for neuroblastoma patients treated with ¹³¹I-mIBG

Internal dosimetry is challenging and relies on estimates using MIRD or ICRP biokinetic models. To address this, we looked at gene expression analysis in whole blood from radiotherapy patients. Patients with relapsed or refractory neuroblastoma who received ¹³¹I-mIBG at UCSF were used to correlate internal ionizing radiation (IR) dose with selected gene expression. 40 patients, median age 7 years, had blood drawn at baseline, 72, 96, and 120 hours after ¹³¹I-mIBG infusion. A total of 14 patients received mIBG treatment only, while 19 patients received Irinotecan and 7 received Vorinostat in combination with mIBG. Whole body absorbed dose was calculated for each patient based on the mIBG treatment doses using MIRD internal dosimetry models. Two models were used and compared with the decision being to use a model that was predictive based on an average of three patient’s responses. We then assessed transcripts using RT-PCR that were the most significant for describing the mixed therapeutic treatments over time. Modulation was evaluated statistically using multiple regression analysis for data at hours 0, 72, 96. A total of 6 genes were analyzed across 40 patients: CDKN1A, FDXR, GADD45A, BCLXL, STAT5B, and BAX. Four genes were significantly modulated upon exposure to ¹³¹I-mIBG at 72 hours, as well as at 96 hours, when controlling for dose and chemotherapy. Five genes showed significant responses to Irinotecan combined with mIBG and 2 had significant responses to Vorinostat combined with mIBG, all when controlling for time and dose. A model was then developed to predict absorbed dose based on modulation of gene transcripts within white blood cells. This study represents a unique effort of using radiotherapy patients to characterize biomarkers that may be useful for biodosimetry and treatment. Our data indicates that transcripts, which have been previously identified as biomarkers of external exposures in ex vivo whole blood and in vivo radiotherapy patients, are also good indicators of internal exposure over time. The characterization of internal irradiation-responsive genes will provide valuable understanding of the genetic mechanisms related to internal exposures

Toenail Manganese: A Sensitive and Specific Biomarker of Exposure to Manganese in Career Welders

Manganese (Mn) is an essential trace metal. It is also a component of welding fume. Chronic inhalation of manganese from welding fume has been associated with decreased neurological function. Currently, there is not a universally recognized biomarker for Mn exposure; however, hair and toenails have shown promise. In a cohort of 45 male welders and 35 age-matched factory control subjects, we assessed the sensitivity and specificity of toenail Mn to distinguish occupationally exposed subjects from unexposed controls. Further we examined the exposure time window that best correlates with the proposed biomarker, and investigated if non-occupational exposure factors impacted toenail Mn concentrations. Toenail clippings were analyzed for Mn using Inductively Coupled Plasma Mass Spectrometry (ICP-MS). Exposure to respirable Mn-containing particles (<4 µm) was estimated using an exposure model that combines personal air monitoring, work history information, and dietary intake to estimate an individual's exposure to Mn from inhalation of welding fume. We assessed the group differences in toenail concentrations using a Student's t-test between welders and control subjects and performed a receiver operating characteristic (ROC) curve analysis to identify a threshold in toenail concentration that has the highest sensitivity and specificity in distinguishing welders from control subjects. Additionally, we performed mixed-model regressions to investigate the association between different exposure windows and toenail Mn concentrations. We observed that toenail Mn concentrations were significantly elevated among welders compared to control subjects (6.87 ± 2.56 versus 2.70 ± 1.70 µg g-1; P < 0.001). Our results show that using a toenail Mn concentration of 4.14 µg g-1 as cutoff allows for discriminating between controls and welders with 91% specificity and 94% sensitivity [area under curve (AUC) = 0.98]. Additionally, we found that a threshold of 4.66 µg g-1 toenail Mn concentration enables a 90% sensitive and 90% specific discrimination (AUC = 0.96) between subjects with average exposure above or below the American Conference of Governmental Industrial Hygienist (ACGIH) Threshold Limit Value (TLV) of 0.02 mg m-3 during the exposure window of 7-12 months prior to the nail being clipped. Investigating which exposure window was best reflected by toenail Mn reproduced the result from another study of toenail Mn being significantly (P < 0.001) associated with exposure 7-12 months prior to the nail being clipped. Lastly, we found that dietary intake, body mass index, age, smoking status, and ethnicity had no significant effect on toenail Mn concentrations. Our results suggest that toenail Mn is a sensitive, specific, and easy-to-acquire biomarker of Mn exposure, which is feasible to be used in an industrial welder population

Meta-Analysis of Perceived Stress and Its Association With Incident Coronary Heart Disease

