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BackgroundIncreasing the availability of non-alcoholic options is a promising population-level intervention to reduce alcohol consumption, currently unassessed in naturalistic settings. This study in an online retail context aimed to estimate the impact of increasing the proportion of non-alcoholic (relative to alcoholic) drinks, on selection and purchasing of alcohol.Methods and ResultsAdults (n=737) residing in England and Wales who regularly purchased alcohol online were recruited between March-July 2021. Participants were randomly assigned to one of three groups: ‘25% non-alcoholic/75% alcoholic’; ‘50% non-alcoholic/50% alcoholic’; ‘75% non-alcoholic/25% alcoholic’, then selected drinks in a simulated online supermarket, before purchasing them in an actual online supermarket. The primary outcome was the number of alcohol units selected (with intention to purchase); secondary outcomes included actual purchasing. 607 participants (60% female, mean age = 38 years [range: 18-76]) completed the study and were included in the primary analysis. In the first part of a hurdle model, a greater proportion of participants in the ‘75% non-alcoholic’ group did not select any alcohol (13.1%) compared to the ‘25% non-alcoholic’ group (3.4%; 95% confidence interval [CI] - 2.09, -0.63; p < 0.001). There was no evidence of a difference between the ‘75% non-alcoholic’ and the ‘50% non-alcoholic’ (7.2%) groups (95% CI 0.10, 1.34; p = 0.022) or between the ‘50% non-alcoholic’ and the ‘25% non-alcoholic’ groups (95% CI -1.44, 0.17; p = 0.121). In the second part of a hurdle model in participants (559/607) selecting any drinks containing alcohol, the ‘75% non-alcoholic’ group selected fewer alcohol units compared to the ‘50% non-alcoholic’ (95% CI -0.44, -0.14; p < 0.001) and ‘25% non-alcoholic’ (95% CI - 0.54, -0.24; p < 0.001) groups, with no evidence of a difference between the ‘50% non-alcoholic’ and ‘25% non-alcoholic’ groups (95% CI -0.24, 0.05; p = 0.178). Overall, across all participants, 17.46 units (95% CI 15.24, 19.68) were selected in the ‘75% non-alcoholic’ group; 25.51 units (95% CI 22.60, 28.43) in the ‘50% non-alcoholic’ group; and 29.40 units (95% CI 26.39, 32.42) in the ‘25% non-alcoholic’ group. This corresponds to 8.1 fewer units (a 32% reduction) in the ‘75% non-alcoholic’ compared to the ‘50% non-alcoholic’ group, and 11.9 fewer alcohol units (41% reduction) compared to the ‘25% non-alcoholic’ group; 3.9 fewer units (13% reduction) were selected in the ‘50% non-alcoholic’ group than in the ‘25% non-alcoholic’ group.For all other outcomes, alcohol selection and purchasing were consistently lowest in the ‘75% non-alcoholic’ group.Study limitations include the setting not being entirely naturalistic due to using a simulated online supermarket as well as an actual online supermarket, and that there was substantial dropout between selection and purchasing.ConclusionsThis study provides evidence that substantially increasing the proportion of non-alcoholic drinks – from 25% to 50% or 75% - meaningfully reduces alcohol selection and purchasing. Further studies are warranted to assess whether these effects are realised in a range of real-world settings.Trial registrationISRCTN:11004483; OSF:https://osf.io/qfupwAuthor summaryWhy was this study done?Excessive alcohol consumption contributes to the global burden of non-communicable diseases, including cancer, heart disease and stroke. Interventions that change physical and economic environments have the potential to reduce alcohol consumption.Interventions targeting physical environments include availability interventions that involve changing the proportion of healthier options that are available, relative to less healthy options.A previous online study found that increasing the availability of non-alcoholic compared to alcoholic drinks reduced the hypothetical selection of alcoholic drinks, but there is an absence of evidence from naturalistic settings.What did the researchers do and find?This study evaluated the impact of increasing the proportion of non-alcoholic (relative to alcoholic) drinks, on selection and actual purchasing of alcohol.In a randomised controlled trial, 737 participants were randomly assigned to one of three groups with varying proportions of alcoholic versus non-alcoholic drinks ‘25% non-alcoholic/75% alcoholic’; ‘50% non-alcoholic/50% alcoholic’; ‘75% non-alcoholic/25% alcoholic’).Participants selected drinks from 64 options in a simulated online supermarket which was designed to look and function similarly to an online supermarket. Participants were then required to immediately purchase the same drinks in an actual online supermarket.It was found that increasing the proportion of non-alcoholic drinks – from 25% to 50% or 75% – reduced the amount of alcohol selected and bought, in this online supermarket setting.What do these findings mean?This study provides evidence that increasing the proportion of non-alcoholic drinks could reduce alcohol selection and purchasing, highlighting the potential for availability interventions to reduce alcohol sales at population level.Further studies are warranted to assess whether these effects are realised in a range of real-world settings

Background An artificial intelligence model that assesses primary bone tumors on radiographs may assist in the diagnostic workflow. Purpose To develop a multitask deep learning (DL) model for simultaneous bounding box placement, segmentation, and classification of primary bone tumors on radiographs. Materials and Methods This retrospective study analyzed bone tumors on radiographs acquired prior to treatment and obtained from patient data from January 2000 to June 2020. Benign or malignant bone tumors were diagnosed in all patients by using the histopathologic findings as the reference standard. By using split-sample validation, 70% of the patients were assigned to the training set, 15% were assigned to the validation set, and 15% were assigned to the test set. The final performance was evaluated on an external test set by using geographic validation, with accuracy, sensitivity, specificity, and 95% CIs being used for classification, the intersection over union (IoU) being used for bounding box placements, and the Dice score being used for segmentations. Results Radiographs from 934 patients (mean age, 33 years ± 19 [standard deviation]; 419 women) were evaluated in the internal data set, which included 667 benign bone tumors and 267 malignant bone tumors. Six hundred fifty-four patients were in the training set, 140 were in the validation set, and 140 were in the test set. One hundred eleven patients were in the external test set. The multitask DL model achieved 80.2% (89 of 111; 95% CI: 72.8, 87.6) accuracy, 62.9% (22 of 35; 95% CI: 47, 79) sensitivity, and 88.2% (67 of 76; CI: 81, 96) specificity in the classification of bone tumors as malignant or benign. The model achieved an IoU of 0.52 ± 0.34 for bounding box placements and a mean Dice score of 0.60 ± 0.37 for segmentations. The model accuracy was higher than that of two radiologic residents (71.2% and 64.9%

Summary OBJECTIVE To compare progression over 8 years in knee compositional cartilage degeneration and structural joint abnormalities in knees with different types of anterior cruciate ligament (ACL) abnormalities over 8 years. Method Baseline MR images of the right knees of 1899 individuals of the Osteoarthritis Initiative (OAI) with no evidence of or mild to moderate radiographic osteoarthritis were assessed for nontraumatic ACL abnormalities. The knees of 91 individuals showed nontraumatic ACL abnormalities (age 60.6 ± 9.8 y, 46 females; mucoid degeneration (MD), N = 37; complete tear (CT), N = 22; partial tear (PT), N = 32) and were frequency-matched to 91 individuals with normal ACL. MRIs were assessed for knee joint abnormalities using the Whole-Organ Magnetic Resonance Imaging Score (WORMS) and cartilage T2 mapping at baseline, 4- and 8-year follow-up. Results Over 8 years, cartilage T2 values of the medial tibia showed a significantly greater increase in individuals with MD, PT or CT compared to those with normal ACL (adjusted rate of change/year [95% confidence interval], normal ACL: 0.06 [0.01, 0.23], MD: 0.34 [0.07, 0.73], PT, 0.21 [0.02, 0.33], CT, 0.51 [0.16, 0.78]), indicating an association of ACL abnormalities and an increased progression rate of cartilage degeneration in subjects with and without knee joint degeneration. This effect was also seen in cartilage T2 values averaged over all compartments (normal ACL: 0.08 [0.05, 0.20] vs abnormal ACL: 0.27 [0.06, 0.56]). Conclusions Over 8 years, higher progression rates of cartilage degeneration, especially in the medial tibia, were associated with ACL abnormalities compared to those with normal ACL, in subjects with and without knee joint abnormalities.

