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Central European winters have warmed markedly since the mid-20th century. Yet cold winters are still associated with severe societal impacts on energy systems, infrastructure, and public health. It is therefore crucial to anticipate storylines of worst-case cold winter conditions and to understand whether an extremely cold winter, such as the coldest winter on the historical record of Germany in 1963 (−6.3 °C or −3.4σ seasonal December–January–February (DJF) temperature anomaly relative to 1981–2010), is still possible in a warming climate. Here, we first show based on multiple attribution methods that a winter of similar circulation conditions to 1963 would still lead to an extreme seasonal cold anomaly of about −4.9 to −4.7 °C (best estimates across methods) under present-day climate. This would rank as the second-coldest winter in the last 75 years. Second, we conceive storylines of worst-case cold winter conditions based on two independent rare event sampling methods (climate model boosting and empirical importance sampling): a winter as cold as 1963 is still physically possible in central Europe today, albeit very unlikely. While cold winter hazards become less frequent and less intense in a warming climate overall, it remains crucial to anticipate the possibility of an extremely cold winter to avoid potential maladaptation and increased vulnerability.

In every Intergovernmental Panel on Climate Change (IPCC) Assessment cycle, a multitude of scenarios are assessed, with different scope and emphasis throughout the various Working Group reports and special reports, as well as their respective chapters. Within the reports, the ambition is to integrate knowledge on possible climate futures across the Working Groups and scientific research domains based on a small set of “framing pathways” such as the so-called representative concentration pathways (RCPs) in the Fifth IPCC Assessment Report (AR5) and the shared socioeconomic pathway (SSP) scenarios in the Sixth Assessment Report (AR6). This perspective, initiated by discussions at the IPCC Bangkok workshop in April 2023 on the “Use of Scenarios in AR6 and Subsequent Assessments”, is intended to serve as one of the community contributions to highlight the needs for the next generation of framing pathways that is being advanced under the Coupled Model Intercomparison Project (CMIP) umbrella, which will influence or even predicate the IPCC AR7 consideration of framing pathways. Here we suggest several policy research objectives that such a set of framing pathways should ideally fulfil, including mitigation needs for meeting the Paris Agreement objectives, the risks associated with carbon removal strategies, the consequences of delay in enacting that mitigation, guidance for adaptation needs, loss and damage, and for achieving mitigation in the wider context of societal development goals. Based on this context, we suggest that the next generation of climate scenarios for Earth system models should evolve towards representative emission pathways (REPs) and suggest key categories for such pathways. These framing pathways should address the most critical mitigation policy and adaptation plans that need to be implemented over the next 10 years. In our view, the most important categories are those relevant in the context of the Paris Agreement long-term goal, specifically an immediate action (low overshoot) 1.5 °C pathway and a delayed action (high overshoot) 1.5 °C pathway. Two other key categories are a pathway category approximately in line with current (as expressed by 2023) near- and long-term policy objectives, as well as a higher-emission category that is approximately in line with “current policies” (as expressed by 2023). We also argue for the scientific and policy relevance in exploring two “worlds that could have been”. One of these categories has high-emission trajectories well above what is implied by current policies and the other has very-low-emission trajectories which assume that global mitigation action in line with limiting warming to 1.5 °C without overshoot had begun in 2015. Finally, we note that the timely provision of new scientific information on pathways is critical to inform the development and implementation of climate policy. Under the Paris Agreement, for the second global stocktake, which will occur in 2028, and to inform subsequent development of nationally determined contributions (NDCs) up to 2040, scientific inputs are required by 2027. These needs should be carefully considered in the development timeline of community modelling activities, including those under CMIP7.

Abstract Whether individuals with mild cognitive impairment (MCI) and a history of major depressive disorder (MDD) are at a higher risk for cognitive decline than those with MCI alone is still not clear. Previous work suggests that a reduction in prefrontal cortical theta phase-gamma amplitude coupling (TGC) is an early marker of cognitive impairment. This study aimed to determine whether using a TGC cutoff is better at separating individuals with MCI or MCI with remitted MDD (MCI+rMDD) on cognitive performance than their clinical diagnosis. Our hypothesis was that global cognition would differ more between TGC-based groups than diagnostic groups. We analyzed data from 128 MCI (mean age: 71.8, SD: 7.3) and 85 MCI+rMDD (mean age: 70.9, SD: 4.7) participants. Participants completed a comprehensive neuropsychological battery; TGC was measured during the N-back task. An optimal TGC cutoff was determined during the performance of the 2-back. This TGC cutoff was used to classify participants into low vs. high-TGC groups. We then compared Cohen’s d of the difference in global cognition between the high and low TGC groups to Cohen’s d between the MCI and MCI+rMDD groups. We used bootstrapping to determine 95% confidence intervals for Cohen’s d values using the whole sample. As hypothesized, Cohen’s d for the difference in global cognition between the TGC groups was larger (0.64 [0.32, 0.88]) than between the diagnostic groups (0.10 [0.004, 0.37]) with a difference between these two Cohen’s d’s of 0.54 [0.10, 0.80]. Our findings suggest that TGC is a useful marker to identify individuals at high risk for cognitive decline, beyond clinical diagnosis. This could be due to TGC being a sensitive marker of prefrontal cortical dysfunction that would lead to an accelerated cognitive decline.

Background Germany is challenged by an increasing shortage in general practice services, especially in non-urban areas. Task shifting from general practitioners (GPs) to other health professionals may improve practice efficiency to address this mismatch.Objectives Exploring GPs’ motives and beliefs towards task shifting in non-urban Germany and identifying potential factors influencing these.Methods The cross-sectional survey was disseminated by mail in three waves between July 2021 and August 2022 among all GPs in non-urban Baden-Wuerttemberg, Germany. It included items on demographics and practice characteristics as well as 15 Likert-scale items addressing motives and beliefs towards task shifting, based on the Theoretical Domain Framework. Likert-scale items were analysed descriptively, influencing factors on motives and beliefs were identified using multiple linear regression.Results Response rate was 24.2% (281/1162), with respondents comparable in age and gender to all GPs in Baden-Wuerttemberg. GPs’ motives and beliefs towards task shifting are positive overall. The majority expects task shifting to reduce their workload (87.9%) and increase practice efficiency (74.7%). They are open to shift additional tasks to other professionals (69.1%), even in the currently prohibited form of substitution (51.2%). Motives and beliefs were significantly more positive among younger GPs and those participating in the GP-centred care programme.Conclusion This study describes GPs’ motives and beliefs towards task shifting in non-urban Germany. Identifying younger GPs and those participating in the GP-centred care programme as particularly endorsing may help design future interventions aiming to improve efficiency in general practice in non-urban Germany.

IntroductionClinician implicit racial bias (IB) may lead to lower quality care and adverse health outcomes for Black patients. Educational efforts to train clinicians to mitigate IB vary widely and have insufficient evidence of impact. We developed and pilot-tested an evidence-based clinician IB curriculum, “REACHing Equity.”MethodsTo assess acceptability and feasibility, we conducted an uncontrolled one-arm pilot trial with post-intervention assessments. REACHing Equity is designed for clinicians to: (1) acquire knowledge about IB and its impact on healthcare, (2) increase awareness of one's own capacity for IB, and (3) develop skills to mitigate IB in the clinical encounter. We delivered REACHing Equity virtually in three facilitated, interactive sessions over 7–9 weeks. Participants were health care providers who completed baseline and end-of-study evaluation surveys.ResultsOf approximately 1,592 clinicians invited, 37 participated, of whom 29 self-identified as women and 24 as non-Hispanic White. Attendance averaged 90% per session; 78% attended all 3 sessions. Response rate for evaluation surveys was 67%. Most respondents agreed or strongly agreed that the curriculum objectives were met, and that REACHing Equity equipped them to mitigate the impact of implicit bias in clinical care. Participants consistently reported higher self-efficacy for mitigating IB after compared to before completing the curriculum.ConclusionsDespite apparent barriers to clinician participation, we demonstrated feasibility and acceptability of the REACHing Equity intervention. Further research is needed to develop objective measures of uptake and clinician skill, test the impact of REACHing Equity on clinically relevant outcomes, and refine the curriculum for uptake and dissemination.ClinicalTrials.gov ID: NCT03415308.

