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There is no multi-country/multi-language study testing a-priori multivariable associations between non-modifiable/modifiable factors and validated wellbeing/multidimensional mental health outcomes before/during the COVID-19 pandemic. Moreover, studies during COVID-19 pandemic generally do not report on representative/weighted non-probability samples. The Collaborative Outcomes study on Health and Functioning during Infection Times (COH-FIT) is a multi-country/multi-language survey conducting multivariable/LASSO-regularized regression models and network analyses to identify modifiable/non-modifiable factors associated with wellbeing (WHO-5)/composite psychopathology (P-score) change. It enrolled general population-representative/weighted-non-probability samples (26/04/2020-19/06/2022). Participants included 121,066 adults (age=42±15.9 years, females=64 %, representative sample=29 %) WHO-5/P-score worsened (SMD=0.53/SMD=0.74), especially initially during the pandemic. We identified 15 modifiable/nine non-modifiable risk and 13 modifiable/three non-modifiable protective factors for WHO-5, 16 modifiable/11 non-modifiable risk and 10 modifiable/six non-modifiable protective factors for P-score. The 12 shared risk/protective factors with highest centrality (network-analysis) were, for non-modifiable factors, country income, ethnicity, age, gender, education, mental disorder history, COVID-19-related restrictions, urbanicity, physical disorder history, household room numbers and green space, and socioeconomic status. For modifiable factors, we identified medications, learning, internet, pet-ownership, working and religion as coping strategies, plus pre-pandemic levels of stress, fear, TV, social media or reading time, and COVID-19 information. In multivariable models, for WHO-5, additional non-modifiable factors with |B|>1 were income loss, COVID-19 deaths. For modifiable factors we identified pre-pandemic levels of social functioning, hobbies, frustration and loneliness, and social interactions as coping strategy. For P-scores, additional non-modifiable/modifiable factors were income loss, pre-pandemic infection fear, and social interactions as coping strategy. COH-FIT identified vulnerable sub-populations and actionable individual/environmental factors to protect well-being/mental health during crisis times. Results inform public health policies, and clinical practice., Competing Interests: Conflict of interest Conflict of interest statements of all authors are detailed in eTable 12., (Copyright © 2024. Published by Elsevier B.V.)

International studies measuring wellbeing/multidimensional mental health before/ during the COVID-19 pandemic, including representative samples for >2 years, identifying risk groups and coping strategies are lacking. COH-FIT is an online, international, anonymous survey measuring changes in well-being (WHO-5) and a composite psychopathology P-score, and their associations with COVID-19 deaths/restrictions, 12 a-priori defined risk individual/cumulative factors, and coping strategies during COVID-19 pandemic (26/04/2020-26/06/2022) in 30 languages (representative, weighted non-representative, adults). T-test, χ 2 , penalized cubic splines, linear regression, correlation analyses were conducted. Analyzing 121,066/142,364 initiated surveys, WHO-5/P-score worsened intra-pandemic by 11.1±21.1/13.2±17.9 points (effect size d=0.50/0.60) (comparable results in representative/weighted non-probability samples). Persons with WHO-5 scores indicative of depression screening (<50, 13% to 32%) and major depression (<29, 3% to 12%) significantly increased. WHO-5 worsened from those with mental disorders, female sex, COVID-19-related loss, low-income country location, physical disorders, healthcare worker occupations, large city location, COVID-19 infection, unemployment, first-generation immigration, to age=18-29 with a cumulative effect. Similar findings emerged for P-score. Changes were significantly but minimally related to COVID-19 deaths, returning to near-pre-pandemic values after >2 years. The most subjectively effective coping strategies were exercise and walking, internet use, social contacts. Identified risk groups, coping strategies and outcome trajectories can inform global public health strategies., Competing Interests: Declaration of competing interest Conflict of interest statements of all authors are detailed in eTable 8., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Aims: To examine educational outcomes among adolescents with type 1 diabetes and determine the role of comorbidity., Methods: We conducted a nationwide register-based cohort study including 3370 individuals born between 1991 and 2003 and diagnosed with type 1 diabetes before the age of 16. They were all matched with up to four individuals without type 1 diabetes on age, gender, parents' educational level and immigration status. Information on comorbidity was based on hospital diagnoses. The individuals were followed in registers to determine whether they finished compulsory school (9th grade, usually at the age of 15-16 years), and were enrolled in secondary education by age 18 years., Results: Individuals with type 1 diabetes were more likely not to complete compulsory school (OR 1.44, 95% CI 1.26-1.64), and not being enrolled in an upper secondary education by age 18 (OR 1.50, 95% CI 1.31-1.73) compared to their peers. A total of 1869 (56%) individuals with type 1 diabetes were registered with at least one somatic (n = 1709) or psychiatric comorbidity (n = 389). Those with type 1 diabetes and psychiatric comorbidity were more likely not to complete compulsory school (OR 2.47, 95% CI 1.54-3.96), and not being enrolled in an upper secondary education by age 18 (OR 3.66, 95% CI 2.27-5.91) compared to those with type 1 diabetes only. Further, there was a tendency towards an association between having somatic comorbidity and adverse educational outcomes (OR 1.25, 95% CI 0.97-1.63; OR 1.26, 95% CI 0.95-1.66) among adolescents with type 1 diabetes. The associations differed markedly between diagnostic comorbidity groups., Conclusion: Type 1 diabetes affects educational attainment and participation among adolescents. Psychiatric comorbidity contributes to adverse educational outcomes in this group, and there is a tendency that somatic comorbidity also plays a role., (© 2024 Diabetes UK.)