A 7-year-old male neutered, 6.5 kg, Maltese breed dog was referred with a history of dysuria after undergoing two cystotomies to remove calcium oxalate uroliths. Survey radiographs were inconclusive. Excretory urography allowed visualization of two filling defects in the cranioventral urinary bladder region. Ultrasonography showed urinary bladder sediments, a diffusely thickened wall, and two circumscribed intramural/intraluminal structures with an anechoic interior and a smooth and regular surface. The cystoscopic diagnosis was urinary bladder abscesses and urine cultures were positive for Escherichia coli. Antimicrobial/anti-inflammatory therapy was started with good clinical outcomes and negative culture after 21 days.

Background The optimal duration of transmission-based precautions among immunocompromised patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is unknown. Methods Retrospective review of patients with solid organ transplant with positive SARS-CoV-2 polymerase chain reaction result from nasopharyngeal specimens admitted to the hospital between March 13, 2020 and May 15, 2020. Results Twenty-one percent of solid organ transplant recipients with positive SARS-CoV-2 polymerase chain reaction detected ≥20 d after symptom onset (or after first positive test among asymptomatic individuals) had a low cycle threshold (ie, high viral load). The majority of these patients were asymptomatic or symptomatically improved. Conclusions Solid organ transplant recipients may have prolonged high viral burden of SARS-CoV-2. Further data are needed to understand whether cycle threshold data can help inform strategies for prevention of healthcare-associated transmission of SARS-CoV-2 and for appropriate discontinuation of transmission-based precautions.

Focal segmental glomerulosclerosis (FSGS) is the main pathology underlying steroid-resistant nephrotic syndrome (SRNS) and a leading cause of chronic kidney disease. Monogenic forms of pediatric SRNS are predominantly caused by recessive mutations, while the contribution of de novo variants (DNVs) to this trait is poorly understood. Using exome sequencing (ES) in a proband with FSGS/SRNS, developmental delay, and epilepsy, we discovered a nonsense DNV in TRIM8, which encodes the E3 ubiquitin ligase tripartite motif containing 8. To establish whether TRIM8 variants represent a cause of FSGS, we aggregated exome/genome-sequencing data for 2,501 pediatric FSGS/SRNS-affected individuals and 48,556 control subjects, detecting eight heterozygous TRIM8 truncating variants in affected subjects but none in control subjects (p = 3.28 × 10(−11)). In all six cases with available parental DNA, we demonstrated de novo inheritance (p = 2.21 × 10(−15)). Reverse phenotyping revealed neurodevelopmental disease in all eight families. We next analyzed ES from 9,067 individuals with epilepsy, yielding three additional families with truncating TRIM8 variants. Clinical review revealed FSGS in all. All TRIM8 variants cause protein truncation clustering within the last exon between residues 390 and 487 of the 551 amino acid protein, indicating a correlation between this syndrome and loss of the TRIM8 C-terminal region. Wild-type TRIM8 overexpressed in immortalized human podocytes and neuronal cells localized to nuclear bodies, while constructs harboring patient-specific variants mislocalized diffusely to the nucleoplasm. Co-localization studies demonstrated that Gemini and Cajal bodies frequently abut a TRIM8 nuclear body. Truncating TRIM8 DNVs cause a neuro-renal syndrome via aberrant TRIM8 localization, implicating nuclear bodies in FSGS and developmental brain disease.

Objective Determination of coronary artery calcium scoring (CACS) in non-contrast computed tomography (CT) images has been shown to be an important prognostic factor in coronary artery disease (CAD). The objective of this study was to evaluate the accuracy of CACS from virtual non-contrast (VNC) imaging generated from spectral data in comparison to standard (true) non-contrast (TNC) imaging in a representative patient cohort with clinically approved software. Methods One hundred three patients referred to coronary CTA with suspicion of CAD were investigated on a dual-layer spectral detector CT (SDCT) scanner. CACS was calculated from both TNC and VNC images by software certified for medical use. Patients with a CACS of 0 were excluded from analysis. Results The mean age of the study population was 61 ± 11 years with 48 male patients (67%). Inter-quartile range of clinical CACS was 22–282. Correlation of measured CACS from true- and VNC images was high (0.95); p < 0.001. The slope was 3.83, indicating an underestimation of VNC CACS compared to TNC CACS by that factor. Visual analysis of the Bland-Altman plot of CACS showed good accordance with both methods after correction of VNC CACS by the abovementioned factor. Conclusions In clinical diagnostics of CAD, the determination of CACS is feasible using VNC images generated from spectral data obtained on a dual-layer spectral detector CT. When multiplied by a correction factor, results were in good agreement with the standard technique. This could enable radiation dose reductions by obviating the need for native scans typically used for CACS. Key Points • Calcium scoring is feasible from contrast-enhanced CT images using a dual-layer spectral detector CT scanner. • When multiplied by a correction factor, calcium scoring from virtual non-contrast images shows good agreement with the standard technique. • Omitting native scans for calcium scoring could enable radiation dose reduction.

DNA hypomethylation at theWe conducted multiple independent experiments to assess whether DNA hypomethylation atObservationally, DNA methylation atSmoking-induced epigenetic DNA hypomethylation at

Background Dark-field chest radiography allows for assessment of lung alveolar structure by exploiting wave optical properties of x-rays. Purpose To evaluate the qualitative and quantitative features of dark-field chest radiography in participants with pulmonary emphysema as compared with those in healthy control subjects. Materials and Methods In this prospective study conducted from October 2018 to October 2020, participants aged at least 18 years who underwent clinically indicated chest CT were screened for participation. Inclusion criteria were an ability to consent to the procedure and stand upright without help. Exclusion criteria were pregnancy, serious medical conditions, and any lung condition besides emphysema that was visible on CT images. Participants were examined with a clinical dark-field chest radiography prototype that simultaneously acquired both attenuation-based radiographs and dark-field chest radiographs. Dark-field coefficients were tested for correlation with each participant's CT-based emphysema index using the Spearman correlation test. Dark-field coefficients of adjacent groups in the semiquantitative Fleischner Society emphysema grading system were compared using a Wilcoxon Mann-Whitney

PURPOSE: Contrast-enhanced-ultrasound (CEUS) has been frequently used in assessment of cystic renal lesions. OBJECTIVE: The aim of this study was to investigate the Bosniak classification in CEUS compared to CT and MRI in a multi-center setting. METHODS: Bosniak classification in CEUS examinations of cystic renal lesions were compared to imaging findings in computed-tomography (ceCT) and magnetic-resonance-imaging (ceMRI). Imaging results were correlated to histopathological reports. All examinations were performed by experts (EFSUMB level 3) using up-to-date CEUS examination-protocols. RESULTS: Overall, 173 cystic renal lesions were compared to subgroups CT (n = 87) and MRI (n = 86). Using Bosniak-classification 64/87 renal cysts (73.6%) were rated equal compared to CT with upgrade of four lesions (4.6%) and downgrade of 19 lesions (21.8%) by CT (Intra-class-correlation [ICC] coefficient of 0.824 [p