Abstract Background Following SARS-CoV-2 infection, a relevant proportion of patients suffer from persistent or recurring sequela, even after initially mild primary illness. Many patients experience exhaustion and fatigue, rendering them incapable of working. Long COVID exerts a substantial burden on society and the healthcare system: at least 65 million people are currently affected worldwide. The underlying pathobiology is a complex derangement in several organ systems. To date, causal pharmaceutical therapies remain elusive. Waiting lists for specialist care are long. Rapidly scalable digital interventions offering support for the frequent subgroup of patients with mild to moderate impairment from Long COVID are urgently needed. The MiLoCoDaS study compares three intensities of a potentially rapidly scalable digital intervention aiming to accelerate recovery. The overall objective is to figure out if there is a difference in the effect sizes between these modalities. Methods The online intervention uses a learning platform (LMS, TYPO3 framework) comprising 12 sessions of medical, psychological, physiotherapeutic, and nutritional content. The three modalities differ as follows: patient information only (sham intervention, control), information plus interactive digital workbook including practical exercises (digital intervention), and the digital workbook augmented by once-weekly online seminars and discussion groups (person and peer-contact). Eligible patients are 18–67 years old satisfying Long COVID diagnostic criteria. Patients are recruited through primary care physicians and randomly allocated. The primary endpoint is the number of sick leave days during the 6-month observation period; secondary endpoints are patient-reported symptoms, quality of life, and work ability. The study size provides a power of 80% at a type I error of < 0.05 to show an effect size of Cohen = 0.3 between the augmented and the sham intervention (N = 152 per arm, total accounting for attrition N = 600). Discussion If one of the two interventions is superior to providing information alone, MiLoCoDaS would provide the starting point for a rapidly scalable digital intervention for the frequent and currently underserved patient group with mild to moderate impairment from Long COVID. Several caveats pertain to the heterogeneity of Long COVID manifestation and duration prior to inclusion. It is conceivable that the possible effect of the intervention may differ across subgroups. Therefore, a priori defined secondary analysis will be conducted. Trial registration German Clinical Trials Register (DRKS) DRKS00028964. Registered on 24 August 2022.

Recently, the German Federal Institute for Medicines and Medical Products restricted the use of fosfomycin in transrectal biopsy of the prostate (TRBP). Accordingly, the need for other antibiotic agents for prophylaxis in TRBP is urgent since antibiotic prophylaxis is mandatory in accordance with these guidelines. After the restriction of the use of ciprofloxacin, and before the use of fosfomycin in Germany was falsely allowed, amoxicillin/clavulanic acid was evaluated as an alternative for antibiotic prophylaxis in TRBP. Regarding hospitalization for post-interventional infections, 359 patients at the Department of Urology of the University of Regensburg, at Caritas-St. Josef Medical Center as a single center, underwent TRBP between 2 July 2019 and 30 June 2020. Regarding antibiotic prophylaxis, the post-interventional hospitalization rate due to bacterial complications was relevant. Of the 359 patients, 10 (2.8%) had an infection requiring hospitalization post-TRBP. A total of 349 (97.2%) patients had no infection-related hospitalization. This corresponds to an incidence rate of only 2.8%. Referring to the previous infection rates under the now obsolete ciprofloxacin, amoxicillin/clavulanic acid can show a similar, if not tendentially even lower, risk of infection, and so this substance can be an alternative for antibiotic prophylaxis in TRBP. Another advantage is that, according to the WHO’s AWaRe classification, amoxicillin/clavulanic acid is one of the so-called Access antibiotics. This study is limited as rectal swabs and urine cultures were not performed on every patient before TRBP.

BackgroundDriving is the preferred mode of transportation for adults across the healthy age span. However, motor vehicle crashes are among the leading causes of injury and death, especially for older adults, and under distracted driving conditions. Understanding the neuroanatomical basis of driving may inform interventions that minimize crashes. This exploratory study examined the neuroanatomical correlates of undistracted and distracted simulated straight driving.MethodsOne-hundred-and-thirty-eight participants (40.6% female) aged 17–85 years old (mean and SD = 58.1 ± 19.9 years) performed a simulated driving task involving straight driving and turns at intersections in a city environment using a steering wheel and foot pedals. During some straight driving segments, participants responded to auditory questions to simulate distracted driving. Anatomical T1-weighted MRI was used to quantify grey matter volume and cortical thickness for five brain regions: the middle frontal gyrus (MFG), precentral gyrus (PG), superior temporal cortex (STC), posterior parietal cortex (PPC), and cerebellum. Partial correlations controlling for age and sex were used to explore relationships between neuroanatomical measures and straight driving behavior, including speed, acceleration, lane position, heading angle, and time speeding or off-center. Effects of interest were noted at an unadjusted p-value threshold of 0.05.ResultsDistracted driving was associated with changes in most measures of straight driving performance. Greater volume and cortical thickness in the PPC and cerebellum were associated with reduced variability in lane position and heading angle during distracted straight driving. Cortical thickness of the MFG, PG, PPC, and STC were associated with speed and acceleration, often in an age-dependent manner.ConclusionPosterior regions were correlated with lane maintenance whereas anterior and posterior regions were correlated with speed and acceleration, especially during distracted driving. The regions involved and their role in straight driving may change with age, particularly during distracted driving as observed in older adults. Further studies should investigate the relationship between distracted driving and the aging brain to inform driving interventions.

Abstract Species occurrence data are foundational for research, conservation, and science communication, but the limited availability and accessibility of reliable data represents a major obstacle, particularly for insects, which face mounting pressures. We present BeeBDC, a new R package, and a global bee occurrence dataset to address this issue. We combined >18.3 million bee occurrence records from multiple public repositories (GBIF, SCAN, iDigBio, USGS, ALA) and smaller datasets, then standardised, flagged, deduplicated, and cleaned the data using the reproducible BeeBDC R-workflow. Specifically, we harmonised species names (following established global taxonomy), country names, and collection dates and, we added record-level flags for a series of potential quality issues. These data are provided in two formats, “cleaned” and “flagged-but-uncleaned”. The BeeBDC package with online documentation provides end users the ability to modify filtering parameters to address their research questions. By publishing reproducible R workflows and globally cleaned datasets, we can increase the accessibility and reliability of downstream analyses. This workflow can be implemented for other taxa to support research and conservation.

Abstract Background An increasing number of studies reveal that more meaning in life is positively related to mental well-being. Meaning in life can be derived from different sources, including the workplace. The aim of this study was to explore the longitudinal directional association of meaningful work with mental well-being. Methods Prospective data from 292 persons at two timepoints (two-week interval) were used to estimate the cross-lagged relationship and directionality of meaningful work with mental well-being. Results The cross-lagged panel model had a good fit to the data (Chi2 ms(90) = 150.9; p

Abstract Background Alzheimer’s dementia (AD) is associated with electroencephalography (EEG) abnormalities including in the power ratio of beta to theta frequencies. EEG studies in mild cognitive impairment (MCI) have been less consistent in identifying such abnormalities. One potential reason is not excluding the EEG aperiodic components, which are less associated with cognition than the periodic components. Here, we investigate whether aperiodic and periodic EEG components are disrupted differently in AD or MCI vs. healthy control (HC) individuals and whether a periodic based beta/theta ratio differentiates better MCI from AD and HC groups than a ratio based on the full spectrum. Methods Data were collected from 44 HC (mean age (SD) = 69.1 (5.3)), 114 MCI (mean age (SD) = 72.2 (7.5)), and 41 AD (mean age (SD) = 75.7 (6.5)) participants. Aperiodic and periodic components and full spectrum EEG were compared among the three groups. Receiver operating characteristic curves obtained via logistic regression classifications were used to distinguish the groups. Last, we explored the relationships between cognitive performance and the beta/theta ratios based on the full or periodic spectrum. Results Aperiodic EEG components did not differ among the three groups. In contrast, AD participants showed an increase in full spectrum and periodic relative powers for delta, theta, and gamma and a decrease for beta when compared to HC or MCI participants. As predicted, MCI group differed from HC participants on the periodic based beta/theta ratio (Bonferroni corrected p-value = 0.036) measured over the occipital region. Classifiers based on beta/theta power ratio in EEG periodic components distinguished AD from HC and MCI participants, and outperformed classifiers based on beta/theta power ratio in full spectrum EEG. Beta/theta ratios were comparable in their association with cognition. Conclusions In contrast to a full spectrum EEG analysis, a periodic-based analysis shows that MCI individuals are different on beta/theta ratio when compared to healthy individuals. Focusing on periodic components in EEG studies with or without other biological markers of neurodegenerative diseases could result in more reliable findings to separate MCI from healthy aging, which would be valuable for designing preventative interventions.