Aims: To investigate if diabetic complications increase the risk of depression and/or anxiety among adults with type 2 diabetes., Methods: This register-based, prospective study included 265,799 adult individuals diagnosed with type 2 diabetes between 1997 and 2017 without a recent history of depression or anxiety. Diabetic complications included cardiovascular disease, amputation of lower extremities, neuropathy, nephropathy and retinopathy. Both diabetic complications and depression and anxiety were defined by hospital contacts and prescription-based medication. All individuals were followed from the date of type 2 diabetes diagnosis until the date of incident depression or anxiety, emigration, death or 31 December 2018, whichever occurred first., Results: The total risk time was 1,915,390 person-years. The incidence rate of depression and/or anxiety was 3368 per 100,000 person-years among individuals with diabetic complications and 1929 per 100,000 person-years among those without. Having or developing any diabetic complication was associated with an increased risk of depression and/or anxiety (HR 1.77, 95% CI 1.73-1.80). The risk for depression and/or anxiety was increased for all types of diabetic complications. The strongest association was found for amputation of lower extremities (HR 2.16, 95% CI 2.01-2.31) and the weakest for retinopathy (HR 1.13, 95% CI 1.09-1.17)., Conclusion: Individuals with type 2 diabetes and diabetic complications are at increased risk of depression and anxiety. This points towards the importance of an increased clinical focus on mental well-being among individuals with type 2 diabetes and complications., (© 2023 Diabetes UK.)

Introduction: The incidence of type 2 diabetes is increasing globally. Recent research suggests that loneliness could be a potential risk factor for the development of type 2 diabetes. We aimed to investigate the association between loneliness and type 2 diabetes and the modifying effect of mental disorders., Research Design and Methods: We conducted a prospective study including 465 290 adults (aged ≥16 years) who participated in either the Danish Health and Morbidity Survey or the Danish National Health Survey between 2000 and 2017. Loneliness was based on self-report, while type 2 diabetes was measured using an algorithm combining several health registers including type 2 diabetes patients treated both within the hospital sector and general practice. Cox proportional hazards regressions were used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs)., Results: During a mean follow-up time of 6.3 years, 13 771 individuals (3%) developed type 2 diabetes. Feeling lonely once in a while was associated with a 14% increased risk of type 2 diabetes (95% CI 1.09 to 1.20), while feeling lonely often was associated with a 24% increased risk (95% CI 1.14 to 1.34), independent of sociodemographic factors and body mass index. The association was stronger among individuals without a mental disorder (HR 1.21, 95% CI 1.10 to 1.34 among those feeling lonely often) compared with those with a mental disorder (HR 1.07, 95% CI 0.93 to 1.23)., Conclusions: Loneliness independently increased the risk of type 2 diabetes. The effect was more pronounced in individuals without a mental disorder, as having a mental disorder itself likely increases the risk of type 2 diabetes. These findings emphasize the importance of addressing loneliness as a modifiable risk factor in preventing type 2 diabetes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The Collaborative Outcome study on Health and Functioning during Infection Times (COH-FIT; www.coh-fit.com) is an anonymous and global online survey measuring health and functioning during the COVID-19 pandemic. The aim of this study was to test concurrently the validity of COH-FIT items and the internal validity of the co-primary outcome, a composite psychopathology "P-score"., Methods: The COH-FIT survey has been translated into 30 languages (two blind forward-translations, consensus, one independent English back-translation, final harmonization). To measure mental health, 1-4 items ("COH-FIT items") were extracted from validated questionnaires (e.g. Patient Health Questionnaire 9). COH-FIT items measured anxiety, depressive, post-traumatic, obsessive-compulsive, bipolar and psychotic symptoms, as well as stress, sleep and concentration. COH-FIT Items which correlated r ≥ 0.5 with validated companion questionnaires, were initially retained. A P-score factor structure was then identified from these items using exploratory factor analysis (EFA) and confirmatory factor analyses (CFA) on data split into training and validation sets. Consistency of results across languages, gender and age was assessed., Results: From >150,000 adult responses by May 6th, 2022, a subset of 22,456 completed both COH-FIT items and validated questionnaires. Concurrent validity was consistently demonstrated across different languages for COH-FIT items. CFA confirmed EFA results of five first-order factors (anxiety, depression, post-traumatic, psychotic, psychophysiologic symptoms) and revealed a single second-order factor P-score, with high internal reliability (ω = 0.95). Factor structure was consistent across age and sex., Conclusions: COH-FIT is a valid instrument to globally measure mental health during infection times. The P-score is a valid measure of multidimensional mental health., Competing Interests: Conflict of interest Conflict of interest statements of all authors are detailed in Supplementary Table 7., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objectives of this study were to assess (1) prevalence of worries and symptoms of distress, and (2) perceived change in symptoms of distress by sociodemographic factors and preexisting vulnerabilities, among young Danes under the first COVID-19 related lockdown. Data were derived from online surveys, collected 7th-18th of May 2020. The study population included 11,245 young people (15-20 years of age), of which 1807 had participated in The Danish National Youth Study 2019 (DNYS19). Descriptive statistics and linear regressions analyses, including robust standard errors, were performed. All analyses were based on cross-sectional data, except analyses of preexisting vulnerabilities among responders from DNYS19. Few young people were very worried to get infected with coronavirus. Females reported a higher frequency of symptoms of distress than males. Perceived change in symptoms of distress, did not vary systematically based on age, cohabitation, nor physical health conditions. Individuals working, perceived a lower increase in symptoms of distress, than those studying etc. Females with symptoms of anxiety pre-pandemic, mental health disorders, and in families with economic hardship had a marginal higher perceived increase in symptoms of distress, than females without these difficulties. The tendencies were similar but nonsignificant among males, and for symptoms of depression pre-pandemic. In conclusion, during the lockdown, young females reported a higher frequency of symptoms of distress than males, and individuals with symptoms of anxiety pre-pandemic, mental health disorders, and in families with economic hardship were more likely to perceive the lockdown to be associated with an increase in symptoms of distress, than individuals without these difficulties., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Aim: In this study, using national survey data from 2014 and 2019, we tested the hypothesis that students at schools who introduced a common alcohol policy in 2017 drank less than students at schools without a common policy., Methods: We used survey data from 41 high schools that participated in the Danish National Youth Study in 2014 and 2019. We perceived the introduction of a common high-school alcohol policy in 2017 among local groups of high schools as a natural experiment and assessed it using difference-in-difference analyses. We assessed drinking patterns from 2014 and 2019 among students at schools with and without a common alcohol policy combined and stratified by sex in negative binominal regression and logistic regression models. Drinking patterns were measured as average weekly alcohol use, average alcohol intake at last school party, proportion of non-drinkers and frequent binge drinkers., Results: Drinking patterns were similar among students in schools with and without a common alcohol policy. For example, among students at schools with a common alcohol policy, the average alcohol intake at the last school party among drinkers was 8.7 units in 2014 and 8.5 units in 2019, whereas average alcohol intake among students at schools without a common alcohol policy was 8.8 units in 2014 and 8.9 units in 2019 ( p =0.413)., Conclusions: No statistically significant effects were observed following the introduction of a common alcohol policy on students' drinking patterns, and alcohol consumption among high-school students was stable and remained high in 2014 and in 2019.