ObjectivesTo estimate the causal effect of health conditions and risk factors on social and socioeconomic outcomes in UK Biobank. Evidence on socioeconomic impacts is important to understand because it can help governments, policy-makers and decision-makers allocate resources efficiently and effectively.DesignWe used Mendelian randomization to estimate the causal effects of eight health conditions (asthma, breast cancer, coronary heart disease, depression, eczema, migraine, osteoarthritis, type 2 diabetes) and five health risk factors (alcohol intake, body mass index [BMI], cholesterol, systolic blood pressure, smoking) on 19 social and socioeconomic outcomes.SettingUK Biobank.Participants337,009 men and women of white British ancestry, aged between 39 and 72 years.Main outcome measuresAnnual household income, employment, deprivation (measured by the Townsend deprivation index [TDI]), degree level education, happiness, loneliness, and 13 other social and socioeconomic outcomes.ResultsResults suggested that BMI, smoking and alcohol intake affect many socioeconomic outcomes. For example, smoking was estimated to reduce household income (mean difference = −£24,394, 95% confidence interval (CI): −£33,403 to −£15,384), the chance of owning accommodation (absolute percentage change [APC] = −21.5%, 95% CI: −29.3% to −13.6%), being satisfied with health (APC = −32.4%, 95% CI: −48.9% to −15.8%), and of obtaining a university degree (APC = −73.8%, 95% CI: −90.7% to −56.9%), while also increasing deprivation (mean difference in TDI = 1.89, 95% CI: 1.13 to 2.64, approximately 236% of a decile of TDI). There was evidence that asthma increased deprivation and decreased both household income and the chance of obtaining a university degree, and migraine reduced the chance of having a weekly leisure or social activity, especially in men. For other associations, estimates were null.ConclusionsHigher BMI, alcohol intake and smoking were all estimated to adversely affect multiple social and socioeconomic outcomes. Effects were not detected between health conditions and socioeconomic outcomes using Mendelian randomization, with the exceptions of depression, asthma and migraines. This may reflect true null associations, selection bias given the relative health and age of participants in UK Biobank, and/or lack of power to detect effects.What is known?Studies have shown associations between poor health and adverse social (e.g. wellbeing, social contact) and socioeconomic (e.g. educational attainment, income, employment) outcomes, but there is also strong evidence that social and socioeconomic factors influence health.These bidirectional relationships make it difficult to establish whether health conditions and health risk factors have causal effects on social and socioeconomic outcomes.Mendelian randomization is a technique that uses genetic variants robustly related to an exposure of interest (here, health conditions and risk factors for poor health) as a proxy for the exposure.Since genetic variants are randomly allocated at conception, they tend to be unrelated to the factors that typically confound observational studies, and are less likely to suffer from reverse causality, making causal inference from Mendelian randomization analyses more plausible.What this study addsThis study suggests causal effects of higher BMI, smoking and alcohol use on a range of social and socioeconomic outcomes, implying that population-level improvements in these risk factors may, in addition to the well-known health benefits, have social and socioeconomic benefits for individuals and society.There was evidence that asthma increased deprivation, decreased household income and the chance of having a university degree, migraine reduced the chance of having a weekly leisure or social activity, especially in men, and depression increased loneliness and decreased happiness.There was little evidence for causal effects of cholesterol, systolic blood pressure or breast cancer on social and socioeconomic outcomes.

Background: Research suggests that acute alcohol consumption impairs processing of emotional faces. As emotion processing plays a key role in effective social interaction, these impairments may be one mechanism by which alcohol changes social behaviour. This study investigated the effect of individual differences on this relationship by comparing emotion recognition performance after acute alcohol consumption in individuals with high and low trait aggression. Methods: Regular non-dependent drinkers, either high or low in trait aggression participated in a double-blind placebo-controlled experiment ( N = 88, 50% high trait aggressive). Participants attended two sessions. In one they consumed an alcoholic drink (0.4 g/kg) and in the other they consumed a matched placebo. They then completed two computer-based tasks: one measured global and emotion-specific recognition performance across six primary emotions (anger, sadness, happiness, disgust, fear, surprise), the other measured processing bias of two ambiguously expressive faces (happy–angry/happy–sad). Results: There was evidence of poorer global emotion recognition after alcohol. In addition, there was evidence of poorer sensitivity to sadness and fear after alcohol. There was also evidence for a reduced bias towards happiness following alcohol and weak evidence for an increased bias towards sadness. Conclusions: These findings suggest that alcohol impairs global emotion recognition. They also highlight a reduced ability to detect sadness and fearful facial expressions. As sadness and fear are cues of submission and distress (i.e. function to curtail aggression), failure to successfully detect these emotions when intoxicated may increase the likelihood of aggressive responding. This coupled with a reduced bias towards seeing happiness may collectively contribute to aggressive behaviour.

Understanding the origin and maintenance of adaptive phenotypic novelty is a central goal of evolutionary biology. However, both hybridization and incomplete lineage sorting can lead to genealogical discordance between the regions of the genome underlying adaptive traits and the remainder of the genome, decoupling inferences about character evolution from population history. Here, to disentangle these effects, we investigated the evolutionary origins and maintenance of Batesian mimicry between North American admiral butterflies (Limenitis arthemis) and their chemically defended model (Battus philenor) using a combination of de novo genome sequencing, whole-genome resequencing, and statistical introgression mapping. Our results suggest that balancing selection, arising from geographic variation in the presence or absence of the unpalatable model, has maintained two deeply divergent color patterning haplotypes that have been repeatedly sieved among distinct mimetic and nonmimetic lineages of Limenitis via introgressive hybridization.

(68)Ga-DOTATOC PET/MRI combines the advantages of PET in the acquisition of metabolic–functional information with the high soft-tissue contrast of MRI. SUVs in tumors have been suggested to be a measure of somatostatin receptor expression. A challenge with receptor ligands is that the distribution volume is confined to tissues with tracer uptake, potentially limiting SUV quantification. In this study, various functional 3-dimensional SUV apparent diffusion coefficient (ADC) parameters and arterial tumor enhancement were tested for ability to characterize gastroenteropancreatic (GEP) neuroendocrine tumors (NETs). Methods: For this single-center, cross-sectional study, 22 patients with 24 histologically confirmed GEP NET lesions (15 men and 7 women; median age, 61 y; range, 43–81 y) who underwent hybrid (68)Ga-DOTA PET/MRI at 3 T between January 2017 and July 2019 met the eligibility criteria. SUV, tumor-to-background ratio, total functional tumor volume, and mean and minimum ADC were measured on the basis of volumes of interest and examined with receiver-operating-characteristic analysis to determine cutoffs for differentiation between low- and intermediate-grade GEP NETs. The Spearman rank correlation coefficient was used to assess correlations between functional imaging parameters. Results: The ratio of PET-derived SUV(mean) and diffusion-weighted imaging–derived minimum ADC was introduced as a combined variable to predict tumor grade, outperforming single predictors. On the basis of a threshold ratio of 0.03, tumors could be classified as grade 2 with a sensitivity of 86% and a specificity of 100%. SUV and functional ADCs, as well as arterial contrast enhancement parameters, showed nonsignificant and mostly negligible correlations. Conclusion: Because receptor density and tumor cellularity appear to be independent, potentially complementary phenomena, the combined ratio of PET/MRI and SUV(mean)/ADC(min) may be used as a novel biomarker allowing differentiation between grade 1 and grade 2 GEP NETs.