Most studies examining potential associations between psychological factors and cardiovascular outcomes have focused on depression or anxiety. The effect of perceived stress on incident coronary heart disease (CHD) has yet to be reviewed systematically. We conducted a systematic review and meta-analysis of the association between perceived stress and incident CHD. Ovid, MEDLINE, and PsycINFO were searched as data sources. Prospective observational cohort studies were selected that measured self-reported perceived stress and assessed incident CHD at ≥6 months. We extracted study characteristics and estimates of the risk of incident CHD associated with high perceived stress versus low perceived stress. We identified 23 potentially relevant articles, of which 6 met our criteria (n = 118,696). Included studies measured perceived stress with validated measurements and nonvalidated simple self-report surveys. Incident CHD was defined as new diagnosis of, hospitalization for, or mortality secondary to CHD. Meta-analysis yielded an aggregate risk ratio of 1.27 (95% confidence interval 1.12 to 1.45) for the magnitude of the relation between high perceived stress and incident CHD. In conclusion, this meta-analysis suggests that high perceived stress is associated with a moderately increased risk of incident CHD

Anxiety sensitivity and medication nonadherence in patients with uncontrolled hypertension

Objective Anxiety sensitivity—fear of the negative social, physical, or cognitive consequences of anxiety related sensations—has been linked to cardiovascular disease and adverse cardiovascular health behaviors. Medication nonadherence may account for this association. We examined whether anxiety sensitivity was independently associated with objectively measured medication nonadherence in a multi-ethnic primary care sample. Methods Eighty-eight patients with uncontrolled hypertension completed the Anxiety Sensitivity Index and had their adherence to blood pressure (BP) medications measured during the interval between two primary care visits using an electronic pillbox (MedSignals®). Multivariable Poisson regressions were conducted to determine the relative risks of medication nonadherence associated with anxiety sensitivity after adjustment for age, gender, Hispanic/Latino ethnicity, education, total number of prescribed medications, and depressive and posttraumatic stress disorder (PTSD) symptoms. Results Nearly twice as many patients with high anxiety sensitivity were nonadherent to BP medications compared to patients with low anxiety sensitivity (65.0% vs. 36.8%; p = 0.03). Patients with high anxiety sensitivity had higher relative risks of medication nonadherence than their low anxiety sensitivity counterparts (adjusted relative risk [RR] = 1.76; 95% CI: 1.03–3.03). Conclusions In this first study of the association between anxiety sensitivity and medication adherence, we found that high anxiety sensitivity was strongly associated with BP medication nonadherence, even after adjustment for known confounders. Our results suggest that teaching patients who have uncontrolled hypertension adaptive strategies to manage their anxiety sensitivity may help improve their medication adherence, and thereby lower their cardiovascular risk

An inexpensive device for monitoring patients' weights via automated hovering

Daily weight monitoring is integral to the management of heart failure (HF) [1]. Indeed, weight gain is a marker of HF decompensation, and daily weight monitoring has been associated with favorable prognosis [2]. Until now, assessment of weight has required patients to attend an in-person visit, which provides only an infrequent snapshot of their weight. Remote hovering practices have gained considerable traction during the past several years [3–7], but their use outside of research settings has been limited

Whole-brain R1 predicts manganese exposure and biological effects in welders

Manganese (Mn) is a neurotoxicant that, due to its paramagnetic property, also functions as a magnetic resonance imaging (MRI) T1 contrast agent. Previous studies in Mn toxicity have shown that Mn accumulates in the brain, which may lead to parkinsonian symptoms. In this article, we trained support vector machines (SVM) using whole-brain R1 (R1 = 1/T1) maps from 57 welders and 32 controls to classify subjects based on their air Mn concentration ([Mn]Air), Mn brain accumulation (ExMnBrain), gross motor dysfunction (UPDRS), thalamic GABA concentration (GABAThal), and total years welding. R1 was highly predictive of [Mn]Air above a threshold of 0.20 mg/m3 with an accuracy of 88.8% and recall of 88.9%. R1 was also predictive of subjects with GABAThal having less than or equal to 2.6 mM with an accuracy of 82% and recall of 78.9%. Finally, we used an SVM to predict age as a method of verifying that the results could be attributed to Mn exposure. We found that R1 was predictive of age below 48 years of age with accuracies ranging between 75 and 82% with recall between 94.7% and 76.9% but was not predictive above 48 years of age. Together, this suggests that lower levels of exposure (< 0.20 mg/m3 and < 18 years of welding on the job) do not produce discernable signatures, whereas higher air exposures and subjects with more total years welding produce signatures in the brain that are readily identifiable using SVM

A Magnetic Resonance Spectroscopy Study of Superior Visual Search Abilities in Children with Autism Spectrum Disorder