Background: Recruiting young people for health and intervention studies by traditional methods has become increasingly challenging. The widespread access to the internet may offer new strategies for online recruitment., Objective: This study aims to assess the feasibility of online recruitment for a randomized controlled trial evaluating the effectiveness of Mindhelper, an online national youth mental health promotion service. The target group was young Danes aged 15-25 in need of mental health promotion., Methods: Advertisements for recruitment were set up on Facebook and Instagram. Browser history was collected for a subsample of participants. We compared basic characteristics of participants who completed the baseline survey and those who did not, as well as of participants who completed the follow-up survey and those who were lost to follow-up. The significance of these differences was tested with the Pearson chi-square test., Results: A total of 560 Danes aged 15-25 were recruited within 1 month (ie, had completed the baseline survey). Among these participants, 356 (63.6%) were at risk of developing depression or stress. The average advertisement price per participant completing the baseline questionnaire was 31 DKK (approximately €4 [US $4.2]). The follow-up survey was sent to 545 participants, of whom 318 (58.3%) completed the survey. No statistically significant differences were observed in baseline characteristics of participants who completed the follow-up and those who were lost to follow-up in terms of gender (P=.45), age (P=.35), occupation (P=.17), cohabitation (P=.90), mental well-being (P=.26), mental illness (P=.44; impact of the illness, P=.05), or use of the internet when having a hard time (P=.92)., Conclusions: We conclude that it is feasible to recruit young Danes online for a large-scale randomized controlled trial assessing the effectiveness of Mindhelper., Trial Registration: ClinicalTrials.gov NCT04650906; https://clinicaltrials.gov/ct2/show/NCT04650906., (©Sofie Have Hoffmann, Anna Paldam Folker, Mark Buskbjerg, Marie Paldam Folker, Andrea Huber Jezek, Durita Lyngsø Svarta, Ida Nielsen Sølvhøj, Lau Thygesen. Originally published in JMIR Formative Research (https://formative.jmir.org), 25.05.2022.)

Background: . High-quality comprehensive data on short-/long-term physical/mental health effects of the COVID-19 pandemic are needed., Methods: . The Collaborative Outcomes study on Health and Functioning during Infection Times (COH-FIT) is an international, multi-language (n=30) project involving >230 investigators from 49 countries/territories/regions, endorsed by national/international professional associations. COH-FIT is a multi-wave, on-line anonymous, cross-sectional survey [wave 1: 04/2020 until the end of the pandemic, 12 months waves 2/3 starting 6/24 months threreafter] for adults, adolescents (14-17), and children (6-13), utilizing non-probability/snowball and representative sampling. COH-FIT aims to identify non-modifiable/modifiable risk factors/treatment targets to inform prevention/intervention programs to improve social/health outcomes in the general population/vulnerable subgrous during/after COVID-19. In adults, co-primary outcomes are change from pre-COVID-19 to intra-COVID-19 in well-being (WHO-5) and a composite psychopathology P-Score. Key secondary outcomes are a P-extended score, global mental and physical health. Secondary outcomes include health-service utilization/functioning, treatment adherence, functioning, symptoms/behaviors/emotions, substance use, violence, among others., Results: . Starting 04/26/2020, up to 14/07/2021 >151,000 people from 155 countries/territories/regions and six continents have participated. Representative samples of ≥1,000 adults have been collected in 15 countries. Overall, 43.0% had prior physical disorders, 16.3% had prior mental disorders, 26.5% were health care workers, 8.2% were aged ≥65 years, 19.3% were exposed to someone infected with COVID-19, 76.1% had been in quarantine, and 2.1% had been COVID 19-positive., Limitations: . Cross-sectional survey, preponderance of non-representative participants., Conclusions: . Results from COH-FIT will comprehensively quantify the impact of COVID-19, seeking to identify high-risk groups in need for acute and long-term intervention, and inform evidence-based health policies/strategies during this/future pandemics., (Copyright © 2021. Published by Elsevier B.V.)