Abstract Background Neuropsychiatric symptoms (NPS) are a core feature of most neurodegenerative and cerebrovascular diseases. White matter hyperintensities and brain atrophy have been implicated in NPS. We aimed to investigate the relative contribution of white matter hyperintensities and cortical thickness to NPS in participants across neurodegenerative and cerebrovascular diseases. Methods Five hundred thirteen participants with one of these conditions, i.e. Alzheimer’s Disease/Mild Cognitive Impairment, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, Parkinson’s Disease, or Cerebrovascular Disease, were included in the study. NPS were assessed using the Neuropsychiatric Inventory – Questionnaire and grouped into hyperactivity, psychotic, affective, and apathy subsyndromes. White matter hyperintensities were quantified using a semi-automatic segmentation technique and FreeSurfer cortical thickness was used to measure regional grey matter loss. Results Although NPS were frequent across the five disease groups, participants with frontotemporal dementia had the highest frequency of hyperactivity, apathy, and affective subsyndromes compared to other groups, whilst psychotic subsyndrome was high in both frontotemporal dementia and Parkinson’s disease. Results from univariate and multivariate results showed that various predictors were associated with neuropsychiatric subsyndromes, especially cortical thickness in the inferior frontal, cingulate, and insula regions, sex(female), global cognition, and basal ganglia-thalamus white matter hyperintensities. Conclusions In participants with neurodegenerative and cerebrovascular diseases, our results suggest that smaller cortical thickness and white matter hyperintensity burden in several cortical-subcortical structures may contribute to the development of NPS. Further studies investigating the mechanisms that determine the progression of NPS in various neurodegenerative and cerebrovascular diseases are needed.

Abstract Introduction Associations between structural inequalities and health are well established. However, there is limited work examining this link in relation to mental health, or that centres public perspectives. This study explores people's experience and sense‐making of inequality in their daily lives, with particular consideration of impacts on mental health. Methods We conducted a peer research study. Participants had to live in one of two London Boroughs and have an interest in inequalities and mental health. Using social media, newsletters, local organisations and our peer researchers' contacts, we recruited 30 participants who took photos representing their experience of inequality and discussed them during semi‐structured interviews. Data were analysed using reflexive thematic analysis. Results Three themes were identified in this study: (1) inequalities are unjust, multilayered and intertwined with mental health. Accounts demonstrated a deep understanding of inequalities and their link to mental health outcomes, describing inequalities as ‘suffering’ and ‘not good for anyone’. Financial, housing, immigration and healthcare problems exacerbated poor mental health, with racism, gender‐based violence and job loss also contributing factors for both poor mental health and experiences of inequality; (2) inequalities exclude and have far‐reaching mental health consequences, impacting personal sense of belonging and perceived societal value and (3) moving forwards—addressing long‐standing inequality and poor public mental health necessitated coping and resilience strategies that are often unacknowledged and undervalued by support systems. Conclusion Lived experience expertise was central in this study, creating an innovative methodological approach. To improve public mental health, we must address the everyday, painful structural inequalities experienced by many as commonplace and unfair. New policies and strategies must be found that involve communities, redistributing resources and power, building on a collective knowledge base, to coproduce actions combatting inequalities and improving population mental health. Patient or Public Contribution This study was peer‐led, designed and carried out by researchers who had experiences of poor mental health. Six authors of the paper worked as peer researchers on this study.

BackgroundSince September 2020, the National Health Service (NHS) COVID-19 contact-tracing app has been used to mitigate the spread of COVID-19 in the United Kingdom. Since its launch, this app has been a part of the discussion regarding the perceived social agency of decision-making algorithms. On the social media website Twitter, a plethora of views about the app have been found but only analyzed for sentiment and topic trajectories thus far, leaving the perceived social agency of the app underexplored. ObjectiveWe aimed to examine the discussion of social agency in social media public discourse regarding algorithm-operated decisions, particularly when the artificial intelligence agency responsible for specific information systems is not openly disclosed in an example such as the COVID-19 contact-tracing app. To do this, we analyzed the presentation of the NHS COVID-19 App on Twitter, focusing on the portrayal of social agency and the impact of its deployment on society. We also aimed to discover what the presentation of social agents communicates about the perceived responsibility of the app. MethodsUsing corpus linguistics and critical discourse analysis, underpinned by social actor representation, we used the link between grammatical and social agency and analyzed a corpus of 118,316 tweets from September 2020 to July 2021 to see whether the app was portrayed as a social actor. ResultsWe found that active presentations of the app—seen mainly through personalization and agency metaphor—dominated the discourse. The app was presented as a social actor in 96% of the cases considered and grew in proportion to passive presentations over time. These active presentations showed the app to be a social actor in 5 main ways: informing, instructing, providing permission, disrupting, and functioning. We found a small number of occasions on which the app was presented passively through backgrounding and exclusion. ConclusionsTwitter users presented the NHS COVID-19 App as an active social actor with a clear sense of social agency. The study also revealed that Twitter users perceived the app as responsible for their welfare, particularly when it provided instructions or permission, and this perception remained consistent throughout the discourse, particularly during significant events. Overall, this study contributes to understanding how social agency is discussed in social media discourse related to algorithmic-operated decisions This research offers valuable insights into public perceptions of decision-making digital contact-tracing health care technologies and their perceptions on the web, which, even in a postpandemic world, may shed light on how the public might respond to forthcoming interventions.

We present an interpretation of the recent Daniel K. Inouye Solar Telescope (DKIST) observations of propagating wave fronts in the lower solar atmosphere. Using MPS/University of Chicago MHD radiative magnetohydrodynamic simulations spanning the solar photosphere, the overshoot region, and the lower chromosphere, we identify three acoustic-wave source mechanisms, each occur at a different atmospheric height. We synthesize the DKIST Visible Broadband Imager G -band, blue-continuum, and Ca ii K signatures of these waves at high spatial and temporal resolution, and conclude that the wave fronts observed by DKIST likely originate from acoustic sources at the top of the solar photosphere overshoot region and in the chromosphere proper. The overall importance of these local sources to the atmospheric energy and momentum budget of the solar atmosphere is unknown, but one of the excitation mechanisms identified (upward propagating shock interaction with down-welling chromospheric plasma resulting in acoustic radiation) may be an important shock dissipation mechanism. Additionally, the observed wave fronts may prove useful for ultralocal helioseismological inversions and promise to play an important diagnostic role at multiple atmospheric heights.

This study's aim was to identify risk factors associated with sensorineural and neurocognitive function (brain aging) in older adults. In N = 1,478 Epidemiology of Hearing Loss Study participants (aged 64–100 years, 59% women), we conducted sensorineural and cognitive tests, which were combined into a summary measure using Principal Component Analysis (PCA). Participants with a PCA score

This paper summarizes the structure and findings from the first Workshop on Troubles and Failures in Conversations between Humans and Robots. The workshop was organized to bring together a small, interdisciplinary group of researchers working on miscommunication from two complementary perspectives. One group of technology-oriented researchers was made up of roboticists, Human-Robot Interaction (HRI) researchers and dialogue system experts. The second group involved experts from conversation analysis, cognitive science, and linguistics. Uniting both groups of researchers is the belief that communication failures between humans and machines need to be taken seriously and that a systematic analysis of such failures may open fruitful avenues in research beyond current practices to improve such systems, including both speech-centric and multimodal interfaces. This workshop represents a starting point for this endeavour. The aim of the workshop was threefold: Firstly, to establish an interdisciplinary network of researchers that share a common interest in investigating communicative failures with a particular view towards robotic speech interfaces; secondly, to gain a partial overview of the “failure landscape” as experienced by roboticists and HRI researchers; and thirdly, to determine the potential for creating a robotic benchmark scenario for testing future speech interfaces with respect to the identified failures. The present article summarizes both the “failure landscape” surveyed during the workshop as well as the outcomes of the attempt to define a benchmark scenario.