Background Mycophenolate mofetil (MMF) plays an increasingly important role in the treatment of children with nephrotic syndrome, especially in steroid sparing protocols. Recent publications show the relationship of exposure to its active moiety mycophenolic acid (MPA) and clinical efficacy. Performance of full-time pharmacokinetic (PK) profiles, however, is inconvenient and laborious. Established limited sampling strategies (LSS) to estimate the area under the concentration (AUC) versus time curve of MPA (MPA-AUC) in pediatric renal transplant recipients cannot be easily transferred to children suffering from nephrotic syndrome, mainly because of the lack of concomitant immunosuppressive therapy. We therefore aimed for the generation and validation of a LSS to estimate MPA exposure to facilitate therapeutic drug monitoring in children with nephrotic syndrome. Methods We performed 27 complete PK profiles in 23 children in remission [mean age (±SD):12.3 ± 4.26 years] to generate and validate an LSS. Sampling time points were before administration (C0) and 0.5, 1, 1.5, 2, 4, 6, 8, and 12 hours after the administration of MMF. MPA was measured by enzyme multiplied immunoassay technique. There was no concomitant treatment with calcineurin inhibitors. Results Mean daily dose of MMF was 927 ± 209 mg/m of body surface area resulting in a mean MPA-AUC0-12 value of 59.2 ± 29.3 mg × h/L and a predose level of 3.03 ± 2.24 mg/L. Between-patient variability of dose-normalized MPA-AUC0-12 was high (coefficient of variation: 45.5%). Correlation of predose levels with the corresponding MPA-AUC0-12 was moderate (r = 0.59) in a subgroup of 18 patients (20 PK profiles, generation group). An algorithm based on 3 PK sampling time points during the first 2 hours after MMF dosing (estimated AUC0-12 = 8.7 + 4.63 × C0 + 1.90 × C1 + 1.52 × C2) was able to predict MPA-AUC with a low percentage prediction error (3.88%) and a good correlation of determination (r = 0.90). Validation of this algorithm in a randomized separate group of 6 patients (7 PK profiles, validation group) resulted in comparably good correlation (r = 0.95) and low percentage prediction error (5.57%). Conclusions An abbreviated profile within the first 2 hours after MMF dosing gives a good estimate of MPA exposure in children with nephrotic syndrome and hence has the potential to optimize MMF therapy.

Rationale and objectivesLittle evidence exists on the health effects of e-cigarette use. DNA methylation may serve as a biomarker for exposure and could be predictive of future health risk. We aimed to investigate the DNA methylation profile of e-cigarette use.MethodsAmong 117 smokers, 117 non-smokers and 116 non-smoking vapers, we evaluated associations between e-cigarette use and epigenome-wide methylation from saliva. We tested associations between e-cigarette use and methylation scores known to predict smoking and smoking-related disease. We assessed the ability of a methylation score for predicting e-cigarette use and for discriminating lung cancer.Measurements and Main Results7 CpGs were identified in relation to e-cigarette use at p−5 and none at p−8. 13 CpGs were associated with smoking at p−5 and one at p−8. CpGs associated with e-cigarette use were largely distinct from those associated with smoking. There was strong enrichment of known smoking-related CpGs in the smokers but not the vapers. A methylation score for e-cigarette use showed poor prediction internally (AUC 0.55, 0.41-0.69) and externally (AUC 0.57, 0.36-0.74) compared with a smoking score (AUCs 0.80) and was less able to discriminate lung squamous cell carcinoma from adjacent normal tissue (AUC 0.64, 0.52-0.76 versus AUC 0.73, 0.61-0.85).ConclusionsThe DNA methylation profile for e-cigarette use is largely distinct from that of cigarette smoking, did not replicate in independent samples, and was unable to discriminate lung cancer from normal tissue. The extent to which methylation related to long-term e-cigarette use translates into chronic effects requires further investigation.Key MessagesWhat is the key question?Is there a DNA methylation signature of e-cigarette use and is it distinct from that of smoking?What is the bottom line?Smoke exposure is known to lead to widespread changes in DNA methylation which have been identified in different populations and samples, persist for many years after smoking cessation, and may act as a biomarker for smoking-related disease risk and mortality. Whether a similar methylation profile exists in relation to e-cigarette use has not been widely investigated.Why read on?We obtained saliva samples from 116 e-cigarette users and compared their DNA methylation profile with 117 smokers and 117 non-smokers. The e-cigarette users in this study had a minimal smoking history, and so we were able to distinguish the effects of e-cigarette use from those of smoke exposure. Overall, we found that the methylation profile associated with e-cigarette use is less pronounced and distinct from that associated with cigarette smoking.

ObjectivesTo estimate occupation risk from COVID-19 among teachers and others working in schools using publicly available data on mortality in England and Wales.DesignAnalysis of national death registration data from the Office for National Statistics.SettingEngland and Wales, 8 March–28 December 2020, during the COVID-19 pandemic.ParticipantsThe total working age population in England and Wales plus those still working aged over 65 years.Primary and secondary outcomesDeath with COVID-19 as a primary outcome and death from all causes as a secondary outcome.ResultsAcross occupational groups, there was a strong correlation between COVID-19 mortality and both non-COVID-19 and all-cause mortality. The absolute mortality rates for deaths with COVID-19 were low among those working in schools (from 10 per 100 000 in female primary school teachers to 39 per 100 000 male secondary school teachers) relative to many other occupations (range: 9–50 per 100 000 in women; 10–143 per 100 000 in men). There was weak evidence that secondary school teachers had slightly higher risks of dying with COVID-19 compared with the average for all working-aged people, but stronger evidence of a higher risk compared with the average for all professionals; primary school teachers had a lower risk. All-cause mortality was also higher among all teachers compared with all professionals. Teaching and lunchtime assistants were not at higher risk of death from COVID-19 compared with all working-aged people.ConclusionThere was weak evidence that COVID-19 mortality risk for secondary school teachers was above expectation, but in general school staff had COVID-19 mortality risks which were proportionate to their non-COVID-19 mortality risk.

Background Education is inversely associated with cardiovascular disease (CVD). Several mediators of this have been established; however, a proportion of the protective effect remains unaccounted for. Mental health is a proposed mediator, but current evidence is mixed and subject to bias from confounding factors and reverse causation. Mendelian randomization is an instrumental variable technique that uses genetic proxies for exposures and mediators to reduce such bias. Methods and Results We performed logistic regression and 2‐step Mendelian randomization analyses using UK Biobank data and genetic summary statistics to investigate whether educational attainment affects risk of mental health disorders. We then performed mediation analyses to explore whether mental health disorders mediate the association between educational attainment and cardiovascular risk. Higher levels of educational attainment were associated with reduced depression, anxiety, and CVD in observational analyses (odds ratio [OR], 0.79 [95% CI, 0.77–0.81], 0.76 [95% CI, 0.73–0.79], and 0.75 [95% CI, 0.74–0.76], respectively), and Mendelian randomization analyses provided evidence of causality (OR, 0.72 [95% CI, 0.67–0.77], 0.50 [95% CI, 0.42–0.59], and 0.62 [95% CI, 0.58–0.66], respectively). Both anxiety and depression were associated with CVD in observational analyses (OR, 1.63 [95% CI, 1.49–1.79] and 1.70 [95% CI, 1.59–1.82], respectively) but only depression showed evidence of causality in the Mendelian randomization analyses (OR, 1.09; 95% CI, 1.03–1.15). An estimated 2% of the total protective effect of education on CVD was mediated by depression. Conclusions Higher levels of educational attainment protect against mental health disorders, and reduced depression accounts for a small proportion of the total protective effect of education on CVD.