Background: The COVID-19 pandemic has altered daily routines and family functioning, led to closing schools, and dramatically limited social interactions worldwide. Measuring its impact on mental health of vulnerable children and adolescents is crucial., Methods: The Collaborative Outcomes study on Health and Functioning during Infection Times (COH-FIT - www.coh-fit.com) is an on-line anonymous survey, available in 30 languages, involving >230 investigators from 49 countries supported by national/international professional associations. COH-FIT has thee waves (until the pandemic is declared over by the WHO, and 6-18 months plus 24-36 months after its end). In addition to adults, COH-FIT also includes adolescents (age 14-17 years), and children (age 6-13 years), recruited via non-probability/snowball and representative sampling and assessed via self-rating and parental rating. Non-modifiable/modifiable risk factors/treatment targets to inform prevention/intervention programs to promote health and prevent mental and physical illness in children and adolescents will be generated by COH-FIT. Co-primary outcomes are changes in well-being (WHO-5) and a composite psychopathology P-Score. Multiple behavioral, family, coping strategy and service utilization factors are also assessed, including functioning and quality of life., Results: Up to June 2021, over 13,000 children and adolescents from 59 countries have participated in the COH-FIT project, with representative samples from eleven countries., Limitations: Cross-sectional and anonymous design., Conclusions: Evidence generated by COH-FIT will provide an international estimate of the COVID-19 effect on children's, adolescents' and families', mental and physical health, well-being, functioning and quality of life, informing the formulation of present and future evidence-based interventions and policies to minimize adverse effects of the present and future pandemics on youth., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Aim: the objective was to test the hypothesis that a higher proportion of students with non-Western origin in high school classes is associated with lower and less frequent alcohol consumption among ethnic Danish students., Method: data on country of origin was obtained from the Danish Civil Registration System, while information on drinking habits were derived from the Danish National Youth Study 2014. Multilevel zero-inflated binominal regression was used to assess the association between class proportion of students with non-Western origin and odds of non-drinking and mean weekly alcohol consumption, while multilevel logistic regression was used to assess the association with frequent binge drinking., Results: a higher proportion of students with non-Western origin in class was associated with higher odds of non-drinking among ethnic Danish student in the same class. For example, ethnic Danish boys in classes with more than 15% of the students of non-Western origin had 77% higher odds of being non-drinkers, compared to ethnic Danish boys in classes where 0-5% had non-Western origin (OR: 1.77, 95% CI; 1.42-2.20). Among ethnic Danish students that did consume alcohol, class proportion of students with non-Western origin was not associated with weekly alcohol consumption, while a higher proportion of students with non-Western origin in class was associated with lower odds of frequent binge drinking., Conclusion: the downward drinking trend among adolescents in Western countries may be partly explained by the higher proportion of youth with non-Western origin, influencing the prevalence of drinking and frequency of binge drinking among adolescents in the ethnic majority population., (© The Author(s) 2020. Medical Council on Alcohol and Oxford University Press. All rights reserved.)

Objectives: We aimed to determine the effect of workplace violence on long-term sickness absence, and whether social support from supervisors and colleagues buffer this effect., Methods: Information on workplace violence and social support were derived from the Danish Work Environment Cohort Study in 2000, 2005, and 2010 and the Swedish Longitudinal Occupational Survey of Health in 2006 and 2008. Individual- and joint-effects on register-based long-term sickness absence were determined using logistic regression models for repeated measurements. Cohort-specific estimates were combined in random effect meta-analyses., Results: Workplace violence and low social support were independently associated with a higher risk of long-term sickness absence, and we did not find evidence of an interaction., Conclusion: Exposure to workplace violence is a risk factor for long-term sickness absence while social support is associated with a lower risk of long-term sickness absence.

Background: Clear documentation of the understanding of the problem, process of development, and content of interventions is essential to enable other researchers to understand why interventions succeed or fail and to enable researcher to build on previous evidence and replicate and adapt findings in other contexts. In this paper we describe the rationale, intervention development, and final design of the 'High schools High on life' intervention; a high school-based, multi-component intervention to reduce excessive drinking among Danish high school students. Methods: The development of the intervention 'High schools High on life' was guided by the planning steps of the Intervention Mapping protocol (IM) in combination with the behavior change wheel and the behavior change techniques, theory, evidence, practice, and new empirical studies of contextual factors in the Danish high school setting. Results: The development process resulted in a multi-component intervention with the following intervention elements: a school environmental component targeting school alcohol policies and norms, a school educational component addressing students' social norms around alcohol, and a parental component encouraging parent-child communication around alcohol. Discussion: Not all steps of IM were followed rigidly. However, IM proved useful as a planning tool in combination with the behavior change wheel and the behavior change techniques, as it provided a systematic approach to the intervention development process. IM forced the research group to be explicit about decisions and choices throughout the planning process. The transparency of the developmental process and theoretical, empirical and practical/contextual foundation of the 'High schools High on life' intervention may enable future intervention studies to build on our findings and accumulate knowledge to reduce excessive drinking among young people. Trial registration: The trial was registered at clinicaltrials.gov (Trial registration number NCT03906500) prior to randomization., (Copyright © 2020 Pisinger, Hoffmann, Pålsson, Dalum, Grønbæk, Tolstrup, Thygesen and Krølner.)