Abstract Background We aimed to prospectively compare the diagnostic performance of gadoxetic acid-enhanced MRI (EOB-MRI) and contrast-enhanced Computed Tomography (CECT) for hepatocellular carcinoma (HCC) detection and liver transplant (LT) eligibility assessment in cirrhotic patients with explant histopathology correlation. Methods In this prospective, single-institution ethics-approved study, 101 cirrhotic patients were enrolled consecutively from the pre-LT clinic with written informed consent. Patients underwent CECT and EOB-MRI alternately every 3 months until LT or study exclusion. Two blinded radiologists independently scored hepatic lesions on CECT and EOB-MRI utilizing the liver imaging reporting and data system (LI-RADS) version 2018. Liver explant histopathology was the reference standard. Pre-LT eligibility accuracies with EOB-MRI and CECT as per Milan criteria (MC) were assessed in reference to post-LT explant histopathology. Lesion-level and patient-level statistical analyses were performed. Results Sixty patients (49 men; age 33–72 years) underwent LT successfully. One hundred four non-treated HCC and 42 viable HCC in previously treated HCC were identified at explant histopathology. For LR-4/5 category lesions, EOB-MRI had a higher pooled sensitivity (86.7% versus 75.3%, p

Abstract Objectives To compare the diagnostic performance of international hepatocellular carcinoma (HCC) guidelines with gadoxetic acid-enhanced MRI (EOB-MRI) and contrast-enhanced Computed tomography (CECT) and their impact on liver transplant (LT) allocation in cirrhotic patients with explant histopathology correlation. Methods In this prospective single-centre ethics-approved study, 101 cirrhotic patients were consecutively enrolled with informed consent from the pre-LT clinic. They underwent CECT and EOB-MRI alternately at three monthly intervals until LT or removal from LT list. Two abdominal radiologists, blinded to explant histopathology, independently recorded liver lesions visible on CECT and EOB-MRI. Imaging-based HCC scores were assigned to non-treated liver lesions utilizing Liver Imaging Reporting and Data System (LI-RADS), European Association for the Study of the Liver (EASL), Asian-Pacific Association for the Study of the Liver (APASL) and Korean Liver Cancer Association-National Cancer Center (KLCA) guidelines. Liver explant histopathology was the reference standard. Simulated LT eligibility was assessed as per Milan criteria (MC) in reference to explant histopathology. Results One hundred and three non-treated HCC and 12 non-HCC malignancy were identified at explant histopathology in 34 patients (29 men, 5 women, age 55–73 years). Higher HCC sensitivities of statistical significance were observed with EOB-MRI for LI-RADS 4 + 5, APASL and KLCA compared to LI-RADS 5 and EASL with greatest sensitivity obtained for LIRADS 4 + 5 lesions. HCC sensitivities by all guidelines with both EOB-MRI and CECT were significantly lower if all histopathology-detected HCCs were included in the analysis, compared to imaging-visible lesions only. A significantly greater variation in HCC sensitivity was noted across the guidelines with EOB-MRI compared to CECT. No significant differences in simulated LT eligibility based on MC were observed across the HCC scoring guidelines with EOB-MRI or CECT. Conclusion HCC sensitivities are variable depending on scoring guideline, lesion size and imaging modality utilised. Prior studies that included only lesions visible on pre-operative imaging overestimate the diagnostic performance of HCC scoring guidelines. Per-lesion differences in HCC diagnosis across these guidelines did not impact patient-level LT eligibility based on MC.

Plain language summary We conducted a study to explore and understand the social barriers women face in seeking and obtaining quality safe abortion care in Ethiopia. We implemented focus group discussions with both men and women in four different regions of Ethiopia. We analyzed our findings into themes around stigma, barriers, and the changing nature of attitudes around abortion. Our results show that women seeking abortions are still heavily stigmatized. We found that abortion was deemed unacceptable in most cases. However, we also saw promising indications that changes are taking place in Ethiopian society’s view of abortion, and several participants indicated progress toward a more supportive environment overall for women seeking abortion care. Still, this progress may be limited by variable knowledge of abortion laws. Most participants noted the importance of education and outreach to improve abortion attitudes and norms. We concluded that further awareness is needed in Ethiopia on the availability of quality abortion services in public health facilities and the indications for legal abortion. These efforts should consider gender equality to ensure enduring changes for women’s reproductive choice throughout the country.

Abstract Ambivalence in social interactions has been linked to health-related outcomes in private relationships and recent research has started to expand this evidence to ambivalent leadership at the workplace by showing that ambivalent supervisor-employee relationships are related to higher stress levels in employees. However, the mental health consequences of ambivalent leadership have not been examined yet. Using a multilevel approach, this study estimated associations of ambivalent leadership with mental health indicators (depression, anxiety, vital exhaustion, fatigue) in 993 employees from 27 work groups. A total effect of ambivalent leadership was found for all four mental health measures, as well as within-group and between-group effects. The consistent relationships of ambivalent leadership with higher symptoms of mental ill-health at the individual- (i.e., within-group) and the group-level (i.e., between-group) support the existence of an un-confounded association, as well as group effects of collective ambivalence.

Objective: The Job Demand & Resources model suggests work characteristics are related to mental well-being and work engagement. Previous work describes the development of a combined construct ‘engaged well-being at work’ (EWB). To what extent changes in measures of this construct are responsive to changes in job demands and resources or associated with changes in job-related attitudes has not been established. Methods: Longitudinal employee-level data from three waves (German Linked Personnel Panel) were used. Logistic and linear fixed effects regression analyses explored longitudinal associations between changes in EWB for participants over a three-year period with changes in job demands and resources and job-related attitudes (job commitment, satisfaction, and turnover intentions). Results: While job resources were associated with increased odds for a change into a healthier and/or more engaged category of EWB, job demands reduced them. Job resources were more strongly related to higher EWB (ORrange = 1.22 – 1.61) than job demands (ORrange = 0.79 – 0.96). Especially psychological job demands showed negative associations with improved EWB (OR = 0.79). A change from the least desirable category ‘disengaged strain’ to any other category of EWB was associated with greater odds by up to 20.6 % for increased commitment and job satisfaction and lower odds for turnover intentions. Discussion: Improving work characteristics, especially job resources, could increase employees' EWB, emphasizing the importance of job characteristics for a healthy workplace. Because EWB seems to be associated with job attitudes, an improvement of this indicator would be relevant for employees and employers.

IntroductionThreatening environmental cues often generate enduring fear memories, but how these are formed and stored remains actively investigated. Recall of a recent fear memory is thought to reflect reactivation of neurons, in multiple brain regions, activated during memory formation, indicating that anatomically distributed and interconnected neuronal ensembles comprise fear memory engrams. The extent to which anatomically specific activation-reactivation engrams persist during long-term fear memory recall, however, remains largely unexplored. We hypothesized that principal neurons in the anterior basolateral amygdala (aBLA), which encode negative valence, acutely reactivate during remote fear memory recall to drive fear behavior.MethodsUsing adult offspring of TRAP2 and Ai14 mice, persistent tdTomato expression was used to “TRAP” aBLA neurons that underwent Fos-activation during contextual fear conditioning (electric shocks) or context only conditioning (no shocks) (n = 5/group). Three weeks later, mice were re-exposed to the same context cues for remote memory recall, then sacrificed for Fos immunohistochemistry.ResultsTRAPed (tdTomato +), Fos +, and reactivated (double-labeled) neuronal ensembles were larger in fear- than context-conditioned mice, with the middle sub-region and middle/caudal dorsomedial quadrants of aBLA displaying the greatest densities of all three ensemble populations. Whereas tdTomato + ensembles were dominantly glutamatergic in context and fear groups, freezing behavior during remote memory recall was not correlated with ensemble sizes in either group.DiscussionWe conclude that although an aBLA-inclusive fear memory engram forms and persists at a remote time point, plasticity impacting electrophysiological responses of engram neurons, not their population size, encodes fear memory and drives behavioral manifestations of long-term fear memory recall.

We conducted a survey amongst 5177 German employees asking about current mental well-being, mental health shame, help-seeking and presenteeism likelihood. Low mental well-being was reported in 22.9% of respondent; 65.5% stated that they would feel ashamed for own mental health problems. 54.1% said they were likely to go to work without talking to colleagues and supervisors despite mental health problems. Most participants would rather ask their partners or close family members for support, whereas work-related contacts were rarely endorsed. Since presenteeism is associated with mental health shame, reducing mental illness stigma is essential for improving mental health at the workplace.