Background X-ray dark-field radiography takes advantage of the wave properties of x-rays, with a relatively high signal in the lungs due to the many air-tissue interfaces in the alveoli. Purpose To describe the qualitative and quantitative characteristics of x-ray dark-field images in healthy human subjects. Materials and Methods Between October 2018 and January 2020, patients of legal age who underwent chest CT as part of their diagnostic work-up were screened for study participation. Inclusion criteria were a normal chest CT scan, the ability to consent, and the ability to stand upright without help. Exclusion criteria were pregnancy, serious medical conditions, and changes in the lung tissue, such as those due to cancer, pleural effusion, atelectasis, emphysema, infiltrates, ground-glass opacities, or pneumothorax. Images of study participants were obtained by using a clinical x-ray dark-field prototype, recently constructed and commissioned at the authors' institution, to simultaneously acquire both attenuation-based and dark-field thorax radiographs. Each subject's total dark-field signal was correlated with his or her lung volume, and the dark-field coefficient was correlated with age, sex, weight, and height. Results Overall, 40 subjects were included in this study (average age, 62 years ± 13 [standard deviation]; 26 men, 14 women). Normal human lungs have high signal, while the surrounding osseous structures and soft tissue have very low and no signal, respectively. The average dark-field signal was 2.5 m-1 ± 0.4 of examined lung tissue. There was a correlation between the total dark-field signal and the lung volume (r = 0.61, P < .001). No difference was found between men and women (P = .78). Also, age (r = -0.18, P = .26), weight (r = 0.24, P = .13), and height (r = 0.01, P = .96) did not influence dark-field signal. Conclusion This study introduces qualitative and quantitative values for x-ray dark-field imaging in healthy human subjects. The quantitative x-ray dark-field coefficient is independent from demographic subject parameters, emphasizing its potential in diagnostic assessment of the lung. ©RSNA, 2021 See also the editorial by Hatabu and Madore in this issue.

Background The obesity epidemic may have substantial implications for the global workforce, including causal effects on employment, but clear evidence is lacking. Obesity may prevent people from being in paid work through poor health or through social discrimination. We studied genetic variants robustly associated with body mass index (BMI) to investigate its causal effects on employment. Dataset/methods White UK ethnicity participants of working age (men 40–64 years, women 40–59 years), with suitable genetic data were selected in the UK Biobank study (N = 230,791). Employment status was categorised in two ways: first, contrasting being in paid employment with any other status; and second, contrasting being in paid employment with sickness/disability, unemployment, early retirement and caring for home/family. Socioeconomic indicators also investigated were hours worked, household income, educational attainment and Townsend deprivation index (TDI). We conducted observational and two-sample Mendelian randomisation (MR) analyses to investigate the effect of increased BMI on employment-related outcomes. Results Regressions showed BMI associated with all the employment-related outcomes investigated. MR analyses provided evidence for higher BMI causing increased risk of sickness/disability (OR 1.08, 95% CI 1.04, 1.11, per 1 Kg/m2 BMI increase) and decreased caring for home/family (OR 0.96, 95% CI 0.93, 0.99), higher TDI (Beta 0.038, 95% CI 0.018, 0.059), and lower household income (OR 0.98, 95% CI 0.96, 0.99). In contrast, MR provided evidence for no causal effect of BMI on unemployment, early retirement, non-employment, hours worked or educational attainment. There was little evidence for causal effects differing by sex or age. Robustness tests yielded consistent results. Discussion BMI appears to exert a causal effect on employment status, largely by affecting an individual’s health rather than through increased unemployment arising from social discrimination. The obesity epidemic may be contributing to increased worklessness and therefore could impose a substantial societal burden.

Dual energy computed tomography (DECT) allows the quantification of specific materials such as iodine contrast agent in human body tissue, potentially providing additional diagnostic data. Yet full diagnostic value can only be achieved if physiological normal values for iodine concentrations are known. We retrospectively evaluated abdominal DECT scans of 105 patients with healthy liver between March and August 2018 (age 17 to 86 years, 43 female and 62 male). The iodine concentrations within ROIs of the liver parenchyma as well as of the abdominal aorta and main portal vein were obtained. We evaluated the absolute iodine concentration and blood-normalized iodine concentrations relating the measured iodine concentration of the liver parenchyma to those of the supplying vessels. The influence of age and gender on the iodine uptake was assessed. The absolute iodine concentration was significantly different for the male and female cohort, but the difference was eliminated by the blood-normalized values. The average blood-normalized iodine concentrations were 2.107 mg/ml (+/- 0.322 mg/ml), 2.125 mg/ml (+/- 0.426 mg/ml) and 2.103 mg/ml (+/- 0.317 mg/ml) for the portal vein normalized, aorta normalized and mixed blood normalized iodine concentrations, respectively. A significant negative correlation between the patients’ age and the iodine concentration was detected only for the blood-normalized values. A physiological range for iodine concentration in portal venous phase contrast enhanced DECT images can be defined for absolute and blood-normalized values. Deviations of blood-normalized iodine concentration values might be a robust biomarker for diagnostic evaluation. Patient age but not the gender influences the blood-normalized iodine concentrations in healthy liver parenchyma.

Objectives The aims of this study were to discriminate among prostate cancers (PCa's) with Gleason scores 6, 7, and ≥8 on biparametric magnetic resonance imaging (bpMRI) of the prostate using radiomics and to evaluate the added value of image augmentation and quantitative T1 mapping. Materials and methods Eighty-five patients with subsequently histologically proven PCa underwent bpMRI at 3 T (T2-weighted imaging, diffusion-weighted imaging) with 66 patients undergoing additional T1 mapping at 3 T. The PCa lesions as well as the peripheral and transition zones were segmented pixel by pixel in multiple slices of the 3D MRI data sets (T2-weighted images, apparent diffusion coefficient, and T1 maps). To increase the size of the data set, images were augmented for contrast, brightness, noise, and perspective multiple times, effectively increasing the sample size 10-fold, and 322 different radiomics features were extracted before and after augmentation. Four different machine learning algorithms, including a random forest (RF), stochastic gradient boosting (SGB), support vector machine (SVM), and k-nearest neighbor, were trained with and without features from T1 maps to differentiate among 3 different Gleason groups (6, 7, and ≥8). Results Support vector machine showed the highest accuracy of 0.92 (95% confidence interval [CI], 0.62-1.00) for classifying the different Gleason scores, followed by RF (0.83; 95% CI, 0.52-0.98), SGB (0.75; 95% CI, 0.43-0.95), and k-nearest neighbor (0.50; 95% CI, 0.21-0.79). Image augmentation resulted in an average increase in accuracy between 0.08 (SGB) and 0.48 (SVM). Removing T1 mapping features led to a decline in accuracy for RF (-0.16) and SGB (-0.25) and a higher generalization error. Conclusions When data are limited, image augmentations and features from quantitative T1 mapping sequences might help to achieve higher accuracy and lower generalization error for classification among different Gleason groups in bpMRI by using radiomics.

Summary Background Childhood maltreatment is associated with poor mental and physical health. However, the mechanisms of gene–environment correlations and the potential causal effects of childhood maltreatment on health are unknown. Using genetics, we aimed to delineate the sources of gene–environment correlation for childhood maltreatment and the causal relationship between childhood maltreatment and health. Methods We did a genome-wide association study meta-analysis of childhood maltreatment using data from the UK Biobank (n=143 473), Psychiatric Genomics Consortium (n=26 290), Avon Longitudinal Study of Parents and Children (n=8346), Adolescent Brain Cognitive Development Study (n=5400), and Generation R (n=1905). We included individuals who had phenotypic and genetic data available. We investigated single nucleotide polymorphism heritability and genetic correlations among different subtypes, operationalisations, and reports of childhood maltreatment. Family-based and population-based polygenic score analyses were done to elucidate gene–environment correlation mechanisms. We used genetic correlation and Mendelian randomisation analyses to identify shared genetics and test causal relationships between childhood maltreatment and mental and physical health conditions. Findings Our meta-analysis of genome-wide association studies (N=185 414) identified 14 independent loci associated with childhood maltreatment (13 novel). We identified high genetic overlap (genetic correlations 0·24–1·00) among different maltreatment operationalisations, subtypes, and reporting methods. Within-family analyses provided some support for active and reactive gene–environment correlation but did not show the absence of passive gene–environment correlation. Robust Mendelian randomisation suggested a potential causal role of childhood maltreatment in depression (unidirectional), as well as both schizophrenia and ADHD (bidirectional), but not in physical health conditions (coronary artery disease, type 2 diabetes) or inflammation (C-reactive protein concentration). Interpretation Childhood maltreatment has a heritable component, with substantial genetic correlations among different operationalisations, subtypes, and retrospective and prospective reports of childhood maltreatment. Family-based analyses point to a role of active and reactive gene–environment correlation, with equivocal support for passive correlation. Mendelian randomisation supports a (primarily bidirectional) causal role of childhood maltreatment on mental health, but not on physical health conditions. Our study identifies research avenues to inform the prevention of childhood maltreatment and its long-term effects. Funding Wellcome Trust, UK Medical Research Council, Horizon 2020, National Institute of Mental Health, and National Institute for Health Research Biomedical Research Centre.