Background and Purpose: In the setting of an extended time window for endovascular treatment (EVT) for acute stroke patients, computed tomography perfusion (CTP) has become a major tool in patient selection. However, there are some data suggesting that the initial ischemic core may be overestimated by CTP depending on stroke onset time. This study aims to evaluate possible predictors of overestimation of infarct core by CTP., Methods: We studied all consecutive stroke patients undergoing EVT during 1 year who underwent CTP at admission and had a successful recanalization. Admission infarct core was measured on cerebral blood volume maps generated using the Intellispace Portal (Philips Healthcare, Best, the Netherlands) and final infarct was measured on noncontrast follow-up computed tomography at 24 hours. We defined overestimation of the infarct core as initial core minus final infarct >10 mL., Results: Out of 107 patients undergoing EVT in the study period, 60 were anterior circulation and had CTP done at our institute, and of them 31 were compatible with the inclusion criteria (known time of onset, no hemorrhagic conversion, and good recanalization). Median National Institute of Health Stroke Scale on admission was 13. Median time from symptoms to CTP was 148 minutes. Seventeen patients were found to have overestimation of the infarct core. Logistic regression analyses showed time from symptom onset to CTP to be inversely related to overestimation with a cutoff of 170 minutes (sensitivity 94% and specificity 43%)., Conclusion: Over estimation of the infarct core by CTP in patients undergoing EVT is time dependent and so CTP results among early arrivers should be interpreted cautiously., (© 2020 by the American Society of Neuroimaging.)

Introduction: Medical students and interns are the principal communicators during inpatient bedside patient- and family-centered rounds. Excellent presenters are able to share information during rounds in a manner that is accurate, effective, and easy for all to understand. We previously identified the behaviors of excellent presenters and developed a term for them: presenter empowerment actions., Methods: To promote the use of presenter empowerment actions, an interactive workshop was created to teach them to medical students and interns. This educational summary contains information on how to facilitate a workshop to promote presenter empowerment actions, which includes both a didactic presentation and an interactive game., Results: Interns reported increases in confidence and knowledge of empowerment actions, as well as strong intent to incorporate presenter empowerment actions during inpatient rounds., Discussion: A workshop with an interactive game is an effective way to teach empowerment actions to learners. To reinforce presenter empowerment action use after the workshop, we recommend direct observation using the Suspected Observable Presenter Empowerment Action Checklist to provide formative feedback to the presenters., Competing Interests: None to report.

Purpose: The aim was to optimally combine multichannel coil array data in sodium ((23) Na) MRI., Methods: (23) Na MRI was conducted on a 3 Tesla MR system using a 30-channel head receive coil array. The parameters used for the adaptive combination (ADC) reconstruction of the low signal-to-noise ratio (SNR) dataset have been optimized by finding the maximum mean SNR. A pseudo multiple-replica approach has been used to obtain SNR maps of the combined images. To prove reproducibility of the combination algorithm, the procedure was repeated for several measurements., Results: For low SNR data, sum-of-squares (SOS) reconstruction leads to high background noise and a signal bias in the imaged object. The ADC reconstruction clearly reduces noise in the image and leads to an increase of the mean SNR in the range of 8% to 50%, compared to weighted SOS depending on the absolute SNR of the image. The evaluation of the effects of different noise scans showed that a small number of projections can be used to estimate noise statistics of the coil array without substantially decreasing the resulting SNR., Conclusion: (23) Na MRI can be markedly improved by using a 30-channel receive array and ADC reconstruction. The ADC reconstruction showed robust results for all measurements without the need for sensitivity maps., (© 2015 Wiley Periodicals, Inc.)