Abstract Background Neuropsychiatric symptoms (NPS) are common in individuals with Alzheimer’s disease (AD) dementia, but substantial heterogeneity exists in the manifestation of NPS. Sex differences may explain this clinical variability. We aimed to investigate the sex differences in the prevalence and severity of NPS in AD dementia. Methods Literature searches were conducted in Embase, MEDLINE/PubMed, Web of Science Core Collection, Cochrane Central Register of Controlled Trials, PsycINFO, and Google Scholar from inception to February 2021. Study selection, data extraction, and quality assessment were conducted in duplicate. Effect sizes were calculated as odds ratios (OR) for NPS prevalence and Hedges’ g for NPS severity. Data were pooled using random-effects models. Sources of heterogeneity were examined using meta-regression analyses. Results Sixty-two studies were eligible representing 21,554 patients (61.2% females). The majority of the included studies had an overall rating of fair quality (71.0%), with ten studies of good quality (16.1%) and eight studies of poor quality (12.9%). There was no sex difference in the presence of any NPS (k = 4, OR = 1.35 [95% confidence interval 0.78, 2.35]) and overall NPS severity (k = 13, g = 0.04 [− 0.04, 0.12]). Regarding specific symptoms, female sex was associated with more prevalent depressive symptoms (k = 20, OR = 1.60 [1.28, 1.98]), psychotic symptoms (general psychosis k = 4, OR = 1.62 [1.12, 2.33]; delusions k = 12, OR = 1.56 [1.28, 1.89]), and aberrant motor behavior (k = 6, OR = 1.47 [1.09, 1.98]). In addition, female sex was related to more severe depressive symptoms (k = 16, g = 0.24 [0.14, 0.34]), delusions (k = 10, g = 0.19 [0.04, 0.34]), and aberrant motor behavior (k = 9, g = 0.17 [0.08, 0.26]), while apathy was more severe among males compared to females (k = 11, g = − 0.10 [− 0.18, − 0.01]). There was no association between sex and the prevalence and severity of agitation, anxiety, disinhibition, eating behavior, euphoria, hallucinations, irritability, and sleep disturbances. Meta-regression analyses revealed no consistent association between the effect sizes across studies and method of NPS assessment and demographic and clinical characteristics. Discussion Female sex was associated with a higher prevalence and greater severity of several specific NPS, while male sex was associated with more severe apathy. While more research is needed into factors underlying these sex differences, our findings may guide tailored treatment approaches of NPS in AD dementia.

State-of-the-art noisy digital quantum computers can only execute short-depth quantum circuits. Variational algorithms are a promising route to unlock the potential of noisy quantum computers since the depth of the corresponding circuits can be kept well below hardware-imposed limits. Typically, the variational parameters correspond to virtual R_{Z} gate angles, implemented by phase changes of calibrated pulses. By encoding the variational parameters directly as hardware pulse amplitudes and durations, we succeed in further shortening the pulse schedule and overall circuit duration. This decreases the impact of qubit decoherence and gate noise. As a demonstration, we apply our pulse-based variational algorithm to the calculation of the ground state of different hydrogen-based systems (H_{2}, H_{3}, and H_{4}) using IBM cross-resonance-based hardware. We observe a reduction in schedule duration of up to 5× compared to cnot-based Ansätze, while also reducing the measured energy. In particular, we observe a sizable improvement of the minimal energy configuration of H_{3} compared to a cnot-based variational form. Finally, we discuss possible future developments including error-mitigation schemes and schedule optimizations, which will enable further improvements of our approach, paving the way towards the simulation of larger systems on noisy quantum devices.

Cognitive resilience in Alzheimer’s disease (AD) can be defined as retention of high cognition despite presence of considerable cerebral AD lesions. We sought to identify factors associated with this phenomenon.Data were obtained from National Alzheimer’s Coordinating Centre (NACC) dataset. Subjects with severe AD neuropathology, based on National Institute on Aging–Reagan (NIA-Reagan) criteria, no other primary neuropathology, and a ≤ 2-year interval between last follow-up and death were included. Mini-mental status examination score ≥ 24 was used as a proxy for normal cognition.In total, 654 cases were included; 59 (9%) were cognitively resilient. Multivariable logistic regression model showed that resilient participants were more educated, had a lower body mass index (BMI), were more likely to be lifetime/recent smoker or use an anticoagulant/antiplatelet agent, compared with cognitively impaired subjects.In addition to expected protective factors such as higher education and lower BMI, our results showed that smoking (especially recent smoking) and anticoagulant/antiplatelet consumption are associated with resilience to clinical cognitive expression of severe AD pathology. Pharmacological approaches using this information might be explored for clinical AD amelioration.

Abstract In partially ordered magnets, order and disorder coexist in the same magnetic phase, distinct from both spin liquids and spin solids. Here, we determine the nature of partial magnetic ordering in the canonical frustrated antiferromagnet Gd2Ti2O7, in which Gd3+ spins occupy a pyrochlore lattice. Using single-crystal neutron-diffraction measurements in applied magnetic field, magnetic symmetry analysis, inelastic neutron-scattering measurements, and spin-wave modeling, we show that its low-temperature magnetic structure involves two propagation vectors (2-k structure) with suppressed ordered magnetic moments and enhanced spin-wave fluctuations. Our experimental results are consistent with theoretical predictions of thermal fluctuation-driven order in Gd2Ti2O7, and reveal that inelastic neutron-scattering measurements on powder samples can solve the longstanding problem of distinguishing single-k and multi-k magnetic structures.

Abstract Genetic factors contribute to neurodegenerative diseases, with high heritability estimates across diagnoses; however, a large portion of the genetic influence remains poorly understood. Many previous studies have attempted to fill the gaps by performing linkage analyses and association studies in individual disease cohorts, but have failed to consider the clinical and pathological overlap observed across neurodegenerative diseases and the potential for genetic overlap between the phenotypes. Here, we leveraged rare variant association analyses (RVAAs) to elucidate the genetic overlap among multiple neurodegenerative diagnoses, including Alzheimer’s disease, amyotrophic lateral sclerosis, frontotemporal dementia (FTD), mild cognitive impairment, and Parkinson’s disease (PD), as well as cerebrovascular disease, using the data generated with a custom-designed neurodegenerative disease gene panel in the Ontario Neurodegenerative Disease Research Initiative (ONDRI). As expected, only ~3% of ONDRI participants harboured a monogenic variant likely driving their disease presentation. Yet, when genes were binned based on previous disease associations, we observed an enrichment of putative loss of function variants in PD genes across all ONDRI cohorts. Further, individual gene-based RVAA identified significant enrichment of rare, nonsynonymous variants in PARK2 in the FTD cohort, and in NOTCH3 in the PD cohort. The results indicate that there may be greater heterogeneity in the genetic factors contributing to neurodegeneration than previously appreciated. Although the mechanisms by which these genes contribute to disease presentation must be further explored, we hypothesize they may be a result of rare variants of moderate phenotypic effect contributing to overlapping pathology and clinical features observed across neurodegenerative diagnoses.

BackgroundDigital contact tracing (DCT) apps have been implemented as a response to the COVID-19 pandemic. Research has focused on understanding acceptance and adoption of these apps, but more work is needed to understand the factors that may contribute to their sustained use. This is key to public health because DCT apps require a high uptake rate to decrease the transmission of the virus within the general population. ObjectiveThis study aimed to understand changes in the use of the National Health Service Test & Trace (T&T) COVID-19 DCT app and explore how public trust in the app evolved over a 1-year period. MethodsWe conducted a longitudinal mixed methods study consisting of a digital survey in December 2020 followed by another digital survey and interview in November 2021, in which responses from 9 participants were explored in detail. Thematic analysis was used to analyze the interview transcripts. This paper focuses on the thematic analysis to unpack the reasoning behind participants’ answers. ResultsIn this paper, 5 themes generated through thematic analysis are discussed: flaws in the T&T app, usefulness and functionality affecting trust in the app, low trust in the UK government, varying degrees of trust in other stakeholders, and public consciousness and compliance dropping over time. Mistrust evolved from participants experiencing sociotechnical flaws in the app and led to concerns about the app’s usefulness. Similarly, mistrust in the government was linked to perceived poor pandemic handling and the creation and procurement of the app. However, more variability in trust in other stakeholders was highlighted depending on perceived competence and intentions. For example, Big Tech companies (ie, Apple and Google), large hospitality venues, and private contractors were seen as more capable, but participants mistrust their intentions, and small hospitality venues, local councils, and the National Health Service (ie, public health system) were seen as well-intentioned but there is mistrust in their ability to handle pandemic matters. Participants reported complying, or not, with T&T and pandemic guidance to different degrees but, overall, observed a drop in compliance over time. ConclusionsThese findings contribute to the wider implications of changes in DCT app use over time for public health. Findings suggest that trust in the wider T&T app ecosystem could be linked to changes in the use of the app; however, further empirical and theoretical work needs to be done to generalize the results because of the small, homogeneous sample. Initial novelty effects occurred with the app, which lessened over time as public concern and media representation of the pandemic decreased and normalization occurred. Trust in the sociotechnical capabilities of the app, stakeholders involved, and salience maintenance of the T&T app in conjunction with other measures are needed for sustained use.