The in vivo assessment of tissue metabolism represents a novel strategy for the evaluation of oncologic disease. Hepatocellular carcinoma (HCC) is a high-prevalence, high-mortality tumor entity often discovered at a late stage. Recent evidence indicates that survival differences depend on metabolic alterations in tumor tissue, with particular focus on glucose metabolism and lactate production. Here, we present an in vivo imaging technique for metabolic tumor phenotyping in rat models of HCC. Endogenous HCC was induced in Wistar rats by oral diethyl-nitrosamine administration. Peak lactate-to-alanine signal ratios (L/A) were assessed with hyperpolarized magnetic resonance spectroscopic imaging (HPMRSI) after [1

Although negative selection of developing B cells in the periphery is well described, yet poorly understood, evidence of naive B cell positive selection remains elusive. Using 2 humanized mouse models, we demonstrate that there was strong skewing of the expressed immunoglobulin repertoire upon transit into the peripheral naive B cell pool. This positive selection of expanded naive B cells in humanized mice resembled that observed in healthy human donors and was independent of autologous thymic tissue. In contrast, negative selection of autoreactive B cells required thymus-derived Tregs and MHC class II–restricted self-antigen presentation by B cells. Indeed, both defective MHC class II expression on B cells of patients with rare bare lymphocyte syndrome and prevention of self-antigen presentation via HLA-DM inhibition in humanized mice resulted in the production of autoreactive naive B cells. These latter observations suggest that Tregs repressed autoreactive naive B cells continuously produced by the bone marrow. Thus, a model emerged, in which both positive and negative selection shaped the human naive B cell repertoire and that each process was mediated by fundamentally different molecular and cellular mechanisms.

In B lymphopoiesis, activation of the pre-B cell antigen receptor (pre-BCR) is associated with both cell cycle exit and Igk recombination. Yet how the pre-BCR mediates these functions remains unclear. Here, we demonstrate that the pre-BCR initiates a feed-forward amplification loop mediated by the transcription factor interferon regulatory factor 4 and the chemokine receptor C-X-C motif chemokine receptor 4 (CXCR4). CXCR4 ligation by C-X-C motif chemokine ligand 12 activates the mitogen-activated protein kinase extracellular-signal-regulated kinase, which then directs the development of small pre- and immature B cells, including orchestrating cell cycle exit, pre-BCR repression, Igk recombination and BCR expression. In contrast, pre-BCR expression and escape from interleukin-7 have only modest effects on B cell developmental transcriptional and epigenetic programs. These data show a direct and central role for CXCR4 in orchestrating late B cell lymphopoiesis. Furthermore, in the context of previous findings, our data provide a three-receptor system sufficient to recapitulate the essential features of B lymphopoiesis in vitro.

Molecular MRI is a promising in-vivo modality to detect and quantify morphological and molecular vessel-wall changes in atherosclerosis. The combination of different molecular biomarkers may improve the risk stratification of patients. This study aimed to investigate the feasibility of simultaneous visualization and quantification of plaque-burden and inflammatory activity by dual-probe molecular MRI in a mouse-model of progressive atherosclerosis and in response-to-therapy. Homozygous apolipoprotein E knockout mice (ApoE-/-) were fed a high-fat-diet (HFD) for up to four-months prior to MRI of the brachiocephalic-artery. To assess response-to-therapy, a statin was administered for the same duration. MR imaging was performed before and after administration of an elastin-specific gadolinium-based and a macrophage-specific iron-oxide-based probe. Following in-vivo MRI, samples were analyzed using histology, immunohistochemistry, inductively-coupled-mass-spectrometry and laser-inductively-coupled-mass-spectrometry. In atherosclerotic-plaques, intraplaque expression of elastic-fibers and inflammatory activity were not directly linked. While the elastin-specific probe demonstrated the highest accumulation in advanced atherosclerotic-plaques after four-months of HFD, the iron-oxide-based probe showed highest accumulation in early atherosclerotic-plaques after two-months of HFD. In-vivo measurements for the elastin and iron-oxide-probe were in good agreement with ex-vivo histopathology (Elastica-van-Giesson stain: y = 298.2 + 5.8, R2 = 0.83, p

Some genes have repeatedly been found to control diverse adaptations in a wide variety of organisms. Such gene reuse reveals not only the diversity of phenotypes these unique genes control but also the composition of developmental gene networks and the genetic routes available to and taken by organisms during adaptation. However, the causes of gene reuse remain unclear. A small number of large-effect Mendelian loci control a huge diversity of mimetic butterfly wing color patterns, but reasons for their reuse are difficult to identify because the genetic basis of mimicry has primarily been studied in two systems with correlated factors: female-limited Batesian mimicry in Papilio swallowtails (Papilionidae) and non-sex-limited Müllerian mimicry in Heliconius longwings (Nymphalidae). Here, we break the correlation between phylogenetic relationship and sex-limited mimicry by identifying loci controlling female-limited mimicry polymorphism Hypolimnas misippus (Nymphalidae) and non-sex-limited mimicry polymorphism in Papilio clytia (Papilionidae). The Papilio clytia polymorphism is controlled by the genome region containing the gene cortex, the classic P supergene in Heliconius numata, and loci controlling color pattern variation across Lepidoptera. In contrast, female-limited mimicry polymorphism in Hypolimnas misippus is associated with a locus not previously implicated in color patterning. Thus, although many species repeatedly converged on cortex and its neighboring genes over 120 My of evolution of diverse color patterns, female-limited mimicry polymorphisms each evolved using a different gene. Our results support conclusions that gene reuse occurs mainly within ∼10 My and highlight the puzzling diversity of genes controlling seemingly complex female-limited mimicry polymorphisms.

Background and purpose Quantitative susceptibility mapping (QSM) of the brain has become highly reproducible and has applications in an expanding array of diseases. To translate QSM from bench to bedside, it is important to automate its reconstruction immediately after data acquisition. In this work, a server system that automatically reconstructs QSM and exchange images with the scanner using the DICOM standard is demonstrated using a multi-site, multi-vendor reproducibility study and a large, single-site, multi-scanner image quality review study in a clinical environment. Methods A single healthy subject was scanned with a 3D multi-echo gradient echo sequence at nine sites around the world using scanners from three manufacturers. A high-resolution (HiRes, .5 × .5 × 1 mm3 reconstructed) and standard-resolution (StdRes, .5 × .5 × 3 mm3 ) protocol was performed. ROI analysis of various white matter and gray matter regions was performed to investigate reproducibility across sites. At one institution, a retrospective multi-scanner image quality review was carried out of all clinical QSM images acquired consecutively in 1 month. Results Reconstruction times using a GPU were 29 ± 22 seconds (StdRes) and 55 ± 39 seconds (HiRes). ROI standard deviation across sites was below 24 ppb (StdRes) and 17 ppb (HiRes). Correlations between ROI averages across sites were on average .92 (StdRes) and .96 (HiRes). Image quality review of 873 consecutive patients revealed diagnostic or excellent image quality in 96% of patients. Conclusion Online QSM reconstruction for a variety of sites and scanner platforms with low cross-site ROI standard deviation is demonstrated. Image quality review revealed diagnostic or excellent image quality in 96% of 873 patients.