Purpose: Implementation, evaluation and application of a pulse sequence for retrospectively-gated sodium magnetic resonance imaging of the human heart., Methods: Measurements were conducted at a magnetic field strength of 7.0 Tesla. A 3D projection reconstruction technique using a standard (ST) and a golden angle (GA) acquisition scheme for short echo time (23)Na MR was applied. Data were acquired continuously without cardiac triggering using a free breathing regime. Arbitrary phases of the cardiac cycle were reconstructed using synchronization with a physiological trigger signal and different temporal resolutions. Phantom measurements and examinations of healthy subjects were performed to evaluate the performance of the ST and GA acquisition schemes. A signal-to-background ratio (SBR)--that compromises both the signal-to-noise ratio and artifacts--was calculated for benchmarking the GA and ST scheme., Results: In phantom measurements, the measured SBR of the GA acquisition scheme was up to 88% higher versus ST. Undersampling artifacts were reduced in GA compared to the ST sampling scheme. Whole heart coverage sodium images could be reconstructed with a nominal spatial resolution of (6 mm)(3) and a temporal resolution of Δt=0.1 s for covering the entire cardiac cycle. Changes in overall heart volume and myocardial wall thickness throughout the cardiac cycle were clearly visible in the reconstructed images. For the in vivo data and the imaging protocol used, GA provided a mean SBR of 38.0±5.5 while ST provided a mean SBR of 37.2±2.2., Conclusion: Retrospectively-gated CINE (23)Na imaging of the heart at 7.0 T using density-adapted 3D projection reconstruction is feasible. The GA acquisition scheme is superior to the ST acquisition., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The objective of this work was to examine the feasibility of three-dimensional (3D) and whole heart coverage (23)Na cardiac MRI at 7.0 T including single-cardiac-phase and cinematic (cine) regimes. A four-channel transceiver RF coil array tailored for (23)Na MRI of the heart at 7.0 T (f = 78.5 MHz) is proposed. An integrated bow-tie antenna building block is used for (1)H MR to support shimming, localization and planning in a clinical workflow. Signal absorption rate simulations and assessment of RF power deposition were performed to meet the RF safety requirements. (23) Na cardiac MR was conducted in an in vivo feasibility study. 3D gradient echo (GRE) imaging in conjunction with Cartesian phase encoding (total acquisition time T(AQ)  = 6 min 16 s) and whole heart coverage imaging employing a density-adapted 3D radial acquisition technique (T(AQ)  = 18 min 20 s) were used. For 3D GRE-based (23)Na MRI, acquisition of standard views of the heart using a nominal in-plane resolution of (5.0 × 5.0) mm(2) and a slice thickness of 15 mm were feasible. For whole heart coverage 3D density-adapted radial (23)Na acquisitions a nominal isotropic spatial resolution of 6 mm was accomplished. This improvement versus 3D conventional GRE acquisitions reduced partial volume effects along the slice direction and enabled retrospective image reconstruction of standard or arbitrary views of the heart. Sodium cine imaging capabilities were achieved with the proposed RF coil configuration in conjunction with 3D radial acquisitions and cardiac gating. Cardiac-gated reconstruction provided an enhancement in blood-myocardium contrast of 20% versus the same data reconstructed without cardiac gating. The proposed transceiver array enables (23)Na MR of the human heart at 7.0 T within clinical acceptable scan times. This capability is in positive alignment with the needs of explorations that are designed to examine the potential of (23)Na MRI for the assessment of cardiovascular and metabolic diseases., (Copyright © 2015 John Wiley & Sons, Ltd.)

The concentration of sodium is a functional cell parameter and absolute quantification can be interesting for diagnostical purposes. The accuracy of sodium magnetic resonance imaging ((23)Na-MRI) is strongly biased by partial volume effects (PVEs). Hence our purpose was to establish a partial volume correction (PVC) method for (23)Na-MRI. The existing geometric transfer matrix (GTM) correction method was transferred from positron emission tomography (PET) to (23)Na-MRI and tested in a phantom study. Different parameters, as well as accuracy of registration and segmentation were evaluated prior to first in vivo measurements. In vivo sodium data-sets of the human brain were obtained at B0=7T with a nominal spatial resolution of (3mm)(3) using a density adapted radial pulse sequence. A volunteer study with four healthy subjects was performed to measure partial volume (PV) corrected tissue sodium concentration (TSC) which was verified by means of an intrinsic correction control. In the phantom study the PVC algorithm yielded a good correction performance and reduced the discrepancy between the measured sodium concentration value and the expected value in the smallest compartments of the phantom by 11% to a mean PVE induced discrepancy of 5.7% after correction. The corrected in vivo data showed a reduction of PVE bias for the investigated compartments for all volunteers, resulting in a mean reduction of discrepancy between two separate CSF compartments from 36% to 7.6%. The absolute TSC for two separate CSF compartments (sulci, lateral ventricles), gray and white brain matter after correction were 129±8mmol/L, 138±4mmol/L, 48±1mmol/L and 43±3mmol/L, respectively. The applied PVC algorithm reduces the PV-bias in quantitative (23)Na-MRI. Accurate, high-resolution anatomical data is required to enable appropriate PVC. The algorithm and segmentation approach is robust and leads to reproducible results., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Object: In tumor cells the energy production is shifted from aerobic to anaerobic metabolization of glucose, which makes the cerebral metabolic rate of oxygen consumption (CMRO2) a diagnostic parameter for tissue viability. Direct oxygen-17 ((17)O) MRI during inhalation of (17)O gas allows for a non-invasive determination of the CMRO2. However, the low spatial resolution and the fast transverse relaxation of (17)O lead to partial volume effects that severely bias the quantification of signal intensities. The aim of this work was to determine the CMRO2 in a tumor patient by (17)O MRI in combination with a partial volume correction (PVC) scheme., Materials and Methods: Direct (17)O MRI was performed in a glioblastoma patient (F, 51 years) prior to surgery at 7 T. The 'geometric transfer matrix' algorithm for volume of interest based PVC was adapted to (17)O MRI to recover the true signal intensities. We determined the CMRO2 values of gray matter (GM), white matter (WM), cerebrospinal fluid (CSF) and the tumor areas of the contrast enhancing rim (CE), the necrotic center (NE), and the perifocal edema (PE) using a three-phase metabolic model., Results: Large differences in the signal increase during (17)O2 inhalation were obtained ranging from less than 2% in the tumor center up to more than 20% in GM areas. After PVC of the signal time curves, we determined CMRO2 values of 0.67 ± 0.08 μmol/g/min (WM), 3.57 ± 0.67 μmol/g/min (GM), 0.35 ± 0.09 μmol/g/min (CE), and 0.42 ± 0.05 μmol/g/min (PE). In CSF and NE no oxygen uptake (i.e. CMRO2 = 0) was determined from the corrected signals, well in accordance with the underlying physiology in these regions., Conclusion: The results show that PVC has a strong effect on the resulting CMRO2 values obtained by (17)O MRI. We found substantial differences-especially in GM tissue-between corrected and non-corrected CMRO2 values. Additionally, we demonstrated the feasibility of CMRO2 assessment in a glioblastoma patient by (17)O MRI.