Although diagnosed on the basis of deficits in social communication and interaction, autism spectrum disorder (ASD) is also characterized by superior performance on a variety of visuospatial tasks, including visual search. In neurotypical individuals, region-specific concentrations of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) are associated with individual differences in attention and perception. While it has been hypothesized that ASD may be associated with an excitatory-inhibitory imbalance, it remains unclear how this may contribute to accelerated visual search performance in individuals with ASD. To investigate this, 21 children with ASD and 20 typically developing children participated in a visual search task and a magnetic resonance spectroscopy study to detect neurochemical concentrations, including GABA. Region-specific neurochemicals were examined in the right frontal eye fields, right temporal-parietal junction (rTPJ), and bilateral visual cortex (VIS). GABA concentrations did not differ between groups; however, in children with ASD, greater GABA concentration in the VIS was related to more efficient search. Additionally, lower VIS GABA levels were also associated with increased social impairment. Finally, we found reduced N-acetyl aspartate, total creatine, glutamate and glutamine (Glx), GABA/Glx in the rTPJ, suggestive of neuronal dysfunction in a critical network hub. Our results show that GABA concentrations in the VIS are related to efficient search in ASD, thus providing further evidence of enhanced discrimination in ASD. Autism Res 2020, 13: 550-562. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Children with autism spectrum disorder (ASD) often perform better than their non-ASD peers on visual search tasks; however, it is unclear how they achieve this superior performance. Using magnetic resonance spectroscopy to measure neurochemicals in the brain, we found that the level of one, gamma-aminobutyric acid, in the visual cortex was directly related to search abilities in children with ASD. These results suggest that faster search may relate to enhanced perceptual functioning in children with ASD

Associations between sensory processing and electrophysiological and neurochemical measures in children with ASD: an EEG-MRS study

Background: Autism spectrum disorder (ASD) is associated with hyper- and/or hypo-sensitivity to sensory input. Spontaneous alpha power, which plays an important role in shaping responsivity to sensory information, is reduced across the lifespan in individuals with ASD. Furthermore, an excitatory/inhibitory imbalance has also been linked to sensory dysfunction in ASD and has been hypothesized to underlie atypical patterns of spontaneous brain activity. The present study examined whether resting-state alpha power differed in children with ASD as compared to TD children, and investigated the relationships between alpha levels, concentrations of excitatory and inhibitory neurotransmitters, and atypical sensory processing in ASD. Methods: Participants included thirty-one children and adolescents with ASD and thirty-one age- and IQ-matched typically developing (TD) participants. Resting-state electroencephalography (EEG) was used to obtain measures of alpha power. A subset of participants (ASD = 16; TD = 16) also completed a magnetic resonance spectroscopy (MRS) protocol in order to measure concentrations of excitatory (glutamate + glutamine; Glx) and inhibitory (GABA) neurotransmitters. Results: Children with ASD evidenced significantly decreased resting alpha power compared to their TD peers. MRS estimates of GABA and Glx did not differ between groups with the exception of Glx in the temporal-parietal junction. Inter-individual differences in alpha power within the ASD group were not associated with region-specific concentrations of GABA or Glx, nor were they associated with sensory processing differences. However, atypically decreased Glx was associated with increased sensory impairment in children with ASD. Conclusions: Although we replicated prior reports of decreased alpha power in ASD, atypically reduced alpha was not related to neurochemical differences or sensory symptoms in ASD. Instead, reduced Glx in the temporal-parietal cortex was associated with greater hyper-sensitivity in ASD. Together, these findings may provide insight into the neural underpinnings of sensory processing differences present in ASD

Planar localisation analyses: a novel application of a centre of mass approach

Sound localisation is one of the key roles for listening, and measuring localisation performance is a mainstay of the hearing research laboratory. Such measurements consider both accuracy and, for incorrect trials, the size of the error. In terms of error analysis, localisation studies have frequently used general univariate techniques in conjunction with either mean signed or unsigned error measurements. This approach can make inappropriate distributional assumptions and so more suitable alternatives based on directional statistics (e.g. based on von Mises distributed data) have also been used. However these are not readily computed using most commercially available, commonly used statistical software, and are generally only defined for simple experimental designs. We describe a novel use of a 'centre of mass' approach for describing localisation data jointly in terms of accuracy and size of error. This spatial method offers powerful, yet flexible, statistical analysis using standard multivariate analysis of variance (MANOVA)

Measurement and analysis of household carbon: the case of a UK city

There is currently a lack of data recording the carbon and emissions inventory at household level. This paper presents a multi-disciplinary, bottom-up approach for estimation and analysis of the carbon emissions, and the organic carbon (OC) stored in gardens, using a sample of 575 households across a UK city. The annual emission of carbon dioxide emissions from energy used in the homes was measured, personal transport emissions were assessed through a household survey and OC stores estimated from soil sampling and vegetation surveys. The results showed that overall carbon patterns were skewed with highest emitting third of the households being responsible for more than 50% of the emissions and around 50% of garden OC storage. There was diversity in the relative contribution that gas, electricity and personal transport made to each household’s total and different patterns were observed for high, medium and low emitting households. Targeting households with high carbon emissions from one source would not reliably identify them as high emitters overall. While carbon emissions could not be offset by growing trees in gardens, there were considerable amounts of stored OC in gardens which ought to be protected. Exploratory analysis of the multiple drivers of emissions was conducted using a combination of primary and secondary data. These findings will be relevant in devising effective policy instruments for combatting city scale green-house gas emissions from domestic end-use energy demand