Gate-based quantum computers typically encode and process information in two-dimensional units called qubits. Using d-dimensional qudits instead may offer intrinsic advantages, including more efficient circuit synthesis, problem-tailored encodings and embedded error correction. In this work, we design a superconducting qudit-based quantum processor wherein the logical space of transmon qubits is extended to higher-excited levels. We propose a universal gate set featuring a two-qudit cross-resonance entangling gate, for which we predict fidelities beyond 99% in the d=4 case of ququarts with realistic experimental parameters. Furthermore, we present a decomposition routine that compiles general qudit unitaries into these elementary gates, requiring fewer entangling gates than qubit alternatives. As proof-of-concept applications, we numerically demonstrate the synthesis of SU(16) gates for noisy quantum hardware and an embedded error-correction sequence that encodes a qubit memory in a transmon ququart to protect against pure dephasing noise. We conclude that universal qudit control—a valuable extension to the operational toolbox of superconducting quantum information processing—is within reach of current transmon-based architectures and has applications to near-term and long-term hardware.

This paper aims to reconstruct Middle Bronze Age (MBA; 1600–1250 BCE) land use practices in the northwestern Alpine foreland (SW Germany, Hegau). We used a multi-proxy approach including the analysis of biogeochemical proxies from colluvial deposits and buried topsoils in the surroundings of the well-documented settlement site of Anselfingen and off-site pollen data from two peat bogs. This approach allowed for in-depth insights into the MBA subsistence economy and shows that the MBA in the northwestern Alpine foreland was a period of establishing settlements with sophisticated land management and land use practices. The reconstruction of phases of colluvial deposition was based on ages from optically stimulated luminescence (OSL) and radiocarbon (AMS14C) dating from multi-layered colluvial deposits and supports the local archaeological record with the first phase of major colluvial deposition occurring during the MBA followed by phases of colluvial deposition during the Iron Age, the Medieval period and modern times. The on-site deposition of charred archaeobotanical remains and animal bones from archaeological features, as well as polycyclic aromatic hydrocarbons (PAHs), charcoal spectra, phytoliths, soil microstructure, urease enzymatic activity, microbial biomass carbon (Cmic) and heavy metal contents from colluvial deposits, were used as proxies for on-site and near-site land use practices. The charcoal spectra indicate MBA forest management which favored the dominance of Quercus in the woodland vegetation in the surrounding area north of the settlement site. Increased levels of 5β stanols (up to 40 %) and the occurrence of pig bones (up to 14 %) support the presence of a forest pasture mainly used for pig farming. In the surrounding area south of the settlement, an arable field with a buried MBA plow horizon (2Apb) could be verified by soil micromorphological investigations and high concentrations of grass phytoliths from leaves and stems. Agricultural practices (e.g., plowing) focussed on five staple crops (Hordeum distichon/vulgare, Triticum dicoccum, Triticum monococcum, Triticum spelta, Triticum aestivum/turgidum), while the presence of stilted pantries as storage facilities and of heat stones indicate post-harvest processing of cereal crops and other agrarian products within the settlement. In the area surrounding the settlement, increased levels of urease activity, compared to microbial biomass carbon (up to 2.1 µg N µg Cmic-1), and input of herbivorous and omnivorous animal faeces indicate livestock husbandry on fallow land. The PAH suites and their spatial distribution support the use of fire for various purposes, e.g., for opening and maintaining the landscape, for domestic burning and for technical applications. The off-site palynological data support the observed change in on-site and near-site vegetation as well as the occurrence of related land use practices. During the Early and Middle Bronze Age, fire played a major role in shaping the landscape (peak of micro-charcoal during the MBA), and anthropogenic activities promoted Quercus-dominated forest ecosystems at the expense of natural beech forests. This indicates a broader regional human influence in the northwestern Alpine foreland at low- and mid-altitude inland sites during the Middle Bronze Age.

Abstract Background Although genetic factors are known to contribute to neurodegenerative disease susceptibility, there remains a large amount of heritability unaccounted for across the diagnoses. Copy number variants (CNVs) contribute to these phenotypes, but their presence and influence on disease state remains relatively understudied. Methods Here, we applied a depth of coverage approach to detect CNVs in 80 genes previously associated with neurodegenerative disease within participants of the Ontario Neurodegenerative Disease Research Initiative (n = 519). Results In total, we identified and validated four CNVs in the cohort, including: (1) a heterozygous deletion of exon 5 in OPTN in an Alzheimer's disease participant; (2) a duplication of exons 1–5 in PARK7 in an amyotrophic lateral sclerosis participant; (3) a duplication of >3 Mb, which encompassed ABCC6, in a cerebrovascular disease (CVD) participant; and (4) a duplication of exons 7–11 in SAMHD1 in a mild cognitive impairment participant. We also identified 43 additional CNVs that may be candidates for future replication studies. Conclusion The identification of the CNVs suggests a portion of the apparent missing heritability of the phenotypes may be due to these structural variants, and their assessment is imperative for a thorough understanding of the genetic spectrum of neurodegeneration.

Introduction Primary care faces substantial challenges worldwide through an increasing mismatch in supply and demand, particularly in rural areas. One option to address this mismatch might be increasing efficiency by delegation of tasks to non-physician medical staff. Possible influencing factors, motives and beliefs regarding delegation to non-physician medical staff and the potential of an expanded role, as perceived by primary care physicians, however, remain unclear. The aim of this study is to assess these factors to guide development of potential interventions for expanding the role of non-physician medical staff in delivering primary care services in rural Germany.Methods and analysis This mixed-methods study based on the theoretical domains framework (TDF) consists of survey and interviews conducted sequentially. The survey, to be sent to all primary care physicians active in rural Baden-Wuerttemberg (estimated n=1250), includes 37 items: 15 assessing personal and practice characteristics, 15 matching TDF domains and 7 assessing opportunities for delegation. The interview, to be performed in a subsample (estimated n=12–20), will be informed by results of the survey. The initial interview guide consists of 11 questions covering additional TDF domains. Perspectives towards delegation will be maximised by comparing data emerging in either part of the study, seeking confirmation, disagreement or further details.Ethics and dissemination The Ethics Committee of Heidelberg University approved this study (approval number: 2021–530). Written informed consent will be obtained before each interview; consent for participation in the survey will be assumed when the survey has been returned. Results will be disseminated via publications in peer-reviewed journals and talks at conferences. By combining quantitative and qualitative methods, our results will support future research for crafting potential interventions to expand the role of non-physician medical staff in rural primary care.

Solar granulation is the visible signature of convective cells at the solar surface. The granulation cellular pattern observed in the continuum intensity images is characterised by diverse structures e.g., bright individual granules of hot rising gas or dark intergranular lanes. Recently, the access to new instrumentation capabilities has given us the possibility to obtain high-resolution images, which have revealed the overwhelming complexity of granulation (e.g., exploding granules and granular lanes). In that sense, any research focused on understanding solar small-scale phenomena on the solar surface is sustained on the effective identification and localization of the different resolved structures. In this work, we present the initial results of a proposed classification model of solar granulation structures based on neural semantic segmentation. We inspect the ability of the U-net architecture, a convolutional neural network initially proposed for biomedical image segmentation, to be applied to the dense segmentation of solar granulation. We use continuum intensity maps of the IMaX instrument onboard the Sunrise I balloon-borne solar observatory and their corresponding segmented maps as a training set. The training data have been labeled using the multiple-level technique (MLT) and also by hand. We performed several tests of the performance and precision of this approach in order to evaluate the versatility of the U-net architecture. We found an appealing potential of the U-net architecture to identify cellular patterns in solar granulation images reaching an average accuracy above 80% in the initial training experiments.