An efficient breathing system was designed for direct (17)O MRI to perform oxygen metabolism studies of the human brain. The breathing system consists of a demand oxygen delivery device for (17)O(2) supply and a custom-built re-breathing circuit with pneumatic switching valve. To efficiently deliver the (17)O gas to the alveoli of the lungs, the system applies short gas pulses upon an inspiration trigger via a nasal cannula. During and after (17)O(2) administration, the exhaled gas volumes are stored and filtered in the re-breathing section to make the most efficient use of the rare (17)O gas. In an inhalation experiment, 2.2 ± 0.1 L of 70%-enriched (17)O(2) were administered to a healthy volunteer and direct (17)O MRI was performed for a total imaging time of 38 min with a temporal resolution of 50 s per 3D data set. Mapping of the maximum signal increase was carried out showing regional variations of oxygen concentration of up to 30% over the natural abundance of (17)O water., (Copyright © 2011 Wiley-Liss, Inc.)

Our previous work showed that a 6-hour cyclic stretch significantly decreases TRPC4 protein expression and capacitative Ca(2+) entry in vascular smooth muscle cells from Sprague-Dawley rats. To parallel these studies, mesenteric smooth muscle cells from spontaneously hypertensive rats (SHR) and their normotensive controls, Wistar Kyoto (WKY) rats, were subjected to stretch. TRPC4 protein expression was evaluated by Western blot and Ca(2+) mobilization was measured using fura-2. As in Sprague-Dawley cells, a 6-hour stretch resulted in a significant down-regulation of TRPC4 protein in both SHR and WKY mesenteric smooth muscle cells. While WKY cells showed a stretch-induced decrease in Ca(2+) dynamics to accompany the reduction in TRPC4 expression, mesenteric smooth muscle cells from SHR showed a stretch-induced increase in both the release of stored Ca(2+) and capacitative Ca(2+) entry. TRPC4 proteins may be working as store-operated channels in normotensive vascular smooth muscle cells and their down-regulation by stretch may be a protective mechanism to prevent additional Ca(2+) influx during stretch. The stretch-induced increase in capacitative Ca(2+) entry in SHR may be due to a compensatory upregulation of non-TRPC4 channels or an increase in store-operated signaling or channel activity.

The mRen2.Lewis congenic strain is an estrogen-sensitive model of hypertension whereby estrogen depletion produces a significant and sustained increase in blood pressure. The recent identification of G protein-coupled receptor 30 (GPR30) as a third estrogen receptor isotype prompted us to test the hypothesis that this novel receptor exhibits beneficial cardiovascular actions in the hypertensive female mRen2.Lewis rat. Intact female, ovariectomized female (OVX), and male mRen2.Lewis rats were treated with the selective GPR30 agonist G-1 or vehicle via osmotic minipump for 2 wk. G-1 significantly reduced systolic blood pressure in OVX (178 +/- 7 to 142 +/- 10 mm Hg, P < 0.001, n = 8) but not intact female (144 +/- 3 to 143 +/- 5 mm Hg, P > 0.05, n = 5) or male mRen2.Lewis rats (207 +/- 7 to 192 +/- 5 mm Hg, P > 0.05, n = 7). G-1 did not alter uterine or body weight in OVX, suggesting activation of a receptor distinct from estrogen receptor-alpha and -beta. In isolated aortic rings from OVX, G-1 reduced constriction in response to angiotensin II. Vascular angiotensin-converting enzyme and angiotensin type 1 receptor mRNA were also lower, whereas angiotensin-converting enzyme-2 mRNA was increased. G-1 treatment in OVX was not associated with alterations in either endothelial nitric oxide synthase expression or acetylcholine-induced relaxation. Immunohistochemical staining for GPR30 was evident in both the intima and media of the aorta. We conclude that the novel estrogen receptor GPR30 may contribute to the beneficial cardiovascular actions of estrogen in female mRen2.Lewis rats through regulation of vascular components of the renin-angiotensin system.

To investigate the impact of aromatic residues within transmembrane helix 6 (TMH6) of the human gonadotropin-releasing hormone receptor (GnRH-R) on agonist and antagonist binding, residues Y(283), Y(284), W(289), Y(290), W(291), and F(292) were exchanged to alanine and analyzed comprehensively in functional reporter gene and ligand binding assays. Whereas receptor mutants Y(283)A, Y(284)A, and W(291)A were capable of neither ligand binding nor signal transduction, mutants W(289)A, Y(290)A, and F(292)A were functional: the F(292)A mutant behaved like wild-type receptor, while mutants W(289)A and Y(290)A differentiated between agonistic and antagonistic ligands. On the basis of the high-resolution X-ray structure of bovine rhodopsin as well as available data on GnRH-R mutants, models for ligand-receptor interactions are proposed. The model for D-Trp(6)-GnRH (Triptorelin) binding, representing a superagonistic ligand, is in full accordance to available data. Furthermore, new interactions are proposed: pGlu(1) interacts with N(212) in transmembrane helix 5, Tyr(5) with Y(290), and D-Trp(6) with W(289). The binding behavior of mutants W(289)A and Y(290)A corresponds to the proposed binding model for the antagonist Cetrorelix. In summary, our data as presented indicate that Y(290) plays a key function in agonist but not antagonist binding.