Grindstaff, TL, Palimenio, MR, Franco, M, Anderson, D, Bagwell, JJ, and Katsavelis, D. Optimizing between-session reliability for quadriceps peak torque and rate of torque development measures. J Strength Cond Res 33(7): 1840-1847, 2019-Quadriceps peak torque and rate of torque development (RTD) have relevance for athletic performance and recovery after knee injury. The number of repetitions performed to determine RTD varies between studies, and the associated measurement error has not been established. The purpose of this study was to determine the number of repetitions necessary to optimize the between-session reliability for isometric quadriceps peak torque and RTD measures and to quantify estimates of measurement error. Twenty participants (age = 21.7 ± 1.7 years, height = 172.5 ± 16.0 cm, body mass = 76.0 ± 15.5 kg, and Tegner = 7.1 ± 1.2) volunteered for this study. Quadriceps isometric peak torque and RTD (50, 100, 150, 200, and 250 ms, and maximum torque) were obtained during 2 testing sessions. Between-session reliability was determined using intraclass correlation coefficients (ICC2,k), using the minimal detectable change (MDC) and coefficient of variation (CoV) to quantify measurement error. Between-session reliability was best maximized by using the average of the 3 repetitions with the highest peak torque. Reliability was good for quadriceps peak torque (ICC2,3 = 0.98; MDC = 51.1 N·m; CoV = 38.0%) and ranged from moderate to good for quadriceps RTD measures (ICC2,3 = 0.61 to 0.91; MDC = 264.8 to 738.3 N·m·s; CoV = 38.1-57.9%). Measures of late RTD were less variable and more reliable than early RTD and average RTD measures. These results provide confidence when measuring between-session changes for late RTD measures, but changes in early RTD may be more difficult to distinguish from measurement error. Methods should be used to minimize variability between repetitions and sessions.

Background Smoking is an important cause of mortality and recent studies have suggested that even low-intensity smoking might be associated with increased mortality. Still, smoking is associated with lower socio-economic status as well as other potential risk factors, and disease onset might motivate smoking cessation, thus residual confounding and reverse causality might bias results. We aimed to assess the evidence of a causal relationship between smoking intensity and cause-specific as well as all-cause-mortality using Mendelian randomization analyses. Methods We included 56 019 participants from the Norwegian HUNT2 Study and 337 103 participants from UK Biobank, linked to national registry data on causes of death. We estimated associations of self-reported smoking as well as the genetic variant rs1051730 as an instrument for smoking intensity with all-cause and cause-specific mortality. We subsequently meta-analysed the results from the two cohorts. Results Each effect allele of the rs1051730 was associated with a 9% increased hazard of all-cause mortality [95% confidence interval (CI) 6–11] among ever smokers. Effect alleles were also associated with death by neoplasms [hazard ratio (HR) 1.11, 95% CI 1.06–1.15], circulatory diseases (HR 1.06, 95% CI 1.01–1.11) and respiratory diseases (HR 1.15, 95% CI 1.05–1.26) among ever smokers. The association was stronger among ever than never smokers for all-cause mortality (p Conclusions Our results indicate a causal effect of smoking intensity on all-cause mortality and death by neoplasms and respiratory diseases. There was weaker evidence of a causal effect of smoking intensity on death by circulatory diseases.

This study sought to investigate the potential of the noninvasive albumin-binding probe gadofosveset-enhanced cardiac magnetic resonance (GE-CMR) for detection of coronary plaques that can cause acute coronary syndromes (ACS).ACS are frequently caused by rupture or erosion of coronary plaques that initially do not cause hemodynamically significant stenosis and are therefore not detected by invasive x-ray coronary angiography (XCA).A total of 25 patients with ACS or symptoms of stable coronary artery disease underwent GE-CMR, clinically indicated XCA, and optical coherence tomography (OCT) within 24 h. GE-CMR was performed approximately 24 h following a 1-time application of gadofosveset-trisodium. Contrast-to-noise ratio (CNR) was quantified within coronary segments in comparison with blood signal.A total of 207 coronary segments were analyzed on GE-CMR. Segments containing a culprit lesion in ACS patients (n = 11) showed significant higher signal enhancement (CNR) following gadofosveset-trisodium application than segments without culprit lesions (n = 196; 6.1 [3.9 to 16.5] vs. 2.1 [0.5 to 3.5]; p 0.001). GE-CMR was able to correctly identify culprit coronary lesions in 9 of 11 segments (sensitivity 82%) and correctly excluded culprit coronary lesions in 162 of 195 segments (specificity 83%). Additionally, segmented areas of thin-cap fibroatheroma (n = 22) as seen on OCT demonstrated significantly higher CNR than segments without coronary plaque or segments containing early atherosclerotic lesions (n = 185; 9.2 [3.3 to 13.7] vs. 2.1 [0.5 to 3.4]; p = 0.001).In this study, we demonstrated for the first time the noninvasive detection of culprit coronary lesions and thin-cap fibroatheroma of the coronary arteries in vivo by using GE-CMR. This method may represent a novel approach for noninvasive cardiovascular risk prediction.

To investigate the ability of T1 mapping to visualize and quantify the short-term and mid-term response of autoimmune pancreatitis (AIP) to corticosteroid treatment (CST) and to correlate T1 relaxation time of the pancreas with clinical status and serum IgG4 level. The institutional review board approved this prospective study, and all patients provided written informed consent. Pancreatic MRI including native T1 mapping was performed in 39 AIP patients before and during CST, and 40 patients without pancreatic diseases served as control. T1 relaxation time of the pancreatic head, body, and tail was measured in each patient. Clinical symptoms and serum IgG4 level of the patients were recorded. The native T1 relaxation time of AIP was significantly elongated compared to normal pancreatic tissue (1124.5 ms ± 95.7 ms vs 784.3 ms ± 41.8 ms, p

Objectives Using magnetic resonance imaging (MRI) as the standard of reference, we aimed to evaluate the diagnostic accuracy of dual-energy computed tomography (DECT) in assessing disk injuries in patients aged more than 50 years with vertebral fractures. Methods This prospective study was approved by the local ethics committee (EA1/372/14), and all patients gave written informed consent. Patients with suspected fractures underwent spinal DECTs and MRIs. Three readers scored DECT collagen maps for the presence or absence of disk injuries and also scored MR images according to the Sander classification (0–3). Only disks at risk (target disks) were included in the analysis. Sensitivity and specificity were calculated. Fleiss’s κ was used to evaluate interrater agreement. Attenuation, in Hounsfield units, was compared between affected and unaffected disks in DECT. Results Analyzing 295 disks in 67 patients, DECT was both sensitive (0.85) and specific (0.75). Sensitivity varied with the severity of disk damage, as assessed using the Sander scale (grade 1, 0.80; 2, 0.85; and 3, 0.98). Fleiss’s κ was 0.41 for MRI and 0.51 for DECT. In the DECT collagen maps, attenuation was lower in injured disks compared to that in normal disks (80.3 ± 35.2 vs. 97.9 ± 41.0, p