The Scenario Model Intercomparison Project (ScenarioMIP) defines and coordinates the main set of future climate projections, based on concentration-driven simulations, within the Coupled Model Intercomparison Project phase 6 (CMIP6). This paper presents a range of its outcomes by synthesizing results from the participating global coupled Earth system models. We limit our scope to the analysis of strictly geophysical outcomes: mainly global averages and spatial patterns of change for surface air temperature and precipitation. We also compare CMIP6 projections to CMIP5 results, especially for those scenarios that were designed to provide continuity across the CMIP phases, at the same time highlighting important differences in forcing composition, as well as in results. The range of future temperature and precipitation changes by the end of the century (2081–2100) encompassing the Tier 1 experiments based on the Shared Socioeconomic Pathway (SSP) scenarios (SSP1-2.6, SSP2-4.5, SSP3-7.0 and SSP5-8.5) and SSP1-1.9 spans a larger range of outcomes compared to CMIP5, due to higher warming (by close to 1.5 ∘C) reached at the upper end of the 5 %–95 % envelope of the highest scenario (SSP5-8.5). This is due to both the wider range of radiative forcing that the new scenarios cover and the higher climate sensitivities in some of the new models compared to their CMIP5 predecessors. Spatial patterns of change for temperature and precipitation averaged over models and scenarios have familiar features, and an analysis of their variations confirms model structural differences to be the dominant source of uncertainty. Models also differ with respect to the size and evolution of internal variability as measured by individual models' initial condition ensemble spreads, according to a set of initial condition ensemble simulations available under SSP3-7.0. These experiments suggest a tendency for internal variability to decrease along the course of the century in this scenario, a result that will benefit from further analysis over a larger set of models. Benefits of mitigation, all else being equal in terms of societal drivers, appear clearly when comparing scenarios developed under the same SSP but to which different degrees of mitigation have been applied. It is also found that a mild overshoot in temperature of a few decades around mid-century, as represented in SSP5-3.4OS, does not affect the end outcome of temperature and precipitation changes by 2100, which return to the same levels as those reached by the gradually increasing SSP4-3.4 (not erasing the possibility, however, that other aspects of the system may not be as easily reversible). Central estimates of the time at which the ensemble means of the different scenarios reach a given warming level might be biased by the inclusion of models that have shown faster warming in the historical period than the observed. Those estimates show all scenarios reaching 1.5 ∘C of warming compared to the 1850–1900 baseline in the second half of the current decade, with the time span between slow and fast warming covering between 20 and 27 years from present. The warming level of 2 ∘C of warming is reached as early as 2039 by the ensemble mean under SSP5-8.5 but as late as the mid-2060s under SSP1-2.6. The highest warming level considered (5 ∘C) is reached by the ensemble mean only under SSP5-8.5 and not until the mid-2090s.

Abstract Background Mental well-being and work engagement are both desirable, positive states of mind that help employees to better function in the workplace. While occupational researchers have argued in favor of considering both states concurrently, it is less clear how this might be translated to provide an instrument characterizing the workforce accordingly. The present study describes empirical efforts to operationalize a construct called engaged well-being. Methods We used employee-level data (n = 13,538) from three waves of the German linked personnel panel (LPP; 2012–2017). Exploratory factor analysis and a combination of hierarchical and non-hierarchical cluster analyses linked with within-sum-of-squares statistics were used to identify distinct profiles describing mental well-being and work engagement concurrently. These profiles were then used as the basis to identify cut-offs to create replicable categories of engaged well-being. Using the longitudinal data from a subgroup providing data across more than one wave, we observed whether the newly constructed indicator changed over time. Results The exploratory factor analysis suggested that both states were two distinct factors. Cluster analysis linked with within-sum-of-squares statistics suggested a four-cluster solution: engaged well-being (46.9%), disengaged well-being (27.5%), engaged strain (8.8%), and disengaged strain (16.8%). One cut-off for each state was identified to replicate the cluster solution. Across observation periods, we could observe changes in engaged well-being. Conclusions Our measure of engaged well-being can be used to simultaneously characterize a workforce’s mental well-being and work engagement. Changes in this measure over time suggest its potential utility in organizational interventions. Future studies are needed to further explore both the antecedents, correlates, and potential effects of engaged well-being.

Reliable quantitative vegetation reconstructions for Europe during the Holocene are crucial to improving our understanding of landscape dynamics, making it possible to assess the past effects of environmental variables and land-use change on ecosystems and biodiversity, and mitigating their effects in the future. We present here the most spatially extensive and temporally continuous pollen-based reconstructions of plant cover in Europe (at a spatial resolution of 1° × 1°) over the Holocene (last 11.7 ka BP) using the ‘Regional Estimates of VEgetation Abundance from Large Sites’ (REVEALS) model. This study has three main aims. First, to present the most accurate and reliable generation of REVEALS reconstructions across Europe so far. This has been achieved by including a larger number of pollen records compared to former analyses, in particular from the Mediterranean area. Second, to discuss methodological issues in the quantification of past land cover by using alternative datasets of relative pollen productivities (RPPs), one of the key input parameters of REVEALS, to test model sensitivity. Finally, to validate our reconstructions with the global forest change dataset. The results suggest that the RPPs.st1 (31 taxa) dataset is best suited to producing regional vegetation cover estimates for Europe. These reconstructions offer a long-term perspective providing unique possibilities to explore spatial-temporal changes in past land cover and biodiversity.

Although myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has a specific and distinctive profile of clinical features, the disease remains an enigma because causal explanation of the pathobiological matrix is lacking. Several potential disease mechanisms have been identified, including immune abnormalities, inflammatory activation, mitochondrial alterations, endothelial and muscular disturbances, cardiovascular anomalies, and dysfunction of the peripheral and central nervous systems. Yet, it remains unclear whether and how these pathways may be related and orchestrated. Here we explore the hypothesis that a common denominator of the pathobiological processes in ME/CFS may be central nervous system dysfunction due to impaired or pathologically reactive neuroglia (astrocytes, microglia and oligodendrocytes). We will test this hypothesis by reviewing, in reference to the current literature, the two most salient and widely accepted features of ME/CFS, and by investigating how these might be linked to dysfunctional neuroglia. From this review we conclude that the multifaceted pathobiology of ME/CFS may be attributable in a unifying manner to neuroglial dysfunction. Because the two key features – post exertional malaise and decreased cerebral blood flow – are also recognized in a subset of patients with post-acute sequelae COVID, we suggest that our findings may also be pertinent to this entity.

ObjectivesThe use of liquid biopsies (LB) in patients with solid malignancies enables comprehensive genomic profiling (CGP) of circulating tumor DNA (ctDNA) and has the potential to guide therapy stratification and support disease monitoring. To examine clinical uptake of LB in a real-world setting, LB implementation was analyzed at two German cancer centers (LMU Munich and Charité - Universitätsmedizin Berlin) between 2017 and 2021, with focus on colorectal cancer (CRC) patients.MethodsIn this retrospective analysis, all patients who received a LB between January 2017 and December 2021 as part of routine clinical management were included. To provide adequate context, we collected disease characteristics and technical specifications of the LB methods applied. Additionally, we examined the concordance of RAS status in tumor tissue and LB. Finally, we discuss the potential of LB as a diagnostic tool to drive personalized treatment in CRC patients and how to implement LB in clinical routine.ResultsIn total, our cohort included 86 CRC patients and 161 LB conducted in these patients between 2017 and 2021. In 59 patients, comparison between tissue-based and liquid-based molecular diagnostics, revealed a divergence in 23 (39%) of the evaluable samples.ConclusionOur real-world data analysis indicates that the possibilities of LB are not yet exploited in everyday clinical practice. Currently, the variety of methods and lack of standardization, as well as restricted reimbursement for liquid based CGP hinder the use of LB in clinical routine. To overcome these issues, prospective clinical trials are needed to provide evidence driving the implementation of LB into the management of CRC patients and to support their implementation into clinical guidelines.