To understand the ligand binding properties of the human GnRH receptor (hGnRH-R), 24 site-specific mutants within transmembrane helices (TMH) 1, 2, and 5 and the extracellular loop 2 (E2) were generated. These mutants were analyzed by using a functional reporter gene assay, monitoring receptor signaling via adenylate cyclase to a cAMP-responsive element fused to Photinus pyralis luciferase. The functional behavior of 14 receptor mutants, capable of G-protein coupling and signaling, was studied in detail with different well described agonistic and antagonistic peptide ligands. Furthermore, the binding constants were determined in displacement binding experiments with the antagonist [125I]Cetrorelix. The substitution of residues K36, Q204, W205, H207, Q208, F20, F213, F216, and S217 for alanine had no or only a marginal effect on ligand binding and signaling. In contrast, substitution of N87, Eg9, D9, R179, W206, Y211, F214, and T215 for alanine resulted in receptor proteins neither capable of ligand binding nor signal transduction. Within those mutants affecting ligand binding and signaling to various degrees, W101A, N102A, and N212Q differentiate between agonists and antagonists. Thus, in addition to N102 already described, the residues W101 in TMH2 and N212 in TMH5 are important for the architecture of the ligand-binding pocket. Based on the experimental data, three-dimensional models for binding of the superagonist D-Trp6-GnRH (Triptorelin) and the antagonist Cetrorelix to the hGnRH-R are proposed. Both decapeptidic ligands are bound to the receptor in a bent conformation with distinct interactions within the binding pocket formed by all TMHs, E2, and E3. The antagonist Cetrorelix with bulky hydrophobic N-terminal amino acids interacts with quite different receptor residues, a hint at the failure to induce an active, G protein-coupling receptor conformation.

The pleiotropic cytokine IL-4 transmits cellular signals mainly via the IL-4 receptor complex, with the alpha-chain as the high affinity binding subunit. Here we describe the overexpression of a soluble IL-4R alpha-chain (sIL-4R) as a fusion to immunoglobulin gamma 1 heavy chain, consisting of the H-CH2-CH3 domains, in baby hamster kidney cells. The dimeric fusion protein named sIL-4R:E gamma 1 was purified from culture supernatant by protein-A affinity chromatography, yielding up to 10 mg/l homogenous protein which was highly stable. The antibody-like features of the sIL-4R:E gamma 1 fusion protein allowed immobilization on a biosensor matrix for surface plasmon resonance measurements by direct amine coupling as well as immobilization on microtiter plates coated with protein A for displacement binding. Kinetic parameters (kon and koff) for binding of IL-4 or the antagonistic mutant IL-4(Y124D) to the sIL-4R:E gamma 1 fusion protein on the chip as determined with the BIAcore instrument showed a high affinity binding with KD = 239 +/- 35 pM and KD=148 +/- 33 pM, respectively. The extremely high kon rate and the relatively slow koff rate for both ligands highlighted the limits of the BIAcore technology. The binding affinity as calculated in displacement binding studies with biotinylated IL-4 was similar for IL-4 and IL-4(Y124D) (IC50=1.1nM), thus offering a simple alternative for initial characterization of IL-4 mutants., (Copyright 1997 Academic Press.)

Ribavirin is a broad-spectrum antiviral agent useful for treatment of infants. To study the effects in developing mammalian lungs, four groups of jill ferrets and their litters were given whole body inhalation exposures for 6 h a day for 10 or 30 consecutive days to concentrations of 0 (vehicle control), 162, 355 or 620 mg/m3. The effects, including special lung observations in suckling kits, were evaluated after exposures at weaning and at puberty. First the high dose, then the mid dose jills developed lactation failure. Probably due to nutritional deficiency, approximately half of the mid dose and three quarters of the high dose kits were found dead or killed whilst moribund. There were no test compound-related deaths in the control or low dose level groups. Reductions in body weight gain were observed in both 10 and 30 day exposed kits, and high dose kits actually lost weight as exposure continued. Some recovery was apparent in survivors. Some discoloration of the liver was seen in malnourished kits at necropsy. There were no gross or histopathologic lesions in the lungs or tracheas of suckling ferrets attributable to the test material. Ribavirin exposure had no effect on the lavageable cell pool, while lung DNA to protein ratios showed a mild, reversible, proliferative response in smaller kits. There were no differences in lung function between controls and low dose kits of either group. Effects seen in the higher dose groups are due to differences in size. While there may have been a real dose-related enlargement of alveolar diameters at 40 days of age, this disappeared in males by puberty and did not seem toxicologically significant in females. The low dose, which corresponds to an exposure dose 4 to 6 times that used clinically, appeared to be a no-effect level.

Ribavirin, a new synthetic antiviral agent, was studied for dominant lethal effects in male CD rats. The drug was administered intraperitoneally at doses of 50, 100 and 200 mg/kg/day for 5 days. Males were mated weekly with 8 consecutive batches of female rats. Marginal increase in early foetal death detected in Assessment Weeks 3 and 8 in females mated with the low-dose and high-dose males were not dose-related and were most probably chance events caused by the particularly low vehicle control frequencies for these 2 weeks. Also, the slightly reduced pregnancy proportion among females mated with the high-dose treated males was to a substantial extent the effect of a single male rate which failed to fertilize any females. Ribavirin was, therefore, regarded as being devoid of any mutagenic potential demonstrable by a rat dominant lethal assay.