Objective.To compare proton density–weighted short-tau inversion recovery (PD-STIR) and T2-weighted fat-suppressed turbo spin echo (T2-FS) sequences for detecting osteitis lesions of the sacroiliac joints (SIJ) in patients with chronic low back pain (CLBP).Methods.This prospective study included 110 patients with CLBP and suspected spondyloarthritis and 18 healthy controls. All 128 participants (age range: 19–57 yrs) underwent 3.0 Tesla magnetic resonance imaging (MRI) of the SIJ including PD-STIR and T2-FS. Two readers independently scored PD-STIR and T2-FS images for osteitis in separate sessions. Sum scores and signal-to-noise (SNR) and contrast-to-noise (CNR) ratios were calculated. Images were further analyzed as to whether they fulfilled the Assessment of SpondyloArthritis international Society (ASAS) criterion of a positive MRI (MRI+). Interreader agreement was calculated using intraclass correlation coefficients.Results.Average osteitis sum scores were higher for T2-FS images (mean sum score of 4.10 in T2-FS vs 2.55 in PD-STIR, p = 0.017). Mean SNR was 16.54 for PD-STIR and 37.30 for T2-FS (p = 0.0289). Mean CNR was 4.14 for PD-STIR and 20.20 for T2-FS (p = 0.0212). For both readers, the ASAS MRI+ definition was more often fulfilled by T2-FS than by PD-STIR images, resulting in more patients being classified as having axial spondyloarthritis (axSpA): 68 patients using T2-FS versus 58 patients using PD-STIR. Interreader intraclass correlation coefficients were very good for both PD-STIR (0.91) and T2-FS (0.86).Conclusion.T2-FS sequences improve image quality and hence the detection of osteitis compared to the PD-STIR sequence. More patients were classified as axSpA based on a positive MRI by T2-FS.

Purpose To evaluate the use of susceptibility-weighted MRI for the differentiation of predominantly osteoblastic and osteolytic spine metastases. Materials and Methods For this prospective study, 53 study participants (mean age, 54.5 years ± 14.3 [range, 22-88 years]; 27 men with a mean age of 55.3 years ± 12.7 [range, 22-72 years] and 26 women with a mean age of 53.8 years ± 15.7 [range, 23-88 years]) with clinically suspected spine metastases underwent imaging with standard MRI sequences, susceptibility-weighted MRI, and CT. Sensitivities and specificities of MRI sequences for the detection of predominantly osteoblastic and osteolytic metastases were determined by using CT as the reference standard. The metastases-to-vertebral body signal intensity ratio (MVR) was calculated to compare modalities. Phantom measurements were obtained to correlate bone densities between MRI sequences and CT. Results A total of 64 metastases (38 predominantly osteoblastic, 26 predominantly osteolytic) were detected. Susceptibility-weighted MRI achieved a sensitivity of 100% (38 of 38) and specificity of 96% (25 of 26) for predominantly osteoblastic metastases and a sensitivity of 96% (25 of 26) and specificity of 100% (38 of 38) for predominantly osteolytic metastases. Standard MRI sequences achieved a sensitivity of 89% (34 of 38) and specificity of 73% (19 of 26) for predominantly osteoblastic metastases and a sensitivity of 73% (19 of 26) and specificity of 92% (35 of 38) for predominantly osteolytic metastases. MVR measurements obtained with susceptibility-weighted MRI demonstrated a strong correlation with those obtained with CT (R2 = 0.75), whereas those obtained with T1-weighted MRI, T2-weighted MRI, and turbo inversion-recovery magnitude MRI showed a weak to moderate correlation (R2 = 0.00, R2 = 0.35, and R2 = 0.39, respectively). Susceptibility-weighted MRI showed a strong correlation with CT with regard to metastases size (R2 = 0.91). In phantom measurements, susceptibility-weighted MRI enabled the reliable differentiation of different degrees of mineralization (R2 = 0.92 compared with CT). Conclusion Susceptibility-weighted MRI enables the reliable differentiation between predominantly osteoblastic and osteolytic spine metastases with a higher accuracy than standard MRI sequences. © RSNA, 2018 Online supplemental material is available for this article. See also the editorial by Schweitzer in this issue.

Background Although falling is becoming a major problem in the elderly, little is known about the long-term incidence of postoperative periprosthetic femoral fractures (PFF) after total hip arthroplasty (THA) using uncemented stems with a minimum follow-up of 26 years postoperatively. Methods In a consecutive series, the cumulative incidence of PFF after uncemented THA using a straight, collarless, tapered titanium stem was retrospectively reviewed in 354 hips (326 patients). After a mean follow-up of 28 (26-32) years postoperatively, 179 hips had died and 5 hips had been lost to follow-up. Kaplan-Meier survival analysis was used to estimate cumulative percentage probability of PFF. Results At final follow-up, a total of 27 fractures in 27 patients had occurred. In 15 hips, the stem had to be revised, and in 10 the fracture was treated by open reduction and internal fixation. Two patients declined further surgery. The cumulative percentage probability of PFF was 1.6% (95% confidence interval, 0.7 to 3.8) at 10 years and 13.2% (95% confidence interval, 8.5 to 20.2) at 29 years after primary THA. There was no association between the occurrence of fracture and gender, age at primary THA, cup revision, or canal fill index. Conclusion Our findings indicate that PFF is the major mode of failure in the long term after uncemented THA using a tapered titanium stem. More research is needed to evaluate the reasons and risk factors for PFF after THA, thus providing better prophylaxis for those at risk and to compare the long-term incidence using different fixation methods and implants. Level of evidence IV.

To evaluate the diagnostic potential of susceptibility-weighted imaging (SWI) for the detection of erosions of the hand, compared to T1-weighted (T1w) magnetic resonance imaging (MRI). Computed tomography (CT) was used as a reference standard. We prospectively investigated 37 patients with suspected arthritic activity of the hand. All patients underwent T1w, SWI, and CT on the same day. Patients were randomized to MRI or CT first. CT, T1w, SWI, and T1w/SWI were scored for erosions according to OMERACT RAMRIS guidelines. Specificity, sensitivity, and diagnostic accuracy were separately calculated for T1w, SWI, and T1w/SWI on a per-patient and per-bone basis using CT as reference. The one-tailed McNemar test was performed to test the number of erosion-positive patients in T1w, SWI, and T1w/SWI for non-inferiority. Measured erosion sizes were compared using Pearson’s test. CT was positive for erosions in 16 patients and 55 bones. SWI and T1w/SWI had superior diagnostic accuracy (91.2 and 93.8%) compared to T1w (87.8%) driven by a higher specificity (93.8 and 96.5%) compared to T1w (88.8%). On the patient level, SWI and T1w/SWI showed non-inferiority (p = 0.11 and p = 0.38) but not T1w alone (p

An association between maternal smoking in pregnancy and autism may be biologically plausible, but the evidence to date is inconsistent. We aimed to investigate the causal relationship between maternal smoking during pregnancy and offspring autism using conventional analysis and causal inference methods. In the Avon Longitudinal Study of Parents and Children we investigated the association of maternal smoking during pregnancy (exposure) with offspring autism spectrum disorder (ASD) or possible ASD diagnosis (n = 11,946) and high scores on four autism-related traits (outcomes) (n = 7402–9152). Maternal smoking was self-reported and also measured using an epigenetic score (n = 866–964). Partner’s smoking was used as a negative control for intrauterine exposure (n = 6616–10,995). Mendelian randomisation (n = 1002–2037) was carried out using a genetic variant at the CHRNA3 locus in maternal DNA as a proxy for heaviness of smoking. In observational analysis, we observed an association between smoking during pregnancy and impairments in social communication [OR = 1.56, 95% CI = 1.29, 1.87] and repetitive behaviours, but multivariable adjustment suggested evidence for confounding. There was weaker evidence of such association for the other traits or a diagnosis of autism. The magnitude of association for partner’s smoking with impairments in social communication was similar [OR = 1.56, 95% CI = 1.30, 1.87] suggesting potential for shared confounding. There was weak evidence for an association of the epigenetic score or genetic variation at CHRNA3 with ASD or any of the autism-related traits. In conclusion, using several analytic methods, we did not find enough evidence to support a causal association between maternal smoking during pregnancy and offspring autism or related traits.