The immune contexture of pancreatic ductal adenocarcinoma (PDAC) is generally immunosuppressive. A role for immune checkpoint inhibitors (ICIs) in PDAC has only been demonstrated for the rare and hypermutated mismatch repair (MMR) deficient (MMR-d) subtype. Homologous recombination repair (HR) deficient (HR-d) PDAC is more prevalent and may encompass up to 20% of PDAC. Its genomic instability may promote a T-cell mediated anti-tumor response with therapeutic sensitivity to ICIs. To investigate the immunogenicity of HR-d PDAC, we used multiplex immunohistochemistry (IHC) to compare the density and spatial distribution of CD8+ cytotoxic T-cells, FOXP3+ regulatory T-cells (Tregs), and CD68+ tumor-associated macrophages (TAMs) in HR-d versus HR/MMR-intact PDAC. We also evaluated the IHC positivity of programmed death-ligand 1 (PD-L1) across the subgroups. 192 tumors were evaluated and classified as HR/MMR-intact (n=166), HR-d (n=25) or MMR-d (n=1) based on germline testing and tumor molecular hallmarks. Intra-tumoral CD8+ T-cell infiltration was higher in HR-d versus HR/MMR-intact PDAC (p=1, whereas none of the HR/MMR-intact cases met this threshold (p

Abstract Background Absence from work due to sickness impairs organizational productivity and performance. Even in organizations with perfect work conditions, some inevitable baseline sickness absence exists amongst working populations. The excess sickness absence observed above this baseline rate has become the focus of traditional health promotion efforts, addressing preventable physical illness, health behavior and mental health at the personal level. However, a health and safety approach following the TOP-rule would consider work-group psychosocial work characteristics as a potential risk factor amenable to organizational measures. To date, there is a scarcity of studies relating psychosocial work characteristics to possible reduction of excess sickness-absence rates. Methods We aimed to estimate the potentially avoidable excess fraction of absence attributable to work-group psychosocial characteristics. We considered work-group averaged perception of psychosocial work characteristics as a proxy to the methodologically elusive objective assessment of organizational characteristics. Participants were recruited from multiple sites of a German automotive manufacturer with individuals nested within work groups. We predicted 12-month follow-up work-group sickness absence rates using data from a baseline comprehensive health examination assessing work characteristics, health behavior, and biomedical risk factors. We considered the quartile of work-groups yielding favorable psychosocial work characteristics as a realistic existing benchmark. Using the population attributable fraction method we estimated the potentially amenable sickness absence from improving work-group psychosocial characteristics. Results Data from 3992 eligible participants from 29 work groups were analyzed (39% participation rate, average age 41.4 years (SD = 10.3 years), 89.9% males and 49% manual workers.). Work-group absence rates at follow up varied from 2.1 to 8.9% (mean 5.1%, 11.7 missed days). A prediction model of seven psychosocial work characteristics at the work group level explained 70% of the variance of future absence rates. The estimated reduction from improving psychosocial work characteristics to the benchmark level amounted to 32% of all sickness absence, compared to a 31% reduction from eliminating health behavioral and medical risk factors to the benchmark target. Conclusions Psychosocial characteristics at the work-group level account for a relevant proportion of all sickness absence. Health promotion interventions should therefore address psychosocial characteristics at the work group level.

Background: Patients who present at night following penetrating abdominal trauma are thought to have more severe injuries and increased risk for morbidity and mortality. The current literature is at odds regarding this belief. The purpose of this study was to evaluate time of day on outcomes following laparotomy for penetrating abdominal trauma. Methods: Patients undergoing laparotomy following penetrating abdominal trauma over a 12-month period at a level I trauma center were stratified by age, sex, severity of shock, injury, operative complexity, and time of day (DAY = 0700–1900, NIGHT = 1901–0659). Outcomes of damage control laparotomy, ventilator days, intensive care unit length of stay, hospital length of stay, morbidity, and mortality were compared between DAY and NIGHT. Results: A total of 210 patients were identified: 145 (69%) comprised NIGHT, and 65 (31%) comprised DAY. Overall mortality was 2.9%. Both injury severity and intraoperative transfusions were increased with NIGHT with no difference in morbidity (37% vs 40%, P = 0.63) or mortality (2.1% vs 4.6%, P = 0.31). Adjusting for sex, time of day, injury severity, and operative complexity, only abdominal abbreviated injury severity (odds ratio 1.46; 95% confidence interval 1.07–1.99, P = .019) and operative transfusions (odds ratio 1.18; 95% confidence interval 1.09–1.28, P

Abstract Background Assessing the early development of children at a population level in educational settings, may be useful for public health and policy decision making. In this study, we evaluated the psychometric properties and the contextual appropriateness of a German language version of the Early Development Instrument (EDI), a survey-based instrument originally developed in Canada, which assesses developmental vulnerability for children in preschool settings. Methods Sixty preschool teachers from six preschool organizations (22% of organizations contacted) in three cities in southwest Germany participated. They administered a German version of the EDI (GEDI) to 225 children (51% of eligible children). We assessed internal consistency, test-retest and interrater reliability. Preschool teachers assisted in determining face-validity by reviewing item coverage and comprehensibility. Exploratory factor analysis (EFA) was used to evaluate convergent validity. Concurrent validity was measured using correlations and agreements (Bland-Altman plots) between GEDI and other validated instrument scores. Additionally, we compared associations between GEDI domain scores and sociodemographic characteristics with similar associations in EDI studies worldwide. Results GEDI domains showed good to excellent internal consistency (0.73 0.99) and moderate to good test-retest and interrater reliability (0.50 to 0.81 and 0.48 to 0.71, respectively [p-value

During the COVID-19 pandemic, digital contact-tracing has been employed in many countries to monitor and manage the spread of the disease. However, to be effective such a system must be adopted by a substantial proportion of the population; therefore, public trust plays a key role. This paper examines the NHS COVID-19 smartphone app, the digital contact-tracing solution in the UK. A series of interviews were carried out prior to the app's release (n = 12) and a large scale survey examining attitudes towards the app (n = 1,001) was carried out after release. Extending previous work reporting high level attitudes towards the app, this paper shows that prevailing negative attitudes prior to release persisted, and affected the subsequent use of the app. They also show significant relationships between trust, app features, and the wider social and societal context. There is lower trust amongst non-users of the app and trust correlates to many other aspects of the app, a lack of trust could hinder adoption and effectiveness of digital contact-tracing. The design of technology requiring wide uptake, e.g., for public health, should embed considerations of the complexities of trust and the context in which the technology will be used.

Non-graphitic carbons (NGCs), such as glass-like carbons, pitch cokes, and activated carbon consist of small graphene layer building stacks arranged in a turbostratic order. Both structure features, including the single graphene sheets as well as the stacks, possess structural disorder, which can be determined using wide-angle X-ray or neutron scattering (WAXS/WANS). Even if WANS data of NGCs have already been extensively reported and evaluated in different studies, there are still open questions with regard to their validation with WAXS, which is usually used for routine characterization. In particular, using WAXS for the damping of the atomic form factor and the limited measured range prevent the analysis of higher-ordered reflections, which are crucial for determining the stack/layer size (La, Lc) and disorder (σ1, σ3) based on the reflection widths. Therefore, in this study, powder WANS was performed on three types of carbon materials (glass-like carbon made out of a phenol-formaldehyde resin (PF-R), a mesophase pitch (MP), and a low softening-point pitch (LSPP)) using a beamline at ILL in Grenoble, providing a small wavelength and thus generating WANS data covering a large range of scattering vectors (0.052 Å−1 < s < 3.76 Å−1). Merging these WANS data with WANS data from previous studies, possessing high resolution in the small s range, on the same materials allowed us to determine both the interlayer and the interlayer structure as accurately as possible. As a main conclusion, we found that the structural disorder of the graphene layers themselves was significantly smaller than previously assumed.

The cell cortex is an active viscoelastic self-deforming sheet at the periphery of animal cells. It constricts animal cells during cell division. For some egg cells, the actomyosin cortex was shown to exhibit counter-rotating chiral flows along the axis of division. Such chiral surface flows were shown to contribute to spatial rearrangements and left-right symmetry breaking in developing organisms. In spite of this prospective biological importance, the effect of chiral forces on the flows and emergent shape dynamics of a deformable surface are completely unknown. To shed a first light on that matter, we present here a numerical study of an axisymmetric viscoelastic surface embedded in a viscous fluid. We impose a generic counter-rotating force field on this surface and study the resulting chiral flow field and shape dynamics for various surface mechanical parameters. Notably, we find that the building of a neck, as is observed during cell division, occurs if the surface contains a strong shear elastic component. Furthermore, we find that a large areal relaxation time results in flows towards the equator of the surface. These flows assist the transport of a surface concentration during the formation of a contractile ring. Accordingly, we show that chiral forces by themselves can drive pattern formation and stabilise contractile rings at the equator. These results provide first mechanistic evidence that chiral flows can play a significant role to orchestrate cell division.